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Sample records for familial creutzfeldt-jakob disease

  1. Creutzfeldt-Jakob disease.

    PubMed

    Sikorska, Beata; Knight, Richard; Ironside, James W; Liberski, Paweł P

    2012-01-01

    Creutzfeldt-Jakob disease (CJD), a neurodegenerative disorder that is the commonest form of human prion disease or transmissible spongiform encephalopathies (TSEs). Four types of CJD are known: Sporadic (sCJD), familial or genetic (gCJD); iatrogenic (iCJD) and variant CJD (vCJD). The latter results from transmission of bovine spongiform encephalopathy (BSE) from cattle to humans. The combination of PrP(Sc) peptide (either 21 kDa or 19 kDa) and the status of the codon 129 of the gene (PRNP) encoding for PrP (either Methionine or Valine) is used to classify sCJD into 6 types: MM1 and MV1, the most common; VV2; MV2 (Brownell/Oppenheimer syndrome); MM2; VV1 and sporadic fatal insomnia, in that order of prevalence. Genetic CJD is caused by diverse mutations in the PRNP gene. The neuropathology of CJD consists of spongiform change, astro- and microgliosis and poorly defined neuronal loss. In a proportion of cases, amyloid plaques, like those of kuru, are seen. PrP immunohistochemistry reveals different types of PrP(Sc) deposits - the most common is the synaptic-type, but perivacuolar, perineuronal and plaque-like deposits may be also detected.

  2. Creutzfeldt-Jakob disease.

    PubMed

    de Villemeur, Thierry Billette

    2013-01-01

    Prion diseases are rare in children. Three types are known: kuru, variant Creutzfeldt-Jakob disease (CJD), and iatrogenic CJD. All three affect children and young adults, and are transmitted by infectious contamination. Kuru was the result of ritual funeral practices similar to cannibalism; variant CJD affects young people who have eaten meat from cows with mad cow disease (mostly in the UK); and iatrogenic CJD is secondary to graft of human tissues performed in the 1980s (dura mater, pituitary extracted growth hormone). The disease appears after 4-30 years of incubation. The initial symptomatology is frequently neurological (cerebellar ataxia, oculomotor disturbance, peripheral nerve pain, pyramidal syndrome) followed by dementia. There is no biological test available that can give a definite diagnosis of prion disease apart from neuropathology, although prion accumulation in vCJD can be demonstrated in pharyngeal tonsil by immunohistochemical techniques. This devastating disease results inevitably in death. No specific treatment is available.

  3. Creutzfeldt-Jakob disease segregating in a three generation Danish family.

    PubMed

    Holm, I E; Abelskov, K; Bojsen-Møller, M; Nielsen, A L; Jørgensen, A L

    2001-03-01

    A three generation family is presented in which rapidly progressive, early-onset Creutzfeldt-Jakob disease without typical EEG changes segregates as an autosomal dominant disease. An aspartic acid to asparagine mutation at codon 178 of the prion gene, PRNP, co-segregates with the disease. As expected, the disease allele also carries the valine codon of the polymorphic valine/methionine codon 129 of the gene. In family members homozygous for this valine codon the disease was more rapidly progressive than in a heterozygous family member, who had a variant clinical phenotype. Definite neuropathological diagnosis required prion staining with specific antibodies.

  4. Creutzfeldt-Jakob Disease

    MedlinePlus

    ... acquired CJD. CJD belongs to a family of human and animal diseases known as the transmissible spongiform ... CJD is the most common of the known human TSEs. Other human TSEs include kuru, fatal familial ...

  5. Creutzfeldt-Jakob disease

    MedlinePlus

    ... be the same one that causes vCJD in humans. Varient CJD causes less than 1% of all ... Scrapie (found in sheep) Other very rare inherited human diseases, such as Gerstmann-Straussler-Scheinker disease and ...

  6. Creutzfeldt-Jakob Disease

    MedlinePlus

    ... can get a disease related to CJD called bovine spongiform encephalopathy (BSE) or "mad cow disease." There is concern that people can get a variant of CJD from eating beef from an infected animal, ... this. NIH: National Institute of Neurological Disorders and Stroke

  7. Familial Creutzfeldt-Jakob Disease: Case report and role of genetic counseling in post mortem testing.

    PubMed

    Clift, Kristin; Guthrie, Kimberly; Klee, Eric W; Boczek, Nicole; Cousin, Margot; Blackburn, Patrick; Atwal, Paldeep

    2016-11-01

    Here we present a case of an asymptomatic 53-year-old woman who sought genetic testing for Familial Creutzfeldt-Jakob Disease (fCJD) after learning that her mother had fCJD. The patient's mother had a sudden onset of memory problems and rapidly deteriorating mental faculties in her late 70s, which led to difficulties ambulating, progressive non-fluent aphasia, dysphagia and death within ∼1 y of symptom onset. The cause of death was reported as "rapid onset dementia." The patient's family, unhappy with the vague diagnosis, researched prion disorders online and aggressively pursued causation and submitted frozen brain tissue from the mother to the National Prion Disease Surveillance Center, where testing revealed a previously described 5-octapeptide repeat insertion (5-OPRI) in the prion protein gene (PRNP) that is known to cause fCJD. The family had additional questions about the implications of this result and thus independently sought out genetic counseling.  While rare, fCJD is likely underdiagnosed due to clinical heterogeneity, rapid onset, early non-specific symptomatology, and overlap in the differential diagnosis of Alzheimer disease and Lewy body dementias. When fCJD is identified, a multidisciplinary approach to return of results that includes the affected patient's provider, genetics professionals, and mental health professionals is key to the care of the family. We present an example case which discusses the psychosocial issues encountered and the role of genetic counseling in presymptomatic testing for incurable neurodegenerative conditions. Ordering physicians should be aware of the basic issues surrounding presymptomatic genetic testing and identify local genetic counseling resources for their patients.

  8. Creutzfeldt-Jakob disease: implications for gastroenterology.

    PubMed

    Bramble, M G; Ironside, J W

    2002-06-01

    The current clinical views regarding variant Creutzfeldt-Jakob disease, and in particular transmission via endoscopy, of those representing both gastroenterology and the Spongiform Encephalopathy Advisory Committee are presented in an attempt to guide clinicians as to "best practice" given the current state of our knowledge.

  9. Characterization of sleep disorders in patients with E200K familial Creutzfeldt-Jakob disease.

    PubMed

    Cohen, Oren S; Chapman, Joab; Korczyn, Amos D; Warman-Alaluf, Naama; Orlev, Yael; Givaty, Gili; Nitsan, Zeev; Appel, Shmuel; Rosenmann, Hanna; Kahana, Esther; Shechter-Amir, Dalia

    2015-02-01

    The largest cluster of E200K familial Creutzfeldt-Jakob disease (fCJD) which occurs is in Jews of Libyan origin in Israel. Insomnia is a very common early complaint in those patients and may even be the presenting symptom. The aim of this study was to assess and characterize sleep pathology in E200K fCJD patients. To do so, sleep studies of 10 consecutive fCJD patients were compared with those of 39 age and gender-matched controls. All patients presented pathological sleep characterized by fragmentation of sleep, loss of sleep spindles and reduced REM sleep amount. Respiration was characterized by irregular rhythm, periodic breathing, apneas and hypopneas, either central or obstructive. EMG recordings revealed repeated movements in sleep, with loss of REM atonia. Comparing to controls, a significant decrease of total sleep time, sleep efficacy and slow-wave sleep as well as a significant increase in the number of awakenings, apnea-hypopnea index and mixed and central apneas were evident in CJD patients. Comparison of two sequential sleep studies in one patient revealed a 40 % reduction of the total sleep time, a 40 % reduction in sleep efficacy and a 40-fold increase of the number of arousals in the second study. A significant correlation was found between the disease severity, as reflected by the CJD Neurological Scale and Periodic leg movement index. These definite and characteristic sleep pathologies in patients with fCJD associated with the E200K mutation may serve as a new diagnostic tool in the disease.

  10. CJD: Understanding Creutzfeldt-Jakob disease.

    PubMed

    Vacca, Vincent M

    2016-03-01

    Rare, transmissible, and rapidly progressive, Creutzfeldt-Jakob disease (CJD) is an ultimately fatal central nervous system infection caused by accumulation of abnormally shaped prion proteins in neurons (see Understanding prion proteins). Although categorized as an infection, CJD doesn't lead to the immune system or inflammatory response typical of most infectious diseases. This article discusses the pathophysiology and diagnosis of this terminal illness and nursing care for patients with suspected or confirmed CJD.

  11. A Corticobasal Syndrome Variant of Familial Creutzfeldt-Jakob Disease with Stroke-Like Onset

    PubMed Central

    2016-01-01

    Creutzfeldt-Jakob disease (CJD) is an untreatable rare human prion disease characterized by rapidly progressive dementia along with various neurological features, including myoclonus and sometimes other movement disorders. The clinical course is typically insidious and rapid, leading to an early death. In general, the most common form is sporadic CJD; however, Slovakia is typical for a high percentage of genetic cases. We present an unusual case report of a 65-year-old man with a sudden, stroke-like onset of motor aphasia with right-sided levodopa unresponsive parkinsonism, alien hand, and other characteristic features of corticobasal syndrome (CBS), with rapid deterioration and death on the 32nd day of the disease. Various neurodegenerative disorders are manifested with CBS as a clinical phenotype, including corticobasal degeneration (CBD), progressive supranuclear palsy, Alzheimer's disease, and CJD. In our patient, mutation E200K and M129M polymorphism of the PRNP gene and typical immunohistochemical findings pointed to a diagnosis of CJD. The patient's mother died of CJD many years ago. Several CBS-CJD cases were described, but the atypical stroke-like onset of CBS-CJD, an extremely rare presentation of CJD, makes our case unique worldwide. PMID:27803826

  12. Variant Creutzfeldt-Jakob Disease (vCJD)

    MedlinePlus

    ... for the outbreak of prion disease in cows, bovine spongiform encephalopathy (BSE or 'mad cow' disease), is the same ... Links Prion Diseases Creutzfeldt-Jakob Disease, Classic (CJD) Bovine Spongiform Encephalopathy (BSE), or Mad Cow Disease Chronic Wasting Disease ( ...

  13. Visual art therapy in sporadic Creutzfeldt-Jakob disease: a case study.

    PubMed

    Shrestha, Rajeet; Trauger-Querry, Barbara; Loughrin, Athena; Appleby, Brian S

    2016-01-01

    This paper describes the diagnostic and treatment utility of visual art therapy in a case of sporadic Creutzfeldt-Jakob disease. Visual art therapy was compared longitudinally with clinical and neuroimaging data over five-month period in an autopsy-confirmed case of sporadic Creutzfeldt-Jakob disease of MM2-cortical subtype. Art therapy sessions and content were useful in ascertaining neuropsychiatric symptoms during the course of her illness. Art therapy offered a unique emotional and cognitive outlet as illness progressed. Patients and families affected by sporadic Creutzfeldt-Jakob disease may benefit from art therapy despite the rapidly progressive nature of the illness. Art therapy can also be useful for assessment of patients with sporadic Creutzfeldt-Jakob disease by healthcare professionals.

  14. Sleep Pathology in Creutzfeldt-Jakob Disease

    PubMed Central

    Kang, Peter; de Bruin, Gabriela S.; Wang, Leo H.; Ward, Beth A.; Ances, Beau M.; Lim, Miranda M.; Bucelli, Robert C.

    2016-01-01

    Study Objectives: Associations between sleep and neurodegenerative diseases have become increasingly evident. This study aims to characterize the prevalence and type of sleep pathology in Creutzfeldt-Jakob disease (CJD), a rapidly progressive, fatal neurodegenerative disease. Methods: In this observational cross-sectional cohort study, we performed a retrospective analysis of sleep signs and symptoms in a consecutive group of patients with definite CJD at a tertiary care medical center (n = 28). Polysomnography was performed in 14 patients. Results: Although only 5 of 28 patients carried a premorbid sleep diagnosis, signs/symptoms of sleep pathology were present in 25 patients. Eleven reported hypersomnia whereas 13 reported insomnia. Seven had restless legs symptoms and/or periodic limb movements of sleep, and nine reported parasomnias. Of the 14 patients who underwent polysomnography, 1 did not show sleep, 9 (69%) had poorly formed or absent sleep spindles and/or K-complexes, and 10 (77%) had sleep-disordered breathing. Of the 8 patients who experienced rapid eye movement (REM) sleep during the polysomnography, 3 (38%) showed REM sleep without atonia, and 2 patients met criteria for REM sleep behavior disorder. Median total sleep time was 226 (interquartile range [IQR] = 195–282) min. Median sleep efficiency was 58.5% (IQR = 41–65.5 %). Median REM time was 0.35% (IQR = 0–7.125%). Five patients (38%) demonstrated periodic limb movements during polysomnography. One case is presented. Conclusions: Sleep pathology is common in CJD, and screening for sleep pathology is indicated in the evaluation of patients with rapidly progressive dementias. Early identification and treatment of sleep pathology may provide an intervenable target for CJD. Citation: Kang P, de Bruin GS, Wang LH, Ward BA, Ances BM, Lim MM, Bucelli RC. Sleep pathology in Creutzfeldt-Jakob disease. J Clin Sleep Med 2016;12(7):1033–1039. PMID:27250807

  15. Ocular Dipping in Creutzfeldt-Jakob Disease

    PubMed Central

    Llamas, Sara; Gonzalo, Juan Francisco; Sánchez Sánchez, Carmen

    2014-01-01

    Background Ocular dipping (OD), or inverse ocular bobbing, consists of slow, spontaneous downward eye movements with rapid return to the primary position. It has been mainly reported following hypoxic-ischemic encephalopathy, but has also been described in association with other types of diffuse or multifocal encephalopathies and structural brainstem damage. Case Report We report the case of a previously asymptomatic 66-year-old woman who presented with confusion, recent memory disturbances, and abnormal involuntary movements, followed by a coma. Abnormal spontaneous vertical eye movements consistent with OD developed from the fourth day after admission, and the patient died 20 days later. The pathological examination of the brain confirmed the diagnosis of Creutzfeldt-Jakob disease. Conclusions The precise location of damage causing OD is unknown. In contrast to ocular bobbing, OD has no localizing value itself, but structural brainstem damage is likely when it appears combined with other spontaneous vertical eye movements. PMID:24829603

  16. Wernicke encephalopathy and Creutzfeldt-Jakob disease.

    PubMed

    Bertrand, A; Brandel, J P; Grignon, Y; Sazdovitch, V; Seilhean, D; Faucheux, B; Privat, N; Brault, J L; Vital, A; Uro-Coste, E; Pluot, M; Chapon, F; Maurage, C A; Letournel, F; Vespignani, H; Place, G; Degos, C F; Peoc'h, K; Haïk, S; Hauw, J J

    2009-06-01

    We assessed the prevalence of Wernicke encephalopathy (WE) in all 657 cases suspected of Creutzfeldt-Jakob (CJD) referred from 2001 to 2006 to the French Neuropathology Network of CJD. Clinical, biological and imaging data were reviewed when the diagnosis of WE was made at autopsy. No CJD was found in five cases suspected of sporadic CJD. In these five cases, myoclonus had been observed in four, CSF 14-3-3 protein in two. In 14 other cases, WE was combined with CJD, 13 of which were sporadic. These belonged mainly to the molecular variants of sporadic CJD associated with a long duration of disease. This stresses the necessity of remaining alert to the diagnosis of WE when CJD is suspected.

  17. Transmissible familial Creutzfeldt-Jakob disease associated with five, seven, and eight extra octapeptide coding repeats in the PRNP gene

    SciTech Connect

    Goldfarb, L.G.; Brown, P.; McCombie, W.R.; Gibbs, C.J. Jr.; Gajdusek, D.C. ); Goldgaber, D. ); Swergold, G.D. ); Wills, P.R. ); Cervenakova, L. ); Baron, H. )

    1991-12-01

    The PRNP gene, encoding the amyloid precursor protein that is centrally involved in Creutzfeldt-Jakob disease (CJD), has an unstable region of five variant tandem octapeptide coding repeats between codons 51 and 91. The authors screened a total of 535 individuals for the presence of extra repeats in this region, including patients with sporadic and familial forms of spongiform encephalopathy, members of their families, other neurological and non-neurological patients, and normal controls. They identified three CJD families (in each of which the proband's disease was neuropathologically confirmed and experimentally transmitted to primates) that were heterozygous for alleles with 10, 12, or 13 repeats, some of which had wobble nucleotide substitutions. They also found one individual with 9 repeats and no nucleotide substitutions who had no evidence of neurological disease. These observations, together with data on published British patients with 11 and 14 repeats, strongly suggest that the occurrence of 10 or more octapeptide repeats in the encoded amyloid precursor protein predisposes to CJD.

  18. Familial Creutzfeldt-Jakob disease with the E200K mutation: longitudinal neuroimaging from asymptomatic to symptomatic CJD.

    PubMed

    Cohen, Oren S; Chapman, Joab; Korczyn, Amos D; Nitsan, Zeev; Appel, Shmuel; Hoffmann, Chen; Rosenmann, Hanna; Kahana, Esther; Lee, Hedok

    2015-03-01

    Familial Creutzfeldt-Jakob disease (fCJD) in Jews of Libyan ancestry is caused by an E200K mutation in the PRNP gene. While carriers are born with this mutation, they usually remain asymptomatic until middle age. Early detection of conversion is crucial for understanding and eventually for the treatment of the disease. The aim of this study was to report longitudinal MRI data in E200K individuals who eventually converted from healthy mutation carriers to clinically symptomatic CJD. As a part of a prospective study, asymptomatic E200K mutation carriers were scanned annually until their conversion to symptomatic disease. Standardized diffusion and anatomical MR sequences were performed before and after clinical conversion in the subjects and those were compared to 15 non-carrier siblings ("healthy controls"). Blinded radiological readings and region of interest analyses were performed. Radiological readings of individual cases failed to detect characteristic changes in the scans taken before the conversion. Region of interest analysis of diffusion changes in pre-symptomatic stage was inconclusive; however, ADC reduction was found in early and late stages of the disease. Computerized volumetric analysis revealed monotonic volume reductions in thalamus, putamen and caudate following conversion, and the lateral ventricles showed dilatation of up to 62 % after clinical conversion. Although the clinical manifestations at disease onset are variable, the diffusion abnormalities and/or volume changes in the thalamus and basal ganglia during conversion may indicate early involvement of the thalamostriatal neuronal circuit.

  19. The role of stress and anxiety in the onset of familial Creutzfeldt-Jakob Disease (CJD): review.

    PubMed

    Gigi, Ariela

    2009-09-01

    Creutzfeldt-Jakob Disease (CJD) is considered to be a sudden and fatal degenerative brain disorder that leads to death within a few months. In the last decade, we have studied the course of familial CJD (fCJD) among Jews of Libyan descent, one of the largest clusters of fCJD in the world. Recently, we published results that included the identification of abnormal anxiety levels in healthy CJD E200K mutation carriers that were significantly different from those of healthy non-carriers from the same families. All participants were first-degree relatives of patients known to have been carriers of the E200K mutation and had died from CJD, and none of the participants was aware of his/her genetic make-up. In the current review, it is suggested that an abnormality in anxiety levels among the healthy fCJD mutation carriers may reflect the clinical presentation of the disease onset especially during and after any stressful experience. This hypothesis is supported by a summary of relevant literature, dealing with psychological, physiological, and cellular aspects.

  20. Clinical experiences with Creutzfeldt-Jakob disease: three case studies.

    PubMed

    Szucs, Anna; Várallyay, Péter; Osztie, Eva; Papp, Erzsébet; Sólyom, András; Finta, Lehel; Varga, Dániel; Barcs, Gábor; Holló, András; Kamondi, Anita

    2012-11-30

    The clinical picture, electroencephalographic, imaging and cerebrospinal fluid parameters as well as the molecular background of Creutzfeldt-Jakob disease have been well explored. The diagnostic criteria, offering clinicians a fair chance to identify these patients in vivo, have recently been updated. However, the diagnosis is still a challenge in everyday neurological routine. We report on three of our Creutzfeldt-Jakob patients for calling attention to the classical and the recently defined features of the disease. We conclude that based on the rapidly progressing neuropsychiatric syndrome Creutzfeldt-Jakob disease may be suspected; follow-up EEG may reveal the typical (pseudo)-periodic pattern with progressive deterioration of the background activity. In addition, diffusion-weighted brain MRI imaging (DWI) has high diagnostic value. Detection of 14-3-3 protein in the cerebrospinal fluid supports the in vivo diagnosis.

  1. Rapid cognitive decline: not always Creutzfeldt-Jakob disease.

    PubMed

    Randall, A; Ellis, R; Hywel, B; Davies, R R; Alusi, S H; Larner, A J

    2015-01-01

    A patient with rapidly progressive cognitive decline over an approximately four month period was suspected to have sporadic Creutzfeldt-Jakob disease. Features thought to support this diagnosis included psychiatric symptoms (anxiety and depression), visual hallucinations and a visual field defect. However, the finding of papilloedema broadened the differential diagnosis. Although standard brain imaging and electroencephalography had shown only non-specific abnormalities, subsequent cerebral angiography disclosed an intracranial dural arteriovenous fistula. Following embolisation, the patient made a good functional recovery. Intracranial dural arteriovenous fistula merits consideration in any patient with subacute cognitive decline, and should be included in the differential diagnosis of sporadic Creutzfeldt-Jakob disease.

  2. Biological network inferences for a protection mechanism against familial Creutzfeldt-Jakob disease with E200K pathogenic mutation

    PubMed Central

    2014-01-01

    Background Human prion diseases are caused by abnormal accumulation of misfolded prion protein in the brain tissue. Inherited prion diseases, including familial Creutzfeldt-Jakob disease (fCJD), are associated with mutations of the prion protein gene (PRNP). The glutamate (E)-to-lysine (K) substitution at codon 200 (E200K) in PRNP is the most common pathogenic mutation causing fCJD, but the E200K pathogenic mutation alone is regarded insufficient to cause prion diseases; thus, additional unidentified factors are proposed to explain the penetrance of E200K-dependent fCJD. Here, exome differences and biological network analysis between fCJD patients with E200K and healthy individuals, including a non-CJD individual with E200K, were analysed to gain new insights into possible mechanisms for CJD in individuals carrying E200K. Methods Exome sequencing of the three CJD patients with E200K and 11 of the family of one patient (case1) were performed using the Illumina HiSeq 2000. The exome sequences of 24 Healthy Koreans were used as control. The bioinformatic analysis of the exome sequences was performed using the CLC Genomics Workbench v5.5. Sanger sequencing for variants validation was processed using a BigDye Terminator Cycle Sequencing Kit and an ABI 3730xl automated sequencer. Biological networks were created using Cytoscape (v2.8.3 and v3.0.2) and Pathway Studio 9.0 software. Results Nineteen sites were only observed in healthy individuals. Four proteins (NRXN2, KLKB1, KARS, and LAMA3) that harbour rarely observed single-nucleotide variants showed biological interactions that are associated with prion diseases and/or prion protein in our biological network analysis. Conclusion Through this study, we confirmed that individuals can have a CJD-free life, even if they carry a pathogenic E200K mutation. Our research provides a possible mechanism that involves a candidate protective factor; this could be exploited to prevent fCJD onset in individuals carrying E200K. PMID

  3. White matter involvement in sporadic Creutzfeldt-Jakob disease.

    PubMed

    Caverzasi, Eduardo; Mandelli, Maria Luisa; DeArmond, Stephen J; Hess, Christopher P; Vitali, Paolo; Papinutto, Nico; Oehler, Abby; Miller, Bruce L; Lobach, Irina V; Bastianello, Stefano; Geschwind, Michael D; Henry, Roland G

    2014-12-01

    Sporadic Creutzfeldt-Jakob disease is considered primarily a disease of grey matter, although the extent of white matter involvement has not been well described. We used diffusion tensor imaging to study the white matter in sporadic Creutzfeldt-Jakob disease compared to healthy control subjects and to correlated magnetic resonance imaging findings with histopathology. Twenty-six patients with sporadic Creutzfeldt-Jakob disease and nine age- and gender-matched healthy control subjects underwent volumetric T1-weighted and diffusion tensor imaging. Six patients had post-mortem brain analysis available for assessment of neuropathological findings associated with prion disease. Parcellation of the subcortical white matter was performed on 3D T1-weighted volumes using Freesurfer. Diffusion tensor imaging maps were calculated and transformed to the 3D-T1 space; the average value for each diffusion metric was calculated in the total white matter and in regional volumes of interest. Tract-based spatial statistics analysis was also performed to investigate the deeper white matter tracts. There was a significant reduction of mean (P=0.002), axial (P=0.0003) and radial (P=0.0134) diffusivities in the total white matter in sporadic Creutzfeldt-Jakob disease. Mean diffusivity was significantly lower in most white matter volumes of interest (P<0.05, corrected for multiple comparisons), with a generally symmetric pattern of involvement in sporadic Creutzfeldt-Jakob disease. Mean diffusivity reduction reflected concomitant decrease of both axial and radial diffusivity, without appreciable changes in white matter anisotropy. Tract-based spatial statistics analysis showed significant reductions of mean diffusivity within the white matter of patients with sporadic Creutzfeldt-Jakob disease, mainly in the left hemisphere, with a strong trend (P=0.06) towards reduced mean diffusivity in most of the white matter bilaterally. In contrast, by visual assessment there was no white matter

  4. White matter involvement in sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Mandelli, Maria Luisa; DeArmond, Stephen J.; Hess, Christopher P.; Vitali, Paolo; Papinutto, Nico; Oehler, Abby; Miller, Bruce L.; Lobach, Irina V.; Bastianello, Stefano; Geschwind, Michael D.; Henry, Roland G.

    2014-01-01

    Sporadic Creutzfeldt-Jakob disease is considered primarily a disease of grey matter, although the extent of white matter involvement has not been well described. We used diffusion tensor imaging to study the white matter in sporadic Creutzfeldt-Jakob disease compared to healthy control subjects and to correlated magnetic resonance imaging findings with histopathology. Twenty-six patients with sporadic Creutzfeldt-Jakob disease and nine age- and gender-matched healthy control subjects underwent volumetric T1-weighted and diffusion tensor imaging. Six patients had post-mortem brain analysis available for assessment of neuropathological findings associated with prion disease. Parcellation of the subcortical white matter was performed on 3D T1-weighted volumes using Freesurfer. Diffusion tensor imaging maps were calculated and transformed to the 3D-T1 space; the average value for each diffusion metric was calculated in the total white matter and in regional volumes of interest. Tract-based spatial statistics analysis was also performed to investigate the deeper white matter tracts. There was a significant reduction of mean (P = 0.002), axial (P = 0.0003) and radial (P = 0.0134) diffusivities in the total white matter in sporadic Creutzfeldt-Jakob disease. Mean diffusivity was significantly lower in most white matter volumes of interest (P < 0.05, corrected for multiple comparisons), with a generally symmetric pattern of involvement in sporadic Creutzfeldt-Jakob disease. Mean diffusivity reduction reflected concomitant decrease of both axial and radial diffusivity, without appreciable changes in white matter anisotropy. Tract-based spatial statistics analysis showed significant reductions of mean diffusivity within the white matter of patients with sporadic Creutzfeldt-Jakob disease, mainly in the left hemisphere, with a strong trend (P = 0.06) towards reduced mean diffusivity in most of the white matter bilaterally. In contrast, by visual assessment there was no white

  5. Abnormal Eye Movements in Creutzfeldt-Jakob Disease

    NASA Technical Reports Server (NTRS)

    Grant, Michael P.; Cohen, Mark; Petersen, Robert B.; Halmagyi, G. Michael; McDougall, Alan; Tusa, Ronald J.; Leigh, R. John

    1993-01-01

    We report 3 patients with autopsy-proven Creutzfeldt-Jakob disease who, early in their course, developed abnormal eye movements that included periodic alternating nystagmus and slow vertical saccades. These findings suggested involvement of the cerebellar nodulus and uvula, and the brainstem reticular formation, respectively. Cerebellar ataxia was also an early manifestation and, in one patient, a frontal lobe brain biopsy was normal at a time when ocular motor and cerebellar signs were conspicuous. As the disease progressed, all saccades and quick phases of nystagmus were lost, but periodic alternating gaze deviation persisted. At autopsy, 2 of the 3 patients had pronounced involvement of the cerebellum, especially of the midline structures. Creutzfeldt-Jakob disease should be considered in patients with subacute progressive neurological disease when cognitive changes are overshadowed by ocular motor findings or ataxia.

  6. Creutzfeldt-Jakob disease: a case report and differential diagnoses.

    PubMed

    Kojima, Gotaro; Tatsuno, Brent K; Inaba, Michiko; Velligas, Stephanie; Masaki, Kamal; Liow, Kore K

    2013-04-01

    Sporadic Creutzfeldt-Jakob disease is a rare neurodegenerative disorder of unknown etiology that causes rapidly progressive dementia. This disease is uniformly fatal and most patients die within 12 months. Clinical findings include myoclonus, visual disturbances, and cerebellar and pyramidal/extrapyramidal signs in addition to rapidly progressive cognitive and functional impairment. These findings are all non-specific and it is often difficult and challenging to diagnose premortem because of low awareness and clinical suspicion. We present a 66-year-old woman with a 5-month history of rapidly progressive dementia. After a series of extensive diagnostic examinations and continuous follow-up, she was diagnosed with probable sporadic Creutzfeldt-Jakob disease based on Centers for Disease Control and Prevention (CDC) criteria, with key findings of rapidly progressive dementia, blurry vision, extrapyramidal signs (cogwheel rigidity), and abnormal hyperintensity signals on diffusion-weighted MRI. Her symptoms progressively worsened and she died 7 months after the onset. The postmortem brain autopsy demonstrated the presence of abnormal protease-resistant prion protein by Western Blot analysis. A literature review was performed on differential diagnoses that present with rapidly progressive dementia and thereby mimic sporadic Creutzfeldt-Jakob disease. These include Alzheimer's disease, dementia with Lewy Bodies, frontotemporal dementia, meningoencephalitis, corticobasal degeneration, progressive supranuclear palsy, CADASIL, and paraneoplastic encephalomyelitis.

  7. Detection of infectivity in blood of persons with variant and sporadic Creutzfeldt-Jakob disease.

    PubMed

    Douet, Jean Yves; Zafar, Saima; Perret-Liaudet, Armand; Lacroux, Caroline; Lugan, Séverine; Aron, Naima; Cassard, Herve; Ponto, Claudia; Corbière, Fabien; Torres, Juan Maria; Zerr, Inga; Andreoletti, Olivier

    2014-01-01

    We report the presence of infectivity in erythrocytes, leukocytes, and plasma of 1 person with variant Creutzfeldt-Jakob disease and in the plasma of 2 in 4 persons whose tests were positive for sporadic Creutzfeldt-Jakob disease. The measured infectivity levels were comparable to those reported in various animals with transmissible spongiform encephalopathies.

  8. Physical properties of the Creutzfeldt-Jakob disease agent

    SciTech Connect

    Sklaviadis, T.K.; Manuelidis, L.; Manuelidis, E.E.

    1989-03-01

    In this report, the authors present the first physical characterization of the Creutzfeld-Jakob disease agent. Preparations with high yields of infectivity (assayed infectious units) were obtained by a novel, gentle procedure in which initially sedimenting Gp34 (prion protein) was disaggregated by a variety of criteria with no subsequent loss of infectivity. Studies with this preparation indicate that most of the Creutzfeldt-Jakob disease agent has both a viruslike size and density. In velocity sedimentation and isopycnic sucrose gradients, infectivity comigrated with nucleic acid-protein complexes of appreciable size.

  9. Sporadic Creutzfeldt-Jakob disease--a review.

    PubMed

    Sharma, Stuti; Mukherjee, Madhurima; Kedage, Vivekananda; Muttigi, Manjunatha S; Rao, Anjali; Rao, Suryanarayana

    2009-01-01

    The objective is to study a patient with sporadic Creutzfeldt-Jakob disease (CJD). The patient, a 70-year-old woman with a history spanning over 1 month, with acute onset, progressive abnormal behavior, and cognitive decline with generalized asymmetrical myoclonic jerking, startle phenomenon, and cortical blindness, was referred to the hospital. On observation of clinical symptoms, metabolic and hematological investigations, MRI (magnetic resonance imaging), and EEG (electroencephalogram) were done. The clinical symptoms, MRI, and diagnostic EEG were suggestive of sporadic CJD. Other metabolic encephalopathies were ruled out. With sodium valproate and clonezepam, her myoclonic jerks improved slightly. As CJD is an incurable disease, no definitive treatment could be given.

  10. [Creutzfeldt-Jakob disease in Peru: report of eleven cases].

    PubMed

    Torres-Ramírez, Luis; Ramírez-Quiñones, Jorge; Cosentino-Esquerre, Carlos; Vélez-Rojas, Miriam; Flores-Mendoza, Martha; Rivas-Franchini, Diana; Suarez-Reyes, Rafael; Núñez-Coronado, Yesenia

    2014-04-01

    Creutzfeldt-Jakob disease (CJD) is a fatal neurological disease caused by pathological isoform of the human prion protein. Clinical features of six cases of the sporadic form of CJD with definitive diagnosis by histopathology, and five cases with probable diagnosis were reported in patients treated at the Peruvian National Institute of Neurological Sciences. The average age of onset in definite cases was 55.8 years and in probable cases was 59.6, mostly males. The average disease duration was 8.8 months. A typical EEG was found in 50% of definite cases and in 80% of probable. The 14-3-3 protein in cerebrospinal fluid was positive in a probable case, and typical MRI findings were observed in two probable cases. All cases studied had a typical clinical course of the disease, and it is considered as the first report of CJD in Peru.

  11. Creutzfeldt-Jakob disease surveillance in Australia, update to December 2013.

    PubMed

    Klug, Genevieve M; Boyd, Alison; Sarros, Shannon; Stehmann, Christiane; Simpson, Marion; McLean, Catriona A; Masters, Collin L; Collins, Stephen J

    2014-12-31

    Nation-wide surveillance of transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease, is performed by the Australian National Creutzfeldt-Jakob Disease Registry, based at the University of Melbourne. Surveillance has been undertaken since 1993. Over this dynamic period in transmissible spongiform encephalopathy research and understanding, the unit has evolved and adapted to changes in surveillance practices and requirements, the emergence of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness and understanding of Creutzfeldt-Jakob disease and other transmissible spongiform encephalopathies in the health care setting. In 2013, routine surveillance continued and this brief report provides an update of the surveillance data collected by the Australian National Creutzfeldt-Jakob Disease Registry prospectively from 1993 to December 2013, and retrospectively to 1970. The report highlights the recent multi-national collaborative study published that has verified the correlation between surveillance intensity and reported disease incidence.

  12. Creutzfeldt-Jakob disease: report of four cases and review of the literature.

    PubMed

    Atalay, Fatma Öz; Tolunay, Şahsine; Özgün, Gonca; Bekar, Ahmet; Zarifoğlu, Mehmet

    2015-01-01

    Creutzfeldt-Jakob disease is a very rare, progressive neurodegenerative disorder that is incurable and always fatal. It is one of the transmissible spongiform encephalopathies caused by prions. Multiple vacuoles in neuropil and neuronal loss in the gray matter gives the classical sponge-like appearance of brain and are responsible for the typical clinical symptoms. In this report, we present 4 cases referred to the neurology department of Uludağ University with neurological symptoms. Patients were evaluated with electroencephalogram and magnetic resonance imaging, and performed brain biopsies for further investigation. For definitive diagnosis of Creutzfeldt-Jakob disease, accumulation of prion protein in brain was detected immunohistochemically. Patients died within weeks in consequence of rapid progression of the disease. Although Creutzfeldt-Jakob disease is an infrequent disorder, when a patient presents with characteristic clinical symptoms such as rapidly progressive dementia with myoclonus, the diagnosis of Creutzfeldt-Jakob disease should be taken into consideration.

  13. A case of pure autotopagnosia following Creutzfeldt-Jakob disease.

    PubMed

    Tamura, Itaru; Hamada, Shinsuke; Soma, Hiroyuki; Moriwaka, Fumio; Tashiro, Kunio

    2016-12-02

    A 69-year-old male (N.A.) with Creutzfeldt-Jakob disease showed pure autotopagnosia. We administered tests evaluating his ability to name his own body parts, to point to body parts (his own and examiner's), and to recognize positional relationships between his body parts by verbal questions and responses. We found impaired localization of the patient's own body parts by pointing and impaired recognition of positional relationships between his body parts. However, there was no impairment in naming his own body parts or in localizing the examiner's body parts. The results suggest a pure autotopagnosia in N.A. leading to an impairment of recognition of the spatial position of his body parts in a three-dimensional body representation within the egocentric reference frame. We were able to rule out the possibility that his pattern of performance could have been due to a disability in programming reaching movements of the arm.

  14. Review: Laboratory diagnosis and surveillance of Creutzfeldt-Jakob disease.

    PubMed

    Lee, Jeongmin; Hyeon, Jae Wook; Kim, Su Yeon; Hwang, Kyu-Jam; Ju, Young Ran; Ryou, Chongsuk

    2015-01-01

    Creutzfeldt-Jakob disease (CJD) is a representative human transmissible spongiform encephalopathy associated with central nervous system degeneration. Prions, the causative agents of CJD, are composed of misfolded prion proteins and are able to self-replicate. While CJD is a rare disease affecting only 1-1.5 people per million worldwide annually, it has attracted both scientific and public attention as a threatening disease since an epidemic of variant CJD (vCJD) cases appeared in the mid-1990s. Due to its unconventional transmission and invariable fatality, CJD poses a serious risk to public health. The hundreds of sporadic, genetic, and iatrogenic CJD cases as well as potential zoonotic transmission suggest that CJD is an ongoing concern for the field of medicine. Nevertheless, treatment aimed at clinical prevention and treatment that reverses the course of disease does not exist currently. Active surveillance and effective laboratory diagnosis of CJD are, therefore, critical. In this report, the surveillance systems and laboratory tests used currently to diagnose CJD in different countries are reviewed. The current efforts to improve surveillance and diagnosis for CJD using molecular and biochemical findings are also described.

  15. "Preclinical" MSA in definite Creutzfeldt-Jakob disease.

    PubMed

    Rodriguez-Diehl, Roberta; Rey, Maria Jesus; Gironell, Alexandre; Martinez-Saez, Elena; Ferrer, Isidre; Sánchez-Valle, Raquel; Jagüe, Jordi; Nos, Carlos; Gelpi, Ellen

    2012-04-01

    Multiple system atrophy (MSA) is a sporadic alpha-synucleinopathy clinically characterized by variable degrees of parkinsonism, cerebellar ataxia and autonomic dysfunction. The histopathological hallmark of MSA is glial cytoplasmic inclusion (GCI). It is considered to represent the earliest stage of the degenerative process in MSA and to precede neuronal degeneration. Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal, rapidly progressive dementia generally associated with ataxia, pyramidal and extrapyramidal symptoms and myoclonus. Definite diagnosis needs neuropathological demonstration of variable degrees of spongiform degeneration of neuropil, neuronal loss, astro- and microgliosis, and the presence of abnormal deposits of the misfolded prion protein PrP(res) . Both diseases, CJD and MSA are infrequent among neurodegenerative diseases. In the present report we describe clinical and neuropathological findings of a previously healthy 64-year-old woman who developed symptoms of classical CJD. At post mortem examination, the brain showed in addition to classical methionine/methionine PrP(res) type 1 (MM1) sCJD changes and moderate Alzheimer-type pathology, features of "preclinical" MSA with minimal histopathological changes. These were characterized by discrete amounts of alpha-synuclein immunoreacive glial cytoplasmic inclusions in the striato-nigral system, isolated intraneuronal inclusions in pigmented neurons of the substantia nigra, as well as some vermiform intranuclear inclusions. To our knowledge, this is the first report on the coexistence of definite sCJD and "minimal changes" MSA in the same patient.

  16. Visual symptoms in the presentation of Creutzfeldt-Jakob disease.

    PubMed

    Wong, Aaron; Matheos, Kaliopy; Danesh-Meyer, Helen V

    2015-10-01

    We describe a 68-year-old man with a previous history of neurosurgical repair of a skull fracture, who presented to the ophthalmology clinic with progressive visual decline. His initial visual acuity was 6/30 in the right eye and 6/48 in the left, and over 2 weeks this progressed to hand movements in both eyes. No ocular abnormalities were identified. He was noted to be increasingly confused and a subsequent MRI showed extensive bilateral posterior cortical changes consistent with cytotoxic oedema. An electroencephalogram was suggestive of encephalopathy, particularly involving the occipital lobe. He was diagnosed with the Heidenhain variant of Creutzfeldt-Jakob disease (CJD), confirmed by a positive cerebrospinal fluid 14-3-3 protein. Classically, patients with CJD present with rapidly progressive cognitive decline, ataxia and myoclonus. However, visual symptoms are a common and perhaps underrecognised manifestation of CJD. Patients can present with isolated visual symptoms which precede cognitive decline by weeks due to predominantly occipital lobe disease. This presentation is classified as the Heidenhain variant of CJD.

  17. Nestin immunoreactivity of Purkinje cells in Creutzfeldt-Jakob disease.

    PubMed

    Mizuno, Yuji; Ohama, Eisaku; Hirato, Junko; Nakazato, Yoichi; Takahashi, Hitoshi; Takatama, Masamitsu; Takeuchi, Toshiyuki; Okamoto, Koichi

    2006-07-15

    Nestin, an intermediate filament protein, is mainly expressed in neural progenitor/stem cells in the central nervous system. Recently, we reported that nestin is expressed in Purkinje cells in patients with Creutzfeldt-Jakob disease (CJD). In this study, we examined a total of 19 CJD cerebella to analyze the intensity and pattern of nestin immunoreactivity of Purkinje cells in different pathological stages of degeneration in the cerebellar cortex. The results showed that the Purkinje cells were immunoreactive with nestin regardless of the severity of degenerative cerebellar cortex. Furthermore, we noted several different types of nestin immunoreactivity, indicated by diffuse and fine, coarse, and inclusion-like immunostainings within Purkinje cell bodies as well as dot-like staining outside of the cell bodies. In contrast, on examination of cerebella from non-CJD patients, 6 of 30 cases showed nestin immunoreactivity to a lesser extent. Thus, nestin-positive Purkinje cells are more common in CJD cerebella than in non-CJD cerebella. Although the mechanism of nestin expression in Purkinje cells is not yet understood, we suggest that such nestin-positive Purkinje cells are being reactivated to survive the cell death.

  18. Creutzfeldt-Jakob disease surveillance in Australia: update to December 2015.

    PubMed

    Klug, Genevieve M; Boyd, Alison; Sarros, Shannon; Stehmann, Christiane; Simpson, Marion; McLean, Catriona A; Masters, Colin L; Collins, Steven J

    2016-09-30

    Nation-wide surveillance of human transmissible spongiform encephalopathies (also known as prion diseases), the most common being Creutzfeldt-Jakob disease, is performed by the Australian National Creutzfeldt-Jakob Disease Registry, based at the University of Melbourne. Prospective surveillance has been undertaken since 1993 and over this dynamic period in transmissible spongiform encephalopathy research and understanding, the unit has evolved and adapted to changes in surveillance practices and requirements concomitant with the delineation of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness of prion diseases in the health care setting. In 2015, routine national surveillance continued and this brief report provides an update of the cumulative surveillance data collected by the Australian National Creutzfeldt-Jakob Disease Registry prospectively from 1993 to December 2015, and retrospectively to 1970.

  19. Creutzfeldt-Jakob disease surveillance in Australia: update to December 2014.

    PubMed

    Klug, Genevieve M; Boyd, Alison; Sarros, Shannon; Stehmann, Christiane; Simpson, Marion; McLean, Catriona; Masters, Colin L; Collins, Steven J

    2016-06-30

    Nation-wide surveillance of human transmissible spongiform encephalopathies (also known as prion diseases), the most common being Creutzfeldt-Jakob disease, is performed by the Australian National Creutzfeldt-Jakob Disease Registry, based at the University of Melbourne. Prospective surveillance has been undertaken since 1993 and over this dynamic period in transmissible spongiform encephalopathy research and understanding, the unit has evolved and adapted to changes in surveillance practices and requirements concomitant with the emergence of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness of prion diseases in the health care setting. In 2014, routine national surveillance continued and this brief report provides an update of the cumulative surveillance data collected by the Australian National Creutzfeldt-Jakob Disease Registry prospectively from 1993 to December 2014, and retrospectively to 1970.

  20. Pathologically confirmed autoimmune encephalitis in suspected Creutzfeldt-Jakob disease

    PubMed Central

    Maat, Peter; de Beukelaar, Janet W.; Jansen, Casper; Schuur, Maaike; van Duijn, Cornelia M.; van Coevorden, Marleen H.; de Graaff, Esther; Titulaer, Maarten; Rozemuller, Annemieke J.

    2015-01-01

    Objective: To determine the clinical features and presence in CSF of antineuronal antibodies in patients with pathologically proven autoimmune encephalitis derived from a cohort of patients with suspected Creutzfeldt-Jakob disease (CJD). Methods: The Dutch Surveillance Centre for Prion Diseases performed 384 autopsies on patients with suspected CJD over a 14-year period (1998–2011). Clinical information was collected from treating physicians. Antineuronal antibodies were tested in CSF obtained postmortem by immunohistochemistry on fresh frozen rat brain sections, by Luminex assay for the presence of well-characterized onconeural antibodies, and by cell-based assays for antibodies against NMDAR, GABABR1/2, GABAAR GLUR1/2, LGI1, Caspr2, and DPPX. Results: In 203 patients, a diagnosis of definite CJD was made, while in 181 a variety of other conditions were diagnosed, mainly neurodegenerative. In 22 of these 181, the neuropathologist diagnosed autoimmune encephalitis. One patient was excluded because of lack of clinical information. Inflammatory infiltrates were predominantly perivascular and consisted mainly of T cells. The predominant locations were basal ganglia and thalamus (90%) and temporal lobes and hippocampus (81%). In 6 patients (29%), antineuronal antibodies were detected in postmortem CSF, directed against Hu, NMDAR, GABABR1/2, Caspr2, and an unidentified synaptic antigen in 2. The most frequent symptoms were dementia (90%), gait disturbance (86%), cerebellar signs (67%), and neuropsychiatric symptoms (67%). Immunopathologic and clinical findings did not differ between autoantibody-negative patients and patients with antineuronal antibodies. Conclusions: It is important to consider immune-mediated disorders in the differential diagnosis of rapidly progressive neurologic deficits. PMID:26601117

  1. Quinacrine treatment trial for sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Kuo, Amy L.; Wong, Katherine S.; Haman, Aissa; Devereux, Gillian; Raudabaugh, Benjamin J.; Johnson, David Y.; Torres-Chae, Charles C.; Finley, Ron; Garcia, Paul; Thai, Julie N.; Cheng, Hugo Q.; Neuhaus, John M.; Forner, Sven A.; Duncan, Jacque L.; Possin, Katherine L.; DeArmond, Stephen J.; Prusiner, Stanley B.; Miller, Bruce L.

    2013-01-01

    Objective: To determine whether oral quinacrine increases survival in sporadic Creutzfeldt-Jakob disease (sCJD). Methods: This NIH/National Institute on Aging–funded, double-blinded, placebo-controlled, stratified randomization treatment trial was conducted at the University of California, San Francisco from February 2005 through May 2009 (ClinicalTrials.gov, NCT00183092). Subjects were randomized (50:50) to quinacrine (300 mg daily) or placebo with inpatient evaluations at baseline, and planned for months 2, 6, and 12. Subjects returning for their month-2 visit were offered open-label quinacrine. The primary outcome was survival from randomization to month 2. Results: Of 425 patients referred, 69 subjects enrolled, 54 subjects were randomized to active drug or placebo, and 51 subjects with sCJD were included in survival analyses. Survival for the randomized portion of the trial (first 2 months) showed no significant difference between the 2 groups (log-rank statistic, p = 0.43; Cox proportional relative hazard = 1.43, quinacrine compared with placebo, 95% confidence interval = 0.58, 3.53). The quinacrine-treated group, however, declined less on 2 of 3 functional scales, the modified Rankin and Clinical Dementia Rating, than the placebo group during the first 2 months. Conclusion: This interventional study provides Class I evidence that oral quinacrine at 300 mg per day does not improve 2-month survival of patients with sCJD, compared with placebo. Importantly, this study shows that double-blinded, placebo-controlled, randomized treatment trials are possible in prion disease. Furthermore, the quantitative data collected on the course of sCJD will be useful for future trials. Classification of evidence: This study provides Class I evidence that quinacrine does not improve survival for people with sCJD when given orally at a dose of 300 mg per day for 2 months. PMID:24122181

  2. Iatrogenic Creutzfeldt-Jakob disease via surgical instruments.

    PubMed

    Thomas, Jonathan G; Chenoweth, Carol E; Sullivan, Stephen E

    2013-09-01

    Creutzfeldt-Jakob disease (CJD) is a neurodegenerative prion disease that can spread via contaminated neurosurgical instruments previously used on an infected patient. We examine current guidelines on how to recognize, handle, and prevent instrument-related iatrogenic CJD. Despite only four reported patients worldwide implicating contaminated neurosurgical instruments, and none in the past 30 years, the public health consequences of potential instrument-related iatrogenic CJD can be far-reaching. Conventional sterilization and disinfection methods are inadequate in reducing prion infectivity of contaminated instruments, and World Health Organization recommendations for disinfection using bleach or sodium hydroxide are often impractical for routine decontamination. Recently, possible CJD exposure via infected surgical instruments was suspected at a large teaching hospital. Although CJD was later disproven, the intervening investigation exposed the difficulty in tracking infected surgical instruments and in protecting subsequent surgical patients from prion infection. To identify patients at risk for iatrogenic CJD, infectivity of instruments after this index patient is estimated using simple scenario modeling, assuming a certain log reduction of infectivity for each cleansing cycle. Scenario modeling predicts that after six cycles of instrument use with conventional cleansing following an index patient, other patients are highly unlikely to be at risk for iatrogenic CJD. Despite its rarity, the threat of iatrogenic CJD transmission via contaminated instruments poses tremendous challenges to neurosurgeons. Basic prevention strategies should be employed for patients with suspected CJD, including use of disposable instruments where possible and quarantining non-disposable instruments until the diagnosis is ascertained, or using special instrument reprocessing methods if CJD is suspected.

  3. Gerstmann-Sträussler-Scheinker syndrome with the P102L pathogenic mutation presenting as familial Creutzfeldt-Jakob disease: a case report and review of the literature.

    PubMed

    Rusina, Robert; Fiala, Jindřich; Holada, Karel; Matějčková, Milada; Nováková, Jana; Ampapa, Radek; Koukolík, František; Matěj, Radoslav

    2013-01-01

    Gerstmann-Sträussler-Scheinker syndrome is a rare autosomal dominant disease caused by a mutation in the prion gene, usually manifesting as progressive ataxia with late cognitive decline. A 44-year-old woman with a positive family history developed early personality and behavior changes, followed by paresthesias and ataxia, later associated with memory problems, pyramidal signs, anosognosia and very late myoclonus, spasticity, and severe dysexecutive impairment. Magnetic resonance showed caudate, mesio-frontal, and insular hyper-intensities, electroencephalography revealed generalized triphasic periodic complexes. A pathogenic P102L mutation in the prion gene was detected. Our case differed from classical Gerstmann-Sträussler-Scheinker syndrome by rapid progression, severe dementia, abnormal electroencephalography and magnetic resonance findings, which were highly suggestive of familial Creutzfeldt-Jakob disease.

  4. The contribution of different prion protein types and host polymorphisms to clinicopathological variations in Creutzfeldt-Jakob disease.

    PubMed

    Head, Mark W; Ironside, James W

    2012-07-01

    Creutzfeldt-Jakob disease is a fatal neurodegenerative disease that primarily affects the central nervous system. In this respect, it can be considered alongside the more frequently occurring neurodegenerative diseases, such as Alzheimer's disease. Creutzfeldt-Jakob disease is perhaps the paradigmatic protein misfolding disorder, so comparisons between the mechanisms involved in Creutzfeldt-Jakob disease and other neurodegenerative diseases associated with protein misfolding (such as the tauopathies and synucleinopathies) may also be informative. Like many of these diseases, Creutzfeldt-Jakob disease occurs sporadically or can, more rarely, be associated with mutations. However, Creutzfeldt-Jakob disease can also be acquired and is experimentally transmissible. These properties have had profound public health implications and made the disease of interest to virologists, in addition to those interested in protein misfolding disorders and neurodegeneration. The possible causes for the pronounced phenotypic variation among different forms of Creutzfeldt-Jakob disease are beginning to become understood, and these appear to depend in large measure on the genetics of the host (specifically the sequence of the prion protein gene, PRNP) and the epigenetic aspects of the agent (thought to be a misfolded and aggregated form of the PRNP gene product, termed a prion). This review will examine whether this model in its present form has sufficient complexity and subtlety to account for the clinicopathological variation evident in Creutzfeldt-Jakob disease and will outline the ways in which a more complete and informative molecular definition of human prions are currently being sought.

  5. [Presenile dementia (Creutzfeldt-Jakob disease). Clinical and experimental data on a newly reported case].

    PubMed

    Drăgănescu, N

    1988-01-01

    A newly recorded case of presenile dementia (Creutzfeldt-Jakob disease) is discussed. The disease is experimentally transmissible to guinea pigs, after a long incubation period. From a pathomorphological point of view the experimental disease in the guinea pig is characterized by spongiosis, proliferative glial reaction, disappearance of neurons and of Purkinje's cells.

  6. Lingering doubts about spongiform encephalopathy and Creutzfeldt-Jakob disease.

    PubMed

    Narang, H K

    2001-07-01

    Bovine spongiform encephalopathy (BSE) is an infectious disease and has been transmitted orally to many other animals, including humans. There is clear evidence of maternal transmission, although disagreement on the source of the BSE agent remains. The current theories link the origin of BSE to common scrapie in sheep. Twenty different strains of the scrapie agent have been isolated from sheep. A search of the literature indicates two distinct clinical syndromes in sheep, both of which have been called scrapie. I have designated these Type I (the common type), which exhibits itchiness and lose their wool, and Type II, which exhibits trembling and ataxia. Sheep inoculated with BSE develop Type II scrapie and they exhibit trembling. When cattle or mink are injected with the Type I strain, only a few will develop a clinical disease. By contrast, no clinical disease has so far been shown in cattle or mink by feeding them with Type I-infected sheep brains. However, either by injecting or feeding with the BSE strain, 100% of calves and mink develop the clinical disease. Evidence suggests that Type II is the cause of BSE. Identical clinical signs of Type II trembling are found in kuru and many of the recent cases of Creutzfeldt-Jakob disease. The BSE agent has caused spongiform encephalopathies (SEs) in domestic cats, tigers, and in some species of ruminants in zoos. The nature of the BSE agent remains unchanged when passaged through a range of species, irrespective of their genetic make up, demonstrating that variations in the host PrP gene are not a major factor in the susceptibility to the BSE agent. Since more than 85 zoo animals of many species have been diagnosed with SEs, from these studies it seems reasonable to conclude that the BSE agent can infect almost all mammalian species, including humans. For eradication of BSE and to reduce the risk of infection to humans, the development of a vaccine against BSE is suggested. Such a possibility should be fully explored.

  7. Diagnosing Sporadic Creutzfeldt-Jakob Disease: Accuracy of CSF 14-3-3 Protein Test of the Spinal Fluid

    MedlinePlus

    ... JAKOB DISEASE: ACCURACY OF THE 14-3-3 PROTEIN TEST OF THE SPINAL FLUID This information sheet ... help you understand how the 14-3-3 protein test helps in diagnosing sporadic Creutzfeldt-Jakob disease ( ...

  8. Mad cow disease and Creutzfeldt-Jakob disease--is there a link?

    PubMed

    Rist, C E; Nielsen, J O

    1996-01-01

    The report of the Creutzfeldt-Jakob Surveillance Unit from March 1996 regarding 10 cases of a new variant of Creutzfeldt-Jakob disease (CJD) in young adults caused a great deal of uproar when it was suggested that a possible link with bovine spongiform encephalopathy (BSE) could not be excluded. BSE was first noticed in 1986 after the introduction of modified rendering systems in the manufacture of meat and bone meal containing animal wastes contaminated with scraple-like agents. This article reviews available information on CJD, BSE and other diseases caused by prions, transmission studies and the report of the CJD Surveillance Unit and discusses possible links between BSE and the new variant of CJD.

  9. [A Case of Sporadic Creutzfeldt-Jakob Disease That Developed With Psychiatric Symptoms].

    PubMed

    Özkan, Adile; Aydın Cantürk, İlknur; Candan, Fatma; Işık, Nihal; Özışık Karaman, Handan Işın

    2015-01-01

    Creutzfeldt-Jakob disease (CJD) is a fairly rare prion sickness characterized by rapidly progressive dementia and neuropsychiatric symptoms. The diversity of clinical characteristics of the disease causes difficulties during diagnosis. The first finding of the disease might be psychiatric symptoms. The male patient who was diagnosed with CJD after dementia, ataxia, and myoclonus developed rapidly following psychiatric symptoms, was presented in order to draw attention to the onset with psychiatric symptoms in CJD.

  10. Surveillance for Creutzfeldt-Jakob disease in Australia: update to December 2012.

    PubMed

    Klug, Genevieve M; Boyd, Alison; Zhao, Teresa; Stehmann, Christiane; Simpson, Marion; McLean, Catriona A; Masters, Colin L; Collins, Steven J

    2013-06-30

    Nation-wide surveillance for transmissible spongiform encephalopathies including Creutzfeldt-Jakob disease (CJD) is undertaken by the Australian National Creutzfeldt-Jakob disease Registry (ANCJDR), based at the University of Melbourne. Surveillance has been undertaken since 1993. During this period the unit has evolved and adapted to changes in surveillance practices and requirements, the emergence of new disease subtypes, improvements in diagnostic capabilities and the overall heightened awareness and understanding of CJD and other transmissible spongiform encephalopathies in the health care setting. In 2012, routine surveillance continued. This brief report provides an update on the surveillance data collected by the ANCJDR prospectively from 1993 to December 2012, and retrospectively to 1970. It also highlights the recent release of the revised Australian CJD Infection Control Guidelines.

  11. A practical approach to avoiding iatrogenic Creutzfeldt-Jakob disease (CJD) from invasive instruments.

    PubMed

    Brown, Paul; Farrell, Michael

    2015-07-01

    Potential Creutzfeldt-Jakob disease instrument-contamination events continue to occur, causing widespread hospital and patient concern. We propose the use of a combination of diagnostic tests (ie, spinal fluid for 14-3-3 protein or nasal brushing for misfolded prion protein) and instrument handling procedures (ie, using a regional set of dedicated instruments), which if applied to all patients admitted with symptoms of either dementia or cerebellar disease, should eliminate the risk of iatrogenic instrument infection.

  12. Atypical presentation of Creutzfeldt-Jakob disease: a rare but important cause of rapidly progressive dementia.

    PubMed

    Taillefer, Marguerite S; Tangarorang, Glendo L; Kuchel, George A; Menkes, Daniel L

    2011-09-01

    We report an atypical presentation of sporadic Creutzfeldt-Jakob disease (CJD) in a 74-year-old woman that illustrates the difficulty in diagnosing this rare, but important, cause of rapidly progressive dementia. Despite well-established criteria, this diagnosis is often missed or substantially delayed (Table 1). In this case, a precipitous cognitive decline associated with a urinary tract infection initiallysuggested delirium. Although atypical CJD was considered as a cause when symptoms persisted, a definitive diagnosis was established postmortem when the cerebrospinal fluid (CSF) prion protein 14-3-3 tested positive. Creutzfeldt-Jakob disease must be considered in the differential diagnosis of rapidly progressive dementia as Connecticut accounts for approximately three of the more than 200 cases diagnosed nationally.

  13. Codon 219 polymorphism of PRNP in healthy caucasians and Creutzfeldt-Jakob disease patients

    SciTech Connect

    Petraroli, R.; Pocchiari, M.

    1996-04-01

    A number of point and insert mutations of the PrP gene (PRNP) have been linked to familial Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker disease (GSS). Moreover, the methionine/valine homozygosity at the polymorphic codon 129 of PRNP may cause a predisposition to sporadic and iatrogenic CJD or may control the age at onset of familial cases carrying either the 144-bp insertion or codon 178, codon 198, and codon 210 pathogenic mutations in PRNP. In addition, the association of methionine or valine at codon 129 and the point mutation at codon 178 on the same allele seem to play an important role in determining either fatal familial insomnia or CJD. However, it is noteworthy that a relationship between codon 129 polymorphism and accelerated pathogenesis (early age at onset or shorter duration of the disease) has not been seen in familial CJD patients with codon 200 mutation or in GSS patients with codon 102 mutation, arguing that other, as yet unidentified, gene products or environmental factors, or both, may influence the clinical expression of these diseases. 17 refs.

  14. Prion infectivity in the spleen of a PRNP heterozygous individual with subclinical variant Creutzfeldt-Jakob disease.

    PubMed

    Bishop, Matthew T; Diack, Abigail B; Ritchie, Diane L; Ironside, James W; Will, Robert G; Manson, Jean C

    2013-04-01

    Blood transfusion has been identified as a source of human-to-human transmission of variant Creutzfeldt-Jakob disease. Three cases of variant Creutzfeldt-Jakob disease have been identified following red cell transfusions from donors who subsequently developed variant Creutzfeldt-Jakob disease and an asymptomatic red cell transfusion recipient, who did not die of variant Creutzfeldt-Jakob disease, has been identified with prion protein deposition in the spleen and a lymph node, but not the brain. This individual was heterozygous (MV) at codon 129 of the prion protein gene (PRNP), whereas all previous definite and probable cases of variant Creutzfeldt-Jakob disease have been methionine homozygotes (MM). A critical question for public health is whether the prion protein deposition reported in peripheral tissues from this MV individual correlates with infectivity. Additionally it is important to establish whether the PRNP codon 129 genotype has influenced the transmission characteristics of the infectious agent. Brain and spleen from the MV blood recipient were inoculated into murine strains that have consistently demonstrated transmission of the variant Creutzfeldt-Jakob disease agent. Mice were assessed for clinical and pathological signs of disease and transmission data were compared with other transmission studies in variant Creutzfeldt-Jakob disease, including those on the spleen and brain of the donor to the index case. Transmission of variant Creutzfeldt-Jakob disease was observed from the MV blood recipient spleen, but not from the brain, whereas there was transmission from both spleen and brain tissues from the red blood cell donor. Longer incubation times were observed for the blood donor spleen inoculum compared with the blood donor brain inoculum, suggesting lower titres of infectivity in the spleen. The distribution of vacuolar pathology and abnormal prion protein in infected mice were similar following inoculation with both donor and recipient spleen

  15. A transmissible Creutzfeldt-Jakob disease-like agent is prevalent in the human population.

    PubMed Central

    Manuelidis, E E; Manuelidis, L

    1993-01-01

    The etiology of most human dementias is unknown. Creutzfeldt-Jakob disease (CJD), a relatively uncommon human dementia, is caused by a transmissible virus-like agent. Molecular markers that are specific for the agent have not yet been defined. However, the infectious disease can be transmitted to rodents from both brain and infected buffy coat (blood) samples. To determine whether human CJD infections are more widespread than is apparent from the low incidence of neurological disease, we attempted to transmit CJD from buffy coat samples of 30 healthy volunteers who had no family history of dementing illness. Primary transmissions from 26 of 30 individuals produced CJD-like spongiform changes in the brains of recipient hamsters at 200-500 days postinoculation. This positive evidence of viremia was found for individuals in all age groups (20-30, 40-50, and 61-71 years old), whereas 12 negatively scored brain samples failed to produce similar changes in hamsters observed for > 900 days in the same setting. We suggest that a CJD agent endemically infects humans but only infrequently produces an infectious dementia. Disease expression is likely to be influenced by several host factors in combination with viral variants that have altered neurovirulence. Images Fig. 1 PMID:8356076

  16. Ataxic Creutzfeldt-Jakob disease: diagnostic techniques and neuropathologic observations in early disease.

    PubMed

    Jones, H R; Hedley-Whyte, E T; Freidberg, S R; Baker, R A

    1985-02-01

    We studied two cases of ataxic Creutzfeldt-Jakob disease. EEG, CT, evoked responses, and CSF were normal in one purely ataxic patient. Diagnosis was established by cerebellar biopsy. Autopsy demonstrated devastating spongiform changes in the cerebellum, basal ganglia, and thalamus with rare focal changes in cerebral cortex. In the second patient, late generalized changes developed with dementia. Diagnostic studies included abnormal visual evoked responses, CSF with abnormal oligoclonal bands and IgG, and subacute spongiform encephalopathy in frontal lobe biopsy. Early diagnosis is best established by biopsy of brain areas most likely to be involved on the basis of clinical neurologic findings.

  17. Psychiatric presentation of sporadic Creutzfeldt-Jakob disease: a challenge to current diagnostic criteria.

    PubMed

    Ali, Rehiana; Baborie, Atik; Larner, Andrew J; White, Richard

    2013-01-01

    Pathological diagnosis remains the gold standard for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), but being able to differentiate between CJD and non-prion diseases clinically is important because many of the non-prion, rapidly progressive dementias are treatable. Diagnostic criteria need both high sensitivity and specificity while remaining applicable to clinical practice. Despite extensive updates to the clinical criteria for sCJD, there remains a heavy emphasis on neurological signs. We describe a psychiatric presentation of sCJD that did not fulfill the diagnostic criteria until very late in a prolonged disease course and required biopsy for diagnosis.

  18. [Delayed diagnosis in a patient with Creutzfeldt-Jakob disease in a psychiatric hospital].

    PubMed

    Roest, S; Mestdagh, I; de Grave, C; Pals, P

    2016-01-01

    A 51-year-old female teacher of dance was referred to the diagnostic unit of our psychiatric hospital with symptoms of anxiety and depression. The clinical image was suggestive of organic pathology, but this could not be determined with certainty until a late stage. We discuss the course of the patient's illness. Her symptoms appeared to be psychiatric and closely resembled those of Creutzfeldt-Jakob disease. We comment on some of the signs that could have led to an earlier diagnosis and we discuss the tools that are needed.

  19. Creutzfeldt-Jakob disease with a codon 210 mutation: first pathological observation in a Japanese patient.

    PubMed

    Tajima, Yasutaka; Satoh, Chika; Mito, Yasunori; Kitamoto, Tetsuyuki

    2014-01-01

    We herein report a case of Creutzfeldt-Jakob disease (CJD) with a V210I mutation and discuss the pathological findings. The patient's clinical course was quite similar to that of patients with sporadic CJD. Diffusion-weighted magnetic resonance imaging (MRI) disclosed a high signal intensity in the basal ganglia and cerebral cortices. Pathologically, spongiform degeneration of neurons and their processes with reactive astrocytosis was observed. Prion protein immunostaining revealed diffuse positive and plaque-type patterns. Only one Japanese case of CJD with this type of mutation has been reported to date, but without any pathological examination results. Therefore, this report is considered to be highly significant for understanding CJD.

  20. Sporadic Creutzfeldt-Jakob disease (sCJD) with asymmetric findings.

    PubMed

    Khilari, Madhuri; Chakkalakkoombil, Sunitha Vellathussery; Wadwekar, Vaibhav; Nair, Pradeep Pankajakshan

    2014-03-24

    We report a case of a patient with probable Creutzfeldt-Jakob disease (CJD) who had psychiatric manifestation in the form of withdrawn depressive behaviour at the onset, followed by rapidly progressive ataxia, parkinsonism, mutism and cognitive decline with generalised asynchronous multifocal myoclonic jerks. His EEG exhibited focal (lateralised) periodic triphasic sharp waves on the background of generalised delta slowing, which later on became more generalised. MRI of the brain showed hyperintensity in basal ganglia with cortical ribbon sign in bilateral frontal region. Clinical course showed progressive deterioration to an akinetic-abulic stage. He died 2 months after the onset of symptoms.

  1. Development of Dose-Response Models of Creutzfeldt-Jakob Disease Infection in Nonhuman Primates for Assessing the Risk of Transfusion-Transmitted Variant Creutzfeldt-Jakob Disease

    PubMed Central

    Gregori, Luisa; Anderson, Steven A.; Asher, David M.

    2014-01-01

    ABSTRACT Estimates for the risk of transmitting variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion have relied largely on data from rodent experiments, but the relationship between dose (amount of infected blood) and response (vCJD infection) has never been well quantified. The goal of this study was to develop a dose-response model based on nonhuman primate data to better estimate the likelihood of transfusion-transmitted vCJD (TTvCJD) in humans. Our model used dose-response data from nonhuman primates inoculated intracerebrally (i.c.) with brain tissues of patients with sporadic and familial CJD. We analyzed the data statistically by using a beta-Poisson dose-response model. We further adjusted model parameters to account for the differences in infectivity between blood and brain tissue and in transmission efficiency between intravenous (i.v.) and i.c. routes to estimate dose-dependent TTvCJD infection. The model estimates a mean infection rate of 76% among recipients who receive one unit of whole blood collected from an infected donor near the end of the incubation period. The nonhuman primate model provides estimates that are more consistent with those derived from a risk analysis of transfused nonleukoreduced red blood cells in the United Kingdom than prior estimates based on rodent models. IMPORTANCE TTvCJD was recently identified as one of three emerging infectious diseases posing the greatest immediate threat to the safety of the blood supply. Cases of TTvCJD were reported in recipients of nonleukoreduced red blood cells and coagulation factor VIII manufactured from blood of United Kingdom donors. As the quantity of abnormal prions (the causative agent of TTvCJD) varies significantly in different blood components and products, it is necessary to quantify the dose-response relationship for a wide range of doses for the vCJD agent in transfused blood and plasma derivatives. In this paper, we suggest the first mechanistic dose-response model for

  2. Sporadic Creutzfeldt-Jakob disease in a native Puerto Rican patient.

    PubMed

    Del Pilar-Morales, Esteban A; Cali, Ignazio; Chapas, Javier; Bertrán-Pasarell, Jorge; Puoti, Gianfranco; Gambetti, Pierluigi; Nobo, Ulises

    2015-03-01

    The diagnosis of Creutzfeldt-Jakob disease (CJD) is often a challenge for most physicians given its extremely low incidence and different clinico-pathological presentations. We report the case of a 56-year old patient native to Puerto Rico suspected of sporadic Creutzfeldt-Jakob disease (sCD). The symptoms at onset were notorious for bilateral cortical blindness followed by rapidly progressive cognitive decline, visual deficit, increased levels of CSF 14-3-3 and tau along with positive brain MRI and EEG, are highly indicative of CJD. The definite diagnosis was confirmed by the National Prion Disease Pathology Surveillance Center (NPDPSC), in Cleveland, Ohio, USA. Lack of genetic mutations in the prion protein (PrP) gene, widespread histopathological changes and the accumulation of scrapie PrP (PrPSc) in the brain confirmed the diagnosis of sCJD. The patient, admitted to our institution in 2011, represents the first detailed report of sCJD in a native Puerto Rican patient living in Puerto Rico.

  3. Iatrogenic and sporadic Creutzfeldt-Jakob disease in 2 sisters without mutation in the prion protein gene.

    PubMed

    Frontzek, Karl; Moos, Rita; Schaper, Elke; Jann, Lukas; Herfs, Gregor; Zimmermann, Dieter R; Aguzzi, Adriano; Budka, Herbert

    2015-01-01

    Human genetic prion diseases have invariably been linked to alterations of the prion protein (PrP) gene PRNP. Two sisters died from probable Creutzfeldt-Jakob disease (CJD) in Switzerland within 14 y. At autopsy, both patients had typical spongiform change in their brains accompanied by punctuate deposits of PrP. Biochemical analyses demonstrated proteinase K-resistant PrP. Sequencing of PRNP showed 2 wild-type alleles in both siblings. Retrospectively, clinical data revealed a history of dural transplantation in the initially deceased sister, compatible with a diagnosis of iatrogenic CJD. Clinical and familial histories provided no evidence for potential horizontal transmission. This observation of 2 siblings suffering from CJD without mutations in the PRNP gene suggests potential involvement of non-PRNP genes in prion disease etiology.

  4. Creutzfeldt-Jakob disease in Japan: an epidemiological study done in a select prefecture between 1976 and 1986.

    PubMed

    Akai, J; Ishihara, O; Higuchi, S

    1989-01-01

    An epidemiological study was performed with respect to Creutzfeldt-Jakob disease in a designated area in Japan. The subjects were observed in a small rural prefecture where the population generally remains within a limited radius throughout their lives. The patients' life-styles in each area were investigated in detail. Nine cases appeared in 11 years; 6 were definitive and 3 probable. They were all of the subacute type; there were no noteworthy sexual differences, age of onset, course and/or past histories. Three of the nine cases came from two families; the relationship between familial and isolated cases was examined. Revealed facts and time-space clustering were investigated statistically, but no indication of natural transmission was observable.

  5. Creutzfeldt-Jakob disease associated with a V203I homozygous mutation in the prion protein gene.

    PubMed

    Komatsu, Junji; Sakai, Kenji; Hamaguchi, Tsuyoshi; Sugiyama, Yu; Iwasa, Kazuo; Yamada, Masahito

    2014-01-01

    We report a Japanese patient with Creutzfeldt-Jakob disease (CJD) with a V203I homozygous mutation of the prion protein gene (PRNP). A 73-year-old woman developed rapidly progressive gait disturbance and cognitive dysfunction. Four months after the onset, she entered a state of an akinetic mutism. Gene analysis revealed a homozygous V203I mutation in the PRNP. Familial CJD with a V203I mutation is rare, and all previously reported cases had a heterozygous mutation showing manifestations similar to those of typical sporadic CJD. Although genetic prion diseases with homozygous PRNP mutations often present with an earlier onset and more rapid clinical course than those with heterozygous mutations, no difference was found in clinical phenotype between our homozygous case and reported heterozygous cases.

  6. Rare V203I mutation in the PRNP gene of a Chinese patient with Creutzfeldt-Jakob disease.

    PubMed

    Shi, Qi; Chen, Cao; Wang, Xian-Jun; Zhou, Wei; Wang, Ji-Chun; Zhang, Bao-Yun; Gao, Chen; Gao, Chen; Han, Jun; Dong, Xiao-Ping

    2013-01-01

    Here, we report a Chinese case of Creutzfeldt-Jakob disease (CJD) with a rare mutation in the prion protein gene (PRNP) leading to an exchange of amino acid from valine (Val) to isoleucine (I) at codon 203 (V203I). The 80-y-old male presented with sudden memory loss, rapid loss of vocabulary, inattention and slow responses, accompanied by dizziness, blurred vision and ataxia. Two weeks after admission, he exhibited tremor, myoclonus and bilateral Babinski signs. At the end of the clinical course, he developed severe akinetic mutism. The cerebrospinal fluid (CSF) was positive for 14-3-3 protein. Increased bilateral signal intensity in the frontal and parietal lobes was seen on diffusion-weighted imaging (DWI); periodic activity was recorded on an electroencephalogram (EEG). There was no family history of similar symptoms. The total clinical course was approximately two months.

  7. Cerebrospinal Fluid Biomarkers in the Diagnosis of Creutzfeldt-Jakob Disease in Slovak Patients: over 10-Year Period Review.

    PubMed

    Koscova, Silvia; Zakova Slivarichova, Dana; Tomeckova, Ivana; Melicherova, Katarina; Stelzer, Martin; Janakova, Alzbeta; Kosorinova, Dana; Belay, Girma; Mitrova, Eva

    2016-09-24

    Creutzfeldt-Jakob disease is a rare, but rapidly progressive, up to now untreatable and fatal neurodegenerative disorder. Clinical diagnosis of Creutzfeldt-Jakob disease (CJD) is difficult; however, it can be facilitated by suitable biomarkers. Aim of the present study is to compare levels of cerebrospinal fluid biomarkers (total tau protein, phosphorylated-tau protein, protein 14-3-3 and amyloid beta) in Slovak population of CJD suspect cases, retrospectively in over a 10-year period. One thousand three hundred sixty-four CSF samples from patients with suspect CJD, forming a homogenous group in terms of geographical as well as of equal transport conditions, storage and laboratory processing, were analysed. Definite diagnosis of Creutzfeldt-Jakob disease was confirmed in 101 patients with genetic form, and 60 patients with its sporadic form of the disease. Specificity of protein 14-3-3 and total tau in both forms CJD was similar (87 % for P14-3-3/85 % for total tau), sensitivity to P 14-3-3 and total tau was higher in sporadic Creutzfeldt-Jakob disease (sCJD) (90/95 %) than in genetic Creutzfeldt-Jakob disease (gCJD) (89/74 %). As expected, the total tau levels were significantly higher in CJD patients than in controls, but there was also significant difference between gCJD and sCJD (levels in gCJD were lower; p = 0.003). There was no significant difference in p-tau and Aβ 1-42 levels neither between both CJD forms nor between CJD patients and control group.

  8. A case cluster of variant Creutzfeldt-Jakob disease linked to the Kingdom of Saudi Arabia.

    PubMed

    Coulthart, Michael B; Geschwind, Michael D; Qureshi, Shireen; Phielipp, Nicolas; Demarsh, Alex; Abrams, Joseph Y; Belay, Ermias; Gambetti, Pierluigi; Jansen, Gerard H; Lang, Anthony E; Schonberger, Lawrence B

    2016-10-01

    As of mid-2016, 231 cases of variant Creutzfeldt-Jakob disease-the human form of a prion disease of cattle, bovine spongiform encephalopathy-have been reported from 12 countries. With few exceptions, the affected individuals had histories of extended residence in the UK or other Western European countries during the period (1980-96) of maximum global risk for human exposure to bovine spongiform encephalopathy. However, the possibility remains that other geographic foci of human infection exist, identification of which may help to foreshadow the future of the epidemic. We report results of a quantitative analysis of country-specific relative risks of infection for three individuals diagnosed with variant Creutzfeldt-Jakob disease in the USA and Canada. All were born and raised in Saudi Arabia, but had histories of residence and travel in other countries. To calculate country-specific relative probabilities of infection, we aligned each patient's life history with published estimates of probability distributions of incubation period and age at infection parameters from a UK cohort of 171 variant Creutzfeldt-Jakob disease cases. The distributions were then partitioned into probability density fractions according to time intervals of the patient's residence and travel history, and the density fractions were combined by country. This calculation was performed for incubation period alone, age at infection alone, and jointly for incubation and age at infection. Country-specific fractions were normalized either to the total density between the individual's dates of birth and symptom onset ('lifetime'), or to that between 1980 and 1996, for a total of six combinations of parameter and interval. The country-specific relative probability of infection for Saudi Arabia clearly ranked highest under each of the six combinations of parameter × interval for Patients 1 and 2, with values ranging from 0.572 to 0.998, respectively, for Patient 2 (age at infection × lifetime) and

  9. Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Kallenberg, K.; Summers, D. M.; Romero, C.; Taratuto, A.; Heinemann, U.; Breithaupt, M.; Varges, D.; Meissner, B.; Ladogana, A.; Schuur, M.; Haik, S.; Collins, S. J.; Jansen, Gerard H.; Stokin, G. B.; Pimentel, J.; Hewer, E.; Collie, D.; Smith, P.; Roberts, H.; Brandel, J. P.; van Duijn, C.; Pocchiari, M.; Begue, C.; Cras, P.; Will, R. G.; Sanchez-Juan, P.

    2009-01-01

    Several molecular subtypes of sporadic Creutzfeldt–Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt–Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt–Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt–Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt–Jakob disease. Patients with sporadic Creutzfeldt–Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as ‘suspected sporadic Creutzfeldt–Jakob disease’ but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt–Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt–Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic

  10. Pellagra encephalopathy as a differential diagnosis for Creutzfeldt-Jakob disease.

    PubMed

    Kapas, Istvan; Majtenyi, Katalin; Törö, Klara; Keller, Eva; Voigtländer, Till; Kovacs, Gabor G

    2012-06-01

    In the present study we evaluated cases referred as suspected Creutzfeldt-Jakob disease (CJD). Five out of 59 without prion disease showed neuropathological features of pellagra encephalopathy with widespread chromatolytic neurons (age range 40-48 years at death; one woman). These patients presented with a progressive neuropsychiatric disorder lasting for 2 to 24 months. Common symptoms included gait disorder, para- or tetraspasticity, extrapyramidal symptoms, incontinence, and myoclonus. Protein 14-3-3 in the cerebrospinal fluid was examined in a single patient and was positive, allowing the clinical classification as probable sporadic CJD. Pellagra encephalopathy may be considered as a differential diagnosis of CJD including detection of protein 14-3-3.

  11. Recent US Case of Variant Creutzfeldt-Jakob Disease-Global Implications.

    PubMed

    Maheshwari, Atul; Fischer, Michael; Gambetti, Pierluigi; Parker, Alicia; Ram, Aarthi; Soto, Claudio; Concha-Marambio, Luis; Cohen, Yvonne; Belay, Ermias D; Maddox, Ryan A; Mead, Simon; Goodman, Clay; Kass, Joseph S; Schonberger, Lawrence B; Hussein, Haitham M

    2015-05-01

    Variant Creutzfeldt-Jakob disease (vCJD) is a rare, fatal prion disease resulting from transmission to humans of the infectious agent of bovine spongiform encephalopathy. We describe the clinical presentation of a recent case of vCJD in the United States and provide an update on diagnostic testing. The location of this patient's exposure is less clear than those in the 3 previously reported US cases, but strong evidence indicates that exposure to contaminated beef occurred outside the United States more than a decade before illness onset. This case exemplifies the persistent risk for vCJD acquired in unsuspected geographic locations and highlights the need for continued global surveillance and awareness to prevent further dissemination of vCJD.

  12. Unique inflammatory RNA profiles of microglia in Creutzfeldt-Jakob disease

    NASA Astrophysics Data System (ADS)

    Baker, Christopher A.; Manuelidis, Laura

    2003-01-01

    Previous studies in Creutzfeldt-Jakob disease (CJD) have shown that myeloid cells in the periphery as well as derivative microglial cells in the brain are infectious. Microglia can show an activated phenotype before prion protein (PrP) pathology is detectable in brain, and isolated infectious microglia contain very little PrP. To find whether a set of inflammatory genes are significantly induced or suppressed with infection, we analyzed RNA from isolated microglia with relevant cDNA arrays, and identified 30 transcripts not previously examined in any transmissible spongiform encephalopathy. This CJD expression profile contrasted with that of uninfected microglia exposed to prototypic inflammatory stimuli such as lipopolysaccharide and IFN-, as well as PrP amyloid. These findings underscore inflammatory pathways evoked by the infectious agent in brain. Transcript profiles unique for CJD microglia and other myeloid cells provide opportunities for more sensitive preclinical diagnoses of infectious and noninfectious neurodegenerative diseases.

  13. Prion-Seeding Activity Is widely Distributed in Tissues of Sporadic Creutzfeldt-Jakob Disease Patients.

    PubMed

    Takatsuki, Hanae; Fuse, Takayuki; Nakagaki, Takehiro; Mori, Tsuyoshi; Mihara, Ban; Takao, Masaki; Iwasaki, Yasushi; Yoshida, Mari; Murayama, Shigeo; Atarashi, Ryuichiro; Nishida, Noriyuki; Satoh, Katsuya

    2016-10-01

    Human prion diseases are neurodegenerative disorders caused by abnormally folded prion proteins in the central nervous system. These proteins can be detected using the quaking-induced conversion assay. Compared with other bioassays, this assay is extremely sensitive and was used in the present study to determine prion distribution in sporadic Creutzfeldt-Jakob disease patients at autopsy. Although infectivity of the sporadic form is thought to be restricted within the central nervous system, results showed that prion-seeding activities reach 10(6)/g from a 50% seeding dose in non-neuronal tissues, suggesting that prion-seeding activity exists in non-neural organs, and we suggested that non-neural tissues of 10(6)/g SD50 did not exist the infectivity.

  14. Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: background, evolution, and current concerns.

    PubMed Central

    Brown, P.; Will, R. G.; Bradley, R.; Asher, D. M.; Detwiler, L.

    2001-01-01

    The epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom, which began in 1986 and has affected nearly 200,000 cattle, is waning to a conclusion, but leaves in its wake an outbreak of human Creutzfeldt-Jakob disease, most probably resulting from the consumption of beef products contaminated by central nervous system tissue. Although averaging only 10-15 cases a year since its first appearance in 1994, its future magnitude and geographic distribution (in countries that have imported infected British cattle or cattle products, or have endogenous BSE) cannot yet be predicted. The possibility that large numbers of apparently healthy persons might be incubating the disease raises concerns about iatrogenic transmissions through instrumentation (surgery and medical diagnostic procedures) and blood and organ donations. Government agencies in many countries continue to implement new measures to minimize this risk. PMID:11266289

  15. [Iatrogenic Creutzfeldt-Jakob disease. Lessons from cases secondary to extracted growth hormone in France].

    PubMed

    Billette de Villemeur, T; Pradel, A

    1994-01-01

    Thirty cases of Creutzfeldt-Jakob disease (CJD) after cadaveric growth hormone treatment have been counted by the National Reference Center for iatrogenic CJD. The clinic presentation is homogeneous, beginning by neurological troubles (diplopia, unsteady gait) evolving rapidly in few months towards a severe neurological deterioration, insanity and death. All patients were treated between January 1984 and July 1985. The risk to transmit CJD with treatments of human origin (pituitary derived treatment, blood, placentas and corneal and dura mater graft) is analyzed. The selection of donors and techniques of purification on the one hand, the rigor of the indication and the quality of the followup on the other hand, are the only guarantees to reduce the risks secondary to utilization of products of human origin.

  16. Creutzfeldt-Jakob disease with mixed transcortical aphasia: insights into echolalia.

    PubMed

    McPherson, S E; Kuratani, J D; Cummings, J L; Shih, J; Mischel, P S; Vinters, H V

    1994-01-01

    Aphasia is a common manifestation of Creutzfeldt-Jakob disease (CJD), and investigation of the linguistic disorders of CJD patients may provide insights into the neurobiological mechanisms of language and aphasia. We report an autopsy-confirmed case of CJD in which the presenting symptom was change in language abilities. The patient ultimately evidenced mixed transcortical aphasia (MTA) with echolalia. Disruption of frontal-subcortical circuits with environmental dependency accounts for the symptoms in MTA, including intact repetition and echolalia. Observation in this patient and a review of the literature suggest that frontal-subcortical circuit dysfunction may contribute to the syndrome of echolalia. This hypothesis offers an alternative explanation to "isolation" of the speech area as the cause of MTA.

  17. The Heidenhain variant of Creutzfeldt-Jakob disease and concomitant tau pathology: A case report.

    PubMed

    Ehler, Edvard; Pipka, Michael; Meleková, Alena; Mandysová, Petra; Johanidesová, Silvie; Matěj, Radoslav; Rusina, Robert

    2017-02-10

    The Heidenhain form of Creutzfeldt-Jakob disease (CJD) is a rare CJD variant with predominantly visual symptoms in the early stages. Clinical manifestations of metamorphopsia, hemianopia and Balint's syndrome correlate with the involvement of the posterior cortical regions. A 71-year old healthy and very active man was admitted because of impaired visual acuity, hemianopia, and gait disturbance progressing over one week. MRI found typical cortical hyperintensities in the occipital regions while rhythm slowing and sharp waves were seen in the occipital regions on EEG. Protein 14-3-3 was detected in the cerebrospinal fluid. Postmortem neuropathology revealed typical histopathological changes consistent with CJD. Moreover, we found deposits of phosphorylated tau protein in the limbic regions that met the criteria for primary age-related tauopathy (PART); representing an additional and interesting finding in our case.

  18. The nucleus basalis of Meynert in 20 definite cases of Creutzfeldt-Jakob disease.

    PubMed Central

    Cartier, L; Verdugo, R; Vergara, C; Galvez, S

    1989-01-01

    The population of neurons and the neuronal size in the nucleus basalis of Meynert (nbM) were studied in 20 patients with definite Creutzfeldt-Jakob disease (CJD). When compared with a normal control group, the 20 CJD brains showed a significant loss of neurons and reduction of neuronal size, mainly in the middle level of the nbM and mostly affecting the right side. Since these findings show some parallelism with the amount of cortical damage and given the scarce gliosis and spongiosis found in only six of the 20 CJD brains, we postulate that the involvement of the nbM in CJD is a retrograde abnormality secondary to the damage of the neocortex. Images PMID:2647906

  19. Cerebrospinal fluid biomarker supported diagnosis of Creutzfeldt-Jakob disease and rapid dementias: a longitudinal multicentre study over 10 years.

    PubMed

    Stoeck, Katharina; Sanchez-Juan, Pascual; Gawinecka, Joanna; Green, Alison; Ladogana, Anna; Pocchiari, Maurizio; Sanchez-Valle, Raquel; Mitrova, Eva; Sklaviadis, Theodor; Kulczycki, Jerzy; Slivarichova, Dana; Saiz, Albert; Calero, Miguel; Knight, Richard; Aguzzi, Adriano; Laplanche, Jean-Louis; Peoc'h, Katell; Schelzke, Gabi; Karch, Andre; van Duijn, Cornelia M; Zerr, Inga

    2012-10-01

    To date, cerebrospinal fluid analysis, particularly protein 14-3-3 testing, presents an important approach in the identification of Creutzfeldt-Jakob disease cases. However, one special point of criticism of 14-3-3 testing is the specificity in the differential diagnosis of rapid dementia. The constant observation of increased cerebrospinal fluid referrals in the national surveillance centres over the last years raises the concern of declining specificity due to higher number of cerebrospinal fluid tests performed in various neurological conditions. Within the framework of a European Community supported longitudinal multicentre study ('cerebrospinal fluid markers') we analysed the spectrum of rapid progressive dementia diagnoses, their potential influence on 14-3-3 specificity as well as results of other dementia markers (tau, phosphorylated tau and amyloid-β(1-42)) and evaluated the specificity of 14-3-3 in Creutzfeldt-Jakob disease diagnosis for the years 1998-2008. A total of 29 022 cerebrospinal fluid samples were analysed for 14-3-3 protein and other cerebrospinal fluid dementia markers in patients with rapid dementia and suspected Creutzfeldt-Jakob disease in the participating centres. In 10 731 patients a definite diagnosis could be obtained. Protein 14-3-3 specificity was analysed for Creutzfeldt-Jakob disease with respect to increasing cerebrospinal fluid tests per year and spectrum of differential diagnosis. Ring trials were performed to ensure the comparability between centres during the reported time period. Protein 14-3-3 test specificity remained high and stable in the diagnosis of Creutzfeldt-Jakob disease during the observed time period across centres (total specificity 92%; when compared with patients with definite diagnoses only: specificity 90%). However, test specificity varied with respect to differential diagnosis. A high 14-3-3 specificity was obtained in differentiation to other neurodegenerative diseases (95-97%) and non

  20. Altered Prion Protein Expression Pattern in CSF as a Biomarker for Creutzfeldt-Jakob Disease

    PubMed Central

    Torres, Mauricio; Cartier, Luis; Matamala, José Manuel; Hernández, Nancy; Woehlbier, Ute; Hetz, Claudio

    2012-01-01

    Creutzfeldt-Jakob disease (CJD) is the most frequent human Prion-related disorder (PrD). The detection of 14-3-3 protein in the cerebrospinal fluid (CSF) is used as a molecular diagnostic criterion for patients clinically compatible with CJD. However, there is a pressing need for the identification of new reliable disease biomarkers. The pathological mechanisms leading to accumulation of 14-3-3 protein in CSF are not fully understood, however neuronal loss followed by cell lysis is assumed to cause the increase in 14-3-3 levels, which also occurs in conditions such as brain ischemia. Here we investigated the relation between the levels of 14-3-3 protein, Lactate dehydrogenase (LDH) activity and expression of the prion protein (PrP) in CSF of sporadic and familial CJD cases. Unexpectedly, we found normal levels of LDH activity in CJD cases with moderate levels of 14-3-3 protein. Increased LDH activity was only observed in a percentage of the CSF samples that also exhibited high 14-3-3 levels. Analysis of the PrP expression pattern in CSF revealed a reduction in PrP levels in all CJD cases, as well as marked changes in its glycosylation pattern. PrP present in CSF of CJD cases was sensitive to proteases. The alterations in PrP expression observed in CJD cases were not detected in other pathologies affecting the nervous system, including cases of dementia and tropical spastic paraparesis/HTLV-1 associated myelopathy (HAM/TSP). Time course analysis in several CJD patients revealed that 14-3-3 levels in CSF are dynamic and show a high degree of variability during the end stage of the disease. Post-mortem analysis of brain tissue also indicated that 14-3-3 protein is upregulated in neuronal cells, suggesting that its expression is modulated during the course of the disease. These results suggest that a combined analysis of 14-3-3 and PrP expression pattern in CSF is a reliable biomarker to confirm the clinical diagnosis of CJD patients and follow disease progression

  1. A Genome Wide Association Study Links Glutamate Receptor Pathway to Sporadic Creutzfeldt-Jakob Disease Risk

    PubMed Central

    Sanchez-Juan, Pascual; Bishop, Matthew T.; Kovacs, Gabor G.; Calero, Miguel; Aulchenko, Yurii S.; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, Claudia; Calero, Olga; Poleggi, Anna; Carracedo, Ángel; van der Lee, Sven J.; Ströbel, Thomas; Rivadeneira, Fernando; Hofman, Albert; Haïk, Stéphane; Combarros, Onofre; Berciano, José; Uitterlinden, Andre G.; Collins, Steven J.; Budka, Herbert; Brandel, Jean-Philippe; Laplanche, Jean Louis; Pocchiari, Maurizio; Zerr, Inga; Knight, Richard S. G.; Will, Robert G.; van Duijn, Cornelia M.

    2015-01-01

    We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis. PMID:25918841

  2. Creutzfeldt-Jakob disease in mice: persistent viremia and preferential replication of virus in low-density lymphocytes.

    PubMed Central

    Kuroda, Y; Gibbs, C J; Amyx, H L; Gajdusek, D C

    1983-01-01

    The mode of replication of the "unconventional virus" of Creutzfeldt-Jakob disease was studied in BALB/c mice infected intracerebrally. Virus was detected in the brain, spleen, lung, thymus, liver, kidney, and blood, but not in urine, at various time intervals after inoculation. The highest infectivity was present in the spleen from the second through the ninth weeks postinfection. Density gradient separation of spleen cells with colloidal silica (Percoll) revealed that the highest concentration of virus was present in blastoid cells from lower-density (1.05 to 1.07 g/ml) fractions. These results suggest that blastoid cells play an important role as the initial replication site of virus in the pathogenesis of Creutzfeldt-Jakob disease in mice. PMID:6407995

  3. Creutzfeldt-Jakob disease masked by head trauma and features of Wilson's disease.

    PubMed

    Scontrini, Alessandra; Di Bonaventura, Carlo; Fiorelli, Marco; Tiple, Dorina; Colaizzo, Elisa; Ladogana, Anna; Parchi, Piero; Pocchiari, Maurizio

    2015-04-01

    Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder typically characterized by progressive dementia associated with myoclonus, cerebellar and other focal neurological signs. Electroencephalogram, brain MRI and cerebrospinal fluid (CSF) analyses are helpful diagnostic tools, but diagnosis in patients with atypical presenting neurological signs is often difficult to make. A 55-year-old woman developed disorientation, drowsiness and focal motor signs after a traumatic brain injury due to an accidental fall. In two weeks, her symptoms worsened in spite of a brain MRI showed an improvement of traumatic lesions, but the presence of bilateral hyperintensity in the basal nuclei was suggestive of a metabolic or prion encephalopathy. The high 24-h urinary copper level and reduction of ceruloplasmin initially supported the diagnosis of Wilson's disease, but the absence of Kayser-Fleischer rings, and the positivity of 14-3-3 protein test and elevated tau concentrations in the CSF oriented toward a diagnosis of CJD. She died 5 months after the onset, and the postmortem examination of the brain revealed immunochemical features of CJD. This case exemplifies the difficulty of a timely diagnosis when rapid progressive dementia is masked by concomitant factors (i.e., head trauma) and neurological signs are associated with unclear laboratory findings.

  4. An alarming presentation of Creutzfeldt-Jakob disease following a self-inflicted gunshot wound to the head.

    PubMed

    Harnish, Carissa; Gross, Brian; Rittenhouse, Katelyn; Bupp, Katherine; Vellucci, Ashley; Anderson, Jeffrey; Riley, Deborah; Rogers, Frederick B

    2015-05-01

    Transmissible spongiform encephalopathies (TSE), also known as prion diseases, are characterized by rapid and fatal neurological decline. They not only detrimentally affect the patient, but also present additional challenges to healthcare systems due to the infectivity of the tissues and the difficulty of inactivating the prion. The most common TSE is Creutzfeldt-Jakob disease (CJD), which can occur after familial, spontaneous or acquired transmission. TSEs received more attention after the development of variant CJD (vCJD), also known as Mad Cow Disease, in the UK during the mid-1990s. Unlike familial or spontaneous CJD, this variant was connected to consumption of cattle contaminated with the prion disease, bovine spongiform encephalopathy.This development increased interest in the etiology of CJD and other TSEs and the risk it presents as an infectious disease. The following details the case of a 59-year-old male infected with CJD presented to our level II trauma center for treatment following a self-inflicted gunshot wound to the head.

  5. Creutzfeldt-Jakob disease: updated diagnostic criteria, treatment algorithm, and the utility of brain biopsy.

    PubMed

    Manix, Marc; Kalakoti, Piyush; Henry, Miriam; Thakur, Jai; Menger, Richard; Guthikonda, Bharat; Nanda, Anil

    2015-11-01

    Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative condition with a rapid disease course and a mortality rate of 100%. Several forms of the disease have been described, and the most common is the sporadic type. The most challenging aspect of this disease is its diagnosis-the gold standard for definitive diagnosis is considered to be histopathological confirmation-but newer tests are providing means for an antemortem diagnosis in ways less invasive than brain biopsy. Imaging studies, electroencephalography, and biomarkers are used in conjunction with the clinical picture to try to make the diagnosis of CJD without brain tissue samples, and all of these are reviewed in this article. The current diagnostic criteria are limited; test sensitivity and specificity varies with the genetics of the disease as well as the clinical stage. Physicians may be unsure of all diagnostic testing available, and may order outdated tests or prematurely request a brain biopsy when the diagnostic workup is incomplete. The authors review CJD, discuss the role of brain biopsy in this patient population, provide a diagnostic pathway for the patient presenting with rapidly progressive dementia, and propose newer diagnostic criteria.

  6. The prion protein preference of sporadic Creutzfeldt-Jakob disease subtypes.

    PubMed

    Klemm, Helen M J; Welton, Jeremy M; Masters, Colin L; Klug, Genevieve M; Boyd, Alison; Hill, Andrew F; Collins, Steven J; Lawson, Victoria A

    2012-10-19

    Sporadic Creutzfeldt-Jakob disease (CJD) is the most prevalent manifestation of the transmissible spongiform encephalopathies or prion diseases affecting humans. The disease encompasses a spectrum of clinical phenotypes that have been correlated with molecular subtypes that are characterized by the molecular mass of the protease-resistant fragment of the disease-related conformation of the prion protein and a polymorphism at codon 129 of the gene encoding the prion protein. A cell-free assay of prion protein misfolding was used to investigate the ability of these sporadic CJD molecular subtypes to propagate using brain-derived sources of the cellular prion protein (PrP(C)). This study confirmed the presence of three distinct sporadic CJD molecular subtypes with PrP(C) substrate requirements that reflected their codon 129 associations in vivo. However, the ability of a sporadic CJD molecular subtype to use a specific PrP(C) substrate was not determined solely by codon 129 as the efficiency of prion propagation was also influenced by the composition of the brain tissue from which the PrP(C) substrate was sourced, thus indicating that nuances in PrP(C) or additional factors may determine sporadic CJD subtype. The results of this study will aid in the design of diagnostic assays that can detect prion disease across the diversity of sporadic CJD subtypes.

  7. Mutation and polymorphism of the prion protein gene in Libyan Jews with Creutzfeldt-Jakob disease (CJD)

    SciTech Connect

    Gabizon, R.; Rosenmann, H.; Meiner, Z.; Kahana, I. ); Kahana, E. ); Shugart, Y.; Ott, J. ); Prusiner, S.B. )

    1993-10-01

    The inherited prion diseases are neurodegenerative disorders which are not only genetic but also transmissible. More than a dozen mutations in the prion protein gene that result in nonconservative amino acid substitutions segregate with the inherited prion diseases including familial Creutzfeldt-Jakob disease (CJD). In Israel, the incidence of CJD is about 1 case/10[sup 4] Libyan Jews. A Lys[sub 200] substitution segregates with CJD and is reported here to be genetically linked to CJD with a lod score of >4.8. Some healthy elderly Lys[sub 200] carriers > age 65 years were identified, suggesting the possibility of incomplete penetrance. In contrast, no linkage was found between the development of familial CJD and a polymorphism encoding either Met[sub 129] or Val[sub 129]. All Libyan Jewish CJD patients with the Lys[sub 200] mutation encode a Met[sub 129] on the mutant allele. Homozygosity for Met[sub 129] did not correlate with age at disease onset or the duration of illness. The frequency of the Met[sub 129] allele was higher in the affected pedigrees than in a control population of Libyan Jews. The frequency of the Met[sub 129] and Val[sub 129] alleles in the control Libyan population was similar to that found in the general Caucasian population. The identification of three Libyan Jews homozygous for the Lys[sub 200] mutation suggests frequent intrafamilial marriages, a custom documented by genealogical investigations. 26 refs., 3 figs., 6 tabs.

  8. Factors influencing the survival period in Japanese patients with sporadic Creutzfeldt-Jakob disease.

    PubMed

    Iwasaki, Yasushi; Akagi, Akio; Mimuro, Maya; Kitamoto, Tetsuyuki; Yoshida, Mari

    2015-10-15

    Although Japanese cases of sporadic Creutzfeldt-Jakob disease (sCJD) generally involve longer survival periods compared to those from other countries, details regarding the factors influencing survival are unclear. To determine the influence of certain factors on survival, we retrospectively assessed 51 Japanese MM1-type sCJD patients with respect to background, clinical course, and disease management. No significant differences were found between men and women, tracheotomy and nontracheotomy patients, or patients treated in public and other types of hospitals. Although the survival period of tube-fed patients was significantly longer than that of patients who were not tube fed, survival of patients fed via a nasal tube did not differ significantly from that of gastrostomy-fed patients. The proportion of tube-fed patients was 68.6% (35/51). Disease duration was not significantly associated with age or year of onset. However, it was associated with time from onset to first recognition of myoclonus, first recognition of periodic sharp-wave complexes on electroencephalogram, and progression to the akinetic mutism state. Mechanical ventilation was not performed for any patient. Because the total disease duration increased in cases with a slowly progressive clinical course as a natural outcome, we concluded that the most crucial factor contributing to the prolonged survival of Japanese sCJD patients was tube feeding once the akinetic mutism state had been reached.

  9. Cerebrospinal fluid tau levels are a marker for molecular subtype in sporadic Creutzfeldt-Jakob disease.

    PubMed

    Karch, André; Hermann, Peter; Ponto, Claudia; Schmitz, Matthias; Arora, Amandeep; Zafar, Saima; Llorens, Franc; Müller-Heine, Annika; Zerr, Inga

    2015-05-01

    The molecular subtype of sporadic Creutzfeldt-Jakob disease (sCJD) is an important prognostic marker for patient survival. However, subtype determination is not possible during lifetime. Because the rate of disease progression is associated with the molecular subtype, this study aimed at investigating if total tau, a marker of neuronal death, allows premortem diagnosis of molecular subtype when codon 129 genotype is known. Two hundred ninety-six sCJD patients were tested for their cerebrospinal fluid total tau level at the time of diagnosis and were investigated for their sCJD subtype postmortem. There was a significant association between tau levels and the prion protein type in patients with codon 129 MM (p < 0.001), MV (p = 0.004), and VV (p = 0.001) genotype. Receiver operating characteristic analyses showed values of area under the curve of 0.76-0.80 for the different genotypes indicating a good diagnostic validity of the test. Total tau can be used as a diagnostic test for the assessment of prion protein type when codon 129 genotype is known. It provides valuable information for physicians and next of kin about the further course of disease.

  10. On the Question of Sporadic or Atypical Bovine Spongiform Encephalopathy and Creutzfeldt-Jakob Disease

    PubMed Central

    McShane, Lisa M.; Zanusso, Gianluigi; Detwiler, Linda

    2006-01-01

    Strategies to investigate the possible existence of sporadic bovine spongiform encephalopathy (BSE) require systematic testing programs to identify cases in countries considered to have little or no risk of orally acquired disease or to detect a stable occurrence of atypical cases in countries in which orally acquired disease is disappearing. To achieve 95% statistical confidence that the prevalence for sporadic BSE is no greater than 1 per million (i.e., the annual incidence of sporadic Creutzfeldt-Jakob disease [CJD] in humans) would require negative tests in 3 million randomly selected older cattle. A link between BSE and sporadic CJD has been suggested on the basis of laboratory studies but is unsupported by epidemiologic observation. Such a link might yet be established by the discovery of a specific molecular marker or of particular combinations of trends over time of typical and atypical BSE and various subtypes of sporadic CJD, as their numbers are influenced by a continuation of current public health measures that exclude high-risk bovine tissues from the animal and human food chains. PMID:17326930

  11. Neurofilaments in blood and CSF for diagnosis and prediction of onset in Creutzfeldt-Jakob disease

    PubMed Central

    Steinacker, Petra; Blennow, Kaj; Halbgebauer, Steffen; Shi, Song; Ruf, Viktoria; Oeckl, Patrick; Giese, Armin; Kuhle, Jens; Slivarichova, Dana; Zetterberg, Henrik; Otto, Markus

    2016-01-01

    While cerebrospinal fluid (CSF) biomarkers for Creutzfeldt-Jakob disease (CJD) are established and partly included in the diagnostic criteria, no blood biomarkers are available. Here, we assessed the utility of serum neurofilament light chain (NF-L) and tau protein in comparison to CSF markers (NF-L and phosphorylated NF heavy chain (pNF-H), tau, S100B, 14-3-3) and prion conversion assay (real-time quaking induced conversion (RT-QuIC)) for sporadic and genetic CJD. Importantly, a Gerstmann-Sträussler-Scheinker mutation carrier in the asymptomatic phase and at disease onset was included as well. Both NF-L and tau were markedly increased in CJD serum, reaching similar or even better performance as in CSF (sensitivity and specificity for serum NF-L 100% and 85.5%, and for serum tau 84.6% and 96.2%, respectively). Serum S100B showed high sensitivity as well (84.2%), but lower specificity (63%). CSF neurofilaments were increased before symptom onset, while prion seeding assay was negative. Just before a clinical diagnosis could be made, all CSF markers and NF-L in the serum were increased and CSF prion conversion assay was positive. The data suggest that neurofilaments are sensitive and specific blood markers for the diagnosis of genetic and sporadic CJD and might represent promising tools to predict disease onset. PMID:27929120

  12. Rapid detection of Creutzfeldt-Jakob disease and scrapie prion proteins.

    PubMed

    Serban, D; Taraboulos, A; DeArmond, S J; Prusiner, S B

    1990-01-01

    Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler syndrome (GSS) of humans as well as scrapie of animals are caused by prions. The scrapie prion protein isoform (PrPSc) is the only macromolecule identified to date which is a component of the infectious prion particle. PrPSc is converted to PrP 27-30 by limited proteolysis while the cellular isoform, designated PrPC, is completely digested under the same conditions. ELISA studies demonstrated that native PrP 27-30 bound to plastic surfaces resisted proteolysis and exhibited little or no immunoreactivity but after denaturation with guanidinium thiocyanate (GdnSCN), immunoreactivity was greatly enhanced. PrPSc bound to nitrocellulose also exhibited enhanced immunoreactivity after denaturation. PrPSc was readily detected in brain extracts from scrapie-infected hamsters, mice, and sheep by dot-blot immunoassays using limited proteolysis followed by GdnSCN denaturation. The high sensitivity and specificity of the immunoassay allowed detection of regional differences in PrPSc in sheep brain. CJD prion protein isoform (PrPCJD) was also detected in the brains of all 10 patients tested with neuropathologically confirmed CJD and in 1 patient with GSS. Enhanced immunoreactivity of PrPSc or PrPCJD after denaturation cannot only be used for immunodiagnosis of prion diseases but may also form the basis of new assays in experimental studies directed at the chemical structure of the prion particle.

  13. Regulation of human cerebrospinal fluid malate dehydrogenase 1 in sporadic Creutzfeldt-Jakob disease patients

    PubMed Central

    Schmitz, Matthias; Llorens, Franc; Pracht, Alexander; Thom, Tobias; Correia, Ângela; Zafar, Saima; Ferrer, Isidre; Zerr, Inga

    2016-01-01

    The identification of reliable diagnostic biomarkers in differential diagnosis of neurodegenerative diseases is an ongoing topic. A previous two-dimensional proteomic study on cerebrospinal fluid (CSF) revealed an elevated level of an enzyme, mitochondrial malate dehydrogenase 1 (MDH1), in sporadic Creutzfeldt-Jakob disease (sCJD) patients. Here, we could demonstrate the expression of MDH1 in neurons as well as in the neuropil. Its levels are lower in sCJD brains than in control brains. An examination of CSF-MDH1 in sCJD patients by ELISA revealed a significant elevation of CSF-MDH1 levels in sCJD patients (independently from the PRNP codon 129 MV genotype or the prion protein scrapie (PrPSc) type) in comparison to controls. In combination with total tau (tau), CSF-MDH1 detection exhibited a high diagnostic accuracy for sCJD diagnosis with a sensitivity of 97.5% and a specificity of 95.6%. A correlation study of MDH1 level in CSF with other neurodegenerative marker proteins revealed a significant positive correlation between MDH1 concentration with tau, 14-3-3 and neuron specific enolase level. In conclusion, our study indicated the potential of MDH1 in combination with tau as an additional biomarker in sCJD improving diagnostic accuracy of tau markedly. PMID:27852982

  14. The sequential development of abnormal prion protein accumulation in mice with Creutzfeldt-Jakob disease.

    PubMed Central

    Muramoto, T.; Kitamoto, T.; Tateishi, J.; Goto, I.

    1992-01-01

    The distribution and sequential development of prion protein (PrP) accumulation in the central nervous system (CNS) and non-neuronal organs of mice infected with Creutzfeldt-Jakob disease (CJD) were investigated immunohistochemically using a new pretreatment method that greatly enhanced the immunoreactivity of PrP. Prion protein accumulation in the CNS was first detected at 30 days after inoculation and then developed near the inoculation site or periventricular area, and later spread to the whole cerebrum and then to the pons. Its staining took some characteristic forms. Among non-neuronal organs, PrP accumulated in the follicular dendritic cells (FDCs) in spleen, lymph node, Peyer's patch, and thymus. FDCs staining appeared in spleen, lymph node, and Peyer's patch at 21 or 30 days after inoculation, and in thymus at 90 days. Germinal centers developed in the thymus of some CJD-infected mice. No PrP staining was detected in any examined organs of age-matched control mice. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:1376559

  15. Comparison Between Sporadic and Misdiagnosed Sporadic Creutzfeldt-Jakob Disease: A Report of Two Cases.

    PubMed

    Zhao, Xiongfei; Yu, Yingxin; Zhao, Zhiru; Xu, Jiaping

    2015-06-01

    Definite accurate diagnosis for Creutzfeldt-Jakob disease (CJD) depends on neuropathologic examination of brain biopsy or autopsy. However, transmissible nature makes the invasive examination dangerous. This study was set to determine that the clinical features are for the diagnosis of CJD through a comparison study. We compared clinical features of two cases with initial diagnosis of sporadic CJD. One case was finally diagnosed as definite sporadic CJD. According to World Health Organization diagnosis criteria, the other one, which had been diagnosed as probable sporadic CJD, was confirmed as limbic encephalitis after long-term follow-up. Compared with the case of definite sporadic CJD, the misdiagnosed case did not present typical electroencephalogram (EEG) and diffusion-weighted in magnetic resonance images (DWI) of CJD. However, cerebrospinal fluid in the misdiagnosed patient showed 14-3-3 protein positivity. The patient conditions improved after treatment. Through this case comparison, we conclude that EEG and DWI are necessary for accurate diagnosis of sporadic CJD. Further, long-term follow-up is crucial to diagnosis and treatment of CJD.

  16. The French surveillance network of Creutzfeldt-Jakob disease. Epidemiological data in France and worldwide.

    PubMed

    Brandel, J-P; Peckeu, L; Haïk, S

    2013-09-01

    France, involved for a long time in the epidemiological surveillance of transmissible spongiform encephalopathy (TSE), created a national network of surveillance in 1991, because of the description of the first cases of Creutzfeldt-Jakob disease (CJD) linked to a treatment by growth hormone of human origin and the observation of cases of cats infected with the agent of the bovine spongiform encephalopathy in the United Kingdom (UK). The French surveillance network is integrated into the European network of surveillance since its creation in 1993. As in other countries, sporadic CJD is the most frequent form of TSE in France with an annual mortality rate of 1.44 per million. Genetic forms are most often associated with a mutation at codon 200. Among the cases of iatrogenic CJD, 13 cases of CJD after duramater grafts were observed and 119 related to treatment with growth hormone. France is the country worst affected in Europe and the world by this latter form, before the USA and UK. Since 1996, 27 cases of variant of CJD (vCJD) has been observed, making France the second country in the world most affected after the UK. No cases of transfusion-associated vCJD have been observed.

  17. Metabolic disorders with clinical and radiologic features of sporadic Creutzfeldt-Jakob disease.

    PubMed

    Rosenbloom, Michael H; Tartaglia, M Carmela; Forner, Sven A; Wong, Katherine K; Kuo, Amy; Johnson, David Y; Colacurcio, Valerie; Andrews, Bret D; Miller, Bruce L; DeArmond, Stephen J; Geschwind, Michael D

    2015-04-01

    Two patients with metabolic disorders presented with clinical and radiologic features suggestive of sporadic Creutzfeldt-Jakob disease (sCJD). Case 1 was a 50-year-old man with rapid decline in cognitive, behavioral, and motor function following new-onset seizures. MRI was read as consistent with CJD, and he was referred for a treatment trial, but it was determined that he recently experienced rapid correction of hyponatremia resulting in extrapontine myelinolysis. Case 2 was a 66-year-old woman with poorly controlled diabetes mellitus who was found unconscious after a suspected insulin overdose. Examination showed altered mental status and neuroimaging was remarkable for cortical/striatal hyperintensities suggestive of sCJD. On autopsy, she had hypoglycemic/hypoxic nerve cell loss. Although characteristic MRI findings have high sensitivity and specificity for sCJD, potentially reversible metabolic disorders sometimes present rapidly and can resemble sCJD both clinically and radiologically. These cases highlight the importance of establishing a broad differential diagnosis when evaluating a patient with suspected sCJD.

  18. Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Forner, Sven A.; Takada, Leonel T.; Bettcher, Brianne M.; Lobach, Iryna V.; Tartaglia, Maria Carmela; Torres-Chae, Charles; Haman, Aissatou; Thai, Julie; Vitali, Paolo; Neuhaus, John; Bostrom, Alan; Miller, Bruce L.; Rosen, Howard J.

    2015-01-01

    Summary We assessed the diagnostic utility of 3 CSF biomarkers—14-3-3 protein, total tau (T-tau), and neuron-specific enolase (NSE)—from the same lumbar puncture to distinguish between participants with neuropathologically confirmed sporadic Creutzfeldt-Jakob disease (sCJD, n = 57) and controls with nonprion rapidly progressive dementia (npRPD, n = 41). Measures of diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value, as well as logistic regression and area under the receiver operator curve (AUC), were used to assess the ability of these CSF biomarkers, alone or concomitantly, to predict diagnosis. In a subcohort with available MRI (sCJD n = 57, npRPD = 32), we compared visual assessment of diffusion-weighted imaging MRI sequences to these CSF biomarkers. MRI was the best predictor, with an AUC of 0.97 (confidence interval [CI] 0.92–1.00) and a diagnostic accuracy of 97% (CI 90%–100%). Of the CSF biomarkers, T-tau had a higher diagnostic accuracy (79.6%) than 14-3-3 (70.4%, CI for difference 8.7%, 9.7%; p = 0.048) or NSE (71.4%, CI for difference 7.6%, 8.7%; p = 0.03). PMID:26137420

  19. Comparing CSF biomarkers and brain MRI in the diagnosis of sporadic Creutzfeldt-Jakob disease.

    PubMed

    Forner, Sven A; Takada, Leonel T; Bettcher, Brianne M; Lobach, Iryna V; Tartaglia, Maria Carmela; Torres-Chae, Charles; Haman, Aissatou; Thai, Julie; Vitali, Paolo; Neuhaus, John; Bostrom, Alan; Miller, Bruce L; Rosen, Howard J; Geschwind, Michael D

    2015-04-01

    We assessed the diagnostic utility of 3 CSF biomarkers-14-3-3 protein, total tau (T-tau), and neuron-specific enolase (NSE)-from the same lumbar puncture to distinguish between participants with neuropathologically confirmed sporadic Creutzfeldt-Jakob disease (sCJD, n = 57) and controls with nonprion rapidly progressive dementia (npRPD, n = 41). Measures of diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value, as well as logistic regression and area under the receiver operator curve (AUC), were used to assess the ability of these CSF biomarkers, alone or concomitantly, to predict diagnosis. In a subcohort with available MRI (sCJD n = 57, npRPD = 32), we compared visual assessment of diffusion-weighted imaging MRI sequences to these CSF biomarkers. MRI was the best predictor, with an AUC of 0.97 (confidence interval [CI] 0.92-1.00) and a diagnostic accuracy of 97% (CI 90%-100%). Of the CSF biomarkers, T-tau had a higher diagnostic accuracy (79.6%) than 14-3-3 (70.4%, CI for difference 8.7%, 9.7%; p = 0.048) or NSE (71.4%, CI for difference 7.6%, 8.7%; p = 0.03).

  20. [A case of Creutzfeldt-Jakob disease presenting with arm levitation as an initial symptom].

    PubMed

    Kamogawa, Kenji; Ninomiya, Satoko; Okuda, Shinya; Matsumoto, Yushi; Tomita, Hitomi; Okamoto, Kensho; Okuda, Bungo

    2014-01-01

    A 74-year-old, right handed man, developed insidiously with levitation and clumsiness of the right upper limb. His right arm tended to levitate spontaneously, when he was examined. He could put the elevated arm down on command, while the arm resumed to antigravity posture when his attention was diverted. His right arm also exhibited unwilled elevation when performing complex finger movements on the right side. He had a feeling of strangeness of the elevated limb, especially with the eyes closed. In addition to asymmetric limb-kinetic apraxia, combined sensations such as stereognosis were disturbed on the right side. Brain MRI showed high signal lesions predominantly in the left cerebral cortices and basal ganglia. SPECT with (123)I-IMP revealed asymmetric hypoperfusion, predominantly in the left medial frontal and parietal regions. Two months after the onset, levitation of the arm gradually disappeared, with the development of rapidly progressive dementia, frontal signs, dystonia and generalized myoclonus. The diagnosis of Creutzfeldt-Jakob disease (CJD) was made based on the clinical features and cerebrospinal fluid biomarkers. The early manifestation of the patient mimicked corticobasal degeneration which presents with arm levitation or alien hand syndrome. It is suggested that CJD can represent involuntary movements with higher brain dysfunction resembling corticobasal degeneration at the early stage of the illness. Although the underlying mechanism of arm levitation is still unknown, frontal disinhibition and parietal cortical sensory disturbance may contribute to the development of involuntary arm levitation in our patient.

  1. Creutzfeldt-jakob, Parkinson, lewy body dementia and Alzheimer diseases: from diagnosis to therapy.

    PubMed

    Dupiereux, Ingrid; Zorzi, Willy; Quadrio, Isabelle; Perret-Liaudet, Armand; Kovacs, Gabor G; Heinen, Ernst; Elmoualij, Benaïssa

    2009-03-01

    Depositions of proteins in form of amyloid and non-amyloid plaques are common pathogenic signs of more than 20 degenerative diseases affecting the central nervous system or a variety of peripheral tissues. Among the neuropathological conditions, Alzheimer's, Parkinson's and the prion diseases, such as Creutzfeldt-Jakob disease (CJD), present ambiguities as regarding their differential diagnosis. At present, their diagnosis must be confirmed by post-mortem examination of the brain. Currently the ante-mortem diagnosis is still based on the integration of multiple data (clinical, paraclinical and biological analyses) because no unique marker exists for such diseases. The detection of specific biomarkers would be useful to develop a differential diagnostic, distinguishing not only different neurodegenerative diseases but also the disease from the non-pathological effects of aging. Several neurodegenerative biomarkers are present at very low levels during the early stages of the disease development and their ultra-low detection is needed for early diagnosis, which should permit more effective therapeutic interventions, before the disease concerned can progress to a stage where considerable damage to the brain has already occurred. In the case of prion diseases, there are concerns regarding not only patient care, but the wider community too, with regard to the risk of transmission of prions, especially during blood transfusion, for which, four cases of variant CJD infection associated with transfusion of non-leukocyte-depleted blood components have been confirmed. Therefore the development of techniques with high sensitivity and specificity represent the major challenge in the field of the protein misfolding diseases. In this paper we review the current analytical and/or biochemical diagnostic technologies used mainly in prion, but also in Alzheimer and Parkinson diseases and emphasizing work on the protein detection as a surrogates and specific biomarker in the body

  2. Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies.

    PubMed

    López González, Irene; Garcia-Esparcia, Paula; Llorens, Franc; Ferrer, Isidre

    2016-02-04

    Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer's disease (AD) and sporadic Parkinson's disease (sPD). Gene expression studies of cytokines and mediators of the immune response have been made in post-mortem human brain samples in AD, sPD, sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2, Pick's disease (PiD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration linked to mutation P301L in MAPT Frontotemporal lobar degeneration-tau (FTLD-tau). The studies have disclosed variable gene regulation which is: (1) disease-dependent in the frontal cortex area 8 in AD, sPD, sCJD MM1 and VV2, PiD, PSP and FTLD-tau; (2) region-dependent as seen when comparing the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 (FC) in AD; the substantia nigra, putamen, FC, and angular gyrus in PD, as well as the FC and cerebellum in sCJD; (3) genotype-dependent as seen considering sCJD MM1 and VV2; and (4) stage-dependent as seen in AD at different stages of disease progression. These observations show that regulation of inflammation is much more complicated and diverse than currently understood, and that new therapeutic approaches must be designed in order to selectively act on specific targets in particular diseases and at different time points of disease progression.

  3. Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies

    PubMed Central

    López González, Irene; Garcia-Esparcia, Paula; Llorens, Franc; Ferrer, Isidre

    2016-01-01

    Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer’s disease (AD) and sporadic Parkinson’s disease (sPD). Gene expression studies of cytokines and mediators of the immune response have been made in post-mortem human brain samples in AD, sPD, sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2, Pick’s disease (PiD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration linked to mutation P301L in MAPT Frontotemporal lobar degeneration-tau (FTLD-tau). The studies have disclosed variable gene regulation which is: (1) disease-dependent in the frontal cortex area 8 in AD, sPD, sCJD MM1 and VV2, PiD, PSP and FTLD-tau; (2) region-dependent as seen when comparing the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 (FC) in AD; the substantia nigra, putamen, FC, and angular gyrus in PD, as well as the FC and cerebellum in sCJD; (3) genotype-dependent as seen considering sCJD MM1 and VV2; and (4) stage-dependent as seen in AD at different stages of disease progression. These observations show that regulation of inflammation is much more complicated and diverse than currently understood, and that new therapeutic approaches must be designed in order to selectively act on specific targets in particular diseases and at different time points of disease progression. PMID:26861289

  4. Role of the biomarkers for the diagnosis of Creutzfeldt-Jakob disease

    PubMed Central

    Dulamea, A; Solomon, E

    2016-01-01

    Objective: Sporadic Creutzfeldt-Jakob disease (CJD) is a human prion disease, rapidly progressive and fatal, characterized by spongiform encephalopathy. The characteristic triad of signs - rapidly progressive dementia, myoclonus and periodic sharp wave complexes (PSWC) on electroencephalography (EEG) - usually appear in the late stages of the disease. The clinical diagnosis of CJD ante-mortem involves the exclusion of the rapidly progressive non-prionic dementias, the definitive diagnosis requiring brain tissue confirmation. Authors evaluated the methods of clinical diagnosis for sporadic CJD. Methods: This study retrospectively reviewed the medical records of patients diagnosed with probable sporadic CJD, based on brain magnetic resonance imaging (MRI), EEG, cerebrospinal fluid (CSF) analysis and extensive laboratory work-up. Results: Four patients with a mean age of 67 years were included in our study. The mean duration from diagnosis until death was of 3.2 weeks. The clinical features of the disease at onset were atypical. In the final stage of the disease, all patients presented rapidly progressive dementia and myoclonus. High levels of 14-3-3 protein and tau protein and normal levels of amyloid β1-42 were found at CSF analysis, in all patients. PSWC on EEG were present in 3 out of 4 patients at different moments of the disease. MRI showed hyperintense lesions in brain cortex, caudate nucleus, and putamen on T2, FLAIR, and DWI. Conclusion: CJD may present various clinical features and, since brain biopsy is usually difficult to perform, a combination of biomarkers is useful in order to establish the diagnosis in the early phase of the disease. PMID:27453757

  5. The Distribution of Prion Protein Allotypes Differs Between Sporadic and Iatrogenic Creutzfeldt-Jakob Disease Patients.

    PubMed

    Moore, Roger A; Head, Mark W; Ironside, James W; Ritchie, Diane L; Zanusso, Gianluigi; Choi, Young Pyo; Pyo Choi, Young; Priola, Suzette A

    2016-02-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent of the human prion diseases, which are fatal and transmissible neurodegenerative diseases caused by the infectious prion protein (PrP(Sc)). The origin of sCJD is unknown, although the initiating event is thought to be the stochastic misfolding of endogenous prion protein (PrP(C)) into infectious PrP(Sc). By contrast, human growth hormone-associated cases of iatrogenic CJD (iCJD) in the United Kingdom (UK) are associated with exposure to an exogenous source of PrP(Sc). In both forms of CJD, heterozygosity at residue 129 for methionine (M) or valine (V) in the prion protein gene may affect disease phenotype, onset and progression. However, the relative contribution of each PrP(C) allotype to PrP(Sc) in heterozygous cases of CJD is unknown. Using mass spectrometry, we determined that the relative abundance of PrP(Sc) with M or V at residue 129 in brain specimens from MV cases of sCJD was highly variable. This result is consistent with PrP(C) containing an M or V at residue 129 having a similar propensity to misfold into PrP(Sc) thus causing sCJD. By contrast, PrP(Sc) with V at residue 129 predominated in the majority of the UK human growth hormone associated iCJD cases, consistent with exposure to infectious PrP(Sc) containing V at residue 129. In both types of CJD, the PrP(Sc) allotype ratio had no correlation with CJD type, age at clinical onset, or disease duration. Therefore, factors other than PrP(Sc) allotype abundance must influence the clinical progression and phenotype of heterozygous cases of CJD.

  6. The Distribution of Prion Protein Allotypes Differs Between Sporadic and Iatrogenic Creutzfeldt-Jakob Disease Patients

    PubMed Central

    Moore, Roger A.; Head, Mark W.; Ironside, James W.; Ritchie, Diane L.; Zanusso, Gianluigi; Pyo Choi, Young; Priola, Suzette A.

    2016-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent of the human prion diseases, which are fatal and transmissible neurodegenerative diseases caused by the infectious prion protein (PrPSc). The origin of sCJD is unknown, although the initiating event is thought to be the stochastic misfolding of endogenous prion protein (PrPC) into infectious PrPSc. By contrast, human growth hormone-associated cases of iatrogenic CJD (iCJD) in the United Kingdom (UK) are associated with exposure to an exogenous source of PrPSc. In both forms of CJD, heterozygosity at residue 129 for methionine (M) or valine (V) in the prion protein gene may affect disease phenotype, onset and progression. However, the relative contribution of each PrPC allotype to PrPSc in heterozygous cases of CJD is unknown. Using mass spectrometry, we determined that the relative abundance of PrPSc with M or V at residue 129 in brain specimens from MV cases of sCJD was highly variable. This result is consistent with PrPC containing an M or V at residue 129 having a similar propensity to misfold into PrPSc thus causing sCJD. By contrast, PrPSc with V at residue 129 predominated in the majority of the UK human growth hormone associated iCJD cases, consistent with exposure to infectious PrPSc containing V at residue 129. In both types of CJD, the PrPSc allotype ratio had no correlation with CJD type, age at clinical onset, or disease duration. Therefore, factors other than PrPSc allotype abundance must influence the clinical progression and phenotype of heterozygous cases of CJD. PMID:26840342

  7. Genetic variability of the gene cluster CALHM1–3 in sporadic Creutzfeldt-Jakob disease

    PubMed Central

    Calero, Olga; Bullido, María J.; Clarimón, Jordi; Hortigüela, Rafael; Frank-García, Ana; Martínez-Martín, Pablo; Lleó, Alberto; Rey, María Jesús; Sastre, Isabel; Rábano, Alberto; de Pedro-Cuesta, Jesús; Ferrer, Isidro; Calero, Miguel

    2012-01-01

    Perturbations of calcium homeostasis have been associated with several neurodegenerative disorders. A common polymorphism (rs2986017) in the CALHM1 gene, coding for a regulator of calcium homeostasis, is a genetic risk factor for the development of Alzheimer disease (AD). Although some authors failed to confirm these results, a meta-analysis has shown that this polymorphism modulates the age at disease onset. Furthermore, a recent association study has explored the genetic variability of CALHM1 gene and two adjacent paralog genes (CALHM3 and CALHM2) in an Asian population. Since several lines of evidence suggest that AD and prion diseases share pathophysiologic mechanisms, we investigated for the first time the genetic variability of the gene cluster formed by CALHM1 and its paralogs in a series of 235 sporadic Creutzfeldt-Jakob disease (sCJD) patients, and compared the genotypic and allelic frequencies with those presented in 329 controls from the same ancestry. As such, this work also represents the first association analysis of CALHM genes in sCJD. Sequencing analysis of the complete coding regions of the genes demonstrated the presence of 10 single nucleotide polymorphisms (SNP) within the CALHM genes. We observed that rs4918016-rs2986017-rs2986018 and rs41287502-rs41287500 polymorphic sites at CALHM1 were in linkage disequilibrium. We found marginal associations for sCJD risk at CALHM1 polymorphic sites rs41287502 and rs41287500 [coding for two linked missense mutations (p.(Met323Ile); (Gly282Cys)], and rs2986017 [p.(Leu86Pro)]. Interestingly, a TGG haplotype defined by the rs4918016-rs2986017-rs2986018 block was associated with sCJD. These findings underscore the need of future multinational collaborative initiatives in order to corroborate these seminal data. PMID:22874670

  8. Modulation of Creutzfeldt-Jakob disease prion propagation by the A224V mutation

    PubMed Central

    Watts, Joel C.; Giles, Kurt; Serban, Ana; Patel, Smita; Oehler, Abby; Bhardwaj, Sumita; Guan, Shenheng; Greicius, Michael; Miller, Bruce L.; DeArmond, Stephen J.; Geschwind, Michael D.; Prusiner, Stanley B.

    2016-01-01

    Objective Mutations in the gene encoding the prion protein (PrP) are responsible for approximately 10–15% of cases of prion disease in humans, including Creutzfeldt-Jakob disease (CJD). Here we report the discovery of a previously unreported C-terminal PrP mutation (A224V) in a CJD patient exhibiting a disease similar to the rare VV1 subtype of sporadic CJD and investigate the role of this mutation in prion replication and transmission. Methods We generated transgenic (Tg) mice expressing human PrP with the V129 polymorphism and A224V mutation, denoted Tg(HuPrP,V129,A224V) mice, and inoculated them with different subtypes of sporadic (s) CJD prions. Results Transmission of sCJD VV2 or MV2 prions was accelerated in Tg(HuPrP,V129,A224V) mice compared to Tg(HuPrP,V129) mice, with incubation periods of ~110 days and ~210 days, respectively. In contrast, sCJD MM1 prions resulted in longer incubation periods in Tg(HuPrP,V129,A224V) mice compared to Tg(HuPrP,V129) mice (~320 days v. ~210 days). Prion strain fidelity was maintained in Tg(HuPrP,V129,A224V) mice inoculated with sCJD VV2 or MM1 prions, despite the altered replication kinetics. Interpretation Our results suggest that A224V is a risk factor for prion disease and modulates the transmission behavior of CJD prions in a strain-specific manner, arguing that residues near the C-terminus of PrP are important for controlling the kinetics of prion replication. PMID:26094969

  9. Detection of prions in blood from patients with variant Creutzfeldt-Jakob disease.

    PubMed

    Concha-Marambio, Luis; Pritzkow, Sandra; Moda, Fabio; Tagliavini, Fabrizio; Ironside, James W; Schulz, Paul E; Soto, Claudio

    2016-12-21

    Human prion diseases are infectious and invariably fatal neurodegenerative diseases. They include sporadic Creutzfeldt-Jakob disease (sCJD), the most common form, and variant CJD (vCJD), which is caused by interspecies transmission of prions from cattle infected by bovine spongiform encephalopathy. Development of a biochemical assay for the sensitive, specific, early, and noninvasive detection of prions (PrP(Sc)) in the blood of patients affected by prion disease is a top medical priority to increase the safety of the blood supply. vCJD has already been transmitted from human to human by blood transfusion, and the number of asymptomatic carriers of vCJD in the U.K. alone is estimated to be 1 in 2000 people. We used the protein misfolding cyclic amplification (PMCA) technique to analyze blood samples from 14 cases of vCJD and 153 controls, including patients affected by sCJD and other neurodegenerative or neurological disorders as well as healthy subjects. Our results showed that PrP(Sc) could be detected with 100% sensitivity and specificity in blood samples from vCJD patients. Detection was possible in any of the blood fractions analyzed and could be done with as little as a few microliters of sample volume. The PrP(Sc) concentration in blood was estimated to be ~0.5 pg/ml. Our findings suggest that PMCA may be useful for premortem noninvasive diagnosis of vCJD and to identify prion contamination of the blood supply. Further studies are needed to fully validate the technology.

  10. Genetic Cross-Interaction between APOE and PRNP in Sporadic Alzheimer's and Creutzfeldt-Jakob Diseases

    PubMed Central

    Calero, Olga; Bullido, María J.; Clarimón, Jordi; Frank-García, Ana; Martínez-Martín, Pablo; Lleó, Alberto; Rey, María Jesús; Rábano, Alberto; Blesa, Rafael; Gómez-Isla, Teresa; Valdivieso, Fernando; de Pedro-Cuesta, Jesús; Ferrer, Isidro; Calero, Miguel

    2011-01-01

    Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD) represent two distinct clinical entities belonging to a wider group, generically named as conformational disorders that share common pathophysiologic mechanisms. It is well-established that the APOE ε4 allele and homozygosity at polymorphic codon 129 in the PRNP gene are the major genetic risk factors for AD and human prion diseases, respectively. However, the roles of PRNP in AD, and APOE in CJD are controversial. In this work, we investigated for the first time, APOE and PRNP genotypes simultaneously in 474 AD and 175 sporadic CJD (sCJD) patients compared to a common control population of 335 subjects. Differences in genotype distribution between patients and control subjects were studied by logistic regression analysis using age and gender as covariates. The effect size of risk association and synergy factors were calculated using the logistic odds ratio estimates. Our data confirmed that the presence of APOE ε4 allele is associated with a higher risk of developing AD, while homozygosity at PRNP gene constitutes a risk for sCJD. Opposite, we found no association for PRNP with AD, nor for APOE with sCJD. Interestingly, when AD and sCJD patients were stratified according to their respective main risk genes (APOE for AD, and PRNP for sCJD), we found statistically significant associations for the other gene in those strata at higher previous risk. Synergy factor analysis showed a synergistic age-dependent interaction between APOE and PRNP in both AD (SF = 3.59, p = 0.027), and sCJD (SF = 7.26, p = 0.005). We propose that this statistical epistasis can partially explain divergent data from different association studies. Moreover, these results suggest that the genetic interaction between APOE and PRNP may have a biological correlate that is indicative of shared neurodegenerative pathways involved in AD and sCJD. PMID:21799773

  11. Proteomic analysis of host brain components that bind to infectious particles in Creutzfeldt-Jakob disease.

    PubMed

    Kipkorir, Terry; Colangelo, Christopher M; Manuelidis, Laura

    2015-09-01

    Transmissible encephalopathies (TSEs), such as Creutzfeldt-Jakob disease (CJD) and scrapie, are caused by infectious agents that provoke strain-specific patterns of disease. Misfolded host prion protein (PrP-res amyloid) is believed to be the causal infectious agent. However, particles that are stripped of PrP retain both high infectivity and viral proteins not detectable in uninfected mouse controls. We here detail host proteins bound with FU-CJD agent infectious brain particles by proteomic analysis. More than 98 proteins were differentially regulated, and 56 FU-CJD exclusive proteins were revealed after PrP, GFAP, C1q, ApoE, and other late pathologic response proteins were removed. Stripped FU-CJD particles revealed HSC70 (144× the uninfected control), cyclophilin B, an FU-CJD exclusive protein required by many viruses, and early endosome-membrane pathways known to facilitate viral processing, replication, and spread. Synaptosomal elements including synapsin-2 (at 33×) and AP180 (a major FU-CJD exclusive protein) paralleled the known ultrastructural location of 25 nm virus-like TSE particles and infectivity in synapses. Proteins without apparent viral or neurodegenerative links (copine-3), and others involved in viral-induced protein misfolding and aggregation, were also identified. Human sCJD brain particles contained 146 exclusive proteins, and heat shock, synaptic, and viral pathways were again prominent, in addition to Alzheimer, Parkinson, and Huntington aggregation proteins. Host proteins that bind TSE infectious particles can prevent host immune recognition and contribute to prolonged cross-species transmissions (the species barrier). Our infectious particle strategy, which reduces background sequences by >99%, emphasizes host targets for new therapeutic initiatives. Such therapies can simultaneously subvert common pathways of neurodegeneration.

  12. Neuropathological and biochemical criteria to identify acquired Creutzfeldt-Jakob disease among presumed sporadic cases.

    PubMed

    Kobayashi, Atsushi; Parchi, Piero; Yamada, Masahito; Mohri, Shirou; Kitamoto, Tetsuyuki

    2016-06-01

    As an experimental model of acquired Creutzfeldt-Jakob disease (CJD), we performed transmission studies of sporadic CJD using knock-in mice expressing human prion protein (PrP). In this model, the inoculation of the sporadic CJD strain V2 into animals homozygous for methionine at polymorphic codon 129 (129 M/M) of the PRNP gene produced quite distinctive neuropathological and biochemical features, that is, widespread kuru plaques and intermediate type abnormal PrP (PrP(Sc) ). Interestingly, this distinctive combination of molecular and pathological features has been, to date, observed in acquired CJD but not in sporadic CJD. Assuming that these distinctive phenotypic traits are specific for acquired CJD, we revisited the literature and found two cases showing widespread kuru plaques despite the 129 M/M genotype, in a neurosurgeon and in a patient with a medical history of neurosurgery without dura mater grafting. By Western blot analysis of brain homogenates, we revealed the intermediate type of PrP(Sc) in both cases. Furthermore, transmission properties of brain extracts from these two cases were indistinguishable from those of a subgroup of dura mater graft-associated iatrogenic CJD caused by infection with the sporadic CJD strain V2. These data strongly suggest that the two atypical CJD cases, previously thought to represent sporadic CJD, very likely acquired the disease through exposure to prion-contaminated brain tissues. Thus, we propose that the distinctive combination of 129 M/M genotype, kuru plaques, and intermediate type PrP(Sc) , represents a reliable criterion for the identification of acquired CJD cases among presumed sporadic cases.

  13. Enhanced geographically restricted surveillance simulates sporadic Creutzfeldt-Jakob disease cluster.

    PubMed

    Klug, Genevieve M; Wand, Handan; Boyd, Alison; Law, Matthew; Whyte, Scott; Kaldor, John; Masters, Colin L; Collins, Steven

    2009-02-01

    Spatio-temporal clustering of sporadic Creutzfeldt-Jakob disease (sCJD) has been recognized and investigated previously in various global settings including Australia. Generally, despite often extensive investigation, explanations such as point source outbreaks and plausible case-to-case transmission links have not been identified to explain the apparently higher case rates than expected. In the context of national surveillance during the period 1993-2006, an increased number of cases of sCJD were recognized in a circumscribed coastal region of eastern Australia. To assess the significance of this apparent clustering, the Spatial Scan Statistic was used to examine for geographic excess of CJD mortality at spatial and temporal combined, spatial only and temporal only levels. A significant spatial cluster was confirmed, encompassing three contiguous statistical local areas within the state of New South Wales (NSW). Detailed epidemiological analysis did not reveal a plausible cross-over or point source transmission event. Further evaluation prompted the conclusion that vigilant and motivated managing clinicians in this geographically circumscribed area of NSW evinced a sustained higher level of clinical awareness for the broad phenotypic spectrum of CJD with reliable referral of suspect cases for further investigation. In addition, these physicians established and maintained a well-coordinated and active approach to suspect CJD autopsy. This combination of factors translated into a higher intensity of surveillance at approximately twice the rate per population observed in the entire state, culminating in twice the incidence of sCJD at around 2.28 cases/million population/year. The hypothesis that intensity of surveillance for rare disorders can be objectively measured and that this can positively correlate with disease incidence deserves further exploration. It may prove to be an important insight into the varying incidence rates over periods of time within individual

  14. Myoclonus in Creutzfeldt-Jakob disease: polygraphic and video-electroencephalography assessment of 109 patients.

    PubMed

    Binelli, Simona; Agazzi, Pamela; Canafoglia, Laura; Scaioli, Vidmer; Panzica, Ferruccio; Visani, Elisa; Di Fede, Giuseppe; Giaccone, Giorgio; Bizzi, Alberto; Bugiani, Orso; Avanzini, Guiliano; Tagliavini, Fabrizio; Franceschetti, Silvana

    2010-12-15

    We used electroencephalography (EEG)-polygraphic recordings to classify myoclonus in 109 patients with Creutzfeldt-Jakob disease (CJD) on the basis of its electromyography (EMG) pattern, time course, distribution, and EEG correlates. We recorded myoclonic jerks in 55 patients (50.4%), and we classified them as periodic myoclonus in 28, rhythmic in 13, and irregular in 20 (6 patients showed two types of myoclonus). Myoclonus occurred as a prominently negative event (interrupting the EMG discharge) in 10. Periodic sharp-wave complexes (PSWCs) were present in all but one patient with myoclonic jerks but were time-locked with EMG-bursts only in case of periodic myoclonus. Jerk-locked back averaging revealed a variable EEG-EMG transfer-time commonly exceeding that characterizing cortical myoclonus. Myoclonus was frequently associated with Met/Met polymorphism at codon 129 of the prion protein gene, but it was also observed in association with Met/Val or Val/Val polymorphisms provided that the EEG showed the presence of the PSWC pattern. The presence of enlarged somatosensory evoked potentials significantly correlated with the myoclonic presentation, as did MR signal hyperintensity involving the cortical mantle. Our observations on the basis of standard polygraphic criteria suggest that CJD associates with a remarkable variety of myoclonic jerks, and therefore different brain structures are probably involved as generators. The significant association between the presence of all myoclonus types with PSWCs suggests that hyperexcitable corticosubcortical loops are always required to generate (or allow) both myoclonus and the EEG complexes, either they are time locked or not.

  15. Nucleic acid binding proteins in highly purified Creutzfeldt-Jakob disease preparations.

    PubMed Central

    Sklaviadis, T; Akowitz, A; Manuelidis, E E; Manuelidis, L

    1993-01-01

    The nature of the infectious agent causing human Creutzfeldt-Jakob disease (CJD), a slowly progressive dementia, is controversial. As in scrapie, no agent-specific proteins or nucleic acids have been identified. However, biological features of exponential replication and agent strain variation, as well as physical size and density data, are most consistent with a viral structure--i.e., a nucleic acid-protein complex. It is often assumed that nuclease treatment, which does not reduce infectious titer, leaves no nucleic acids of > 50 bp. However, nucleic acids of 500-6000 bp can be extracted from highly purified infectious complexes with a mass of approximately 1.5 x 10(7) daltons. It was therefore germane to search for nucleic acid binding proteins that might protect an agent genome. We here use Northwestern blotting to show that there are low levels of nonhistone nucleic acid binding proteins in highly purified infectious 120S gradient fractions. Several nucleic acid binding proteins were clearly host encoded, whereas others were apparent only in CJD, but not in parallel preparations from uninfected brain. Small amounts of residual host Gp34 (prion protein) did not bind any 32P-labeled nucleic acid probes. Most of the minor "CJD-specific" proteins had an acidic pI, a characteristic of many viral core proteins. Such proteins deserve further study, as they probably contribute to unique properties of resistance described for these agents. It remains to be seen if any of these proteins are agent encoded. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8516321

  16. Alzheimer-type neuropathology in a 28 year old patient with iatrogenic Creutzfeldt-Jakob disease after dural grafting.

    PubMed

    Preusser, M; Ströbel, T; Gelpi, E; Eiler, M; Broessner, G; Schmutzhard, E; Budka, H

    2006-03-01

    We report the case of a 28 year old man who had received a cadaverous dura mater graft after a traumatic open skull fracture with tearing of the dura at the age of 5 years. A clinical suspicion of Creutzfeldt-Jakob disease (CJD) was confirmed by a brain biopsy 5 months prior to death and by autopsy, thus warranting the diagnosis of iatrogenic CJD (iCJD) according to WHO criteria. Immunohistochemistry showed widespread cortical depositions of disease associated prion protein (PrP(sc)) in a synaptic pattern, and western blot analysis identified PrP(sc) of type 2A according to Parchi et al. Surprisingly, we found Alzheimer-type senile plaques and cerebral amyloid angiopathy in widespread areas of the brain. Plaque-type and vascular amyloid was immunohistochemically identified as deposits of beta-A4 peptide. CERAD criteria for diagnosis of definite Alzheimer's disease (AD) were met in the absence of neurofibrillar tangles or alpha-synuclein immunoreactive inclusions. There was no family history of AD, CJD, or any other neurological disease, and genetic analysis showed no disease specific mutations of the prion protein, presenilin 1 and 2, or amyloid precursor protein genes. This case represents (a) the iCJD case with the longest incubation time after dural grafting reported so far, (b) the youngest documented patient with concomitant CJD and Alzheimer-type neuropathology to date, (c) the first description of Alzheimer-type changes in iCJD, and (d) the second case of iCJD in Austria. Despite the young patient age, the Alzheimer-type changes may be an incidental finding, possibly related to the childhood trauma.

  17. Novel prion protein gene mutation at codon 196 (E196A) in a septuagenarian with Creutzfeldt-Jakob disease.

    PubMed

    Zhang, Hongliang; Wang, Meibo; Wu, Limin; Zhang, Haining; Jin, Tao; Wu, Jiang; Sun, Li

    2014-01-01

    Creutzfeldt-Jakob disease (CJD) is a rare and rapidly progressive neurodegenerative disease of the central nervous system, which may occur in inherited, acquired (variant and iatrogenic), or spontaneous (sporadic) forms. We report a 76-year-old Chinese man with CJD found to have a novel mutation in the prion protein gene (PRNP). The 14-3-3 protein was positive in the cerebrospinal fluid; diffusion-weighted MRI revealed ribbon-like high signal intensity in the bilateral cortices; and electroencephalography showed typical periodic synchronous discharge. CJD was diagnosed based on characteristic clinical manifestations. Interestingly, a point mutation of PRNP at codon 196 (E196A: GAG→GCG) was detected. In conclusion, we identified a patient with CJD with a novel PRNP mutation, which expands the spectrum of PRNP mutations in CJD.

  18. Bitemporal hypometabolism in Creutzfeldt-Jakob disease measured by positron emission tomography with (/sup 18/F)-2-fluorodeoxyglucose

    SciTech Connect

    Friedland, R.P.; Prusiner, S.B.; Jagust, W.J.; Budinger, T.F.; Davis, R.L.

    1984-10-01

    It is well established that Creutzfeldt-Jakob disease (CJD) is caused by a slow infectious agent similar to the scrapie prion. However, the pathogenesis of this infection is poorly understood. Positron emission tomography (PET) was performed on a 54-year-old man with autopsy confirmed CJD using (18F)-2-fluorodeoxyglucose (FDG) and the Donner 280-crystal tomograph. Temporal lobe hypometabolism with hemispheric asymmetry was observed. These findings are similar to those previously obtained in PET-FDG studies of patients with clinically defined Alzheimer disease (AD). The similarities in the regional metabolic alterations between CJD and AD provide additional evidence for the possibility that AD may be caused by a slow infectious prion.

  19. Sporadic—but Not Variant—Creutzfeldt-Jakob Disease Is Associated with Polymorphisms Upstream of PRNP Exon 1

    PubMed Central

    Mead, Simon; Mahal, Sukhvir P; Beck, John; Campbell, Tracy; Farrall, Martin; Fisher, Elizabeth; Collinge, John

    2001-01-01

    Human prion diseases have inherited, sporadic, and acquired etiologies. The appearance of the novel acquired prion disease, variant Creutzfeldt-Jakob disease (vCJD), and the demonstration that it is caused by the same prion strain as that causing bovine spongiform encephalopathy, has led to fears of a major human epidemic. The etiology of classical (sporadic) CJD, which has a worldwide incidence, remains obscure. A common human prion-protein–gene (PRNP) polymorphism (encoding either methionine or valine at codon 129) is a strong susceptibility factor for sporadic and acquired prion disease. However, a quantitative-trait–locus study of prion incubation periods in mice has demonstrated an important factor that is close to Prnp but is independent of its coding sequence or that of the nearby prion-like doppel gene (Prnd). We have analyzed the PRNP locus for such tightly linked susceptibility factors. Fifty-six polymorphic sites have been identified within 25 kb of the PRNP open reading frame, including sites within the PRNP promoter and the PRNP 3′ untranslated region. These have been characterized in 61 Centre d’Étude du Polymorphisme Humain (CEPH) families, demonstrating extensive linkage disequilibrium around PRNP and the existence of 11 major European PRNP haplotypes. Haplotype frequencies estimated in healthy U.K. control individuals were very similar to those deduced in the CEPH families. A common haplotype was overrepresented in patients with sporadic CJD (sCJD). Through use of a log-linear modeling approach to simultaneously model Hardy-Weinberg and linkage disequilibria, a significant independent association was found between sCJD and a polymorphism upstream of PRNP exon 1 (P=.005), in addition to the strong susceptibility conferred by codon 129 (P=2×10-8). However, although our sample size was necessarily small, no association was found between these polymorphisms and vCJD or iatrogenic CJD, in keeping with their having distinct disease mechanisms

  20. Magnetic resonance imaging reveals Creutzfeldt-Jakob disease in a patient with apparent dementia with Lewy bodies.

    PubMed

    Tsivgoulis, Georgios; Bonakis, Anastasios; Papathanasiou, Matilda A; Chondrogianni, Maria; Papageorgiou, Sokratis G; Voumvourakis, Konstantinos; Stefanis, Leonidas

    2014-05-15

    The differential diagnosis of dementia with Lewy bodies (DLB) and sporadic Creutzfeldt-Jakob disease (CJD) may be challenging. Patients with the original diagnosis of possible CJD may occasionally prove to have a pathological diagnosis of DLB, while other cases may fulfill the diagnostic clinical criteria for DLB but subsequent clinical course, cerebrospinal fluid (CSF) and neuropathology findings necessitate diagnostic revision to CJD. We describe a 79-year old patient recently diagnosed with dementia with Lewy bodies (DLB) on the basis of subacute cognitive decline, visual hallucinations and Parkinsonian features, who presented with increasing agitation. Brain neuroimaging with MRI raised the diagnostic suspicion of CJD and subsequent diagnostic work-up with electroencephalography (EEG) and CSF analysis led to the establishment of CJD diagnosis. The present case highlights the clinical utility of novel diagnostic CJD criteria that also incorporate neuroimaging findings in the diagnostic CJD panel.

  1. Creutzfeldt-Jakob Disease in a Tertiary Care Hospital in Thailand: A Case Series and Review of the Literature.

    PubMed

    Lolekha, Praween; Rasheed, Ahmed; Yotsarawat, Chutanat

    2015-09-01

    Creutzfeldt-Jakob Disease (CJD) is an incurable and inevitably fatal neurodegenerative disorder. Although CJD has a worldwide distribution, there are no official statistics on CJD in Thailand. A diagnosis of CJD is suspected when a patient develops rapidly progressive dementia with myoclonus. However, CJD may be mistaken for a variety of illnesses because its initial presentation frequently consists of non-specific symptoms. Here, we examined cases of sporadic CJD (sCJD) from Thammasat University Hospital (a tertiary care hospital in Thailand) between January 1, 2012 and December 31, 2014. Three cases of probable and possible sCJD were collected. All cases presented with rapidly progressive cognitive dysfunction accompanied by spontaneous myoclonus. Classical electroencehalography changes and typical abnormal MRI features were observed. All of the cases died within a period of 8 months. None of the patients underwent brain biopsy. Our findings raise questions about the prevalence of CJD in Thailand, which needs further study.

  2. [Perioperative considerations for performing a brain biopsy on a patient with subtype VV2 sporadic Creutzfeldt-Jakob disease].

    PubMed

    Guerrero-Domínguez, R; Rubio-Romero, R; González-González, G; Jiménez, I

    2015-04-01

    Creutzfeldt-Jakob disease (CJD) is the most common transmissible spongiform encephalopathy. It is an infectious, progressive, degenerative neurological disorder, with a presumably long incubation period, but a rapid fatal course. CJD is transmitted by a proteinaceous infectious agent, or «prion». Because the prions are difficult to eradicate and are resistant to the currently used sterilization methods, special precautions must be taken with all surgical instruments. It is recommended the single-use equipment, destruction of contaminated equipment, decontamination of reusable instruments, use of protective clothing, and storing and quarantining surgical instruments. The single-use equipment and some tissues and body fluids from the patient with CJD are highly infectious and must be incinerated. We report a case of a patient who had undergone brain biopsy for suspected of CJD, being confirmed to have sporadic CJD. Specific preventive measures were taken to reduce the risk of transmission to healthcare workers.

  3. Diagnostic profiles of patients with late-onset Creutzfeldt-Jakob disease differ from those of younger Creutzfeldt-Jakob patients: a historical cohort study using data from the German National Reference Center.

    PubMed

    Karch, André; Raddatz, Lena Maria; Ponto, Claudia; Hermann, Peter; Summers, David; Zerr, Inga

    2014-05-01

    In contrast to other neurodegenerative diseases, sporadic Creutzfeldt-Jakob disease (sCJD) is rarely diagnosed in patients older than 75 years. Data describing the characteristics of sCJD in the very old are rare and inconclusive. Therefore, a historical cohort study was designed to evaluate clinical, cerebrospinal fluid (CSF), electroencephalography (EEG), and magnetic resonance imaging (MRI) features of this group. Patients older than 75 years identified via the German surveillance program from 2001 to 2012 (n = 73) were compared to a random subsample of sCJD patients younger than 75 (n = 73) from the same time period using an historical cohort design. Older patients showed a faster disease progression represented by an earlier point of diagnosis and a shorter survival time (p < 0.001). In the early stages of disease, older patients presented slightly more often with dementia (p = 0.127) or dysarthria (p = 0.238), whereas disorders of the extrapyramidal (p = 0.056) and visual system (p = 0.015) were more common in the younger group. Atypical MRI profiles such as MRI lesions restricted to one hemisphere (p < 0.001) or cortical lesions only (p = 0.258) were found more frequently in patients older than 75 years, whereas typical cortical and basal ganglia hyperintensities were more common in the younger group (p = 0.001). We demonstrated for the first time that patients with late-onset sCJD differ from younger sCJD patients with respect to MRI profiles and initial clinical presentation, but not among CSF markers. Misclassification of Creutzfeldt-Jakob disease cases in patients older than 75 years seems likely due to atypical clinical and radiological presentation. This might contribute to lower sCJD incidence rates in this age group.

  4. Lack of prion infectivity in fixed heart tissue from patients with Creutzfeldt-Jakob disease or amyloid heart disease.

    PubMed

    Priola, Suzette A; Ward, Anne E; McCall, Sherman A; Trifilo, Matthew; Choi, Young Pyo; Solforosi, Laura; Williamson, R Anthony; Cruite, Justin T; Oldstone, Michael B A

    2013-09-01

    In most forms of prion disease, infectivity is present primarily in the central nervous system or immune system organs such as spleen and lymph node. However, a transgenic mouse model of prion disease has demonstrated that prion infectivity can also be present as amyloid deposits in heart tissue. Deposition of infectious prions as amyloid in human heart tissue would be a significant public health concern. Although abnormal disease-associated prion protein (PrP(Sc)) has not been detected in heart tissue from several amyloid heart disease patients, it has been observed in the heart tissue of a patient with sporadic Creutzfeldt-Jakob Disease (sCJD), the most common form of human prion disease. In order to determine whether prion infectivity can be found in heart tissue, we have inoculated formaldehyde fixed brain and heart tissue from two sCJD patients, as well as prion protein positive fixed heart tissue from two amyloid heart disease patients, into transgenic mice overexpressing the human prion protein. Although the sCJD brain samples led to clinical or subclinical prion infection and deposition of PrP(Sc) in the brain, none of the inoculated heart samples resulted in disease or the accumulation of PrP(Sc). Thus, our results suggest that prion infectivity is not likely present in cardiac tissue from sCJD or amyloid heart disease patients.

  5. Risk of transmission of Creutzfeldt-Jakob disease via blood and blood products. The French risk-analysis over the last 15 years.

    PubMed

    Martin, M; Trouvin, J-H

    2013-09-01

    Risk of transmission of Creutzfeldt-Jakob disease (infectious agent, responsible of spongiform encephalopathy) via blood and blood components (including the plasma-derived medicinal products such as coagulation factors and immunoglobulins) have been a subject of concern for Health authorities since the early 1980s, with a regain of interest in the 1990s, with the bovine spongiform encephalopathy outbreak followed few years after with the notification of the first cases of variant Creutzfeldt-Jakob disease in humans. The risk-analysis and measures taken by the French authorities in the period 1990-2010 will be described with the various assumptions and working hypothesis used and revisited as new findings become available.

  6. Characteristics of Korean patients with suspected Creutzfeldt-Jakob disease with 14-3-3 protein in cerebrospinal fluid: Preliminary study of the Korean Creutzfeldt-Jakob disease active surveillance program

    PubMed Central

    Lim, Jae-Sung; Kwon, Hyung-Min; Jang, Jae-Won; Ju, Young-Ran; Kim, SuYeon; Park, Young Ho; Park, So Young; Kim, SangYun

    2015-01-01

    Abstract Although Korea had a national surveillance system for Creutzfeldt-Jakob disease (CJD), it was mainly dependent on attending physician's reports. Thus, little prospective data about the epidemiology, characteristics, and final diagnoses of suspected patients were available. We have established a nationwide network for the active surveillance of patients with suspected CJD. When the requested cerebrospinal fluid (CSF) samples tested positive for 14-3-3 protein, we investigated the clinical characteristics of the corresponding patients and followed them until their final diagnoses were confirmed. A total of 218 samples were requested for CSF assays from May 2010 to August 2012, and 106 (48.6%) were positive for 14-3-3 protein. In 89 patients with complete clinical data, 38 (42.7%) were diagnosed with probable CJD and the estimated annual occurrence of CJD was 16.3 persons-per-year. The most common diagnoses of the remainder were central nervous system infection and any-cause encephalopathy. Non-CJD subjects showed worse initial consciousness levels than CJD patients. This preliminary study showed that the number of reported cases of CJD and the true positivity rates of CSF 14-3-3 protein assays were both low in Korea. An active surveillance system is urgently needed to provide the latest nationwide epidemiological data of CJD. PMID:25996401

  7. Characteristics of Korean patients with suspected Creutzfeldt-Jakob disease with 14-3-3 protein in cerebrospinal fluid: Preliminary study of the Korean Creutzfeldt-Jakob disease active surveillance program.

    PubMed

    Lim, Jae-Sung; Kwon, Hyung-Min; Jang, Jae-Won; Ju, Young-Ran; Kim, SuYeon; Park, Young Ho; Park, So Young; Kim, SangYun

    2015-01-01

    Although Korea had a national surveillance system for Creutzfeldt-Jakob disease (CJD), it was mainly dependent on attending physician's reports. Thus, little prospective data about the epidemiology, characteristics, and final diagnoses of suspected patients were available. We have established a nationwide network for the active surveillance of patients with suspected CJD. When the requested cerebrospinal fluid (CSF) samples tested positive for 14-3-3 protein, we investigated the clinical characteristics of the corresponding patients and followed them until their final diagnoses were confirmed. A total of 218 samples were requested for CSF assays from May 2010 to August 2012, and 106 (48.6%) were positive for 14-3-3 protein. In 89 patients with complete clinical data, 38 (42.7%) were diagnosed with probable CJD and the estimated annual occurrence of CJD was 16.3 persons-per-year. The most common diagnoses of the remainder were central nervous system infection and any-cause encephalopathy. Non-CJD subjects showed worse initial consciousness levels than CJD patients. This preliminary study showed that the number of reported cases of CJD and the true positivity rates of CSF 14-3-3 protein assays were both low in Korea. An active surveillance system is urgently needed to provide the latest nationwide epidemiological data of CJD.

  8. MM2-thalamic Creutzfeldt-Jakob disease: neuropathological, biochemical and transmission studies identify a distinctive prion strain.

    PubMed

    Moda, Fabio; Suardi, Silvia; Di Fede, Giuseppe; Indaco, Antonio; Limido, Lucia; Vimercati, Chiara; Ruggerone, Margherita; Campagnani, Ilaria; Langeveld, Jan; Terruzzi, Alessandro; Brambilla, Antonio; Zerbi, Pietro; Fociani, Paolo; Bishop, Matthew T; Will, Robert G; Manson, Jean C; Giaccone, Giorgio; Tagliavini, Fabrizio

    2012-09-01

    In Creutzfeldt-Jakob disease (CJD), molecular typing based on the size of the protease resistant core of the disease-associated prion protein (PrP(Sc) ) and the M/V polymorphism at codon 129 of the PRNP gene correlates with the clinico-pathologic subtypes. Approximately 95% of the sporadic 129MM CJD patients are characterized by cerebral deposition of type 1 PrP(Sc) and correspond to the classic clinical CJD phenotype. The rare 129MM CJD patients with type 2 PrP(Sc) are further subdivided in a cortical and a thalamic form also indicated as sporadic fatal insomnia. We observed two young patients with MM2-thalamic CJD. Main neuropathological features were diffuse, synaptic PrP immunoreactivity in the cerebral cortex and severe neuronal loss and gliosis in the thalamus and olivary nucleus. Western blot analysis showed the presence of type 2A PrP(Sc) . Challenge of transgenic mice expressing 129MM human PrP showed that MM2-thalamic sporadic CJD (sCJD) was able to transmit the disease, at variance with MM2-cortical sCJD. The affected mice showed deposition of type 2A PrP(Sc) , a scenario that is unprecedented in this mouse line. These data indicate that MM2-thalamic sCJD is caused by a prion strain distinct from the other sCJD subtypes including the MM2-cortical form.

  9. Immune responses in rapidly progressive dementia: a comparative study of neuroinflammatory markers in Creutzfeldt-Jakob disease, Alzheimer's disease and multiple sclerosis.

    PubMed

    Stoeck, Katharina; Schmitz, Matthias; Ebert, Elisabeth; Schmidt, Christian; Zerr, Inga

    2014-10-15

    Immunological responses may contribute to disease progression and clinical heterogeneity in neurodegenerative dementia, for example, Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD). Recently, a rapidly progressive form of AD (rpAD) has been described. On neuropathological grounds classical AD and rpAD are not distinguishable at present. All those protein aggregopathies show a state of chronic inflammation with microglia activation and production of proinflammatory cytokines. In this context, it is hypothesized that the severity of the surrounding inflammation substantially contributes to disease progression and accelerated disease courses as seen in rpAD.

  10. Bitemporal hypometabolism in Creutzfeldt-Jakob Disease measured by positron emission tomography with (F-18)2-fluorodeoxyglucose

    SciTech Connect

    Friedland, R.P.; Budinger, T.F.; Prusiner, S.B.; Jagust, W.J.

    1984-01-01

    It is well established that Creutzfeldt-Jakob Disease (CJD) is caused by a slow infectious agent similar to the scrapie prion. However, the pathogenesis of this infection is poorly understood. Positron emission tomography (PET) was performed on a 54 year old male subject with autopsy confirmed CJD using (F-18)2-fluorodeoxyglucose (FDG) and the Donner 280-crystal tomograph. An x-ray computed tomographic study of the brain performed 4 days prior to PET was normal. In the PET study the frontal to temporal cortex difference of activity densities was 30% on the left and 12% on the right, reflecting temporal hypometabolism. The left-right temporal cortex difference of activity density was 25%, documenting marked hemispheric asymmetry. These findings are similar to those previously obtained in PET-FDG studies of patients with clinically defined Alzheimer's Disease (AD) and are distinctly different from PET-FDG finding in patients with other dementing illnesses or in healthy aged subjects. Recent work has demonstrated extensive biological similarities between CJD, scrapie and AD. The similarities in the regional metabolic alterations between CJD and AD provide additional evidence for the hypothesis that AD is caused by a slow infectious (prion-like) pathogen.

  11. Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions.

    PubMed

    Watts, Joel C; Giles, Kurt; Saltzberg, Daniel J; Dugger, Brittany N; Patel, Smita; Oehler, Abby; Bhardwaj, Sumita; Sali, Andrej; Prusiner, Stanley B

    2016-11-01

    The biochemical and neuropathological properties of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) prions are faithfully maintained upon transmission to guinea pigs. However, primary and secondary transmissions of BSE and vCJD in guinea pigs result in long incubation periods of ∼450 and ∼350 days, respectively. To determine if the incubation periods of BSE and vCJD prions could be shortened, we generated transgenic (Tg) mice expressing guinea pig prion protein (GPPrP). Inoculation of Tg(GPPrP) mice with BSE and vCJD prions resulted in mean incubation periods of 210 and 199 days, respectively, which shortened to 137 and 122 days upon serial transmission. In contrast, three different isolates of sporadic CJD prions failed to transmit disease to Tg(GPPrP) mice. Many of the strain-specified biochemical and neuropathological properties of BSE and vCJD prions, including the presence of type 2 protease-resistant PrP(Sc), were preserved upon propagation in Tg(GPPrP) mice. Structural modeling revealed that two residues near the N-terminal region of α-helix 1 in GPPrP might mediate its susceptibility to BSE and vCJD prions. Our results demonstrate that expression of GPPrP in Tg mice supports the rapid propagation of BSE and vCJD prions and suggest that Tg(GPPrP) mice may serve as a useful paradigm for bioassaying these prion isolates.

  12. Clinical and MRI evaluation of anxiety as the first symptom of sporadic Creutzfeldt-Jakob disease: A case report

    PubMed Central

    LIU, WEIBO; LU, YUNRONG; ZHONG, GUODONG; JIANG, BIAO; PAN, ZHIJIE

    2016-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare, transmissible prion disease of the brain, characterized by prominent neurological symptoms and progressive dementia. Early psychiatric manifestations as an initial or sole symptom of sCJD are relatively rare. The current report describes an elderly female patient with sCJD demonstrating anxiety as an initial symptom. The present patient was initially diagnosed with adjustment disorder and anxiety; however, the rapid deterioration of the patient's cognitive and neurological functioning led to a diagnosis of sCJD. Diffusion-weighted magnetic resonance images of the brain supported a diagnosis of sCJD, and it was posited that the abnormalities of gray matter that were observed within the bilateral cingulate cortex may be the pathophysiological basis of the anxiety associated with this case of sCJD. The patient eventually succumbed to inhalational bronchopneumonia 5 months after anxiety onset. The present case report emphasizes the importance of secondary causes of anxiety symptoms in elderly patients, and indicates that brain DWI is a non-invasive and useful examination in the early diagnosis of sCJD. PMID:27073474

  13. Sporadic Creutzfeldt-Jakob Disease MM1+2C and MM1 are Identical in Transmission Properties.

    PubMed

    Kobayashi, Atsushi; Matsuura, Yuichi; Iwaki, Toru; Iwasaki, Yasushi; Yoshida, Mari; Takahashi, Hitoshi; Murayama, Shigeo; Takao, Masaki; Kato, Shinsuke; Yamada, Masahito; Mohri, Shirou; Kitamoto, Tetsuyuki

    2016-01-01

    The genotype (methionine, M or valine, V) at polymorphic codon 129 of the PRNP gene and the type (1 or 2) of abnormal prion protein in the brain are the major determinants of the clinicopathological features of sporadic Creutzfeldt-Jakob disease (CJD), thus providing molecular basis for classification of sporadic CJD, that is, MM1, MM2, MV1, MV2, VV1 or VV2. In addition to these "pure" cases, "mixed" cases presenting mixed neuropathological and biochemical features have also been recognized. The most frequently observed mixed form is the co-occurrence of MM1 and MM2, namely MM1+2. However, it has remained elusive whether MM1+2 could be a causative origin of dura mater graft-associated CJD (dCJD), one of the largest subgroups of iatrogenic CJD. To test this possibility, we performed transmission experiments of MM1+2 prions and a systematic neuropathological examination of dCJD patients in the present study. The transmission properties of the MM1+2 prions were identical to those of MM1 prions because MM2 prions lacked transmissibility. In addition, the neuropathological characteristics of MM2 were totally absent in dCJD patients examined. These results suggest that MM1+2 can be a causative origin of dCJD and causes neuropathological phenotype similar to that of MM1.

  14. Altered Mitochondria, Protein Synthesis Machinery, and Purine Metabolism Are Molecular Contributors to the Pathogenesis of Creutzfeldt-Jakob Disease.

    PubMed

    Ansoleaga, Belén; Garcia-Esparcia, Paula; Llorens, Franc; Hernández-Ortega, Karina; Carmona Tech, Margarita; Antonio Del Rio, José; Zerr, Inga; Ferrer, Isidro

    2016-06-12

    Neuron loss, synaptic decline, and spongiform change are the hallmarks of sporadic Creutzfeldt-Jakob disease (sCJD), and may be related to deficiencies in mitochondria, energy metabolism, and protein synthesis. To investigate these relationships, we determined the expression levels of genes encoding subunits of the 5 protein complexes of the electron transport chain, proteins involved in energy metabolism, nucleolar and ribosomal proteins, and enzymes of purine metabolism in frontal cortex samples from 15 cases of sCJD MM1 and age-matched controls. We also assessed the protein expression levels of subunits of the respiratory chain, initiation and elongation translation factors of protein synthesis, and localization of selected mitochondrial components. We identified marked, generalized alterations of mRNA and protein expression of most subunits of all 5 mitochondrial respiratory chain complexes in sCJD cases. Expression of molecules involved in protein synthesis and purine metabolism were also altered in sCJD. These findings point to altered mRNA and protein expression of components of mitochondria, protein synthesis machinery, and purine metabolism as components of the pathogenesis of CJD.

  15. The epidemics of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: current status and future prospects.

    PubMed Central

    Smith, Peter G.

    2003-01-01

    The large epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom has been in decline since 1992, but has spread to other countries. The extensive control measures that have been put in place across the European Union and also in Switzerland should have brought the transmission of BSE under control in these countries, provided that the measures were properly enforced. Postmortem tests on brain tissue enable infected animals to be detected during the late stages of the incubation period, but tests that can be performed on live animals (including humans) and that will detect infections early are urgently needed. The number of infected animals currently entering the food chain is probably small, and the controls placed on bovine tissues in the European Union and Switzerland should ensure that any risks to human health are small and diminishing. Vigilance is required in all countries, especially in those in which there has been within-species recycling of ruminant feed. Fewer than 150 people, globally, have been diagnosed with variant Creutzfeldt-Jakob disease (vCJD), but there are many uncertainties about the future course of the epidemic because of the long and variable incubation period. Better control measures are necessary to guard against the possibility of iatrogenic transmission through blood transfusion or contaminated surgical instruments. These measures will required sensitive and specific, diagnostic tests and improved decontamination methods. PMID:12751420

  16. Universal white blood cell reduction in Europe: has transmission of variant Creutzfeldt-Jakob disease been prevented?

    PubMed

    Vamvakas, Eleftherios C

    2011-04-01

    Universal white blood cell (WBC) reduction was introduced in Europe to prevent transmission of variant Creutzfeldt-Jakob disease (vCJD) by transfusion. Findings from rodent models indicate that WBC reduction should not prevent vCJD transmission because the residual plasma infectivity suffices to infect transfusion recipients even under optimistic infectivity assumptions. Although infectivity in human blood may not partition in the manner in which it is distributed in rodents, prion-reduction filters remove the residual plasma infectivity in rodent models. Precautionary introduction of prion filtration in the UK--for patients without dietary exposure to bovine spongiform encephalopathy and in the absence of a reported case of vCJD transmission attributable to infectivity residing in plasma--is consistent with the (already in place for such subjects) precautionary importation to the UK of fresh frozen plasma from low-risk countries. Thus, implementation of prion filtration in the UK does not imply that universal WBC reduction--as currently practiced in Europe--does not abrogate transmission of vCJD. Because neither a human case of vCJD transmission through transfusion of WBC-reduced red blood cells nor a case of experimental bovine spongiform encephalopathy transmission by WBC-reduced transfusion to sheep has been reported, it cannot be concluded that ordinary WBC reduction is ineffective in preventing transfusion transmission in humans. Accordingly, universal WBC reduction for the prevention of vCJD in Europe should continue.

  17. Sporadic Creutzfeldt-Jakob Disease: Prion Pathology in Medulla Oblongata-Possible Routes of Infection and Host Susceptibility.

    PubMed

    Iacono, Diego; Ferrari, Sergio; Gelati, Matteo; Zanusso, Gianluigi; Mariotto, Sara; Monaco, Salvatore

    2015-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disorder, is characterized by remarkable phenotypic variability, which is influenced by the conformation of the pathologic prion protein and the methionine/valine polymorphic codon 129 of the prion protein gene. While the etiology of sCJD remains unknown, it has been hypothesized that environmental exposure to prions might occur through conjunctival/mucosal contact, oral ingestion, inhalation, or simultaneous involvement of the olfactory and enteric systems. We studied 21 subjects with definite sCJD to assess neuropathological involvement of the dorsal motor nucleus of the vagus and other medullary nuclei and to evaluate possible associations with codon 129 genotype and prion protein conformation. The present data show that prion protein deposition was detected in medullary nuclei of distinct sCJD subtypes, either valine homozygous or heterozygous at codon 129. These findings suggest that an "environmental exposure" might occur, supporting the hypothesis that external sources of contamination could contribute to sCJD in susceptible hosts. Furthermore, these novel data could shed the light on possible causes of sCJD through a "triple match" hypothesis that identify environmental exposure, host genotype, and direct exposure of specific anatomical regions as possible pathogenetic factors.

  18. Panencephalopathic Creutzfeldt-Jakob disease with distinct pattern of prion protein deposition in a patient with D178N mutation and homozygosity for valine at codon 129 of the prion protein Gene.

    PubMed

    Marcon, Gabriella; Indaco, Antonio; Di Fede, Giuseppe; Suardi, Silvia; Finato, Nicoletta; Moretti, Valentino; Micoli, Sandro; Fociani, Paolo; Zerbi, Pietro; Pincherle, Alessandro; Redaelli, Veronica; Tagliavini, Fabrizio; Giaccone, Giorgio

    2014-03-01

    Prion diseases include sporadic, acquired and genetic forms linked to mutations of the prion protein (PrP) gene (PRNP). In subjects carrying the D178N PRNP mutation, distinct phenotypes can be observed, depending on the methionine/valine codon 129 polymorphism. We present here a 53-year-old woman with D178N mutation in the PRNP gene and homozygosity for valine at codon 129. The disease started at age 47 with memory deficits, progressive cognitive impairment and ataxia. The clinical picture slowly worsened to a state of akinetic mutism in about 2 years and the disease course was 6 years. The neuropathologic examination demonstrated severe diffuse cerebral atrophy with neuronal loss, spongiosis and marked myelin loss and tissue rarefaction in the hemispheric white matter, configuring panencephalopathic Creutzfeldt-Jakob disease. PrP deposition was present in the cerebral cortex, basal ganglia and cerebellum with diffuse synaptic-type pattern of immunoreactivity and clusters of countless, small PrP deposits, particularly evident in the lower cortical layers, in the striatum and in the molecular layer of the cerebellum. Western blot analysis showed the presence of type 1 PrP(Sc) (Parchi classification). These findings underline the clear-cut distinction between the neuropathological features of Creutzfeldt-Jakob disease associated with D178N PRNP mutation and those of fatal familial insomnia.

  19. Genomic Characteristics of Genetic Creutzfeldt-Jakob Disease Patients with V180I Mutation and Associations with Other Neurodegenerative Disorders

    PubMed Central

    Lee, Sol Moe; Chung, Myungguen; Hyeon, Jae Wook; Jeong, Seok Won; Ju, Young Ran; Kim, Heebal; Lee, Jeongmin; Kim, SangYun; An, Seong Soo A.; Cho, Sung Beom; Lee, Yeong Seon; Kim, Su Yeon

    2016-01-01

    Inherited prion diseases (IPDs), including genetic Creutzfeldt-Jakob disease (gCJD), account for 10–15% of cases of prion diseases and are associated with several pathogenic mutations, including P102L, V180I, and E200K, in the prion protein gene (PRNP). The valine to isoleucine substitution at codon 180 (V180I) of PRNP is the most common pathogenic mutation causing gCJD in East Asian patients. In this study, we conducted follow-up analyses to identify candidate factors and their associations with disease onset. Whole-genome sequencing (WGS) data of five gCJD patients with V180I mutation and 145 healthy individuals were used to identify genomic differences. A total of 18,648,850 candidate variants were observed in only the patient group, 29 of them were validated as variants. Four of these validated variants were nonsense mutations, six were observed in genes directly or indirectly related to neurodegenerative disorders (NDs), such as LPA, LRRK2, and FGF20. More than half of validated variants were categorized in Gene Ontology (GO) terms of binding and/or catalytic activity. Moreover, we found differential genome variants in gCJD patients with V180I mutation, including one uniquely surviving 10 years after diagnosis of the disease. Elucidation of the relationships between gCJD and Alzheimer’s disease or Parkinson’s disease at the genomic level will facilitate further advances in our understanding of the specific mechanisms mediating the pathogenesis of NDs and gold standard therapies for NDs. PMID:27341347

  20. Prion Protein-Hemin Interaction Upregulates Hemoglobin Synthesis: Implications for Cerebral Hemorrhage and Sporadic Creutzfeldt-Jakob Disease.

    PubMed

    Tripathi, Ajai K; Singh, Neena

    2016-01-01

    Hemin is known to induce endocytosis of prion-protein (PrP(C)) from the neuronal plasma membrane, potentially limiting propagation of the disease causing PrP-scrapie (PrP(Sc)) isoform. Hemin is therefore an attractive disease-modifying option for sporadic Creutzfeldt-Jakob disease (sCJD), a human prion disorder with no effective treatment. The hemin-PrP(C) interaction is also of interest in cerebral-hemorrhage (CH), a condition where potentially toxic hemin molecules come in contact with neuronal PrP(C). Interestingly, PrP(C) is upregulated in penumbric neurons surrounding CH and is known to confer neuroprotection in a dose-dependent manner. The underlying mechanism, however, is not clear. Here, we report that hemin binds PrP(C) on diverse cell lines, resulting in its aggregation or degradation in a cell-type specific manner. Surprisingly, the hemin-PrP(C) interaction upregulates Hb synthesis in hematopoietic cells, a response reversed by deleting the hemin-binding octa-peptide repeat region of PrP(C). A similar response is noted in brain organotypic cultures where exposure to hemin induces significantly more α-globin in wild-type (PrP(+/+)) relative to PrP-knock-out (PrP(-/-)) samples. Furthermore, red blood cells and brain tissue from PrP(-/-) mice show significantly less α-globin relative to PrP(+/+) controls, indicating a positive effect of PrP(C) on Hb synthesis under physiological conditions as well. Surprisingly, levels of α-globin are significantly higher in sCJD brain tissue relative to controls, suggesting compensatory upregulation of Hb synthesis by surviving neurons or misregulation in diseased brains. These observations reveal a unique function of PrP(C) that is likely to impact the therapeutic management of CH and sCJD.

  1. Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings.

    PubMed

    Baiardi, Simone; Capellari, Sabina; Ladogana, Anna; Strumia, Silvia; Santangelo, Mario; Pocchiari, Maurizio; Parchi, Piero

    2016-01-01

    The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical disease, a high prevalence of periodic sharp-wave complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of "probable" CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2).

  2. Revisiting the Heidenhain Variant of Creutzfeldt-Jakob Disease: Evidence for Prion Type Variability Influencing Clinical Course and Laboratory Findings

    PubMed Central

    Baiardi, Simone; Capellari, Sabina; Ladogana, Anna; Strumia, Silvia; Santangelo, Mario; Pocchiari, Maurizio; Parchi, Piero

    2015-01-01

    The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical disease, a high prevalence of periodic sharp-wave complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of “probable” CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2). PMID:26682685

  3. Sporadic Creutzfeldt-Jakob disease diagnostic accuracy is improved by a new CSF ELISA 14-3-3γ assay.

    PubMed

    Leitão, M J; Baldeiras, I; Almeida, M R; Ribeiro, M H; Santos, A C; Ribeiro, M; Tomás, J; Rocha, S; Santana, I; Oliveira, C R

    2016-05-13

    Protein 14-3-3 is a reliable marker of rapid neuronal damage, specifically increased in cerebrospinal fluid (CSF) of sporadic Creutzfeldt-Jakob disease (sCJD) patients. Its detection is usually performed by Western Blot (WB), prone to methodological issues. Our aim was to evaluate the diagnostic performance of a recently developed quantitative enzyme-linked immunosorbent (ELISA) assay for 14-3-3γ, in comparison with WB and other neurodegeneration markers. CSF samples from 145 patients with suspicion of prion disease, later classified as definite sCJD (n=72) or Non-prion diseases (Non-CJD; n=73) comprised our population. 14-3-3 protein was determined by WB and ELISA. Total Tau (t-Tau) and phosphorylated Tau (p-Tau) were also evaluated. Apolipoprotein E gene (ApoE) and prionic protein gene (PRNP) genotyping was assessed. ELISA 14-3-3γ levels were significantly increased in sCJD compared to Non-CJD patients (p<0.001), showing very good accuracy (AUC=0.982; sensitivity=97%; specificity=94%), and matching WB results in 81% of all cases. It strongly correlated with t-Tau and p-Tau (p<0.0001), showing slightly higher specificity (14-3-3 WB - 63%; Tau - 90%; p-Tau/t-Tau ratio - 88%). From WB inconclusive results (n=44), ELISA 14-3-3γ correctly classified 41 patients. Additionally, logistic regression analysis selected ELISA 14-3-3γ as the best single predictive marker for sCJD (overall accuracy=93%). ApoE and PRNP genotypes did not influence ELISA 14-3-3γ levels. Despite specificity for 14-3-3γ isoform, ELISA results not only match WB evaluation but also help discrimination of inconclusive results. Our results therefore reinforce this assay as a single screening test, allowing higher sample throughput and unequivocal results.

  4. Validation of 14-3-3 Protein as a Marker in Sporadic Creutzfeldt-Jakob Disease Diagnostic.

    PubMed

    Schmitz, Matthias; Ebert, Elisabeth; Stoeck, Katharina; Karch, André; Collins, Steven; Calero, Miguel; Sklaviadis, Theodor; Laplanche, Jean-Louis; Golanska, Ewa; Baldeiras, Ines; Satoh, Katsuya; Sanchez-Valle, Raquel; Ladogana, Anna; Skinningsrud, Anders; Hammarin, Anna-Lena; Mitrova, Eva; Llorens, Franc; Kim, Yong Sun; Green, Alison; Zerr, Inga

    2016-05-01

    At present, the testing of 14-3-3 protein in cerebrospinal fluid (CSF) is a standard biomarker test in suspected sporadic Creutzfeldt-Jakob disease (sCJD) diagnosis. Increasing 14-3-3 test referrals in CJD reference laboratories in the last years have led to an urgent need to improve established 14-3-3 test methods. The main result of our study was the validation of a commercially available 14-3-3 ELISA next to the commonly used Western blot method as a high-throughput screening test. Hereby, 14-3-3 protein expression was quantitatively analyzed in CSF of 231 sCJD and 2035 control patients. We obtained excellent sensitivity/specificity values of 88 and 96% that are comparable to the established Western blot method. Since standard protocols and preanalytical sample handling have become more important in routine diagnostic, we investigated in a further step the reproducibility and stability of 14-3-3 as a biomarker for human prion diseases. Ring trial data from 2009 to 2013 revealed an increase of Fleiss' kappa from 0.51 to 0.68 indicating an improving reliability of 14-3-3 protein detection. The stability of 14-3-3 protein under short-term and long-term storage conditions at various temperatures and after repeated freezing/thawing cycles was confirmed. Contamination of CSF samples with blood appears likely to be an important factor at a concentration of more than 2500 erythrocytes/μL. Hemolysis of erythrocytes with significant release of 14-3-3 protein started after 2 days at room temperature. We first define clear standards for the sample handling, short- and long-term storage of CSF samples as well as the handling of blood- contaminated samples which may result in artificially elevated CSF levels of 14-3-3.

  5. Visualization of viral candidate cDNAs in infectious brain fractions from Creutzfeldt-Jakob disease by representational difference analysis.

    PubMed

    Dron, M; Manuelidis, L

    1996-08-01

    Creutzfeldt-Jakob Disease (CJD), a neurodegenerative and dementing disease of later life, is caused by a viruslike entity that is incompletely characterized. As in scrapie, all more purified infectious brain preparations contain nucleic acids. However, it has not been possible to visualize unique bands that may derive from a viral genome. We here used a subtractive strategy known as representational difference analysis (RDA) to uncover such sequences. To reduce the complexity of starting target nucleic acids, sucrose gradients were first used to select nuclease resistant particles with a defined 120S size. In CJD this single 120S gradient peak is highly enriched for infectivity, and contains reduced amounts of PrP (Proc. Natl. Acad. Sci. 92, 5124-8, 1995). Parallel 120S fractions from uninfected brain were made to generate subtractor sequences. 120S particles were lysed in GdnSCN, and ng amounts of released RNA were purified for random-primed cDNA synthesis. To capture representative fragments of 100-500 bp, cDNAs were cleaved with Mbo I for adaptor ligation and amplification. In the first experiment with moderate RDA selection, it was possible to visualize clones from CJD cDNA that did not hybridize to control cDNA. In the second experiment, more exhaustive subtractions yielded a discrete set of CJD derived gel bands. Competitive hybridization showed a subset of these bands were not present in either the control 120S cDNA or in the hamster genome. This represents the first demonstration of apparently CJD-specific nucleic acid bands in more purified infectious preparations. Although exhaustive cloning, sequencing and correlative titration studies need to be done, it is encouraging that most of the viral candidates selected thus far have no significant homology with any previously described sequence in the database.

  6. Nuclear DNA fragmentation in Creutzfeldt-Jakob disease: does a mere positive in situ nuclear end-labeling indicate apoptosis?

    PubMed

    Ferrer, I

    1999-01-01

    The method of in situ end-labeling of nuclear DNA fragmentation was used in the study of ten patients (two biopsies, eight autopsies) with sporadic Creutzfeldt-Jakob disease (CJD). All the patients had the typical morphological lesions including neuron loss, spongiform change and astrocytosis. Four of them also showed prion protein (PrP) deposits in the cerebral cortex, and two of them kuru-like plaques in the cerebellum. A few cells with DNA breaks were found in the two biopsy cases; one of them, suffering from a panencephalopathic form of the disease, showed positive nuclei not only in the cerebral cortex but also in the subcortical white matter. Variable numbers of positive nuclei were observed in the gray and white matter in the eight autopsy cases, in which, although the distribution of positive cells roughly correlated with the distribution of neuron loss, no clear relationship was found as regards the distribution and degree of cell labeling and the degree of neuron loss. Furthermore, large numbers of positive cells were concentrated in a particular area, whereas a few cells were seen in a neighboring equally affected area. Positive glial cells in the plexiform layer of the CA1 area of the hippocampus, and in the frontal white matter were frequently encountered. Staining of the cytoplasm in a minority of cells was interpreted as the result of nuclear DNA leakage. None of the stained cells had the typical morphology of apoptosis; most particularly, peripheral chromatin condensation and formation of apoptotic bodies were not seen in any case. PrP deposits did not result in an increase of nuclear DNA breaks either within the area or in adjacent regions. Although positive cells were also observed in autopsy cases of controls which were processed in the same way, positive labeling as a whole was higher in CJD than in age-matched controls. These results show that brain nuclear DNA is vulnerable in CJD, and suggest that increased DNA vulnerability has a role in

  7. Characterization of variant Creutzfeldt-Jakob disease prions in prion protein-humanized mice carrying distinct codon 129 genotypes.

    PubMed

    Takeuchi, Atsuko; Kobayashi, Atsushi; Ironside, James W; Mohri, Shirou; Kitamoto, Tetsuyuki

    2013-07-26

    To date, all clinical variant Creutzfeldt-Jakob disease (vCJD) patients are homozygous for methionine at polymorphic codon 129 (129M/M) of the prion protein (PrP) gene. However, the appearance of asymptomatic secondary vCJD infection in individuals with a PRNP codon 129 genotype other than M/M and transmission studies using animal models have raised the concern that all humans might be susceptible to vCJD prions, especially via secondary infection. To reevaluate this possibility and to analyze in detail the transmission properties of vCJD prions to transgenic animals carrying distinct codon 129 genotype, we performed intracerebral inoculation of vCJD prions to humanized knock-in mice carrying all possible codon 129 genotypes (129M/M, 129M/V, or 129V/V). All humanized knock-in mouse lines were susceptible to vCJD infection, although the attack rate gradually decreased from 129M/M to 129M/V and to 129V/V. The amount of PrP deposition including florid/amyloid plaques in the brain also gradually decreased from 129M/M to 129M/V and to 129V/V. The biochemical properties of protease-resistant abnormal PrP in the brain and transmissibility of these humanized mouse-passaged vCJD prions upon subpassage into knock-in mice expressing bovine PrP were not affected by the codon 129 genotype. These results indicate that individuals with the 129V/V genotype may be more susceptible to secondary vCJD infection than expected and may lack the neuropathological characteristics observed in vCJD patients with the 129M/M genotype. Besides the molecular typing of protease-resistant PrP in the brain, transmission studies using knock-in mice carrying bovine PrP may aid the differential diagnosis of secondary vCJD infection, especially in individuals with the 129V/V genotype.

  8. Late-in-life surgery associated with Creutzfeldt-Jakob disease: a methodological outline for evidence-based guidance

    PubMed Central

    2013-01-01

    Background There is increasing epidemiological evidence of etiological links between general surgery and sporadic Creutzfeldt-Jakob disease (sCJD) with long incubation periods. The purpose of this study was to identify specific surgical procedures potentially associated with sCJD to be targeted for preventive presurgical-intervention guidance. Results We propose a three-step clinical guidance outline where surgical procedures associated with sCJD clinical onset – potentially more contaminant - are taken into account. Data on hospital discharges and surgical procedures were obtained from Danish and Swedish national in-patient hospital registries for 167 sCJD cases, onset 1987–2003, and for 835 matched and 2,224 unmatched population controls. Surgery was allocated to different life-time periods as previously reported, and frequencies were compared using logistic regression analysis. In the year preceding clinical onset, persons with sCJD underwent a statistically significant higher number of minor surgical interventions (OR (95% CI): 17.50 (3.64-84.24)), transluminal endoscopies (OR: 2.73 (1.01–7.37)) and gastrointestinal operations (OR: 3.51 (1.21–10.19)) compared to matched controls. Surgical discharges clustered towards clinical onset. These differences increased during the clinical period, with statistically significant higher frequencies for both endoscopies and minor surgery (OR: 13.91 (5.87-32.95), and for main surgical procedures (OR: 2.10 (1.00-4.39)), particularly gastrointestinal surgery (OR: 6.00 (1.83-19.66)), and surgery contacting skeletal muscle. Comparisons with unmatched controls yielded similar results for neurosurgery in the clinical period (OR: 19.40 (2.22-168.34)). Conclusions These results suggest that some types of surgical procedures are associated with sCJD, after clinical onset or particularly just before onset. Selective planning of such surgery to minimize instrument/device contamination or quarantining might be feasible

  9. An experiential learning model applied to nurses working with patients with Creutzfeldt-Jakob disease.

    PubMed

    D'Amour, Rolande; Guimond, Pierrette

    2010-01-01

    Creutzfeldt-Jacob disease (C/D) is a rare neurological disease, transmissible, incurable and always fatal affecting humans, as well as animals. In the 1980s, the "mad cow disease" (MCD) epidemic in the United Kingdom popularized prion diseases worldwide. However, this contributed to the proliferation of disinformation, causing confusion between C/D and MCD in the public, as well as in some health care providers. The purpose of this article is to describe the process utilized to develop, implement, and evaluate a workshop on CJD for nurses and other health care providers. Kolb's experiential teaching/learning model was used as a framework for this workshop. A workbook was developed to complement the participants' learning. Fifteen health care providers from the Alzheimer Society of Canada's Dementia Network agreed to participate in this educational project. The results indicated that the participants had limited knowledge about C/D. They felt ill prepared and uncomfortable in providing quality care to this patient population. The workshop generated new insights and knowledge about the disease and the needs of the patients and their families. Participants exchanged ideas for tailored interventions. An experiential teaching/learning model is a highly effective approach to increase knowledge and skills, as well as fostering reflective practice.

  10. Creutzfeldt-Jakob-Like Syndrome due to Hypercalcemic Encephalopathy.

    PubMed

    Rösche, Johannes; Sieveking, Catharina; Kampf, Christina; Benecke, Reiner

    2015-10-01

    Hypercalcemia can cause a subacute syndrome of progressive dementia and marked changes in the electroencephalogram (EEG). We report a case of iatrogenic hypercalcemia with a close correlation between the clinical course and the EEG changes. A 73-year-old woman presented with a subacute syndrome of progressive dementia and bursts of 1.5 to 2 Hz intermittent rhythmic delta activity superimposed on a low-voltage background activity in the EEG. Clinical and EEG abnormalities rapidly resolved after normalization of serum calcium levels. As part of the diagnostic workup of a subacute progressive dementia, a serum calcium level and an EEG should be obtained to detect a Creutzfeldt-Jakob like syndrome in hypercalcemia. Unlike in Creutzfeldt-Jakob disease, and Creutzfeldt-Jakob-like syndrome induced by lithium intoxication, there are rarely myoclonic jerks and periodic discharges in hypercalcemic encephalopathy.

  11. Alien hand and leg as the presenting feature of probable sporadic Creutzfeldt-Jakob disease: A rare presentation of a rare disease

    PubMed Central

    Kumawat, Banshi Lal; Sharma, Chandra Mohan; Nath, Kunal; Acharya, Mihir; Khandelwal, Dinesh; Jain, Deepak

    2015-01-01

    Sporadic Creutzfeldt-Jakob disease (sCJD) can have varied clinical presentation depending upon the genotype at codon 129. The common presenting clinical features of sCJD are rapid onset cognitive impairment, ataxia, psychosis and visual signs (field defects, distortion, cortical blindness). Alien limb sign was first described in patients with corpus callosal tumors and later with other neurodegenerative conditions like corticobasal degeneration. Alien hand complaints as the presenting feature of sCJD has been described in literature, but simultaneous alien hand and leg has been rarely described as presenting feature of sCJD. We describe here a case of a 55-year-old man who presented with progressive left alien hand and leg as the sole clinical manifestation of probable sCJD. PMID:25745324

  12. Possible underascertainment of variant Creutzfeldt-Jakob disease: a systematic study

    PubMed Central

    Hillier, C; Salmon, R; Neal, J; Hilton, D

    2002-01-01

    Objectives: To predict the size of the vCJD epidemic it is important to know whether the description of cases of vCJD in 1996 represent the first cases of a new disease entity or whether detection was due to increased surveillance of CJD in humans. Detection of earlier cases would suggest a shorter incubation period and might lead to predictions of epidemic size being revised. Methods: All certified deaths (excluding external injury and poisoning) in residents of Wales aged 15–45, between 1985 and 1995, were reviewed to detect vCJD deaths that might have been overlooked. 12 091 deaths were reviewed. "Non-specific fatal disorders compatible with vCJD" were defined. Deaths recorded to diseases other than those defined were rejected from further analysis (8769). Remaining cases (3322) were subdivided. Group A comprised deaths recorded to suicide, transport accidents, and those that could not be ascertained (ICD9 rubrics E950–959, E800–848, and 7999), a total of 2698 cases. Group B comprised deaths due to neurological disease, psychiatric disease, or substance abuse (624). Results: For group A, remaining brain material was identified (n=218, 8.1%) and examined by routine histology and immunocytochemistry for prion protein. No cases of vCJD were detected. For group B, review of remaining clinical information was undertaken. Of 624 cases, information was available on 447 (72%). Brain tissue was examined by routine histology and immunocytochemistry in 47 (7.5%) cases. Sufficient clinical and pathological information was available to exclude all these as potential cases of vCJD. Conclusion: Variant CJD is a new disease entity and not simply the result of better case ascertainment. PMID:11861685

  13. Unusual resistance to ionizing radiation of the viruses of kuru, Creutzfeldt-Jakob disease, and scrapie.

    PubMed

    Gibbs, C J; Gajdusek, D C; Latarjet, R

    1978-12-01

    The titers of several preparations of kuru. Creutzfeldt-Jacob disease, and scrapie viruses were reduced by only 1/10th or less by high doses of gamma radiation of 50 kGy and by only 1/10th-1/1000th or less for 200 kGy. This unusual radiation resistance of the two human viruses further links them with the scrapie virus and suggests that the genetic information of all three viruses is considerably smaller than that of any other known viruses of mammals.

  14. Unusual resistance to ionizing radiation of the viruses of kuru, Creutzfeldt-Jakob disease, and scrapie.

    PubMed Central

    Gibbs, C J; Gajdusek, D C; Latarjet, R

    1978-01-01

    The titers of several preparations of kuru. Creutzfeldt-Jacob disease, and scrapie viruses were reduced by only 1/10th or less by high doses of gamma radiation of 50 kGy and by only 1/10th-1/1000th or less for 200 kGy. This unusual radiation resistance of the two human viruses further links them with the scrapie virus and suggests that the genetic information of all three viruses is considerably smaller than that of any other known viruses of mammals. PMID:104301

  15. Imaging astrocytosis with PET in Creutzfeldt-Jakob disease: case report with histopathological findings

    PubMed Central

    Engler, Henry; Nennesmo, Inger; Kumlien, Eva; Gambini, Juan Pablo; Lundberg, PO; Savitcheva, Irina; Långström, Bengt

    2012-01-01

    In a previous study, patients with suspect Creutzfeldt-Jakob’s disease (CJD) have been examined with Positron Emission Tomography (PET) combining N-[11C-methyl]-L-deuterodeprenyl (DED) and [18F] 2- fluorodeoxyglucose (FDG) in an attempt to detect astrocytosis and neuronal dysfunction, two of the hallmarks in CJD. Increased DED uptake with pronounced hypometabolism matching the areas with high DED retention was found in the fronto-parieto-occipital areas and cerebellum of patients with confirmed CJD. However, the temporal lobes did not present such a pattern. In 6 of the 15 examined patients the autopsy was performed, but a strict comparison between the PET results and the histopathology could not be done. Recently, one patient with suspect CJD was examined with PET using DED and FDG. The results of the examinations in this patient showed a pattern similar to that found in the brain of the CJD patients from the first study. The patient died shortly after the examination and an autopsy could be performed. The autopsy showed neuronal death, astrocytosis and spongiform changes in the brain. The diagnosis of definite sporadic CJD was established by the Western blot analysis, confirming the presence of the prion resistant protein (PrPres). The PET data demonstrated high DED uptake and extreme low glucose uptake in the left brain hemisphere whereas the right side was less affected. The autopsy was performed allowing the comparison between high DED uptake and the histopathological findings of reactive astrocytosis revealed by immunostaining with antibodies against glial fibrillary acid protein (GFAP). The results confirmed the presence of a pattern with high ratio DED/FDG, similar to that found in the previous study and revealing for the first time, a good correlation between high DED uptake and high density of reactive astrocytes as demonstrated by immunostaining. PMID:22567182

  16. Proteomic analysis of host brain components that bind to infectious particles in Creutzfeldt-Jakob disease

    PubMed Central

    Kipkorir, Terry; Colangelo, Christopher M.; Manuelidis, Laura

    2015-01-01

    Transmissible encephalopathies (TSEs), such as CJD and scrapie, are caused by infectious agents that provoke strain-specific patterns of disease. Misfolded host prion protein (PrP-res amyloid) is believed to be the causal infectious agent. However, particles that are stripped of PrP retain both high infectivity and viral proteins not detectable in uninfected mouse controls. We here detail host proteins bound with FU-CJD infectious brain particles by proteomic analysis. More than 98 proteins were differentially regulated, and 56 FU-CJD exclusive proteins were revealed after PrP, GFAP, C1q, ApoE and other late pathologic response proteins were removed. Stripped FU-CJD particles revealed HSC70 (144× the uninfected control), cyclophilin B, an FU-CJD exclusive protein required by many viruses, and early endosome-membrane pathways known to facilitate viral processing, replication, and spread. Synaptosomal elements including synapsin-2 (at 33×) and AP180 (a major FU-CJD exclusive protein) paralleled the known ultrastructural location of 25nm virus-like TSE particles and infectivity in synapses. Proteins without apparent viral or neurodegenerative links (copine-3), and others involved in viral-induced protein misfolding and aggregation, were also identified. Human sCJD brain particles contained 146 exclusive proteins, and heat shock, synaptic and viral pathways were again prominent, in addition to Alzheimer (AD), Parkinson, and Huntington aggregation proteins. Host proteins that bind TSE infectious particles can prevent host immune recognition and contribute to prolonged cross-species transmissions (the species barrier). Our infectious particle strategy, which reduces background sequences by >99%, emphasizes host targets for new therapeutic initiatives. Such therapies can simultaneously subvert common pathways of neurodegeneration. PMID:25930988

  17. Creutzfeldt-Jakob Disease with a prion protein gene codon 180 mutation presenting asymmetric cortical high-intensity on magnetic resonance imaging.

    PubMed

    Amano, Yuko; Kimura, Noriyuki; Hanaoka, Takuya; Aso, Yasuhiro; Hirano, Teruyuki; Murai, Hiroyuki; Satoh, Katsuya; Matsubara, Etsuro

    2015-01-01

    Here we report a genetically confirmed case of Creutzfeldt-Jakob disease with a prion protein gene codon 180 mutation presenting atypical magnetic resonance imaging findings. The present case exhibited an acute onset and lateralized neurologic signs, and progressive cognitive impairment. No myoclonus or periodic synchronous discharges on electroencephalography were observed. Diffusion-weighted images revealed areas of high signal intensity in the right frontal and temporal cortices at onset that extended to the whole cortex and basal ganglia of the right cerebral hemisphere at 3 months. Although the cerebrospinal fluid (CSF) was initially negative for neuron specific enolase, tau protein, 14-3-3 protein, and abnormal prion protein, the CSF was positive for these brain-derived proteins at 3 months after onset.

  18. Sporadic MM2-thalamic + cortical Creutzfeldt-Jakob disease: Utility of diffusion tensor imaging in the detection of cortical involvement in vivo.

    PubMed

    Grau-Rivera, Oriol; Sánchez-Valle, Raquel; Bargalló, Nuria; Lladó, Albert; Gaig, Carles; Nos, Carlos; Ferrer, Isidre; Graus, Francesc; Gelpi, Ellen

    2016-04-01

    In sporadic Creutzfeldt-Jakob disease (sCJD), high signal intensity in fluid attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) sequences in striatum and/or cortical regions of the brain are present in about 83% of cases, reflecting tissue damage, such as spongiform change and abnormal prion protein deposits. Novel diffusion sequences of MRI might improve the detection of CJD characteristic changes in the subset of patients in whom these alterations are absent or less evident. We report a neuropathologically confirmed case of the rare MM2 T + C subtype of sCJD, with mixed clinical and neuropathological features of MM2 thalamic and MM2 cortical subtypes, in whom the use of diffusion tensor imaging helped to identify cortical hyperintensities that could be easily overlooked with conventional DWI.

  19. Creutzfeldt-Jakob Disease

    MedlinePlus

    ... damage leads to rapid decline in thinking and reasoning as well as involuntary muscle movements, confusion, difficulty ... been tested but have not shown any benefit. Clinical studies of potential CJD treatments are complicated by ...

  20. Creutzfeldt-Jakob Disease

    MedlinePlus

    ... that help in the diagnosis of CJD include electroencephalography (which measures brain waves), detection of certain proteins ... that help in the diagnosis of CJD include electroencephalography (which measures brain waves), detection of certain proteins ...

  1. Relation between clinical findings and progression of cerebral cortical pathology in MM1-type sporadic Creutzfeldt-Jakob disease: proposed staging of cerebral cortical pathology.

    PubMed

    Iwasaki, Yasushi; Tatsumi, Shinsui; Mimuro, Maya; Kitamoto, Tetsuyuki; Hashizume, Yoshio; Yoshida, Mari

    2014-06-15

    In our pathologic observation of the cerebral cortex including the neocortex, hippocampus, and limbic cortex in 43 Japanese patients with MM1-type sporadic Creutzfeldt-Jakob disease, the earliest pathologic finding was spongiform change and next was gliosis. Subsequently, neuropil rarefaction appeared, followed by neuron loss. On the basis of these observations, we propose the following cortical pathologic staging: Stage I, spongiform change; Stage II, hypertrophic astrocytosis; Stage III, neuropil rarefaction; Stage IV, neuron loss; Stage V, status spongiosus; and Stage VI, large cavity formation. We also suggest a more simple staging classification: Stages I and II, mild; Stages III and IV, moderate; and Stages V and VI, severe involvement. Based on statistical analysis of the cases, strong correlation coefficients were obtained between the neocortical and limbic pathologic stage and both total disease duration and brain weight. We estimated that the first observation times of cortical hyperintensity on diffusion-weighted images of magnetic resonance imaging, myoclonus, and periodic sharp wave complexes on the electroencephalogram approximately correspond to the early phase of Stage II of the neocortex. The time to reach the akinetic mutism state approximately corresponds to the middle phase of Stage II of the neocortex. Therefore, we think that approximate clinical manifestations at death, total disease duration, and brain weight can be estimated according to the pathologic stage of the neocortex or limbic cortex. Panencephalopathic-type pathology appeared approximately 12 months after disease onset, and this time approximately corresponds to the middle phase of Stage III of the neocortex.

  2. UK Iatrogenic Creutzfeldt-Jakob disease: investigating human prion transmission across genotypic barriers using human tissue-based and molecular approaches.

    PubMed

    Ritchie, Diane L; Barria, Marcelo A; Peden, Alexander H; Yull, Helen M; Kirkpatrick, James; Adlard, Peter; Ironside, James W; Head, Mark W

    2017-04-01

    Creutzfeldt-Jakob disease (CJD) is the prototypic human prion disease that occurs most commonly in sporadic and genetic forms, but it is also transmissible and can be acquired through medical procedures, resulting in iatrogenic CJD (iCJD). The largest numbers of iCJD cases that have occurred worldwide have resulted from contaminated cadaveric pituitary-derived human growth hormone (hGH) and its use to treat primary and secondary growth hormone deficiency. We report a comprehensive, tissue-based and molecular genetic analysis of the largest series of UK hGH-iCJD cases reported to date, including in vitro kinetic molecular modelling of genotypic factors influencing prion transmission. The results show the interplay of prion strain and host genotype in governing the molecular, pathological and temporal characteristics of the UK hGH-iCJD epidemic and provide insights into the adaptive mechanisms involved when prions cross genotypic barriers. We conclude that all of the available evidence is consistent with the hypothesis that the UK hGH-iCJD epidemic resulted from transmission of the V2 human prion strain, which is associated with the second most common form of sporadic CJD.

  3. Deep Learning Representation from Electroencephalography of Early-Stage Creutzfeldt-Jakob Disease and Features for Differentiation from Rapidly Progressive Dementia.

    PubMed

    Morabito, Francesco Carlo; Campolo, Maurizio; Mammone, Nadia; Versaci, Mario; Franceschetti, Silvana; Tagliavini, Fabrizio; Sofia, Vito; Fatuzzo, Daniela; Gambardella, Antonio; Labate, Angelo; Mumoli, Laura; Tripodi, Giovanbattista Gaspare; Gasparini, Sara; Cianci, Vittoria; Sueri, Chiara; Ferlazzo, Edoardo; Aguglia, Umberto

    2017-03-01

    A novel technique of quantitative EEG for differentiating patients with early-stage Creutzfeldt-Jakob disease (CJD) from other forms of rapidly progressive dementia (RPD) is proposed. The discrimination is based on the extraction of suitable features from the time-frequency representation of the EEG signals through continuous wavelet transform (CWT). An average measure of complexity of the EEG signal obtained by permutation entropy (PE) is also included. The dimensionality of the feature space is reduced through a multilayer processing system based on the recently emerged deep learning (DL) concept. The DL processor includes a stacked auto-encoder, trained by unsupervised learning techniques, and a classifier whose parameters are determined in a supervised way by associating the known category labels to the reduced vector of high-level features generated by the previous processing blocks. The supervised learning step is carried out by using either support vector machines (SVM) or multilayer neural networks (MLP-NN). A subset of EEG from patients suffering from Alzheimer's Disease (AD) and healthy controls (HC) is considered for differentiating CJD patients. When fine-tuning the parameters of the global processing system by a supervised learning procedure, the proposed system is able to achieve an average accuracy of 89%, an average sensitivity of 92%, and an average specificity of 89% in differentiating CJD from RPD. Similar results are obtained for CJD versus AD and CJD versus HC.

  4. 14-3-3 Protein isoforms and atypical patterns of the 14-3-3 assay in the diagnosis of Creutzfeldt-Jakob disease.

    PubMed

    Sánchez-Valle, Raquel; Saiz, Albert; Graus, Francesc

    2002-03-01

    A positive 14-3-3 assay is a criterion for probable Creutzfeldt-Jakob disease (CJD). Cerebrospinal fluid (CSF) 14-3-3 is usually detected by immunoblot using an antibody that recognizes all of the 14-3-3 isoforms. In a few cases, the antibody recognizes an inferior band and this pattern is associated with false positive results. We analyzed 43 CSF (26 CJD, 17 controls) samples using antibodies against specific isoforms (beta, epsilon, gamma, tau, xi) and compared the results with those obtained with the standard antibody. The anti-gamma and anti-beta antibody achieved similar results but the presence of atypical patterns made the standard antibody more accurate for the CJD diagnosis. To study the nature of the inferior band, CSF samples were probed with antibodies against light chain immunoglobulins, and immunoblots of human IgG with the standard antibody. The experiments suggested a cross-reaction of the anti-14-3-3 antibody with light chain immunoglobulins.

  5. CSF Concentrations of cAMP and cGMP Are Lower in Patients with Creutzfeldt-Jakob Disease but Not Parkinson's Disease and Amyotrophic Lateral Sclerosis

    PubMed Central

    Oeckl, Patrick; Steinacker, Petra; Lehnert, Stefan; Jesse, Sarah; Kretzschmar, Hans A.; Ludolph, Albert C.; Otto, Markus; Ferger, Boris

    2012-01-01

    Background The cyclic nucleotides cyclic adenosine-3′,5′-monophosphate (cAMP) and cyclic guanosine-3′,5′-monophosphate (cGMP) are important second messengers and are potential biomarkers for Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Creutzfeldt-Jakob disease (CJD). Methodology/Principal Findings Here, we investigated by liquid chromatography/tandem mass spectrometry (LC-MS/MS) the cerebrospinal fluid (CSF) concentrations of cAMP and cGMP of 82 patients and evaluated their diagnostic potency as biomarkers. For comparison with a well-accepted biomarker, we measured tau concentrations in CSF of CJD and control patients. CJD patients (n = 15) had lower cAMP (−70%) and cGMP (−55%) concentrations in CSF compared with controls (n = 11). There was no difference in PD, PD dementia (PDD) and ALS cases. Receiver operating characteristic (ROC) curve analyses confirmed cAMP and cGMP as valuable diagnostic markers for CJD indicated by the area under the curve (AUC) of 0.86 (cAMP) and 0.85 (cGMP). We calculated a sensitivity of 100% and specificity of 64% for cAMP and a sensitivity of 67% and specificity of 100% for cGMP. The combination of both nucleotides increased the sensitivity to 80% and specificity to 91% for the term cAMPxcGMP (AUC 0.92) and to 93% and 100% for the ratio tau/cAMP (AUC 0.99). Conclusions/Significance We conclude that the CSF determination of cAMP and cGMP may easily be included in the diagnosis of CJD and could be helpful in monitoring disease progression as well as in therapy control. PMID:22396786

  6. PrP mRNA and protein expression in brain and PrP(c) in CSF in Creutzfeldt-Jakob disease MM1 and VV2.

    PubMed

    Llorens, Franc; Ansoleaga, Belén; Garcia-Esparcia, Paula; Zafar, Saima; Grau-Rivera, Oriol; López-González, Irene; Blanco, Rosi; Carmona, Margarita; Yagüe, Jordi; Nos, Carlos; Del Río, José Antonio; Gelpí, Ellen; Zerr, Inga; Ferrer, Isidre

    2013-01-01

    Creutzfeldt-Jakob disease (CJD) is a heterogenic neurodegenerative disorder associated with abnormal post-translational processing of cellular prion protein (PrP(c)). CJD displays distinctive clinical and pathological features which correlate with the genotype at the codon 129 (methionine or valine: M or V respectively) in the prion protein gene and with size of the protease-resistant core of the abnormal prion protein PrP(sc) (type 1: 20/21 kDa and type 2: 19 kDa). MM1 and VV2 are the most common sporadic CJD (sCJD) subtypes. PrP mRNA expression levels in the frontal cortex and cerebellum are reduced in sCJD in a form subtype-dependent. Total PrP protein levels and PrP(sc) levels in the frontal cortex and cerebellum accumulate differentially in sCJD MM1 and sCJD VV2 with no relation between PrP(sc) deposition and spongiform degeneration and neuron loss, but with microgliosis, and IL6 and TNF-α response. In the CSF, reduced PrP(c), the only form present in this compartment, occurs in sCJD MM1 and VV2. PrP mRNA expression is also reduced in the frontal cortex in advanced stages of Alzheimer disease, Lewy body disease, progressive supranuclear palsy, and frontotemporal lobe degeneration, but PrP(c) levels in brain varies from one disease to another. Reduced PrP(c) levels in CSF correlate with PrP mRNA expression in brain, which in turn reflects severity of degeneration in sCJD.

  7. PrP mRNA and protein expression in brain and PrPc in CSF in Creutzfeldt-Jakob disease MM1 and VV2

    PubMed Central

    Llorens, Franc; Ansoleaga, Belén; Garcia-Esparcia, Paula; Zafar, Saima; Grau-Rivera, Oriol; López-González, Irene; Blanco, Rosi; Carmona, Margarita; Yagüe, Jordi; Nos, Carlos; del Río, José Antonio; Gelpí, Ellen; Zerr, Inga; Ferrer, Isidre

    2013-01-01

    Creutzfeldt-Jakob disease (CJD) is a heterogenic neurodegenerative disorder associated with abnormal post-translational processing of cellular prion protein (PrPc). CJD displays distinctive clinical and pathological features which correlate with the genotype at the codon 129 (methionine or valine: M or V respectively) in the prion protein gene and with size of the protease-resistant core of the abnormal prion protein PrPsc (type 1: 20/21 kDa and type 2: 19 kDa). MM1 and VV2 are the most common sporadic CJD (sCJD) subtypes. PrP mRNA expression levels in the frontal cortex and cerebellum are reduced in sCJD in a form subtype-dependent. Total PrP protein levels and PrPsc levels in the frontal cortex and cerebellum accumulate differentially in sCJD MM1 and sCJD VV2 with no relation between PrPsc deposition and spongiform degeneration and neuron loss, but with microgliosis, and IL6 and TNF-α response. In the CSF, reduced PrPc, the only form present in this compartment, occurs in sCJD MM1 and VV2. PrP mRNA expression is also reduced in the frontal cortex in advanced stages of Alzheimer disease, Lewy body disease, progressive supranuclear palsy, and frontotemporal lobe degeneration, but PrPc levels in brain varies from one disease to another. Reduced PrPc levels in CSF correlate with PrP mRNA expression in brain, which in turn reflects severity of degeneration in sCJD. PMID:24047819

  8. Is brain copper deficiency in Alzheimer's, Lewy body, and Creutzfeldt Jakob diseases the common key for a free radical mechanism and oxidative stress-induced damage?

    PubMed

    Deloncle, Roger; Guillard, Olivier

    2015-01-01

    In Alzheimer's (AD), Lewy body (LBD), and Creutzfeldt Jakob (CJD) diseases, similar pathological hallmarks have been described, one of which is brain deposition of abnormal protease-resistant proteins. For these pathologies, copper bound to proteins is able to protect against free radicals by reduction from cupric Cu++ to cupreous Cu+. We have previously demonstrated in bovine brain homogenate that free radicals produce proteinase K-resistant prion after manganese is substituted for copper. Since low brain copper levels have been described in transmissible spongiform encephalopathies, in substantia nigra in Parkinson's disease, and in various brain regions in AD, LBD, and CJD, a mechanism has been proposed that may underlie the neurodegenerative processes that occur when copper protection against free radicals is impaired. In peptide sequences, the alpha acid proton near the peptide bond is highly mobile and can be pulled out by free radicals. It will produce a trivalent α-carbon radical and induce a free radical chain process that will generate a D-amino acid configuration in the peptide sequence. Since only L-amino acids are physiologically present in mammalian (human) proteins, it may be supposed that only physiological L-peptides can be recycled by physiological enzymes such as proteases. If a D-amino acid is found in the peptide sequence subsequent to deficient copper protection against free radicals, it will not be recognized and might alter the proteasome L-amino acid recycling from brain peptides. In the brain, there will result an accumulation of abnormal protease-resistant proteins such as those observed in AD, LBD, and CJD.

  9. Alternative application of Tau protein in Creutzfeldt-Jakob disease diagnosis: Improvement for weakly positive 14-3-3 protein in the laboratory

    PubMed Central

    Hyeon, Jae Wook; Kim, Su Yeon; Lee, Jeongmin; Park, Jun Sun; Hwang, Kyu Jam; Lee, Sol Moe; An, SeongSoo A.; Lee, Myung Koo; Ju, Young Ran

    2015-01-01

    The 14-3-3 protein has been used as a biomarker for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). However, weakly positive 14-3-3 leads to false positive results and an incorrect diagnosis. We attempted to use quantitative data for tau protein to provide an accurate diagnosis based on weak 14-3-3 protein. Sixty-two patients with sCJD, including pathologically confirmed, clinically definite, and probable cases, and 89 non-CJD patients were investigated based on a Korean population. Among them, 20 sCJD and 14 non-CJD showed weakly positive 14-3-3. The total tau (t-tau) and phosphorylated tau (p-tau) protein levels were measured by ELISA, and the p-tau to t-tau ratio (p/t ratio) was calculated. The combined use of the 14-3-3 protein assay, t-tau levels, and p/t ratio improved the specificity of diagnosis compared with the use of the 14-3-3 protein assay alone (47% for 14-3-3 alone; 85.94% for 14-3-3 combined with t-tau; 90.62% for 14-3-3 combined with the p/t ratio). In addition, 18 of 20 sCJD and 12 of 14 non-CJD who were weakly positive for 14-3-3 were positive for the p/t ratio and negative for the p/t ratio, respectively. When used in combination with the 14-3-3 protein, the tau protein is useful as a biomarker for the precise diagnosis of sCJD. PMID:26507666

  10. Alternative application of Tau protein in Creutzfeldt-Jakob disease diagnosis: Improvement for weakly positive 14-3-3 protein in the laboratory.

    PubMed

    Hyeon, Jae Wook; Kim, Su Yeon; Lee, Jeongmin; Park, Jun Sun; Hwang, Kyu Jam; Lee, Sol Moe; An, SeongSoo A; Lee, Myung Koo; Ju, Young Ran

    2015-10-28

    The 14-3-3 protein has been used as a biomarker for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). However, weakly positive 14-3-3 leads to false positive results and an incorrect diagnosis. We attempted to use quantitative data for tau protein to provide an accurate diagnosis based on weak 14-3-3 protein. Sixty-two patients with sCJD, including pathologically confirmed, clinically definite, and probable cases, and 89 non-CJD patients were investigated based on a Korean population. Among them, 20 sCJD and 14 non-CJD showed weakly positive 14-3-3. The total tau (t-tau) and phosphorylated tau (p-tau) protein levels were measured by ELISA, and the p-tau to t-tau ratio (p/t ratio) was calculated. The combined use of the 14-3-3 protein assay, t-tau levels, and p/t ratio improved the specificity of diagnosis compared with the use of the 14-3-3 protein assay alone (47% for 14-3-3 alone; 85.94% for 14-3-3 combined with t-tau; 90.62% for 14-3-3 combined with the p/t ratio). In addition, 18 of 20 sCJD and 12 of 14 non-CJD who were weakly positive for 14-3-3 were positive for the p/t ratio and negative for the p/t ratio, respectively. When used in combination with the 14-3-3 protein, the tau protein is useful as a biomarker for the precise diagnosis of sCJD.

  11. Multicentre multiobserver study of diffusion-weighted and fluid-attenuated inversion recovery MRI for the diagnosis of sporadic Creutzfeldt-Jakob disease: a reliability and agreement study.

    PubMed

    Fujita, Koji; Harada, Masafumi; Sasaki, Makoto; Yuasa, Tatsuhiko; Sakai, Kenji; Hamaguchi, Tsuyoshi; Sanjo, Nobuo; Shiga, Yusei; Satoh, Katsuya; Atarashi, Ryuichiro; Shirabe, Susumu; Nagata, Ken; Maeda, Tetsuya; Murayama, Shigeo; Izumi, Yuishin; Kaji, Ryuji; Yamada, Masahito; Mizusawa, Hidehiro

    2012-01-01

    Objectives To assess the utility of the display standardisation of diffusion-weighted MRI (DWI) and to compare the effectiveness of DWI and fluid-attenuated inversion recovery (FLAIR) MRI for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). Design A reliability and agreement study. Setting Thirteen MRI observers comprising eight neurologists and five radiologists at two universities in Japan. Participants Data of 1.5-Tesla DWI and FLAIR were obtained from 29 patients with sCJD and 13 controls. Outcome measures Standardisation of DWI display was performed utilising b0 imaging. The observers participated in standardised DWI, variable DWI (the display adjustment was observer dependent) and FLAIR sessions. The observers independently assessed each MRI for CJD-related lesions, that is, hyperintensity in the cerebral cortex or striatum, using a continuous rating scale. Performance was evaluated by the area under the receiver operating characteristics curve (AUC). Results The mean AUC values were 0.84 (95% CI 0.81 to 0.87) for standardised DWI, 0.85 (95% CI 0.82 to 0.88) for variable DWI and 0.68 (95% CI 0.63 to 0.72) for FLAIR, demonstrating the superiority of DWI (p<0.05). There was a trend for higher intraclass correlations of standardised DWI (0.74, 95% CI 0.66 to 0.83) and variable DWI (0.72, 95% CI 0.62 to 0.81) than that of FLAIR (0.63, 95% CI 0.53 to 0.74), although the differences were not statistically significant. Conclusions Standardised DWI is as reliable as variable DWI, and the two DWI displays are superior to FLAIR for the diagnosis of sCJD. The authors propose that hyperintensity in the cerebral cortex or striatum on 1.5-Tesla DWI but not FLAIR can be a reliable diagnostic marker for sCJD.

  12. Rapid and Highly Sensitive Detection of Variant Creutzfeldt - Jakob Disease Abnormal Prion Protein on Steel Surfaces by Protein Misfolding Cyclic Amplification: Application to Prion Decontamination Studies

    PubMed Central

    Belondrade, Maxime; Nicot, Simon; Béringue, Vincent; Coste, Joliette; Lehmann, Sylvain; Bougard, Daisy

    2016-01-01

    The prevalence of variant Creutzfeldt-Jakob disease (vCJD) in the population remains uncertain, although it has been estimated that 1 in 2000 people in the United Kingdom are positive for abnormal prion protein (PrPTSE) by a recent survey of archived appendix tissues. The prominent lymphotropism of vCJD prions raises the possibility that some surgical procedures may be at risk of iatrogenic vCJD transmission in healthcare facilities. It is therefore vital that decontamination procedures applied to medical devices before their reprocessing are thoroughly validated. A current limitation is the lack of a rapid model permissive to human prions. Here, we developed a prion detection assay based on protein misfolding cyclic amplification (PMCA) technology combined with stainless-steel wire surfaces as carriers of prions (Surf-PMCA). This assay allowed the specific detection of minute quantities (10−8 brain dilution) of either human vCJD or ovine scrapie PrPTSE adsorbed onto a single steel wire, within a two week timeframe. Using Surf-PMCA we evaluated the performance of several reference and commercially available prion-specific decontamination procedures. Surprisingly, we found the efficiency of several marketed reagents to remove human vCJD PrPTSE was lower than expected. Overall, our results demonstrate that Surf-PMCA can be used as a rapid and ultrasensitive assay for the detection of human vCJD PrPTSE adsorbed onto a metallic surface, therefore facilitating the development and validation of decontamination procedures against human prions. PMID:26800081

  13. The reporting of theoretical health risks by the media: Canadian newspaper reporting of potential blood transmission of Creutzfeldt-Jakob disease

    PubMed Central

    Wilson, Kumanan; Code, Catherine; Dornan, Christopher; Ahmad, Nadya; Hébert, Paul; Graham, Ian

    2004-01-01

    Background The media play an important role at the interface of science and policy by communicating scientific information to the public and policy makers. In issues of theoretical risk, in which there is scientific uncertainty, the media's role as disseminators of information is particularly important due to the potential to influence public perception of the severity of the risk. In this article we describe how the Canadian print media reported the theoretical risk of blood transmission of Creutzfeldt-Jakob disease (CJD). Methods We searched 3 newspaper databases for articles published by 6 major Canadian daily newspapers between January 1990 and December 1999. We identified all articles relating to blood transmission of CJD. In duplicate we extracted information from the articles and entered the information into a qualitative software program. We compared the observations obtained from this content analysis with information obtained from a previous policy analysis examining the Canadian blood system's decision-making concerning the potential transfusion transmission of CJD. Results Our search identified 245 relevant articles. We observed that newspapers in one instance accelerated a policy decision, which had important resource and health implication, by communicating information on risk to the public. We also observed that newspapers primarily relied upon expert opinion (47 articles) as opposed to published medical evidence (28 articles) when communicating risk information. Journalists we interviewed described the challenges of balancing their responsibility to raise awareness of potential health threats with not unnecessarily arousing fear amongst the public. Conclusions Based on our findings we recommend that journalists report information from both expert opinion sources and from published studies when communicating information on risk. We also recommend researchers work more closely with journalists to assist them in identifying and appraising relevant

  14. An autopsy-verified case of FTLD-TDP type A with upper motor neuron-predominant motor neuron disease mimicking MM2-thalamic-type sporadic Creutzfeldt-Jakob disease.

    PubMed

    Hayashi, Yuichi; Iwasaki, Yasushi; Takekoshi, Akira; Yoshikura, Nobuaki; Asano, Takahiko; Mimuro, Maya; Kimura, Akio; Satoh, Katsuya; Kitamoto, Tetsuyuki; Yoshida, Mari; Inuzuka, Takashi

    2016-11-01

    Here we report an autopsy-verified case of frontotemporal lobar degeneration (FTLD)-transactivation responsive region (TAR) DNA binding protein (TDP) type A with upper motor neuron-predominant motor neuron disease mimicking MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD). A 69-year-old woman presented with an 11-month history of progressive dementia, irritability, insomnia, and gait disturbance without a family history of dementia or prion disease. Neurological examination revealed severe dementia, frontal signs, and exaggerated bilateral tendon reflexes. Periodic sharp-wave complexes were not observed on the electroencephalogram. Brain diffusion MRI did not reveal abnormal changes. An easy Z score (eZIS) analysis for (99m)Tc-ECD-single photon emission computed tomography ((99m)Tc-ECD-SPECT) revealed a bilateral decrease in thalamic regional cerebral blood flow (rCBF). PRNP gene analysis demonstrated methionine homozygosity at codon 129 without mutation. Cerebrospinal fluid (CSF) analysis showed normal levels of both 14-3-3 and total tau proteins. Conversely, prion protein was slowly amplified in the CSF by a real-time quaking-induced conversion assay. Her symptoms deteriorated to a state of akinetic mutism, and she died of sudden cardiac arrest, one year after symptom onset.  Despite the SPECT results supporting a clinical diagnosis of MM2-thalamic-type sCJD, a postmortem assessment revealed that this was a case of FTLD-TDP type A, and excluded prion disease. Thus, this case indicates that whereas a bilateral decreasing thalamic rCBF detected by (99m)Tc-ECD-SPECT can be useful for diagnosing MM2-thalamic-type sCJD, it is not sufficiently specific. Postmortem diagnosis remains the gold standard for the diagnosis of this condition.

  15. Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent.

    USGS Publications Warehouse

    Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

    2013-01-01

    Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in v

  16. Red-Backed Vole Brain Promotes Highly Efficient In Vitro Amplification of Abnormal Prion Protein from Macaque and Human Brains Infected with Variant Creutzfeldt-Jakob Disease Agent

    PubMed Central

    Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

    2013-01-01

    Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in vCJD-infected human

  17. MM1-type sporadic Creutzfeldt-Jakob disease with 1-month total disease duration and early pathologic indicators.

    PubMed

    Iwasaki, Yasushi; Kato, Hiroko; Ando, Tetsuo; Mimuro, Maya; Kitamoto, Tetsuyuki; Yoshida, Mari

    2017-04-12

    A 62-year-old man presented with abnormal behavior and cognitive impairment. Diffusion-weighted images (DWI) obtained on MRI showed extensive hyperintense regions in the cerebral cortex and striatum. Myoclonus was recognized, and the patient died 1 month after the onset; his condition did not reach the akinetic mutism state. The brain weighed 1300 g and showed no apparent atrophy. Extensive spongiform changes were observed in the cerebral neocortex, striatum, thalamus and cerebellar cortex, but gliosis was mild or absent. Neuropil rarefaction and neuron loss were not apparent. Mild proliferation of anti- GFAP-positive astrocytes was observed in the cerebral cortex, but unaffected regions were noted. Regions without spongiform changes and GFAP-positive astrocytes included the hippocampal formation and subiculum. PrP immunostaining showed extensive diffuse synaptic-type PrP deposition in the gray matter, including the hippocampal region, but it was also mild. PrP gene analysis revealed no mutation with methionine homozygosity at polymorphic codon 129. Western blot analysis of proteinase K-resistant PrP indicated type 1 PrP(Sc) . The clinicopathological findings of the present case confirm several hypotheses: (i) the earliest pathologic evidence observed by HE staining in CJD are spongiform changes; (ii) DWI hyperintense regions indicate these spongiform changes; and (iii) regions without spongiform changes, gliosis and proliferation of GFAP-positive astrocytes, but with PrP deposition, exist in the early disease stage.

  18. R3-R4 deletion in the PRNP gene is associated with Creutzfeldt-Jakob disease (CJD)

    SciTech Connect

    Cervenakova, L.; Brown, P.; Nagle, J.

    1994-09-01

    There are conflicting reports on the association of deletions in the PRNP gene on chromosome 20 with CJD, a rapidly progressive fatal spongiform encephalopathy. We accumulated data suggesting that a deletion of R3-R4 type (parts of the third and fourth repeats are deleted from the area of four repeating 24 bp sequences in the 5{prime} region of the gene) is causing CJD. Screening of 129 unaffected control individuals demonstrated presence of a deletion of R2 type in four (1.55% of the studied chromosomes), but none of them had the R3-R4 type. Of 181 screened patients with spongiform encephalopathies, two had a deletion of R3-R4 type with no other mutations in the coding sequence. Both patients had a classical rapidly progressive dementing disease and diffuse spongiform degeneration, and both cases were apparently sporadic. The same R3-R4 type of deletion was detected in three additional neuropathologically confirmed spongiform encephalopathy patients, of which two had other known pathogenic mutations in the PRNP gene: at codon 178 on the methionine allele exhibiting the phenotype of fatal familial insomnia, and codon 200 causing CJD with severe dementia; the third was a patient with iatrogenic CJD who developed the disease after treatment with growth hormone extracted from cadaveric human pituitary glands. In all cases the deletion coincided with a variant sequence at position 129 coding for methionine.

  19. Insights into the Management of Emerging Infections: Regulating Variant Creutzfeldt-Jakob Disease Transfusion Risk in the UK and the US

    PubMed Central

    Ponte, Maya L

    2006-01-01

    Background Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease caused by infection with the agent of bovine spongiform encephalopathy. After the recognition of vCJD in the UK in 1996, many nations implemented policies intended to reduce the hypothetical risk of transfusion transmission of vCJD. This was despite the fact that no cases of transfusion transmission had yet been identified. In December 2003, however, the first case of vCJD in a recipient of blood from a vCJD-infected donor was announced. The aim of this study is to ascertain and compare the factors that influenced the motivation for and the design of regulations to prevent transfusion transmission of vCJD in the UK and US prior to the recognition of this case. Methods and Findings A document search was conducted to identify US and UK governmental policy statements and guidance, transcripts (or minutes when transcripts were not available) of scientific advisory committee meetings, research articles, and editorials published in medical and scientific journals on the topic of vCJD and blood transfusion transmission between March 1996 and December 2003. In addition, 40 interviews were conducted with individuals familiar with the decision-making process and/or the science involved. All documents and transcripts were coded and analyzed according to the methods and principles of grounded theory. Data showed that while resulting policies were based on the available science, social and historical factors played a major role in the motivation for and the design of regulations to protect against transfusion transmission of vCJD. First, recent experience with and collective guilt resulting from the transfusion-transmitted epidemics of HIV/AIDS in both countries served as a major, historically specific impetus for such policies. This history was brought to bear both by hemophilia activists and those charged with regulating blood products in the US and UK. Second, local specificities, such as the recall

  20. Public health issues and clinical and neurological characteristics of the new variant of Creutzfeldt-Jakob disease and other human and animal transmissible spongiform encephalopathies: memorandum from two WHO meetings.

    PubMed Central

    1996-01-01

    The transmissible spongiform encephalopathies (TSEs) include bovine spongiform encephalopathy (BSE), which was first described in 1986 in cattle in the United Kingdom, but has occurred subsequently also in other countries, and Creutzfeldt-Jakob disease (CJD) in humans, which is rare but with a worldwide distribution. Recently a new variant form of CJD, with a characteristic clinical and pathological phenotype, has been identified in the United Kingdom in a series of 11 young patients. This Memorandum reports the findings of two WHO Consultations. The first, held on 2-3 April 1996, issued conclusions and recommendations on certain animal products in order to protect the health of consumers. The second, held on 14-16 May 1996, examined, inter alia, the findings associated with the new variant of CJD, compared these findings with those for other TSEs, and proposed a protocol for the diagnosis and surveillance of CJD and related diseases. PMID:9002325

  1. Stability and Reproducibility Underscore Utility of RT-QuIC for Diagnosis of Creutzfeldt-Jakob Disease.

    PubMed

    Cramm, Maria; Schmitz, Matthias; Karch, André; Mitrova, Eva; Kuhn, Franziska; Schroeder, Bjoern; Raeber, Alex; Varges, Daniela; Kim, Yong-Sun; Satoh, Katsuya; Collins, Steven; Zerr, Inga

    2016-04-01

    Real-time quaking-induced conversion (RT-QuIC) allows the amplification of miniscule amounts of scrapie prion protein (PrP(Sc)). Recent studies applied the RT-QuIC methodology to cerebrospinal fluid (CSF) for diagnosing human prion diseases. However, to date, there has not been a formal multi-centre assessment of the reproducibility, validity and stability of RT-QuIC in this context, an indispensable step for establishment as a diagnostic test in clinical practice. In the present study, we analysed CSF from 110 prion disease patients and 400 control patients using the RT-QuIC method under various conditions. In addition, "blinded" ring trials between different participating sites were performed to estimate reproducibility. Using the previously established cut-off of 10,000 relative fluorescence units (rfu), we obtained a sensitivity of 85% and a specificity of 99%. The multi-centre inter-laboratory reproducibility of RT-QuIC revealed a Fleiss' kappa value of 0.83 (95% CI: 0.40-1.00) indicating an almost perfect agreement. Moreover, we investigated the impact of short-term CSF storage at different temperatures, long-term storage, repeated freezing and thawing cycles and the contamination of CSF with blood on the RT-QuIC seeding response. Our data indicated that the PrP(Sc) seed in CSF is stable to any type of storage condition but sensitive to contaminations with blood (>1250 erythrocytes/μL), which results in a false negative RT-QuIC response. Fresh blood-contaminated samples (3 days) can be rescued by removal of erythrocytes. The present study underlines the reproducibility and high stability of RT-QuIC across various CSF storage conditions with a remarkable sensitivity and specificity, suggesting RT-QuIC as an innovative and robust diagnostic method.

  2. Decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata determined by an easy Z-score (eZIS) analysis of (99m)Tc-ECD-SPECT images in a case of MM2-thalamic-type sporadic Creutzfeldt-Jakob disease.

    PubMed

    Hayashi, Yuichi; Iwasaki, Yasushi; Yoshikura, Nobuaki; Asano, Takahiko; Hatano, Taku; Tatsumi, Shinsui; Satoh, Katsuya; Kimura, Akio; Kitamoto, Tetsuyuki; Yoshida, Mari; Inuzuka, Takashi

    2015-11-15

    We report a case of autopsy-verified MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD) in a 46-year-old patient with a 16-month history of abnormal behavior, progressive dementia, insomnia, and speech disturbances without family history. Neurological examination revealed progressive dementia, frontal signs, insomnia, speech disturbance, gait disturbance and bilaterally exaggerated tendon reflexes. Both brain MRI and cerebrospinal fluid examinations, including 14-3-3 protein, yielded normal results. An easy Z-score (eZIS) analysis for (99m)Tc-ethyl cysteinate dimer-single photon emission computed tomography ((99m)Tc-ECD-SPECT) revealed decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata. PRNP gene analysis revealed methionine homozygosity at codon 129 without mutation. Neuropathological examinations revealed severe neuronal loss, gliosis, and hypertrophic astrocytosis in the medial thalamus and inferior olivary nucleus. A slight depletion of Purkinje cells was observed. PrP immunostaining showed no obvious PrP deposits in the basal ganglia, thalamus, cerebellum, or brainstem; however, mild synaptic-type PrP deposits with some smaller plaque-like structures were only partially observed in the localized region of the frontal lobe with the spongiform change. Western blot analyses of protease-resistant PrP showed a type 2 pattern. In conclusion, eZIS analysis of (99m)Tc-ECD-SPECT images is useful for detecting both thalamic and medullary lesions. This is the first case of medullary lesions detected in a live patient with MM2-thalamic-type sCJD using SPECT.

  3. Relationship with BSE (Mad Cow Disease)

    MedlinePlus

    ... Related Links Prion Diseases Creutzfeldt-Jakob Disease (CJD) Bovine Spongiform Encephalopathy (BSE), or Mad Cow Disease Chronic Wasting Disease ( ... Related Links Prion Diseases Creutzfeldt-Jakob Disease (CJD) Bovine Spongiform Encephalopathy (BSE), or Mad Cow Disease Chronic Wasting Disease ( ...

  4. An autopsied case of MM1 + MM2-cortical with thalamic-type sporadic Creutzfeldt-Jakob disease presenting with hyperintensities on diffusion-weighted MRI before clinical onset.

    PubMed

    Iwasaki, Yasushi; Mori, Keiko; Ito, Masumi; Mimuro, Maya; Kitamoto, Tetsuyuki; Yoshida, Mari

    2017-02-01

    + MM2-cortical with thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD), which suggests a broader spectrum of sCJD clinicopathological findings.

  5. Human growth hormone-related latrogenic Creutzfeldt-Jakob disease: Search for a genetic susceptibility by analysis of the PRNP coding region

    SciTech Connect

    Jaegly, A.; Boussin, F.; Deslys, J.P.

    1995-05-20

    The human PRNP gene encoding PrP is located on chromosome 20 and consists of two exons and a single intron. The open reading frame is entirely fitted into the second exon. Genetic studies indicate that all of the familial and several sporadic forms of TSSEs are associated with mutations in the PRNP 759-bp coding region. Moreover, homozygosity at codon 129, a locus harboring a polymorphism among the general population, was proposed as a genetic susceptibility marker for both sporadic and iatrogenic CJD. To assess whether additional genetic predisposition markers exist in the PRNP gene, the authors sequenced the PRNP coding region of 17 of the 32 French patients who developed a hGH-related CJD.

  6. Creutzfeldt-Jakob disease-like periodic sharp wave complexes in voltage-gated potassium channel-complex antibodies encephalitis : A Case Report

    PubMed Central

    Savard, Martin; Irani, Sarosh R.; Guillemette, Annie; Gosselin-Lefebvre, Stéphanie; Geschwind, Michael; Jansen, Gerard H.; Gould, Peter V.; Laforce, Robert

    2015-01-01

    Introduction Voltage-gated potassium channel-complex antibodies (VGKC-cAbs) encephalitis, a treatable autoantibody encephalopathy, has been previously reported to clinically mimic sporadic Creutzfeldt-Jacob disease (sCJD). Among available clinical clues to distinguish them, periodic sharp wave complexes (PSWC), a typical finding in sCJD, have never been reported in association with VGKC-cAbs encephalitis. Case presentation A 76 years old man was transferred to a tertiary neurology center with a clinical history of six-month weight loss, cognitive disturbance and non specific generalized weakness. He had two seizures the month before transfer and then evolved to severe encephalopathy, requiring mechanical ventilation. PSWC every 1–2 seconds over slowed background were found on EEG, and MRI showed cerebellar and bifrontal cortical T2/FLAIR/DWI hypersignal without restricted diffusion on ADC mapping. Pancorporal PET-scan was negative. An immunotherapy trial did not improve the patient condition. Therefore, he died after life support withdrawal. Brain autopsy revealed mononuclear neocortex infiltrate without significant spongiosis, and the anti-VGKC test showed a seropositivity of 336 pmol/L (normal: 0–31), three month after the patient deceased. Conclusion This is the first reported case of VGKC-cAbs encephalitis associated with PSWC on EEG, which further confuse the differential diagnosis with sCJD. However, the cortical DWI hypersignal without restriction seem to remain a way to discriminate these two entities appropriately, when present. These clues are of paramount importance since VGKC-cAbs encephalitis is a treatable disease. PMID:26375660

  7. An autopsied case of Creutzfeldt-Jakob disease with mutation in the prion protein gene codon 232 and type 1+2 prion protein.

    PubMed

    Iwasaki, Yasushi; Yokoi, Fuji; Tatsumi, Shinsui; Mimuro, Maya; Iwai, Katsushige; Kitamoto, Tetsuyuki; Yoshida, Mari

    2013-10-01

    A 68-year-old Japanese man gradually showed abnormal behavior and gait disturbance with bradykinesia. Slowly progressive dementia, including memory disturbance and disorientation, was also observed. Cerebral cortical hyperintensity on diffusion-weighted MRI was observed 6 months after onset. The patient progressed to an akinetic mutism state with mild myoclonus, and atypical periodic sharp-wave complexes were observed by electroencephalogram 13 months after onset. He was clinically suspected of having atypical CJD and died after 19 months total disease duration. The brain weighed 1160 g and showed mild atrophy of the cerebrum and cerebellum with ventricular dilatation. Spongiform changes with varying vacuole size and gliosis was extensive in the cerebral cortex and basal ganglia. Neuron loss in the cerebral cortex, basal ganglia and thalamus was relatively mild. The cerebellum showed mild spongiform changes of the molecular layer and mild neuron loss in the Purkinje cell layer. PrP immunostaining showed mainly coarse-type combined with diffuse synaptic-type PrP deposition in the cerebral gray matter. Some perivacuolar-type PrP deposition was also present. Numerous plaque-type PrP depositions were observed in the molecular layer of the cerebellum. Analysis of the PrP gene revealed a methionine-to-arginine (Met-to-Arg) substitution at codon 232 (M232R) with Met homozygosity at codon 129. Western blot analysis of protease-resistant PrP indicated type 2 dominant PrP combined with type 1. Genetic CJD with M232R substitution in the PrP gene has only been reported in Japan. Although two clinical phenotypes (rapid-type and slow-type) were suggested in the M232R CJD cases (despite the presence of the same PrP genotype), the pathological and molecular backgrounds have not been well understood because there have only been a few autopsied case reports. This is the first case report of M232R CJD presenting with 1 + 2 PrP.

  8. Hashimoto's encephalopathy mimicking Creutzfeldt-Jakob disease.

    PubMed

    Gauthier, Angela C; Baehring, Joachim M

    2017-01-01

    Hashimoto's encephalopathy is a rare, imprecisely defined autoimmune neurologic syndrome associated with Hashimoto's thyroiditis that normally responds to corticosteroids. Here, we describe the case of a 55-year-old woman who presented with subacute cognitive decline and ataxia. Neoplastic, paraneoplastic, infectious, and metabolic etiologies were ruled out. Anti-TPO antibody level was markedly elevated at 966U/mL. After one month of 60mg/day of oral prednisone, she felt back to baseline and her Montreal Cognitive Assessment dramatically improved. Physicians should strongly consider this uncommon diagnosis in patients with rapid cognitive decline and no other clear etiology.

  9. Diagnostic Accuracy of a Combined Analysis of Cerebrospinal Fluid t-PrP, t-tau, p-tau, and Aβ42 in the Differential Diagnosis of Creutzfeldt-Jakob Disease from Alzheimer’s Disease with Emphasis on Atypical Disease Variants

    PubMed Central

    Abu Rumeileh, Samir; Lattanzio, Francesca; Stanzani Maserati, Michelangelo; Rizzi, Romana; Capellari, Sabina; Parchi, Piero

    2016-01-01

    According to recent studies, the determination of cerebrospinal fluid (CSF) total tau (t-tau)/phosphorylated tau (p-tau) ratio and total prion protein (t-PrP) levels significantly improves the accuracy of the diagnosis of Alzheimer’s disease (AD) in atypical cases with clinical or laboratory features mimicking Creutzfeldt-Jakob disease (CJD). However, this has neither been validated nor tested in series including atypical CJD variants. Furthermore, the added diagnostic value of amyloid-β (Aβ)42 remains unclear. To address these issues, we measured t-PrP, 14-3-3, t-tau, p-tau, and Aβ42 CSF levels in 45 typical and 44 atypical/rapidly progressive AD patients, 54 typical and 54 atypical CJD patients, and 33 controls. CJD patients showed significantly lower CSF t-PrP levels than controls and AD patients. Furthermore, atypical CJD was associated with lower t-PrP levels in comparison to typical CJD. T-tau, 14-3-3, or t-PrP alone yielded, respectively, 80.6, 63.0, and 73.0% sensitivity and 75.3, 92.1, and 75% specificity in distinguishing AD from CJD. On receiver operating characteristic (ROC) curve analyses of biomarker combinations, the (t-tau×Aβ42)/(p-tau×t-PrP) ratio achieved the best accuracy, with 98.1% sensitivity and 97.7% specificity overall, and 96.2% sensitivity and 95.5% specificity for the “atypical” disease groups. Our results show that the combined analysis of CSF t-PrP, t-tau, p-tau, and Aβ42 is clinically useful in the differential diagnosis between CJD and AD. Furthermore, the finding of reduced CSF t-PrP levels in CJD patients suggest that, likewise Aβ42 in AD, CSF t-PrP levels reflect the extent of PrPc conversion into abnormal PrP (PrPSc) and the burden of PrPSc deposition in CJD. PMID:27886009

  10. Coexistence of mixed phenotype Creutzfeldt-Jakob disease, Lewy body disease and argyrophilic grain disease plus histological features of possible Alzheimer's disease: a multi-protein disorder in an autopsy case.

    PubMed

    Fernández-Vega, Iván; Ruiz-Ojeda, Javier; Juste, Ramon A; Geijo, Maria; Zarranz, Juan Jose; Sánchez Menoyo, Jose Luis; Vicente-Etxenausia, Ikerne; Mediavilla-García, Jennifer; Guerra-Merino, Isabel

    2015-02-01

    We report hereby an autopsy case of sporadic mixed phenotype CJD without hereditary burden and a long-term clinical course. An 80-year old man was diagnosed with mild cognitive impairment 27 months before death, caused by bronchopneumonia and severe respiratory impairment. During this time, the patient developed gradual mental deterioration, some sleeping problems and myoclonus. Other clinical manifestations were progressive gait problems, language deterioration, presence of primitive reflexes and irritability. In keeping with those symptoms, a rapidly evolving dementia was clinically suspected. Cerebrospinal fluid test for 14-3-3 protein was negative. However, an abnormal EEG and MRI at end-stage of disease were finally consistent with CJD. Post-mortem examination revealed a massive cortical neuronal loss with associated reactive astrocytosis, also evident in the white matter. Diffuse spongiform changes involving some basal ganglia, especially medial thalamus, some troncoencephalic nuclei, mainly inferior olivary nucleus and the molecular layer of the cerebellum were seen. Immunorreactive deposits for anti-prion protein antibody were present at different areas of the CNS. Additionally, Lewy bodies were observed at the brainstem and amygdala. Furthermore, argirophilic grains together with oligodendroglial coiled bodies and pre-tangle inclusions in the neurons from the limbic system containing hyperphosphorylated 4R tau were noted. To the best of our knowledge, this is the first case of CJD combined with Lewy body disease and argirophilic grain disease. Furthermore, we believe this case is an extremely rare combination of MM2-cortical-type and MM2-thalamic-type sporadic CJD (sCJD), which explains the broad spectrum of MM2-type sCJD findings and symptoms. Moreover, histological features of possible Alzheimer's disease were also reported.

  11. MM1+2C sporadic Creutzfeldt-Jakob disease presenting as rapidly progressive nonfluent aphasia.

    PubMed

    Allegri, Ricardo F; Bartoloni, Leonardo; Iturry, Mónica; Romero, Carlos; Begué, Christián; Sevlever, Gustavo; Taratuto, Ana Lía

    2014-01-01

    We report a 77-year-old man, presenting with progressive aphasia as an initial symptom, who developed severe dementia over the course of 20 months. Frontal cortex PrPSc western blot was type 2 and codon 129 was MM; brain neuropathology showed cortical vacuoles with perivacuolar PrP immunostaining characteristic of MM2C. Cerebellum showed focal coarse, patchy staining in different sections of the molecular layer, diffuse fine punctuate and coarse PrP immunopositive deposits in the granule cell layer, and focal synaptic immunostaining in the molecular layer, suggestive of MM1+2C by histotyping. This clinical presentation has not yet been described in an MM1+2C subtype by histotyping.

  12. Creutzfeldt-Jakob Disease Fact Sheet for Healthcare Workers and Morticians

    MedlinePlus

    ... for this document is http://www.who.int/csr/resources/publications/bse/WHO_CDS_CSR_APH_2000_3/en/ . To receive a printed ... 27 Switzerland Fax: +41 22 791 4198 Email: csr@who.int , Attention: Publications Research The NINDS is ...

  13. Prion diseases: New considerations.

    PubMed

    Annus, Ádám; Csáti, Anett; Vécsei, László

    2016-11-01

    The transmissible spongiform encephalopathies, which include Creutzfeldt-Jakob disease, are fatal neurodegenerative disorders caused by the pathological accumulation of abnormal prion protein. The diagnosis of Creutzfeldt-Jakob disease is complex. The electroencephalogram, magnetic resonance imaging, lumbar puncture and genetic testing findings can help in the differential diagnosis of rapidly progressive dementia. There has recently been considerable debate as to whether proteins involved in the development of neurodegenerative diseases should be regarded as prions or only share prion-like mechanisms. Two recent reports described the detection of abnormal prion protein in the nasal mucosa and urine of patients with Creutzfeldt-Jakob disease. These findings raise major health concerns regarding the transmissibility of human prion diseases. We set out to address this neurological hot topic and to draw conclusions on the basis of what is known in the literature thus far.

  14. Neuroimaging Biomarkers of Neurodegenerative Diseases and Dementia

    PubMed Central

    Risacher, Shannon L.; Saykin, Andrew J.

    2014-01-01

    Neurodegenerative disorders leading to dementia are common diseases that affect many older and some young adults. Neuroimaging methods are important tools for assessing and monitoring pathological brain changes associated with progressive neurodegenerative conditions. In this review, the authors describe key findings from neuroimaging studies (magnetic resonance imaging and radionucleotide imaging) in neurodegenerative disorders, including Alzheimer’s disease (AD) and prodromal stages, familial and atypical AD syndromes, frontotemporal dementia, amyotrophic lateral sclerosis with and without dementia, Parkinson’s disease with and without dementia, dementia with Lewy bodies, Huntington’s disease, multiple sclerosis, HIV-associated neurocognitive disorder, and prion protein associated diseases (i.e., Creutzfeldt-Jakob disease). The authors focus on neuroimaging findings of in vivo pathology in these disorders, as well as the potential for neuroimaging to provide useful information for differential diagnosis of neurodegenerative disorders. PMID:24234359

  15. Selective Neuronal Vulnerability in Human Prion Diseases

    PubMed Central

    Guentchev, Marin; Wanschitz, Julia; Voigtländer, Till; Flicker, Helga; Budka, Herbert

    1999-01-01

    Human transmissible spongiform encephalopathies (TSEs) or prion diseases are neurodegenerative disorders of infectious, inherited or sporadic origin and include Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), kuru and fatal familial insomnia (FFI). Clinicopathologic features of FFI differ markedly from other human TSEs. Previous studies demonstrated selective neuronal vulnerability of parvalbumin positive (PV+) GABAergic inhibitory interneurons in sporadic CJD and experimental TSEs. In this report we show uniform severe loss of PV+ neurons also in other TSEs such as GSS, kuru, new variant and familial CJD. In contrast, these neurons are mostly well preserved, or only moderately reduced, in FFI. Only PV+ neurons surrounded by isolectin-B4 positive perineuronal nets were severely affected in TSEs, suggesting a factor residing in this type of extracellular matrix around PV+ neurons as modulator for the selective neuronal vulnerability. PMID:10550300

  16. Transgenic fatal familial insomnia mice indicate prion infectivity-independent mechanisms of pathogenesis and phenotypic expression of disease.

    PubMed

    Bouybayoune, Ihssane; Mantovani, Susanna; Del Gallo, Federico; Bertani, Ilaria; Restelli, Elena; Comerio, Liliana; Tapella, Laura; Baracchi, Francesca; Fernández-Borges, Natalia; Mangieri, Michela; Bisighini, Cinzia; Beznoussenko, Galina V; Paladini, Alessandra; Balducci, Claudia; Micotti, Edoardo; Forloni, Gianluigi; Castilla, Joaquín; Fiordaliso, Fabio; Tagliavini, Fabrizio; Imeri, Luca; Chiesa, Roberto

    2015-04-01

    Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg) mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD) mice modeling CJD178. No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype.

  17. Transgenic Fatal Familial Insomnia Mice Indicate Prion Infectivity-Independent Mechanisms of Pathogenesis and Phenotypic Expression of Disease

    PubMed Central

    Bouybayoune, Ihssane; Mantovani, Susanna; Del Gallo, Federico; Bertani, Ilaria; Restelli, Elena; Comerio, Liliana; Tapella, Laura; Baracchi, Francesca; Fernández-Borges, Natalia; Mangieri, Michela; Bisighini, Cinzia; Beznoussenko, Galina V.; Paladini, Alessandra; Balducci, Claudia; Micotti, Edoardo; Forloni, Gianluigi; Castilla, Joaquín; Fiordaliso, Fabio; Tagliavini, Fabrizio; Imeri, Luca; Chiesa, Roberto

    2015-01-01

    Fatal familial insomnia (FFI) and a genetic form of Creutzfeldt-Jakob disease (CJD178) are clinically different prion disorders linked to the D178N prion protein (PrP) mutation. The disease phenotype is determined by the 129 M/V polymorphism on the mutant allele, which is thought to influence D178N PrP misfolding, leading to the formation of distinctive prion strains with specific neurotoxic properties. However, the mechanism by which misfolded variants of mutant PrP cause different diseases is not known. We generated transgenic (Tg) mice expressing the mouse PrP homolog of the FFI mutation. These mice synthesize a misfolded form of mutant PrP in their brains and develop a neurological illness with severe sleep disruption, highly reminiscent of FFI and different from that of analogously generated Tg(CJD) mice modeling CJD178. No prion infectivity was detectable in Tg(FFI) and Tg(CJD) brains by bioassay or protein misfolding cyclic amplification, indicating that mutant PrP has disease-encoding properties that do not depend on its ability to propagate its misfolded conformation. Tg(FFI) and Tg(CJD) neurons have different patterns of intracellular PrP accumulation associated with distinct morphological abnormalities of the endoplasmic reticulum and Golgi, suggesting that mutation-specific alterations of secretory transport may contribute to the disease phenotype. PMID:25880443

  18. Chronic wasting disease and atypical forms of BSE and scrapie are not transmissible to mice expressing wild-type levels of human PrP

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has demonstrated that cattle TSEs can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several new TSEs in shee...

  19. [Prions: definition and diseases].

    PubMed

    Hernández-Albújar, S; García-Tobaruela, A; Torres Rodríguez, E; Pacheco Cuadros, R; Vázquez Rodríguez, J J

    1999-12-01

    In this article we review the concept and terminology of prions, their replication and some current hypothesis on the nature of these infectious agents causing neurodegenerative diseases. This revision also summarizes the etiopathogenic, epidemiological, clinical and neuropathological features of the prion diseases or human transmissible spongiform encephalopathies, and some methods for their early diagnosis. Finally, we discuss the possible link between the bovine spongiform encephalopathy and the new cases of Creutzfeldt-Jakob disease identified in the United Kingdom.

  20. Infectious Disease in the Twenty-First Century: The Need for a Comprehensive Strategy

    DTIC Science & Technology

    1999-04-26

    Zaire, now the Democratic Republic of Congo.7 In addition, creutzfeldt - Jakob disease (“mad cow disease ”) and influenza demonstrated the ability of... Jakob disease tnggered a three-year European Union embargo on U.K. beef.g An 6 XSTC Committee on Intematlonal Science, Engmeermg, and Technology...NATIONAL DEFENSE UNIVERSITY NATIONAL WAR COLLEGE ARCHIVE co??/ INFECTIOUS DISEASE IN THE TWENTY-FIRST CENTURY: THE NEED FOR A COMPREHENSIVE

  1. Prion protein gene analysis in three kindreds with fatal familial insomnia (FFI): Codon 178 mutation and codon 129 polymorphism

    SciTech Connect

    Medori, R.; Tritschler, H.J. )

    1993-10-01

    Fatal familial insomnia (FFI) is a disease linked to a GAC(Asp) [yields] AAC(Asn) mutation in codon 178 of the prion protein (PrP) gene. FFI is characterized clinically by untreatable progressive insomnia, dysautonomia, and motor dysfunctions and is characterized pathologically by selective thalamic atrophy. The authors confirmed the 178[sup Asn] mutation in the PrP gene of a third FFI family of French ancestry. Three family members who are under 40 years of age and who inherited the mutation showed only reduced perfusion in the basal ganglia on single photon emission computerized tomography. Some FFI features differ from the clinical and neuropathologic findings associated with 178[sup Asn] reported elsewhere. However, additional intragenic mutations accounting for the phenotypic differences were not observed in two affected individuals. In other sporadic and familial forms of Creutzfeldt-Jakob disease and Gerstmann-Straeussler syndrome, Met or Val homozygosity at polymorphic codon 129 is associated with a more severe phenotype, younger age at onset, and faster progression. In FFI, young and old individuals at disease onset had 129[sup Met/Val]. Moreover, of five 178[sup Asn] individuals who are above age-at-onset range and who are well, two have 129[sup Met] and three have 129[sup Met/Val], suggesting that polymorphic site 129 does not modulate FFI phenotypic expression. Genetic heterogeneity and environment may play an important role in inter- and intrafamilial variability of the 178[sup Asn] mutation. 32 refs., 5 figs., 1 tab.

  2. [Human prion diseases in the Czech Republic].

    PubMed

    Rohan, Z; Rusina, R; Marešová, M; Matěj, R

    2015-09-01

    Human prion diseases are a group of very rare diseases with a unique pathogenesis and, due to an inauspicious prognosis and unavailability of therapy, with fatal consequences. The etiopathogenetic background is the presence of pathologically misfolded prion protein, highly resistant to denaturation, the aggregation and presence of which in the brain tissue causes irreversible neuronal damage. The most frequent prion disease in humans is Creutzfeldt-Jakob disease (CJD) which occurs in sporadic, hereditary/familial, or acquired/infectious/iatrogenic forms. A new form of CJD, variant CJD, is considered to be linked to dietary exposure to beef products from cattle infected with bovine spongiform encephalopathy (BSE) and to infection via blood transfusion. The clinical picture of these diseases is characterized by a rapidly progressing dementia, cerebellar and extrapyramidal symptoms, and rather specific MRI, EEG, and CSF findings. Clinically, the diagnosis is described as possible or probable prion disease and needs to be confirmed by neuropathological or immunological investigation of the brain tissue. Epidemiological data from the Czech Republic spanning the last decade are presented.

  3. Myoclonus

    MedlinePlus

    ... muscles. Myoclonic jerking may develop in people with multiple sclerosis, Parkinson's disease, Alzheimer's disease, or Creutzfeldt-Jakob disease. ... muscles. Myoclonic jerking may develop in people with multiple sclerosis, Parkinson's disease, Alzheimer's disease, or Creutzfeldt-Jakob disease. ...

  4. Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Correlation of Histopathology and MRI in Prion Disease.

    PubMed

    Mente, Karin P; O'Donnell, James K; Jones, Stephen E; Cohen, Mark L; Thompson, Nicolas R; Bizzi, Alberto; Gambetti, Pierluigi; Safar, Jiri G; Appleby, Brian S

    2017-01-01

    Creutzfeldt-Jakob disease (CJD) and other prion diseases are rapidly progressive spongiform encephalopathies that are invariably fatal. Clinical features and magnetic resonance imaging, electroencephalogram, and cerebrospinal fluid abnormalities may suggest prion disease, but a definitive diagnosis can only be made by means of neuropathologic examination. Fluorodeoxyglucose positron emission tomography (FDG-PET) is not routinely used to evaluate patients with suspected prion disease. This study includes 11 cases of definite prion disease in which FDG-PET scans were obtained. There were 8 sporadic CJD cases, 2 genetic CJD cases, and 1 fatal familial insomnia case. Automated FDG-PET analysis revealed parietal region hypometabolism in all cases. Surprisingly, limbic and mesolimbic hypermetabolism were also present in the majority of cases. When FDG-PET hypometabolism was compared with neuropathologic changes (neuronal loss, astrocytosis, spongiosis), hypometabolism was predictive of neuropathology in 80.6% of cortical regions versus 17.6% of subcortical regions. The odds of neuropathologic changes were 2.1 times higher in cortical regions than subcortical regions (P=0.0265). A similar discordance between cortical and subcortical regions was observed between FDG-PET hypometabolism and magnetic resonance imaging diffusion weighted imaging hyperintensity. This study shows that there may be a relationship between FDG-PET hypometabolism and neuropathology in cortical regions in prion disease but it is unlikely to be helpful for diagnosis.

  5. Molecular pathogenesis of sporadic prion diseases in man.

    PubMed

    Safar, Jiri G

    2012-01-01

    The yeast, fungal and mammalian prions determine heritable and infectious traits that are encoded in alternative conformations of proteins. They cause lethal sporadic, familial and infectious neurodegenerative conditions in man, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), kuru, sporadic fatal insomnia (SFI) and likely variable protease-sensitive prionopathy (VPSPr). The most prevalent of human prion diseases is sporadic (s)CJD. Recent advances in amplification and detection of prions led to considerable optimism that early and possibly preclinical diagnosis and therapy might become a reality. Although several drugs have already been tested in small numbers of sCJD patients, there is no clear evidence of any agent's efficacy. Therefore, it remains crucial to determine the full spectrum of sCJD prion strains and the conformational features in the pathogenic human prion protein governing replication of sCJD prions. Research in this direction is essential for the rational development of diagnostic as well as therapeutic strategies. Moreover, there is growing recognition that fundamental processes involved in human prion propagation - intercellular induction of protein misfolding and seeded aggregation of misfolded host proteins - are of far wider significance. This insight leads to new avenues of research in the ever-widening spectrum of age-related human neurodegenerative diseases that are caused by protein misfolding and that pose a major challenge for healthcare.

  6. Identifying Unstable Regions of Proteins Involved in Misfolding Diseases

    NASA Astrophysics Data System (ADS)

    Guest, Will; Cashman, Neil; Plotkin, Steven

    2009-05-01

    Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and all-atoms molecular dynamics. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

  7. Phosphatidylinositol-Glycan-Phospholipase D Is Involved in Neurodegeneration in Prion Disease

    PubMed Central

    Jin, Jae-Kwang; Jang, Byungki; Jin, Hyoung Tae; Choi, Eun-Kyoung; Jung, Cha-Gyun; Akatsu, Hiroyasu; Kim, Jae-Il; Carp, Richard I.; Kim, Yong-Sun

    2015-01-01

    PrPSc is formed from a normal glycosylphosphatidylinositol (GPI)-anchored prion protein (PrPC) by a posttranslational modification. Most GPI-anchored proteins have been shown to be cleaved by GPI phospholipases. Recently, GPI-phospholipase D (GPI-PLD) was shown to be a strictly specific enzyme for GPI anchors. To investigate the involvement of GPI-PLD in the processes of neurodegeneration in prion diseases, we examined the mRNA and protein expression levels of GPI-PLD in the brains of a prion animal model (scrapie), and in both the brains and cerebrospinal fluids (CSF) of sporadic and familial Creutzfeldt-Jakob disease (CJD) patients. We found that compared with controls, the expression of GPI-PLD was dramatically down-regulated in the brains of scrapie-infected mice, especially in the caveolin-enriched membrane fractions. Interestingly, the observed decrease in GPI-PLD expression levels began at the same time that PrPSc began to accumulate in the infected brains and this decrease was also observed in both the brain and CSF of CJD patients; however, no differences in expression were observed in either the brains or CSF specimens from Alzheimer’s disease patients. Taken together, these results suggest that the down-regulation of GPI-PLD protein may be involved in prion propagation in the brains of prion diseases. PMID:25867459

  8. Structure-Based Prediction of Unstable Regions in Proteins: Applications to Protein Misfolding Diseases

    NASA Astrophysics Data System (ADS)

    Guest, Will; Cashman, Neil; Plotkin, Steven

    2009-03-01

    Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and solution of the Poisson-Boltzmann equation. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

  9. Transgenic mice recapitulate the phenotypic heterogeneity of genetic prion diseases without developing prion infectivity: Role of intracellular PrP retention in neurotoxicity

    PubMed Central

    Chiesa, Roberto; Restelli, Elena; Comerio, Liliana; Del Gallo, Federico; Imeri, Luca

    2016-01-01

    abstract Genetic prion diseases are degenerative brain disorders caused by mutations in the gene encoding the prion protein (PrP). Different PrP mutations cause different diseases, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome and fatal familial insomnia (FFI). The reason for this variability is not known. It has been suggested that prion strains with unique self-replicating and neurotoxic properties emerge spontaneously in individuals carrying PrP mutations, dictating the phenotypic expression of disease. We generated transgenic mice expressing the FFI mutation, and found that they developed a fatal neurological illness highly reminiscent of FFI, and different from those of similarly generated mice modeling genetic CJD and GSS. Thus transgenic mice recapitulate the phenotypic differences seen in humans. The mutant PrPs expressed in these mice are misfolded but unable to self-replicate. They accumulate in different compartments of the neuronal secretory pathway, impairing the membrane delivery of ion channels essential for neuronal function. Our results indicate that conversion of mutant PrP into an infectious isoform is not required for pathogenesis, and suggest that the phenotypic variability may be due to different effects of mutant PrP on intracellular transport. PMID:26864450

  10. Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease.

    PubMed

    Sassi, Celeste; Guerreiro, Rita; Gibbs, Raphael; Ding, Jinhui; Lupton, Michelle K; Troakes, Claire; Lunnon, Katie; Al-Sarraj, Safa; Brown, Kristelle S; Medway, Chirstopher; Lord, Jenny; Turton, James; Mann, David; Snowden, Julie; Neary, David; Harris, Jeniffer; Bras, Jose; Morgan, Kevin; Powell, John F; Singleton, Andrew; Hardy, John

    2014-10-01

    Early-onset Alzheimer's disease (EOAD) represents 1%-2% of the Alzheimer's disease (AD) cases, and it is generally characterized by a positive family history and a rapidly progressive symptomatology. Rare coding and fully penetrant variants in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the only causative mutations reported for autosomal dominant AD. Thus, in this study we used exome sequencing data to rapidly screen rare coding variability in APP, PSEN1, and PSEN2, in a British cohort composed of 47 unrelated EOAD cases and 179 elderly controls, neuropathologically proven. We report 2 novel and likely pathogenic variants in PSEN1 (p.L166V and p.S230R). A comprehensive catalog of rare pathogenic variants in the AD Mendelian genes is pivotal for a premortem diagnosis of autosomal dominant EOAD and for the differential diagnosis with other early onset dementias such as frontotemporal dementia (FTD) and Creutzfeldt-Jakob disease (CJD).

  11. Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease

    PubMed Central

    Sassi, Celeste; Guerreiro, Rita; Gibbs, Raphael; Ding, Jinhui; Lupton, Michelle K.; Troakes, Claire; Al-Sarraj, Safa; Niblock, Michael; Gallo, Jean-Marc; Adnan, Jihad; Killick, Richard; Brown, Kristelle S.; Medway, Christopher; Lord, Jenny; Turton, James; Bras, Jose; Morgan, Kevin; Powell, John F.; Singleton, Andrew; Hardy, John

    2014-01-01

    The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raise the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias. PMID:25104557

  12. One gene, two diseases and three conformations: molecular dynamics simulations of mutants of human prion protein at room temperature and elevated temperatures.

    PubMed

    Shamsir, Mohd S; Dalby, Andrew R

    2005-05-01

    Fatal familial insomnia (FFI) and Creutzfeldt-Jakob disease (CJD) are associated to the same mutation at codon 178 but differentiate into clinicopathologically distinct diseases determined by this mutation and a naturally occurring methionine-valine polymorphism at codon 129 of the prion protein gene. It has been suggested that the clinical and pathological difference between FFI and CJD is caused by different conformations of the prion protein. Using molecular dynamics (MD), we investigated the effect of the mutation at codon 178 and the polymorphism at codon 129 on prion protein dynamics and conformation at normal and elevated temperatures. Four model structures were examined with a focus on their dynamics and conformational changes. The results showed differences in stability and dynamics between polymorphic variants. Methionine variants demonstrated a higher stability than valine variants. Elongation of existing beta-sheets and formation of new beta-sheets was found to occur more readily in valine polymorphic variants. We also discovered the inhibitory effect of proline residue on existing beta-sheet elongation.

  13. The Structure of Intrinsically Disordered Peptides Implicated in Amyloid Diseases: Insights from Fully Atomistic Simulations

    NASA Astrophysics Data System (ADS)

    Wu, Chun; Shea, Joan-Emma

    Protein aggregation involves the self-assembly of proteins into large β-sheet-rich complexes. This process can be the result of aberrant protein folding and lead to "amyloidosis," a condition characterized by deposits of protein aggregates known as amyloids on various organs of the body [1]. Amyloid-related diseases include, among others, Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and type II diabetes [2, 3, 4]. In other instances, however, protein aggregation is not a pathological process, but rather a functional one, with aggregates serving as structural scaffolds in a number of organisms [5].

  14. Genetic Characterization of Movement Disorders and Dementias

    ClinicalTrials.gov

    2017-01-24

    Ataxia; Dystonia; Parkinson's Disease; Amyotrophic Lateral Sclerosis; Corticobasal Degeneration; Multiple System Atrophy; Alzheimer's Disease; Lewy Body Dementia; Parkinson Disease-Dementia; Dentatorubral-pallidoluysian Atrophy; Creutzfeldt-Jakob Disease and Fatal Familial Insomnia; Fragile X-associated Tremor/Ataxia Syndrome; Krabbe's Disease; Niemann-Pick Disease, Type C; Neuronal Ceroid Lipofuscinosis

  15. The EEG in E200K familial CJD: relation to MRI patterns.

    PubMed

    Appel, Shmuel A; Chapman, Joab; Prohovnik, Isak; Hoffman, Chen; Cohen, Oren S; Blatt, Ilan

    2012-03-01

    The aim of the study was to examine the relationship between EEG abnormalities and the pattern of MRI changes in familial Creutzfeldt-Jakob Disease (fCJD) patients with E200K mutation. As part of a controlled, prospective study, 13 E200K fCJD patients underwent comprehensive evaluations, with EEG and an extensive MRI protocol that included one of the most prion-disease sensitive sequences, diffusion-weighted imaging (DWI). The relationship between EEG abnormalities and the pattern of DWI hyperintensities was examined. EEG demonstrated the classical CJD finding of PSWC (periodic sharp wave complexes) in five patients (38%) while in eight patients (62%) the EEG showed only slow activity. Six patients showed the typical cortical changes on MRI, and in five of them (83%) concordance between the MRI and the EEG was found. Five patients had isolated basal ganglia involvement per MRI, and in two of them (40%) concordance between the MRI and the EEG laterality was found. In the remaining two patients MRI did not show any changes suggesting CJD and EEG showed focal slow activity. The EEG of our E200K fCJD patients appears similar to that of the largest prion disease patient group, sporadic CJD (sCJD). EEG abnormalities in E200K fCJD appear to correlate mainly with cortical pathology, as revealed by DWI, rather than basal ganglia pathology. The observation that PSWC abnormalities reflect cortical rather than basal ganglia pathology is significant with respect to theories of the origins of EEG abnormalities in prion disease.

  16. Olfactory Receptors in Non-Chemosensory Organs: The Nervous System in Health and Disease

    PubMed Central

    Ferrer, Isidro; Garcia-Esparcia, Paula; Carmona, Margarita; Carro, Eva; Aronica, Eleonora; Kovacs, Gabor G.; Grison, Alice; Gustincich, Stefano

    2016-01-01

    Olfactory receptors (ORs) and down-stream functional signaling molecules adenylyl cyclase 3 (AC3), olfactory G protein α subunit (Gαolf), OR transporters receptor transporter proteins 1 and 2 (RTP1 and RTP2), receptor expression enhancing protein 1 (REEP1), and UDP-glucuronosyltransferases (UGTs) are expressed in neurons of the human and murine central nervous system (CNS). In vitro studies have shown that these receptors react to external stimuli and therefore are equipped to be functional. However, ORs are not directly related to the detection of odors. Several molecules delivered from the blood, cerebrospinal fluid, neighboring local neurons and glial cells, distant cells through the extracellular space, and the cells’ own self-regulating internal homeostasis can be postulated as possible ligands. Moreover, a single neuron outside the olfactory epithelium expresses more than one receptor, and the mechanism of transcriptional regulation may be different in olfactory epithelia and brain neurons. OR gene expression is altered in several neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2 with disease-, region- and subtype-specific patterns. Altered gene expression is also observed in the prefrontal cortex in schizophrenia with a major but not total influence of chlorpromazine treatment. Preliminary parallel observations have also shown the presence of taste receptors (TASRs), mainly of the bitter taste family, in the mammalian brain, whose function is not related to taste. TASRs in brain are also abnormally regulated in neurodegenerative diseases. These seminal observations point to the need for further studies on ORs and TASRs chemoreceptors in the mammalian brain. PMID:27458372

  17. [Doctor Francoise Cathala and history of prions diseases].

    PubMed

    Court, L; Hauw, J-J

    2015-12-01

    Doctor Françoise Cathala Pagesy, MD, MS, born on July 7, 1921 in Paris, passed away peacefully at home on November 5, 2012. Unconventional, passionate and enthusiastic neurologist and virologist, she devoted her life to research on latent and slow viral infections, specializing mainly on unconventional transmissible agents or prions. As a research member of Inserm (French Institute for Medical Research), she soon joined the team of Carlton Gajdusek (the NINCDS - National Institute of Nervous Central System and Stroke - of NIH), who first demonstrated the transmissibility of kuru and Creutzfeldt-Jakob disease to monkeys. When she came back to Paris, where she was followed by one of NIH members, Paul Brown, she joined the Centre de Recherches du Service de Santé des Armées (Army Health Research Center), in Percy-Clamart, where she found the experimental design and the attentive help needed for her research, which appeared heretical to many French virologists, including some authorities. A large number of research programs were set up with numerous collaborations involving CEA (Center for Atomic Energy) and other institutions in Paris and Marseilles on epidemiology, results of tissue inoculation, electrophysiology and neuropathology of human and animal prions diseases, and resistance of the infectious agent. International symposia were set up, where met, in the Val-de-Grâce hospital in Paris, the research community on "slow viral diseases". Stanley Prusiner introduced the concept - then badly accepted and still in evolution - of prion, a protein only infectious agent. Before retiring from Inserm, Françoise Cathala predicted and was involved in some of the huge sanitary crises in France. These were, first, Creutzfeldt-Jakob disease from contaminated growth hormone extracted from cadavers, which led parents to instigate legal procedure - a quite unusual practice in France. The second was Mad cow disease in the United Kingdom then in France, followed by new variant

  18. Prospects for safe and effective vaccines against prion diseases.

    PubMed

    Mabbott, Neil Andrew

    2015-01-01

    Prion diseases are subacute neurodegenerative diseases that affect humans and animals. An abnormally folded isoform (PrP(Sc)) of the host cellular prion protein is considered to constitute the major, if not sole, component of the infectious prion. The occurrence of variant Creutzfeldt-Jakob disease in humans most likely arose due to consumption of food contaminated with bovine spongiform encephalopathy prions. The demonstration that some prion infections may have the capacity to transmit to other species, especially humans, has focused attention on the development of safe and effective vaccines against these invariably fatal and currently incurable diseases. Although much effort has been invested in the development of safe and effective anti-PrP vaccines, many important issues remain to be resolved.

  19. Copper and the Prion Protein: Methods, Structures, Function, and Disease

    NASA Astrophysics Data System (ADS)

    Millhauser, Glenn L.

    2007-05-01

    The transmissible spongiform encephalopathies (TSEs) arise from conversion of the membrane-bound prion protein from PrPC to PrPSc. Examples of the TSEs include mad cow disease, chronic wasting disease in deer and elk, scrapie in goats and sheep, and kuru and Creutzfeldt-Jakob disease in humans. Although the precise function of PrPC in healthy tissues is not known, recent research demonstrates that it binds Cu(II) in an unusual and highly conserved region of the protein termed the octarepeat domain. This review describes recent connections between copper and PrPC, with an emphasis on the electron paramagnetic resonance elucidation of the specific copper-binding sites, insights into PrPC function, and emerging connections between copper and prion disease.

  20. Rare structural genetic variation in human prion diseases.

    PubMed

    Lukic, Ana; Uphill, James; Brown, Craig A; Beck, John; Poulter, Mark; Campbell, Tracy; Adamson, Gary; Hummerich, Holger; Whitfield, Jerome; Ponto, Claudia; Zerr, Inga; Lloyd, Sarah E; Collinge, John; Mead, Simon

    2015-05-01

    Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfolding of prion protein. Aside from the strong genetic risk conferred by multiple variants of the prion protein gene (PRNP), several other variants have been suggested to confer risk in the most common type, sporadic Creutzfeldt-Jakob disease (sCJD) or in the acquired prion diseases. Large and rare copy number variants (CNVs) are known to confer risk in several related disorders including Alzheimer's disease (at APP), schizophrenia, epilepsy, mental retardation, and autism. Here, we report the first genome-wide analysis for CNV-associated risk using data derived from a recent international collaborative association study in sCJD (n = 1147 after quality control) and publicly available controls (n = 5427). We also investigated UK patients with variant Creutzfeldt-Jakob disease (n = 114) and elderly women from the Eastern Highlands of Papua New Guinea who proved highly resistant to the epidemic prion disease kuru, who were compared with healthy young Fore population controls (n = 395). There were no statistically significant alterations in the burden of CNVs >100, >500, or >1000 kb, duplications, or deletions in any disease group or geographic region. After correction for multiple testing, no statistically significant associations were found. A UK blood service control sample showed a duplication CNV that overlapped PRNP, but these were not found in prion disease. Heterozygous deletions of a 3' region of the PARK2 gene were found in 3 sCJD patients and no controls (p = 0.001, uncorrected). A cell-based prion infection assay did not provide supportive evidence for a role for PARK2 in prion disease susceptibility. These data are consistent with a modest impact of CNVs on risk of late-onset neurologic conditions and suggest that, unlike APP, PRNP duplication is not a causal high-risk mutation.

  1. Quantitative EEG parameters correlate with the progression of human prion diseases

    PubMed Central

    Wehner, Tim; Lowe, Jessica; Porter, Marie-Claire; Kenny, Joanna; Thompson, Andrew; Rudge, Peter; Collinge, John; Mead, Simon

    2016-01-01

    Background Prion diseases are universally fatal and often rapidly progressive neurodegenerative diseases. EEG has long been used in the diagnosis of sporadic Creutzfeldt-Jakob disease; however, the characteristic waveforms do not occur in all types of prion diseases. Here, we re-evaluate the utility of EEG by focusing on the development of biomarkers. We test whether abnormal quantitative EEG parameters can be used to measure disease progression in prion diseases or predict disease onset in healthy individuals at risk of disease. Methods In the National Prion Monitoring Cohort study, we did quantitative encephalography on 301 occasions in 29 healthy controls and 67 patients with prion disease. The patients had either inherited prion disease or sporadic Creutzfeldt-Jakob disease. We computed the main background frequency, the α and θ power and the α/θ power ratio, then averaged these within 5 electrode groups. These measurements were then compared among participant groups and correlated with functional and cognitive scores cross-sectionally and longitudinally. Results We found lower main background frequency, α power and α/θ power ratio and higher θ power in patients compared to control participants. The main background frequency, the power in the α band and the α/θ power ratio also differed in a consistent way among the patient groups. Moreover, the main background frequency and the α/θ power ratio correlated significantly with functional and cognitive scores. Longitudinally, change in these parameters also showed significant correlation with the change in clinical and cognitive scores. Conclusions Our findings support the use of quantitative EEG to follow the progression of prion disease, with potential to help evaluate the treatment effects in future clinical-trials. PMID:27413165

  2. Chronic wasting disease and atypical forms of bovine spongiform encephalopathy and scrapie are not transmissible to mice expressing wild-type levels of human prion protein.

    PubMed

    Wilson, Rona; Plinston, Chris; Hunter, Nora; Casalone, Cristina; Corona, Cristiano; Tagliavini, Fabrizio; Suardi, Silvia; Ruggerone, Margherita; Moda, Fabio; Graziano, Silvia; Sbriccoli, Marco; Cardone, Franco; Pocchiari, Maurizio; Ingrosso, Loredana; Baron, Thierry; Richt, Juergen; Andreoletti, Olivier; Simmons, Marion; Lockey, Richard; Manson, Jean C; Barron, Rona M

    2012-07-01

    The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several novel TSEs in sheep, cattle and deer have been described and the risk posed to humans by these agents is currently unknown. In this study, we inoculated two forms of atypical BSE (BASE and H-type BSE), a chronic wasting disease (CWD) isolate and seven isolates of atypical scrapie into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP). Upon challenge with these ruminant TSEs, gene-targeted Tg mice expressing human PrP did not show any signs of disease pathology. These data strongly suggest the presence of a substantial transmission barrier between these recently identified ruminant TSEs and humans.

  3. Disease Burden of 32 Infectious Diseases in the Netherlands, 2007-2011

    PubMed Central

    Bouwknegt, Martijn; Kretzschmar, Mirjam E.; Mangen, Marie-Josée J.; Wallinga, Jacco; de Melker, Hester E.

    2016-01-01

    Background Infectious disease burden estimates provided by a composite health measure give a balanced view of the true impact of a disease on a population, allowing the relative impact of diseases that differ in severity and mortality to be monitored over time. This article presents the first national disease burden estimates for a comprehensive set of 32 infectious diseases in the Netherlands. Methods and Findings The average annual disease burden was computed for the period 2007–2011 for selected infectious diseases in the Netherlands using the disability-adjusted life years (DALY) measure. The pathogen- and incidence-based approach was adopted to quantify the burden due to both morbidity and premature mortality associated with all short and long-term consequences of infection. Natural history models, disease progression probabilities, disability weights, and other parameters were adapted from previous research. Annual incidence was obtained from statutory notification and other surveillance systems, which was corrected for under-ascertainment and under-reporting. The highest average annual disease burden was estimated for invasive pneumococcal disease (9444 DALYs/year; 95% uncertainty interval [UI]: 8911–9961) and influenza (8670 DALYs/year; 95% UI: 8468–8874), which represents 16% and 15% of the total burden of all 32 diseases, respectively. The remaining 30 diseases ranked by number of DALYs/year from high to low were: HIV infection, legionellosis, toxoplasmosis, chlamydia, campylobacteriosis, pertussis, tuberculosis, hepatitis C infection, Q fever, norovirus infection, salmonellosis, gonorrhoea, invasive meningococcal disease, hepatitis B infection, invasive Haemophilus influenzae infection, shigellosis, listeriosis, giardiasis, hepatitis A infection, infection with STEC O157, measles, cryptosporidiosis, syphilis, rabies, variant Creutzfeldt-Jakob disease, tetanus, mumps, rubella, diphtheria, and poliomyelitis. The very low burden for the latter five

  4. The expanding universe of prion diseases.

    PubMed

    Watts, Joel C; Balachandran, Aru; Westaway, David

    2006-03-01

    Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrP(C). Several mammalian species are affected by the diseases, and in the case of "mad cow disease" (BSE) the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases--including human diseases variant Creutzfeldt-Jakob disease (vCJD) and sporadic fatal insomnia (sFI), bovine amyloidotic spongiform encephalopathy (BASE), and Nor98 of sheep--have been identified in the last ten years, and chronic wasting disease (CWD) of North American deer (Odocoileus Specis) and Rocky Mountain elk (Cervus elaphus nelsoni) is undergoing a dramatic spread across North America. While amplification (BSE) and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk) can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of "sporadic" disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded.

  5. Organic brain syndrome

    MedlinePlus

    ... the skull causing pressure on brain ( subdural hematoma ) Concussion BREATHING CONDITIONS Low oxygen in the body (hypoxia) ... disease Arrhythmias Chronic subdural hematoma CO2 blood test Concussion Confusion Creutzfeldt-Jakob disease Dementia due to metabolic ...

  6. Interagency Coordination in the Case of an Intentional Agroterrorist Incident

    DTIC Science & Technology

    2009-05-11

    contaminated with BSE is connected to the development of a variant of a human disease similar to BSE, called variant Creutzfeldt - Jakob Disease (vCJD... Creutzfeldt - Jakob Disease occurs spontaneously in humans. It is seen primarily in older patients and has a long degenerative period before death occurs...introduction of an animal or plant disease with the goal of generating fear, causing economic losses, and/or undermining social stability.”5 The National

  7. 78 FR 11207 - Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-15

    ... to discuss FDA's draft risk assessment model for potential exposure to the variant Creutzfeldt-Jakob disease (vCJD) agent in Red Blood Cells for transfusion in the United States. FDA intends to...

  8. From Prion Diseases to Prion-Like Propagation Mechanisms of Neurodegenerative Diseases

    PubMed Central

    Acquatella-Tran Van Ba, Isabelle; Imberdis, Thibaut; Perrier, Véronique

    2013-01-01

    Prion diseases are fatal neurodegenerative sporadic, inherited, or acquired disorders. In humans, Creutzfeldt-Jakob disease is the most studied prion disease. In animals, the most frequent prion diseases are scrapie in sheep and goat, bovine spongiform encephalopathy in cattle, and the emerging chronic wasting disease in wild and captive deer in North America. The hallmark of prion diseases is the deposition in the brain of PrPSc, an abnormal β-sheet-rich form of the cellular prion protein (PrPC) (Prusiner 1982). According to the prion hypothesis, PrPSc can trigger the autocatalytic conversion of PrPC into PrPSc, presumably in the presence of cofactors (lipids and small RNAs) that have been recently identified. In this review, we will come back to the original works that led to the discovery of prions and to the protein-only hypothesis proposed by Dr. Prusiner. We will then describe the recent reports on mammalian synthetic prions and recombinant prions that strongly support the protein-only hypothesis. The new concept of “deformed templating” regarding a new mechanism of PrPSc formation and replication will be exposed. The review will end with a chapter on the prion-like propagation of other neurodegenerative disorders, such as Alzheimer's and Parkinson's disease and tauopathies. PMID:24222767

  9. Prion diseases and the gastrointestinal tract.

    PubMed

    Davies, G A; Bryant, Adam R; Reynolds, John D; Jirik, Frank R; Sharkey, Keith A

    2006-01-01

    The gastrointestinal (GI) tract plays a central role in the pathogenesis of transmissible spongiform encephalopathies. These are human and animal diseases that include bovine spongiform encephalopathy, scrapie and Creutzfeldt-Jakob disease. They are uniformly fatal neurological diseases, which are characterized by ataxia and vacuolation in the central nervous system. Although they are known to be caused by the conversion of normal cellular prion protein to its infectious conformational isoform (PrPsc) the process by which this isoform is propagated and transported to the brain remains poorly understood. M cells, dendritic cells and possibly enteroendocrine cells are important in the movement of infectious prions across the GI epithelium. From there, PrPsc propagation requires B lymphocytes, dendritic cells and follicular dendritic cells of Peyer's patches. The early accumulation of the disease-causing agent in the plexuses of the enteric nervous system supports the contention that the autonomic nervous system is important in disease transmission. This is further supported by the presence of PrPsc in the ganglia of the parasympathetic and sympathetic nerves that innervate the GI tract. Additionally, the lymphoreticular system has been implicated as the route of transmission from the gut to the brain. Although normal cellular prion protein is found in the enteric nervous system, its role has not been characterized. Further research is required to understand how the cellular components of the gut wall interact to propagate and transmit infectious prions to develop potential therapies that may prevent the progression of transmissible spongiform encephalopathies.

  10. Familial epidemic of meningococcal disease.

    PubMed

    Smilović, V; Vrbanec-Megla, L; Payerl-Pal, M; Puntarić, D; Baklaić, Z

    1998-03-01

    Two closely related boys from the same house hold (Home 1), aged two and three, were affected with fulminant meningococcal sepsis known as Waterhouse-Friderichsen syndrome. Neisseria meningitidis serogorup B was isolated from their blood and cerebrospinal fluid. The two-year-old boy died one day after the onset of the disease. Epidemiological examination of contacts and pharyngeal swabs were performed in 14 persons from the household, all of them relatives of the affected children, as well as in a number of other contacts. Chemoprophylaxis with cotrimoxazole was simultaneously administered to all contacts. Family histories revealed that two contacts from the household where the patients did not live (Home 2) were inadvertently omitted. Subsequent examinations, following a report of another contagious disease (salmonelosis), revealed that these two persons were Neisseria meningitidis carriers, together with another one in the same household. The carriers most probably caused the infection of a third, five-year-old boy, the deceased boy's brother (Home 1) who also developed fulminant meningococcal sepsis. The failure to take the appropriate prophylaxis led to a prolonged carrier state in the carrier from the second household. Repeated pharyngeal swab sampling revealed two more carriers from both households that had previously been negative. Control of the epidemic was achieved after 5 weeks by repeated and controlled chemoprophylaxis with ciprofloxacin, and by repeated epidemiological examinations, disinfection, and daily health surveillance by the Sanitary Inspectorate. This extremely rare instance of a familial epidemic with three infected persons emphasizes the need for consistent chemoprophylaxis in meningococcal disease contacts.

  11. Huntington's disease in two New Britain families.

    PubMed Central

    Scrimgeour, E M

    1980-01-01

    In East New Britain, Papua New Guinea, two Melanesian families were studied in which the typical features of Hungtington's disease were observed in clinically affected members. Mendelian autosomal dominant inheritance was indicated by the respective family trees. PMID:6447211

  12. Prion disease tempo determined by host-dependent substrate reduction

    PubMed Central

    Mays, Charles E.; Kim, Chae; Haldiman, Tracy; van der Merwe, Jacques; Lau, Agnes; Yang, Jing; Grams, Jennifer; Di Bari, Michele A.; Nonno, Romolo; Telling, Glenn C.; Kong, Qingzhong; Langeveld, Jan; McKenzie, Debbie; Westaway, David; Safar, Jiri G.

    2014-01-01

    The symptoms of prion infection can take years or decades to manifest following the initial exposure. Molecular markers of prion disease include accumulation of the misfolded prion protein (PrPSc), which is derived from its cellular precursor (PrPC), as well as downregulation of the PrP-like Shadoo (Sho) glycoprotein. Given the overlapping cellular environments for PrPC and Sho, we inferred that PrPC levels might also be altered as part of a host response during prion infection. Using rodent models, we found that, in addition to changes in PrPC glycosylation and proteolytic processing, net reductions in PrPC occur in a wide range of prion diseases, including sheep scrapie, human Creutzfeldt-Jakob disease, and cervid chronic wasting disease. The reduction in PrPC results in decreased prion replication, as measured by the protein misfolding cyclic amplification technique for generating PrPSc in vitro. While PrPC downregulation is not discernible in animals with unusually short incubation periods and high PrPC expression, slowly evolving prion infections exhibit downregulation of the PrPC substrate required for new PrPSc synthesis and as a receptor for pathogenic signaling. Our data reveal PrPC downregulation as a previously unappreciated element of disease pathogenesis that defines the extensive, presymptomatic period for many prion strains. PMID:24430187

  13. Could ectoparasites act as vectors for prion diseases?

    PubMed

    Lupi, Omar

    2003-06-01

    Prion diseases are rare neurodegenerative diseases of humans and animals with a lethal evolution. Several cell types found on the human skin, including keratinocytes, fibroblasts and lymphocytes, are susceptible to the abnormal infective isoform of the prion protein, which transforms the skin to produce a potential target for prion infection. Iatrogenic transmission of Creutzfeldt-Jakob disease was also recognized after corneal transplants in humans, and scrapie was successfully transmitted to mice after ocular instillation of infected brain tissue, confirming that these new routes, as well as cerebral inoculation and oral ingestion, could be important in prion infections. Animal prion infections, such as scrapie (sheep) and "mad cow disease" (cattle), have shown a pattern of horizontal transmission in farm conditions and several ectoparasites have been shown to harbor prion rods in laboratory experiments. Fly larvae and mites were exposed to brain-infected material and were readily able to transmit scrapie to hamsters. New lines of evidence have confirmed that adult flies are also able to express prion proteins. Because ocular and cerebral myiases and mite infestation are not rare worldwide, and most cases are caused by fly larvae or hay mites that usually affect sheep and cattle, it is important to discuss the possibility that these ectoparasites could eventually act as reservoirs and/or vectors for prion diseases.

  14. Progress and problems in the biology, diagnostics, and therapeutics of prion diseases

    PubMed Central

    Aguzzi, Adriano; Heikenwalder, Mathias; Miele, Gino

    2004-01-01

    The term “prion” was introduced by Stanley Prusiner in 1982 to describe the atypical infectious agent that causes transmissible spongiform encephalopathies, a group of infectious neurodegenerative diseases that include scrapie in sheep, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. Over the past twenty years, the word “prion” has been taken to signify various subtly different concepts. In this article, we refer to the prion as the transmissible principle underlying prion diseases, without necessarily implying any specific biochemical or structural identity. When Prusiner started his seminal work, the study of transmissible spongiform encephalopathies was undertaken by only a handful of scientists. Since that time, the “mad cow” crisis has put prion diseases on the agenda of both politicians and the media. Significant progress has been made in prion disease research, and many aspects of prion pathogenesis are now understood. And yet the diagnostic procedures available for prion diseases are not nearly as sensitive as they ought to be, and no therapeutic intervention has been shown to reliably affect the course of the diseases. This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields. PMID:15254579

  15. Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation

    PubMed Central

    Lau, Agnes; McDonald, Alex; Daude, Nathalie; Mays, Charles E; Walter, Eric D; Aglietti, Robin; Mercer, Robert CC; Wohlgemuth, Serene; van der Merwe, Jacques; Yang, Jing; Gapeshina, Hristina; Kim, Chae; Grams, Jennifer; Shi, Beipei; Wille, Holger; Balachandran, Aru; Schmitt-Ulms, Gerold; Safar, Jiri G; Millhauser, Glenn L; Westaway, David

    2015-01-01

    The cellular prion protein (PrPC) comprises a natively unstructured N-terminal domain, including a metal-binding octarepeat region (OR) and a linker, followed by a C-terminal domain that misfolds to form PrPSc in Creutzfeldt-Jakob disease. PrPC β-endoproteolysis to the C2 fragment allows PrPSc formation, while α-endoproteolysis blocks production. To examine the OR, we used structure-directed design to make novel alleles, ‘S1’ and ‘S3’, locking this region in extended or compact conformations, respectively. S1 and S3 PrP resembled WT PrP in supporting peripheral nerve myelination. Prion-infected S1 and S3 transgenic mice both accumulated similar low levels of PrPSc and infectious prion particles, but differed in their clinical presentation. Unexpectedly, S3 PrP overproduced C2 fragment in the brain by a mechanism distinct from metal-catalysed hydrolysis reported previously. OR flexibility is concluded to impact diverse biological endpoints; it is a salient variable in infectious disease paradigms and modulates how the levels of PrPSc and infectivity can either uncouple or engage to drive the onset of clinical disease. PMID:25661904

  16. The Leeuwenhoek Lecture 2001. Animal origins of human infectious disease.

    PubMed

    Weiss, R A

    2001-06-29

    Since time immemorial animals have been a major source of human infectious disease. Certain infections like rabies are recognized as zoonoses caused in each case by direct animal-to-human transmission. Others like measles became independently sustained with the human population so that the causative virus has diverged from its animal progenitor. Recent examples of direct zoonoses are variant Creutzfeldt-Jakob disease arising from bovine spongiform encephalopathy, and the H5N1 avian influenza outbreak in Hong Kong. Epidemics of recent animal origin are the 1918-1919 influenza pandemic, and acquired immune deficiency syndrome caused by human immunodeficiency virus (HIV). Some retroviruses jump into and out of the chromosomal DNA of the host germline, so that they oscillate between being inherited Mendelian traits or infectious agents in different species. Will new procedures like animal-to-human transplants unleash further infections? Do microbes become more virulent upon cross-species transfer? Are animal microbes a threat as biological weapons? Will the vast reservoir of immunodeficient hosts due to the HIV pandemic provide conditions permissive for sporadic zoonoses to take off as human-to-human transmissible diseases? Do human infections now pose a threat to endangered primates? These questions are addressed in this lecture.

  17. Role of zinc and copper ions in the pathogenetic mechanisms of Alzheimer's and Parkinson's diseases.

    PubMed

    Stelmashook, E V; Isaev, N K; Genrikhs, E E; Amelkina, G A; Khaspekov, L G; Skrebitsky, V G; Illarioshkin, S N

    2014-05-01

    Disbalance of zinc (Zn2+) and copper (Cu2+) ions in the central nervous system is involved in the pathogenesis of numerous neurodegenerative disorders such as multisystem atrophy, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, Wilson-Konovalov disease, Alzheimer's disease, and Parkinson's disease. Among these, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most frequent age-related neurodegenerative pathologies with disorders in Zn2+ and Cu2+ homeostasis playing a pivotal role in the mechanisms of pathogenesis. In this review we generalized and systematized current literature data concerning this problem. The interactions of Zn2+ and Cu2+ with amyloid precursor protein (APP), β-amyloid (Abeta), tau-protein, metallothioneins, and GSK3β are considered, as well as the role of these interactions in the generation of free radicals in AD and PD. Analysis of the literature suggests that the main factors of AD and PD pathogenesis (oxidative stress, structural disorders and aggregation of proteins, mitochondrial dysfunction, energy deficiency) that initiate a cascade of events resulting finally in the dysfunction of neuronal networks are mediated by the disbalance of Zn2+ and Cu2+.

  18. The influence of PRNP polymorphisms on human prion disease susceptibility: an update.

    PubMed

    Kobayashi, Atsushi; Teruya, Kenta; Matsuura, Yuichi; Shirai, Tsuyoshi; Nakamura, Yoshikazu; Yamada, Masahito; Mizusawa, Hidehiro; Mohri, Shirou; Kitamoto, Tetsuyuki

    2015-08-01

    Two normally occurring polymorphisms of the human PRNP gene, methionine (M)/valine (V) at codon 129 and glutamic acid (E)/lysine (K) at codon 219, can affect the susceptibility to prion diseases. It has long been recognized that 129M/M homozygotes are overrepresented in sporadic Creutzfeldt-Jakob disease (CJD) patients and variant CJD patients, whereas 219E/K heterozygotes are absent in sporadic CJD patients. In addition to these pioneering findings, recent progress in experimental transmission studies and worldwide surveillance of prion diseases have identified novel relationships between the PRNP polymorphisms and the prion disease susceptibility. For example, although 219E/K heterozygosity confers resistance against the development of sporadic CJD, this genotype is not entirely protective against acquired forms (iatrogenic CJD and variant CJD) or genetic forms (genetic CJD and Gerstmann-Sträussler-Scheinker syndrome) of prion diseases. In addition, 129M/V heterozygotes predispose to genetic CJD caused by a pathogenic PRNP mutation at codon 180. These findings show that the effects of the PRNP polymorphisms may be more complicated than previously thought. This review aims to summarize recent advances in our knowledge about the influence of the PRNP polymorphisms on the prion disease susceptibility.

  19. Preclinical detection of infectivity and disease-specific PrP in blood throughout the incubation period of prion disease

    PubMed Central

    Sawyer, Elizabeth B.; Edgeworth, Julie Ann; Thomas, Claire; Collinge, John; Jackson, Graham S.

    2015-01-01

    Variant Creutzfeldt-Jakob disease (vCJD) is a fatal neurodegenerative disorder characterised by accumulation of pathological isoforms of the prion protein, PrP. Although cases of clinical vCJD are rare, there is evidence there may be tens of thousands of infectious carriers in the United Kingdom alone. This raises concern about the potential for perpetuation of infection via medical procedures, in particular transfusion of contaminated blood products. Accurate biochemical detection of prion infection is crucial to mitigate risk and we have previously reported a blood assay for vCJD. This assay is sensitive for abnormal PrP conformers at the earliest stages of preclinical prion disease in mice and precedes the maximum infectious titre in blood. Not only does this support the possibility of screening asymptomatic individuals, it will also facilitate the elucidation of the complex relationship that exists between the ensemble of abnormal PrP conformers present in blood and the relationship to infectivity. PMID:26631638

  20. Novel strain properties distinguishing sporadic prion diseases sharing prion protein genotype and prion type

    PubMed Central

    Cracco, Laura; Notari, Silvio; Cali, Ignazio; Sy, Man-Sun; Chen, Shu G.; Cohen, Mark L.; Ghetti, Bernardino; Appleby, Brian S.; Zou, Wen-Quan; Caughey, Byron; Safar, Jiri G.; Gambetti, Pierluigi

    2017-01-01

    In most human sporadic prion diseases the phenotype is consistently associated with specific pairings of the genotype at codon 129 of the prion protein gene and conformational properties of the scrapie PrP (PrPSc) grossly identified types 1 and 2. This association suggests that the 129 genotype favours the selection of a distinct strain that in turn determines the phenotype. However, this mechanism cannot play a role in the phenotype determination of sporadic fatal insomnia (sFI) and a subtype of sporadic Creutzfeldt-Jakob disease (sCJD) identified as sCJDMM2, which share 129 MM genotype and PrPSc type 2 but are associated with quite distinct phenotypes. Our detailed comparative study of the PrPSc conformers has revealed major differences between the two diseases, which preferentially involve the PrPSc component that is sensitive to digestion with proteases (senPrPSc) and to a lesser extent the resistant component (resPrPSc). We conclude that these variations are consistent with two distinct strains in sFI and sCJDMM2, and that the rarer sFI is the result of a variant strain selection pathway that might be favoured by a different brain site of initial PrPSc formation in the two diseases. PMID:28091514

  1. Reversible symptoms and clearance of mutant prion protein in an inducible model of a genetic prion disease in Drosophila melanogaster.

    PubMed

    Murali, A; Maue, R A; Dolph, P J

    2014-07-01

    Prion diseases are progressive disorders that affect the central nervous system leading to memory loss, personality changes, ataxia and neurodegeneration. In humans, these disorders include Creutzfeldt-Jakob disease, kuru and Gerstmann-Straüssler-Scheinker (GSS) syndrome, the latter being a dominantly inherited prion disease associated with missense mutations in the gene that codes for the prion protein. The exact mechanism by which mutant prion proteins affect the central nervous system and cause neurological disease is not well understood. We have generated an inducible model of GSS disease in Drosophila melanogaster by temporally expressing a misfolded form of the murine prion protein in cholinergic neurons. Flies accumulating this mutant protein develop motor abnormalities which are associated with electrophysiological defects in cholinergic neurons. We find that, upon blocking the expression of the mutant protein, both behavioral and electrophysiological defects can be reversed. This represents the first case of reversibility reported in a model of genetic prion disease. Additionally, we observe that endogenous mechanisms exist within Drosophila that are capable of clearing the accumulated prion protein.

  2. Autism and Autoimmune Disease: A Family Study

    ERIC Educational Resources Information Center

    Money, John; And Others

    1971-01-01

    Described in a family in which the youngest boy has early infantile autism, Addison's disease, and moniliasis and two older boys have autoimmune disease with hypoparathyroidism, Addison's disease, moniliasis, and either alopecia totalis or diabetes mellitus, while the oldest boy and parents are symptom free. (KW)

  3. Anterior-posterior and lateral hemispheric alterations in cortical glucose utilization in Alzheimer's disease

    SciTech Connect

    Friedland, T.F.; Budinger, T.F.; Jaqust, W.J.; Yano, Y.; Huesman, R.H.; Knittel, B.; Koss, E.; Ober, B.A.

    1984-01-01

    The anatomical and chemical features of Alzheimer's disease (AD) are not distributed evenly throughout the brain. However, the nature of this focality has not been well established in vivo. Dynamic studies using the Donner 280-Crystal Positron Tomograph with (F-18)2-fluorodeoxyglucose were performed in 17 subjects meeting current research criteria for AD, and in 7 healthy age-matched control subjects. Glucose metabolic rates in the temporal-parietal cortex are 27% lower in AD than in controls. Ratios of activity density reveal consistently lower metabolic rates in temporal-parietal than frontal cortex in the AD group, while healthy aged subjects have equal metabolic rates in the two areas. Similar findings have been reported by other laboratories. A major finding is a striking lateral asymmetry of cortical metabolism in AD which does not favor either hemisphere. (The asymmetry is 13% in the AD group, 3% in controls, p<.005.) This has not been previously reported in AD. The consistency with which anterior-posterior metabolic differences are found in AD suggests that the focality of the metabolic changes may be used to develop a noninvasive diagnostic test for the disorder. The metabolic asymmetry in AD may be compared to the clinical and pathological asymmetry found in Creutzfeldt-Jakob disease, and may represent an additional link between AD and the subacute spongiform encephalopathies.

  4. An antibody to the aggregated synthetic prion protein peptide (PrP106-126) selectively recognizes disease-associated prion protein (PrP) from human brain specimens.

    PubMed

    Jones, Michael; Wight, Darren; McLoughlin, Victoria; Norrby, Katherine; Ironside, James W; Connolly, John G; Farquhar, Christine F; MacGregor, Ian R; Head, Mark W

    2009-04-01

    Human prion diseases are characterized by the conversion of the normal host cellular prion protein (PrP(C)) into an abnormal misfolded form [disease-associated prion protein (PrP(Sc))]. Antibodies that are capable of distinguishing between PrP(C) and PrP(Sc) may prove to be useful, not only for the diagnosis of these diseases, but also for a better understanding of the molecular mechanisms involved in disease pathogenesis. In an attempt to produce such antibodies, we immunized mice with an aggregated peptide spanning amino acid residues 106 to 126 of human PrP (PrP106-126). We were able to isolate and single cell clone a hybridoma cell line (P1:1) which secreted an IgM isotype antibody [monoclonal antibody (mAb P1:1)] that recognized the aggregated, but not the monomeric form of the immunogen. When used in immunoprecipitation assays, the antibody did not recognize normal PrP(C) from non-prion disease brain specimens, but did selectively immunoprecipitate full-length PrP(Sc) from cases of variant and sporadic Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker disease. These results suggest that P1:1 recognizes an epitope formed during the structural rearrangement or aggregation of the PrP that is common to the major PrP(Sc) types found in the most common forms of human prion disease.

  5. The impact of social amplification and attenuation of risk and the public reaction to mad cow disease in Canada.

    PubMed

    Lewis, Roxanne E; Tyshenko, Michael G

    2009-05-01

    Following the detection of bovine spongiform encephalopathy (BSE) in Canada, and subsequently in the United States, confidence in the safety of beef products remained high. Consumers actually increased their consumption of beef slightly after the news of an increased risk from mad cow disease, which has been interpreted as public support for beef farmers and confidence in government regulators. The Canadian public showed a markedly different reaction to the news of domestic BSE than the furious and panicked responses observed in the United Kingdom, Germany, and Japan. Using the social amplification of risk framework, we show that, while other countries displayed social amplification of risk, Canada experienced a social attenuation of risk. The attenuated reaction in Canada toward mad cow disease and increased human health risks from variant Creutzfeldt-Jakob disease (vCJD) was due to the social context at the time when BSE was discovered domestically. Mortality, morbidity, and psychosocial impacts resulting from other major events such as severe acute respiratory syndrome (SARS), West Nile virus (WNV), and the U.S.-Iraq war made the theoretical risks of BSE and vCJD a lower priority, reducing its concern as a risk issue.

  6. Prion Disease Induces Alzheimer Disease-Like Neuropathologic Changes

    PubMed Central

    Tousseyn, Thomas; Bajsarowicz, Krystyna; Sánchez, Henry; Gheyara, Ania; Oehler, Abby; Geschwind, Michael; DeArmond, Bernadette; DeArmond, Stephen J.

    2016-01-01

    We examined the brains of 266 patients with prion diseases (PrionD) and found that 46 (17%) had Alzheimer disease (AD)-like changes. To explore potential mechanistic links between PrionD and AD, we exposed human brain aggregates (Hu BrnAggs) to brain homogenate from a patient with sporadic Creutzfeldt-Jakob disease (CJD) and found that the neurons in the Hu BrnAggs produced many β-amyloid (β42) inclusions, whereas uninfected, control-exposed Hu BrnAggs did not. Western blots of 20-pooled CJD-infected BrnAggs verified higher Aβ42 levels than controls. We next examined the CA1 region of the hippocampus from 14 patients with PrionD and found that 5 patients had low levels of scrapie-associated prion protein (PrPSc), many Aβ42 intraneuronal inclusions, low APOE-4, and no significant nerve cell loss. Seven patients had high levels of PrPSc, low Aβ42, high APOE-4 and 40% nerve cell loss, suggesting that APOE-4 and PrPSc together cause neuron loss in PrionD. There were also increased levels of hyperphosphorylated tau protein (Hτ) and Hτ-positive neuropil threads and neuron bodies in both PrionD and AD groups. The brains of 6 age-matched control patients without dementia did not contain Aβ42 deposits; however, there were rare Hτ-positive threads in 5 controls and 2 controls had a few Hτ-positive nerve cell bodies. We conclude that PrionD may trigger biochemical changes similar to AD and suggest that PrionD are diseases of PrPSc, Aβ42, APOE-4 and abnormal tau. PMID:26226132

  7. Family Physician Perspectives on Primary Immunodeficiency Diseases

    PubMed Central

    Orange, Jordan S.; Seeborg, Filiz O.; Boyle, Marcia; Scalchunes, Christopher; Hernandez-Trujillo, Vivian

    2016-01-01

    Primary immunodeficiency diseases (PIDs) include over 250 diverse disorders. The current study assessed management of PID by family practice physicians. The American Academy of Allergy, Asthma, and Immunology Primary Immunodeficiency Committee and the Immune Deficiency Foundation conducted an incentivized mail survey of family practice physician members of the American Medical Association and the American Osteopathic Association in direct patient care. Responses were compared with subspecialist immunologist responses from a similar survey. Surveys were returned by 528 (of 4500 surveys mailed) family practice physicians, of whom 44% reported following ≥1 patient with PID. Selective immunoglobulin A deficiency (21%) and chronic granulomatous disease (11%) were most common and were followed by significantly more subspecialist immunologists (P < 0.05). Use of intravenously administered immunoglobulin and live viral vaccinations across PID was significantly different (P < 0.05). Few family practice physicians were aware of professional guidelines for diagnosis and management of PID (4 vs. 79% of subspecialist immunologists, P < 0.05). Family practice physicians will likely encounter patients with PID diagnoses during their career. Differences in how family practice physicians and subspecialist immunologists manage patients with PID underscore areas where improved educational and training initiatives may benefit patient care. PMID:27066486

  8. Benign familial Degos disease worsening during immunosuppression.

    PubMed

    Powell, J; Bordea, C; Wojnarowska, F; Farrell, A M; Morris, P J

    1999-09-01

    We describe a 61-year-old woman with skin lesions consistent with those found in Degos disease, both in clinical and in histological appearance. She had had several of these lesions for many years, as had her mother, sister and niece. In 1991, she underwent cadaveric renal transplantation and was treated with immunosuppression: prednisolone, azathioprine and cyclosporin. At that time, she developed many more characteristic skin lesions, and these were slightly larger and more noticeable than those she had had previously. She and the other affected family members appear to fit into the more benign subgroup of Degos disease, and it seems that her immunosuppression aggravated her cutaneous disease.

  9. Medullary cystic disease: a family study.

    PubMed

    Chen, H C; Chang, J M; Tsai, J H; Lai, Y H

    1998-03-01

    Medullary cystic disease of the kidney is characterized by progressive tubulointerstitial disease with medullary cyst formation and secondary glomerular sclerosis. We treated a patient with chronic renal failure and investigated the family history of renal disease. The patient, an 18-year-old woman, was admitted due to poor appetite and fatigue for several months. Findings on physical examination were normal except for a pale conjunctiva. Urinalysis revealed only mild proteinuria with clear sediment. The hemogram showed normocytic normochromic anemia with hemoglobin 86 g/L. The patient was azotemic and her creatinine clearance rate was 10.7 mL/min. Renal sonography showed contraction of both kidneys with a marked increase in cortical echogenicity. One small cyst was found in the medullary area. Computed tomography (CT) and magnetic resonance imaging revealed several medullary cysts. Percutaneous renal biopsy showed focal and periglomerular sclerosis, marked tubular atrophy, and interstitial fibrosis. Ten of her family members were examined for renal function, and by sonography and CT. Five had medullary cysts, and three of the five showed abnormal renal function. Medullary cystic disease should be considered in the differential diagnosis of patients with renal disease and a positive family history.

  10. Interleukin-1 Family Cytokines in Liver Diseases

    PubMed Central

    Tsutsui, Hiroko; Cai, Xianbin; Hayashi, Shuhei

    2015-01-01

    The gene encoding IL-1 was sequenced more than 30 years ago, and many related cytokines, such as IL-18, IL-33, IL-36, IL-37, IL-38, IL-1 receptor antagonist (IL-1Ra), and IL-36Ra, have since been identified. IL-1 is a potent proinflammatory cytokine and is involved in various inflammatory diseases. Other IL-1 family ligands are critical for the development of diverse diseases, including inflammatory and allergic diseases. Only IL-1Ra possesses the leader peptide required for secretion from cells, and many ligands require posttranslational processing for activation. Some require inflammasome-mediated processing for activation and release, whereas others serve as alarmins and are released following cell membrane rupture, for example, by pyroptosis or necroptosis. Thus, each ligand has the proper molecular process to exert its own biological functions. In this review, we will give a brief introduction to the IL-1 family cytokines and discuss their pivotal roles in the development of various liver diseases in association with immune responses. For example, an excess of IL-33 causes liver fibrosis in mice via activation and expansion of group 2 innate lymphoid cells to produce type 2 cytokines, resulting in cell conversion into pro-fibrotic M2 macrophages. Finally, we will discuss the importance of IL-1 family cytokine-mediated molecular and cellular networks in the development of acute and chronic liver diseases. PMID:26549942

  11. Treatment of Prion Disease with Heterologous Prion Proteins

    PubMed Central

    Skinner, Pamela J.; Kim, Hyeon O.; Bryant, Damani; Kinzel, Nikilyn J.; Reilly, Cavan; Priola, Suzette A.; Ward, Anne E.; Goodman, Patricia A.; Olson, Katherine; Seelig, Davis M.

    2015-01-01

    Prion diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle, and scrapie in sheep are fatal neurodegenerative diseases for which there is no effective treatment. The pathology of these diseases involves the conversion of a protease sensitive form of the cellular prion protein (PrPC) into a protease resistant infectious form (PrPsc or PrPres). Both in vitro (cell culture and cell free conversion assays) and in vivo (animal) studies have demonstrated the strong dependence of this conversion process on protein sequence homology between the initial prion inoculum and the host’s own cellular prion protein. The presence of non-homologous (heterologous) proteins is often inhibitory to this conversion process. We hypothesize that the presence of heterologous prion proteins from one species might therefore constitute an effective treatment for prion disease in another species. To test this hypothesis, we infected mice intracerebrally with murine adapted RML-Chandler scrapie and treated them with heterologous prion protein (purified bacterially expressed recombinant hamster prion protein) or vehicle alone. Treated animals demonstrated reduced disease associated pathology, decreased accumulation of protease-resistant disease-associated prion protein, with delayed onset of clinical symptoms and motor deficits. This was concomitant with significantly increased survival times relative to mock-treated animals. These results provide proof of principle that recombinant hamster prion proteins can effectively and safely inhibit prion disease in mice, and suggest that hamster or other non-human prion proteins may be a viable treatment for prion diseases in humans. PMID:26134409

  12. Celiac disease. CME update for family physicians.

    PubMed Central

    Devlin, Shane M.; Andrews, Christopher N.; Beck, Paul L.

    2004-01-01

    OBJECTIVE: To review current understanding of the epidemiology, pathophysiology, diagnosis, and management of celiac disease. QUALITY OF EVIDENCE: Few recent randomized controlled trials (level I evidence) have studied treatments for celiac disease. There are recent comparative studies (level II evidence) and there is well established consensus (level III evidence) on diagnosis and treatment of celiac disease. MAIN MESSAGE: Celiac disease is an immune-mediated small bowel enteropathy caused by exposure to wheat gluten protein. The disease can be insidious and often presents with only subtle extraintestinal manifestations in a variety of organ systems. Recent epidemiologic surveys suggest celiac disease is much more common in North America than previously thought. Advances in immunology and screening have made diagnosis more reliable than in the past. Removing gluten from the diet is effective in most cases. CONCLUSION: Celiac disease manifests subtly and is an easy diagnosis to miss. Good laboratory screening tests and effective treatment are available. Family practitioners should consider celiac disease in patients who present with confounding symptoms. PMID:15171674

  13. Tay Sachs and Related Storage Diseases: Family Planning

    ERIC Educational Resources Information Center

    Schneiderman, Gerald; And Others

    1978-01-01

    Based on interviews with 24 families, the article discusses family planning and the choices available to those families in which a child has previously died from Tay-Sachs or related lipid storage diseases. (IM)

  14. Clinical Issues-May 2016.

    PubMed

    Van Wicklin, Sharon A

    2016-05-01

    Variations in documenting surgical wound classification Key words: surgical wound classification, clean, clean-contaminated, contaminated, dirty. Wearing long-sleeved jackets while preparing and packaging items for sterilization Key words: long-sleeved jackets, organic material, sterile processing. Endoscopic transmission of prions Key words: prions, high-risk tissue, low-risk tissue, Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD). Wearing gloves when handling flexible endoscopes Key words: gloves, low-protein, powder-free, natural rubber latex gloves, latex-free gloves.

  15. Bilateral familial Hirayama disease in a father and daughter

    PubMed Central

    Pandey, Sanjay; Jain, Shruti

    2016-01-01

    We are reporting a case of bilateral familial Hirayama disease where a father and daughter are the affected members of the family with the similar distribution of their weakness and wasting. To the best of our knowledge, bilateral familial Hirayama disease has not been described in father and daughter. PMID:27293344

  16. The cognitive profile of prion disease: a prospective clinical and imaging study

    PubMed Central

    Caine, Diana; Tinelli, Renata J; Hyare, Harpreet; De Vita, Enrico; Lowe, Jessica; Lukic, Ana; Thompson, Andrew; Porter, Marie-Claire; Cipolotti, Lisa; Rudge, Peter; Collinge, John; Mead, Simon

    2015-01-01

    Objectives Prion diseases are dementing illnesses with poorly defined neuropsychological features. This is probably because the most common form, sporadic Creutzfeldt-Jakob disease, is often rapidly progressive with pervasive cognitive decline making detailed neuropsychological investigation difficult. This study, which includes patients with inherited, acquired (iatrogenic and variant) and sporadic forms of the disease, is the only large-scale neuropsychological investigation of this patient group ever undertaken and aimed to define a neuropsychological profile of human prion diseases. Methods A tailored short cognitive examination of all of the patients (n = 81), with detailed neuropsychological testing in a subset with mild disease (n = 30) and correlation with demographic, clinical, genetic (PRNP mutation and polymorphic codon 129 genotype), and other variables (MRI brain signal change in cortex, basal ganglia or thalamus; quantitative research imaging, cerebrospinal fluid 14-3-3 protein). Results Comparison with healthy controls showed patients to be impaired on all tasks. Principal components analysis showed a major axis of fronto-parietal dysfunction that accounted for approximately half of the variance observed. This correlated strongly with volume reduction in frontal and parietal gray matter on MRI. Examination of individual patients' performances confirmed early impairment on this axis, suggesting characteristic cognitive features in mild disease: prominent executive impairment, parietal dysfunction, a largely expressive dysphasia, with reduced motor speed. Interpretation Taken together with typical neurological features, these results complete a profile that should improve differential diagnosis in a clinical setting. We propose a tailored neuropsychological battery for early recognition of clinical onset of symptoms with potential for use in clinical trials involving at-risk individuals. PMID:26000326

  17. Evidence of subclinical prion disease in aged mice following exposure to bovine spongiform encephalopathy.

    PubMed

    Brown, Karen L; Mabbott, Neil A

    2014-01-01

    The occurrence of variant Creutzfeldt-Jakob (vCJD) disease in humans was almost certainly the result of consumption of food contaminated with bovine spongiform encephalopathy (BSE) prions. Despite probable widespread exposure of the UK population to BSE-contaminated food in the 1980s, vCJD has been identified predominantly in young individuals, and there have been fewer cases of clinical disease than anticipated. The reasons for this are uncertain. Following peripheral exposure, many prions replicate within the lymphoid tissues before infecting the central nervous system. We have shown that the effects of host age on the microarchitecture of the spleen significantly impair susceptibility to mouse-adapted prions after peripheral exposure. The transmission of prions between different mammalian species is considered to be limited by the 'species barrier', which is dependent on several factors, including an intact immune system. Thus, cross-species prion transmission may be much less efficient in aged individuals. To test this hypothesis, we compared prion pathogenesis in groups of young (6-8 weeks old) and aged (600 days old) mice injected with primary BSE brain homogenate. We showed that prion pathogenesis was impaired dramatically in aged mice when compared with young animals. Whereas most young mice succumbed to clinical prion disease, all aged mice failed to develop clinical disease during their lifespans. However, the demonstration that prion accumulation was detected in the lymphoid tissues of some aged mice after injection with primary BSE brain homogenate, in the absence of clinical signs of prion disease, has important implications for human health.

  18. Familial aggregation of Parkinson disease in Utah

    PubMed Central

    Savica, Rodolfo; Pulst, Stefan

    2016-01-01

    Objective: To describe clustering of death from Parkinson disease (PD) in relatives in a large US study. Methods: We analyzed the Utah Population Database resource, which includes genealogy data of more than 2.7 million individuals linked to 519,061 individuals with a Utah death certificate (DC). We identified individuals whose DC included PD as a cause of death using ICD coding. In those individuals whose Utah DC listed PD as a cause of death, the relative risk (RR) of death with PD was determined among close and distant relatives using sex-, birth year–, and birthplace-specific rates. Results: We identified 4,031 individuals whose DC indicated PD. Among 18,127 first-degree relatives of probands with a Utah DC, the RR of death with PD was significantly increased (RR = 1.82, 95% confidence interval [CI] 1.61–2.04). The RR of death with PD was also significantly increased among 40,546 second-degree relatives with a Utah DC (RR = 1.44, 95% CI 1.29–1.60) and among 93,398 third-degree relatives with a Utah DC (RR = 1.10, 95% CI 1.03–1.18). Conclusions: Significant evidence for excess familial clustering was observed for PD deaths. The excess familial clustering and the significantly elevated RRs for PD among close and distant relatives strongly support a genetic contribution to PD mortality. These results confirm and expand the results of previous studies of PD by quantifying the risk of PD death among more distant relatives. PMID:27123483

  19. Retinal function and morphology are altered in cattle infected with the prion disease transmissible mink encephalopathy.

    PubMed

    Smith, J D; Greenlee, J J; Hamir, A N; Richt, J A; Greenlee, M H West

    2009-09-01

    Transmissible spongiform encephalopathies (TSEs) are a group of diseases that result in progressive and invariably fatal neurologic disease in both animals and humans. TSEs are characterized by the accumulation of an abnormal protease-resistant form of the prion protein in the central nervous system. Transmission of infectious TSEs is believed to occur via ingestion of prion protein-contaminated material. This material is also involved in the transmission of bovine spongiform encephalopathy ("mad cow disease") to humans, which resulted in the variant form of Creutzfeldt-Jakob disease. Abnormal prion protein has been reported in the retina of TSE-affected cattle, but despite these observations, the specific effect of abnormal prion protein on retinal morphology and function has not been assessed. The objective of this study was to identify and characterize potential functional and morphologic abnormalities in the retinas of cattle infected with a bovine-adapted isolate of transmissible mink encephalopathy. We used electroretinography and immunohistochemistry to examine retinas from 10 noninoculated and 5 transmissible mink encephalopathy-inoculated adult Holstein steers. Here we show altered retinal function, as evidenced by prolonged implicit time of the electroretinogram b-wave, in transmissible mink encephalopathy-infected cattle before the onset of clinical illness. We also demonstrate disruption of rod bipolar cell synaptic terminals, indicated by decreased immunoreactivity for the alpha isoform of protein kinase C and vesicular glutamate transporter 1, and activation of Müller glia, as evidenced by increased glial fibrillary acidic protein and glutamine synthetase expression, in the retinas of these cattle at the time of euthanasia due to clinical deterioration. This is the first study to identify both functional and morphologic alterations in the retinas of TSE-infected cattle. Our results support future efforts to focus on the retina for the development of

  20. A naturally occurring variant of the human prion protein completely prevents prion disease.

    PubMed

    Asante, Emmanuel A; Smidak, Michelle; Grimshaw, Andrew; Houghton, Richard; Tomlinson, Andrew; Jeelani, Asif; Jakubcova, Tatiana; Hamdan, Shyma; Richard-Londt, Angela; Linehan, Jacqueline M; Brandner, Sebastian; Alpers, Michael; Whitfield, Jerome; Mead, Simon; Wadsworth, Jonathan D F; Collinge, John

    2015-06-25

    Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.

  1. A low molecular-weight ferroxidase is increased in the CSF of sCJD cases: CSF ferroxidase and transferrin as diagnostic biomarkers for sCJD

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Imbalance of brain iron homeostasis is a common feature of neurodegenerative conditions that include sporadic Creutzfeldt-Jakob disease (sCJD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease, among others. However, the mechanisms underlying this change are unclear. In s...

  2. Detecting and quantifying prions: Mass spectrometry-based approaches

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prions are novel pathogens that cause a set of rare fatal neurological diseases know as transmissible spongiform encephalopathies. Examples of these diseases include Creutzfeldt-Jakob disease, scrapie and chronic wasting disease. Prions are able to recruit a normal cellular prion protein and convert...

  3. Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders.

    PubMed

    Islam, Md Torequl

    2017-01-01

    Reactive species play an important role in physiological functions. Overproduction of reactive species, notably reactive oxygen (ROS) and nitrogen (RNS) species along with the failure of balance by the body's antioxidant enzyme systems results in destruction of cellular structures, lipids, proteins, and genetic materials such as DNA and RNA. Moreover, the effects of reactive species on mitochondria and their metabolic processes eventually cause a rise in ROS/RNS levels, leading to oxidation of mitochondrial proteins, lipids, and DNA. Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Multiple sclerosis, and Parkinson's diseases. In addition, oxidative stress causing protein misfold may turn to other NDDs include Creutzfeldt-Jakob disease, Bovine Spongiform Encephalopathy, Kuru, Gerstmann-Straussler-Scheinker syndrome, and Fatal Familial Insomnia. An overview of the oxidative stress and mitochondrial dysfunction-linked NDDs has been summarized in this review.

  4. Detection of PrP(Sc) in peripheral tissues of clinically affected cattle after oral challenge with bovine spongiform encephalopathy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative prion disease that affects cattle and can be transmitted to human beings as new variant Creutzfeldt-Jakob disease (vCJD). A protease-resistant, disease-associated isoform of the prion protein (PrP**Sc) accumulates in the central ner...

  5. Study of familial Parkinson's disease in Russia, Uzbekistan, and Zambia

    PubMed Central

    Atadzhanov, M; Zumla, A; Mwaba, P

    2005-01-01

    Objective: The aims of this study were (A) to determine inheritance patterns of familial Parkinson's disease in three different geographical areas (Russia, Uzbekistan, and Zambia); (B) compare clinical characteristics of familial with sporadic Parkinson's disease; and (C) assess whether there were ethnic differences in clinical manifestations of the disease. Methods: Fifty two index cases of familial Parkinson's disease in Moscow, 55 in Tashkent, and 27 in Lusaka were selected on the basis of the typical clinical features of Parkinson's disease with a familial history. The sex ratio, transmission patterns, and segregation ratio were determined by pedigree analysis. Results: Familial Parkinson's disease was found in all three countries (30 families in Russia, 12 in Uzbekistan, and seven in Zambia), and appeared more common in Russia. Both autosomal dominant and autosomal recessive patterns of inheritance were seen, but autosomal dominance was more common in all countries. Conclusions: In all three countries men have a higher risk of developing Parkinson's disease than women and there are ethnic differences in clinical manifestations of the disease. The onset of both familial and sporadic Parkinson's disease in Zambian patients occurs at a younger age and is associated with slow progression and a benign course, and generally responds well to levodopa treatment. PMID:15701745

  6. Presymptomatic cortical thinning in familial Alzheimer disease

    PubMed Central

    Nicholas, Jennifer M.; Lehmann, Manja; Ryan, Natalie S.; Liang, Yuying; Macpherson, Kirsty; Modat, Marc; Rossor, Martin N.; Schott, Jonathan M.; Ourselin, Sebastien; Fox, Nick C.

    2016-01-01

    Objective: To identify a cortical signature pattern of cortical thinning in familial Alzheimer disease (FAD) and assess its utility in detecting and tracking presymptomatic neurodegeneration. Methods: We recruited 43 FAD mutation carriers—36 PSEN1, 7 APP (20 symptomatic, 23 presymptomatic)—and 42 healthy controls to a longitudinal clinical and MRI study. T1-weighted MRI scans were acquired at baseline in all participants; 55 individuals (33 mutation carriers; 22 controls) had multiple (mean 2.9) follow-up scans approximately annually. Cortical thickness was measured using FreeSurfer. A cortical thinning signature was identified from symptomatic FAD participants. We then examined cortical thickness changes in this signature region in presymptomatic carriers and assessed associations with cognitive performance. Results: The cortical signature included 6 regions: entorhinal cortex, inferior parietal cortex, precuneus, superior parietal cortex, superior frontal cortex, and supramarginal gyrus. There were significant differences in mean cortical signature thickness between mutation carriers and controls 3 years before predicted symptom onset. The earliest significant difference in a single region, detectable 4 years preonset, was in the precuneus. Rate of change in cortical thickness became significantly different in the cortical signature at 5 years before predicted onset, and in the precuneus at 8 years preonset. Baseline mean signature thickness predicted rate of subsequent thinning and correlated with presymptomatic cognitive change. Conclusions: The FAD cortical signature appears to be similar to that described for sporadic AD. All component regions showed significant presymptomatic thinning. A composite signature may provide more robust results than a single region and have utility as an outcome measure in presymptomatic trials. PMID:27733562

  7. Transmission of scrapie prions to primate after an extended silent incubation period

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Classical bovine spongiform encephalopathy (c-BSE) is an animal prion disease that also causes variant Creutzfeldt-Jakob disease in humans. Over the past decades, c-BSE's zoonotic potential has been the driving force in establishing extensive protective measures for animal and human health. In compl...

  8. Mass Spectrometry of Prions: Approaches to Conformational Distinction

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prions are the agents that cause a set of fatal neurological diseases that include Creutzfeldt-Jakob disease. Prions are composed solely of protein. Unlike viral, bacterial, or fungal pathogens, the information necessary to propagate the infection is contained in the conformation of the prion isofor...

  9. The cost of stress: a dilemma with healthy mutation carriers.

    PubMed

    Gigi, Ariela

    2009-12-01

    Literature poses the question of whether people bear a prior physiological tendency to react to stress that makes them more susceptible to onset of diseases or whether traumatic events are powerful enough to trigger a physiological reaction that ultimately induces a disease. Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder with a sudden and rapid onset and progression. Thus far, no therapeutic or prophylactic treatment has been available. Recently, it was found that apparently healthy mutation carriers of CJD demonstrate higher anxiety levels than noncarriers from the same families. Furthermore, there seems to be a connection between stressful life events and the onset of CJD. Over the past few years, people whose relatives died due to CJD are becoming increasingly interested in genetic consultation based on a fear that they too are carrying the mutation. The dilemma of "cost-benefit" of making available such information in this unique stressed population is discussed.

  10. Genetic defect causing familial Alzheimer's disease maps on chromosome 21

    SciTech Connect

    St. George-Hyslop, P.H.; Tanzi, R.E.; Polinsky, R.J.; Haines, J.L.; Nee, L.; Watkins, P.C.; Myers, R.H.; Feldman, R.G.; Pollen, D.; Drachman, D.; Growdon, J.

    1987-02-20

    Alzheimer's disease is a leading cause of morbidity and mortality among the elderly. Several families have been described in which Alzheimer's disease is caused by an autosomal dominant gene defect. The chromosomal location of this defective gene has been discovered by using genetic linkage to DNA markers on chromosome 21. The localization on chromosome 21 provides an explanation for the occurrence of Alzheimer's disease-like pathology in Down syndrome. Isolation and characterization of the gene at this locus may yield new insights into the nature of the defect causing familial Alzheimer's disease and possibly, into the etiology of all forms of Alzheimer's disease.

  11. Mutation Analysis of HTRA2 Gene in Chinese Familial Essential Tremor and Familial Parkinson's Disease.

    PubMed

    He, Ya-Chao; Huang, Pei; Li, Qiong-Qiong; Sun, Qian; Li, Dun-Hui; Wang, Tian; Shen, Jun-Yi; Du, Juan-Juan; Cui, Shi-Shuang; Gao, Chao; Fu, Rao; Chen, Sheng-Di

    2017-01-01

    Background. HTRA2 has already been nominated as PARK13 which may cause Parkinson's disease, though there are still discrepancies among these results. Recently, Gulsuner et al.'s study found that HTRA2 p.G399S is responsible for hereditary essential tremor and homozygotes of this allele develop Parkinson's disease by examining a six-generation family segregating essential tremor and essential tremor coexisting with Parkinson's disease. We performed this study to validate the condition of HTRA2 gene in Chinese familial essential tremor and familial Parkinson's disease patients, especially essential tremor. Methods. We directly sequenced all eight exons, exon-intron boundaries, and part of the introns in 101 familial essential tremor patients, 105 familial Parkinson's disease patients, and 100 healthy controls. Results. No exonic variant was identified, while one exon-intron boundary variant (rs2241028) and one intron variant (rs2241027) were detected, both with no clinical significance and uncertain function. There was no difference in allele, genotype, and haplotype between groups. Conclusions. HTRA2 exonic variant might be rare among Chinese Parkinson's disease and essential tremor patients with family history, and HTRA2 may not be the cause of familial Parkinson's disease and essential tremor in China.

  12. Mutation Analysis of HTRA2 Gene in Chinese Familial Essential Tremor and Familial Parkinson's Disease

    PubMed Central

    Li, Qiong-Qiong; Fu, Rao

    2017-01-01

    Background. HTRA2 has already been nominated as PARK13 which may cause Parkinson's disease, though there are still discrepancies among these results. Recently, Gulsuner et al.'s study found that HTRA2 p.G399S is responsible for hereditary essential tremor and homozygotes of this allele develop Parkinson's disease by examining a six-generation family segregating essential tremor and essential tremor coexisting with Parkinson's disease. We performed this study to validate the condition of HTRA2 gene in Chinese familial essential tremor and familial Parkinson's disease patients, especially essential tremor. Methods. We directly sequenced all eight exons, exon-intron boundaries, and part of the introns in 101 familial essential tremor patients, 105 familial Parkinson's disease patients, and 100 healthy controls. Results. No exonic variant was identified, while one exon-intron boundary variant (rs2241028) and one intron variant (rs2241027) were detected, both with no clinical significance and uncertain function. There was no difference in allele, genotype, and haplotype between groups. Conclusions. HTRA2 exonic variant might be rare among Chinese Parkinson's disease and essential tremor patients with family history, and HTRA2 may not be the cause of familial Parkinson's disease and essential tremor in China. PMID:28243480

  13. Fluorescence of tissues fluororophores such as lipofuscin as a possible basis for the detection of CNS tissues on bovine carcasses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative transmissible spongiform encephalopathy (TSE) which is thought to cause variant of Creutzfeldt-Jakob disease (vCJD) in humans. It is believed that humans contract vCJD by consumption of meat contaminated with bovine tissue containi...

  14. Typical and atypical cases of bovine spongiform encephalopathy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy of cattle, first detected in 1986 in the United Kingdom and subsequently in other countries. It is the most likely cause of variant Creutzfeldt-Jakob disease (vCJD) in humans, but the origin of BSE has not been eluci...

  15. 75 FR 55803 - Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-14

    ... the variant Creutzfeldt-Jakob disease (vCJD) agent in U.S.-licensed plasma-derived Factor VIII and (2) labeling of blood and blood components and plasma-derived products, including plasma-derived albumin and products containing plasma-derived albumin, to address the possible risk of transmission of vCJD....

  16. The influence of spirituality on family management of Parkinson's disease.

    PubMed

    Bingham, Vicki; Habermann, Barbara

    2006-12-01

    This study examined the role of spirituality in defining and managing Parkinson's disease (PD) for people with PD and their families. A content-analysis approach was used to interpret and analyze individual and family interviews from 27 families. Participants primarily were Caucasian dyads representing different geographic areas and socioeconomic statuses. Findings revealed that the ways persons with PD and their families managed the chronic illness were influenced by belief and faith, purpose and meaning, prayer, the support of family and friends, and hope. Healthcare providers need to understand the role of spirituality in influencing ways that persons with PD and their families define and manage the disease and to support people in their efforts.

  17. Congenital heart disease in spondylothoracic dysostosis: two familial cases.

    PubMed Central

    Simpson, J M; Cook, A; Fagg, N L; MacLachlan, N A; Sharland, G K

    1995-01-01

    Two familial cases of spondylothoracic dysostosis are reported. Both cases had severe congenital heart disease in addition to the skeletal malformations which are characteristic of the condition. Images PMID:7473656

  18. In the Event of Bioterrorism: Protecting Families from Deadly Diseases

    MedlinePlus

    ... Español Text Size Email Print Share In the Event of Bioterrorism: Protecting Families from Deadly Diseases Page ... exposure. Talking to Children about Bioterrorism In the event of bioterrorism, knowing how to talk to your ...

  19. Endpoint Quaking-Induced Conversion: a Sensitive, Specific, and High-Throughput Method for Antemortem Diagnosis of Creutzfeldt-Jacob Disease

    PubMed Central

    Vendramelli, Robert; Sloan, Angela; Waitt, Brooks; Podhorodecki, Lisa; Godal, Debra

    2016-01-01

    The Prion Laboratory Section of the Public Health Agency of Canada supports heath care professionals dealing with patients suspected to have Creutzfeldt-Jakob disease (CJD) by testing cerebrospinal fluid (CSF) for protein markers of CJD. To better serve Canadian diagnostic requirements, a quaking-induced conversion (QuIC)-based assay has been added to the test panel. The QuIC tests exploit the ability of disease-associated prion protein, found in the CSF of a majority of CJD patients, to convert a recombinant prion protein (rPrP) into detectable amounts of a misfolded, aggregated form of rPrP. The rPrP aggregates interact with a specific dye, causing a measurable change in the dye's fluorescence emission spectrum. Optimal test and analysis parameters were empirically determined. Taking both practical and performance considerations into account, an endpoint QuIC (EP-QuIC) configuration was chosen. EP-QuIC uses a thermo-mixer to perform the shaking necessary to produce the quaking-induced conversions. Fluorescence readings are obtained from a microwell fluorescence reader only at the beginning and the end of EP-QuIC reactions. Samples for which the relative fluorescence unit ratio between the initial and final readings represent a ≥4 increase in signal intensity in at least two of the three replicates are classified as positive. A retrospective analysis of 91 CSF samples that included 45 confirmed cases of CJD and 46 non-CJD cases was used to estimate the performance characteristics of the EP-QuIC assay. The diagnostic sensitivity and specificity of the EP-QuIC test of this set of samples were 98 and 91%, respectively. PMID:27076662

  20. Interdisciplinary psychosocial care for families with inherited cardiovascular diseases.

    PubMed

    Caleshu, Colleen; Kasparian, Nadine A; Edwards, Katharine S; Yeates, Laura; Semsarian, Christopher; Perez, Marco; Ashley, Euan; Turner, Christian J; Knowles, Joshua W; Ingles, Jodie

    2016-10-01

    Inherited cardiovascular diseases pose unique and complex psychosocial challenges for families, including coming to terms with life-long cardiac disease, risk of sudden death, grief related to the sudden death of a loved one, activity restrictions, and inheritance risk to other family members. Psychosocial factors impact not only mental health but also physical health and cooperation with clinical recommendations. We describe an interdisciplinary approach to the care of families with inherited cardiovascular disease, in which psychological care provided by specialized cardiac genetic counselors, nurses, and psychologists is embedded within the cardiovascular care team. We report illustrative cases and the supporting literature to demonstrate common scenarios, as well as practical guidance for clinicians working in the inherited cardiovascular disease setting.

  1. [Update in family medicine: Periodontal disease].

    PubMed

    López Silva, M C; Diz-Iglesias, P; Seoane-Romero, J M; Quintas, V; Méndez-Brea, F; Varela-Centelles, P

    2017-03-01

    About 85-94% of the Spanish adults older than 35 experience gum problems, and about 15-30% suffer from periodontitis, being severe in up to 5-11% of them. Unlike other inflammatory conditions, periodontal disease rarely causes discomfort, or limits life or causes functional limitations until its advanced stages, when clinical signs and symptoms arise (gingival recession, pathological teeth migration, or mobility). Lack of knowledge about the disease, together with the idea that tooth loss is linked to ageing, frequently results in a late diagnosis, requiring extensive treatments with a worse prognosis. At Primary Care level, there is series of drugs have been related to periodontal disease (anticonvulsants, immunosuppressive drugs, and calcium channel blockers) as secondary effects, which vary as regards their frequency and severity depending of the amount of accumulated plaque. Stress and depression have also been reported to alter the immune response and to increase the inflammatory response as well as periodontal susceptibility. Certain systemic conditions, such as diabetes mellitus, cardiovascular disorders, respiratory diseases, as well as low-weight pre-term birth, have also been linked to periodontitis.

  2. Familial periodontal disease in the Cayo Santiago rhesus macaques.

    PubMed

    Gonzalez, Octavio A; Orraca, Luis; Kensler, Terry B; Gonzalez-Martinez, Janis; Maldonado, Elizabeth; Ebersole, Jeffrey L

    2016-01-01

    Substantial ongoing research continues to explore the contribution of genetics and environment to the onset, extent and severity of periodontal disease(s). Existing evidence supports that periodontal disease appears to have an increased prevalence in family units with a member having aggressive periodontitis. We have been using the nonhuman primate as a model of periodontal disease for over 25 years with these species demonstrating naturally occurring periodontal disease that increases with age. This report details our findings from evaluation of periodontal disease in skulls from 97 animals (5-31 years of age) derived from the skeletons of the rhesus monkeys (Macaca mulatta) on Cayo Santiago. Periodontal disease was evaluated by determining the distance from the base of the alveolar bone defect to the cemento-enamel junction on 1st/2nd premolars and 1st/2nd molars from all four quadrants. The results demonstrated an increasing extent and severity of periodontitis with aging across the population of animals beyond only compensatory eruption. Importantly, irrespective of age, extensive heterogeneity in disease expression was observed among the animals. Linking these variations to multi-generational matriarchal family units supported familial susceptibility of periodontitis. As the current generations of animals that are descendants from these matrilines are alive, studies can be conducted to explore an array of underlying factors that could account for susceptibility or resistance to periodontal disease.

  3. Addressing Emerging Infectious Disease Threats A Strategic Plan for the Department of Defense

    DTIC Science & Technology

    1998-01-01

    pulmonary syndrome in Argentina 1997 Staphylococcus aureus infection with reduced sensitivity to vancomycin in Japan 1996 Variant Creutzfeldt-Jakob...defined "postwar syndromes ," a proactive, anticipa- The primary mission of DoD is to defend the tory strategy is indicated. The problem of emerging...infectious agents before they "postwar syndromes ," and many routine military disrupt training, readiness, or combat operations or public health problems

  4. The expanded octarepeat domain selectively binds prions and disrupts homomeric prion protein interactions.

    PubMed

    Leliveld, Sirik Rutger; Dame, Remus Thei; Wuite, Gijs J L; Stitz, Lothar; Korth, Carsten

    2006-02-10

    Insertion of additional octarepeats into the prion protein gene has been genetically linked to familial Creutzfeldt Jakob disease and hence to de novo generation of infectious prions. The pivotal event during prion formation is the conversion of the normal prion protein (PrPC) into the pathogenic conformer PrPSc, which subsequently induces further conversion in an autocatalytic manner. Apparently, an expanded octarepeat domain directs folding of PrP toward the PrPSc conformation and initiates a self-replicating conversion process. Here, based on three main observations, we have provided a model on how altered molecular interactions between wild-type and mutant PrP set the stage for familial Creutzfeldt Jakob disease with octarepeat insertions. First, we showed that wild-type octarepeat domains interact in a copper-dependent and reversible manner, a "copper switch." This interaction becomes irreversible upon domain expansion, possibly reflecting a loss of function. Second, expanded octarepeat domains of increasing length gradually form homogenous globular multimers of 11-21 nm in the absence of copper ions when expressed as soluble glutathione S-transferase fusion proteins. Third, octarepeat domain expansion causes a gain of function with at least 10 repeats selectively binding PrPSc in a denaturant-resistant complex in the absence of copper ions. Thus, the combination of both a loss and gain of function profoundly influences homomeric interaction behavior of PrP with an expanded octarepeat domain. A multimeric cluster of prion proteins carrying expanded octarepeat domains may therefore capture and incorporate spontaneously arising short-lived PrPSc-like conformers, thereby providing a matrix for their conversion.

  5. Examination of Huntington's disease in a Chinese family.

    PubMed

    Yu, Mingxia; Li, Xiaogai; Wu, Sanyun; Shen, Ji; Tu, Jiancheng

    2014-02-15

    We report brain imaging and genetic diagnosis in a family from Wuhan, China, with a history of Huntington's disease. Among 17 family members across three generations, four patients (II2, II6, III5, and III9) show typical Huntington's disease, involuntary dance-like movements. Magnetic resonance imaging found lateral ventricular atrophy in three members (II2, II6, and III5). Moreover, genetic analysis identified abnormally amplified CAG sequence repeats (> 40) in two members (III5 and III9). Among borderline cases, with clinical symptoms and brain imaging features of Huntington's disease, two cases were identified (II2 and II6), but shown by mutation analysis for CAG expansions in the important transcript 15 gene, to be non-Huntington's disease. Our findings suggest that clinical diagnosis of Huntington's disease requires a combination of clinical symptoms, radiological changes, and genetic diagnosis.

  6. Familial prion diseases in the Basque Country (Spain).

    PubMed

    Zarranz, Juan J; Digon, Anton; Atarés, Begoña; Arteagoitia, José M; Carrera, Nieves; Fernández-Manchola, Iñaki; Fernández-Martínez, Manuel; Fernández-Maiztegui, Covadonga; Forcadas, Isabel; Galdos, Luis; Ibáñez, Agustín; Lezcano, Elena; Martí-Massó, José F; Mendibe, María M; Urtasun, Miguel; Uterga, Juan M; Saracibar, Nieves; Velasco, Fernando; González de Galdeano, Luis

    2005-01-01

    In 1995, a surveillance system for prion diseases was set up in the Basque Country, an autonomous region in northern Spain (2.1 million inhabitants). In the period from January 1993 to December 2003, we diagnosed 21 patients with familial prion diseases prospectively and another 4 patients retrospectively. They represent 35% of all the cases referred to the epidemiological registry. Two main possible explanations for this unusual high incidence of familial prion diseases are proposed: first, comprehensive case ascertainment by public health neurologists; second, a probable cluster of the D178N mutation within families of Basque origin related to a still unconfirmed common ancestor. Further genetic and genealogical studies should resolve this issue.

  7. Aluminium in brain tissue in familial Alzheimer's disease.

    PubMed

    Mirza, Ambreen; King, Andrew; Troakes, Claire; Exley, Christopher

    2017-03-01

    The genetic predispositions which describe a diagnosis of familial Alzheimer's disease can be considered as cornerstones of the amyloid cascade hypothesis. Essentially they place the expression and metabolism of the amyloid precursor protein as the main tenet of disease aetiology. However, we do not know the cause of Alzheimer's disease and environmental factors may yet be shown to contribute towards its onset and progression. One such environmental factor is human exposure to aluminium and aluminium has been shown to be present in brain tissue in sporadic Alzheimer's disease. We have made the first ever measurements of aluminium in brain tissue from 12 donors diagnosed with familial Alzheimer's disease. The concentrations of aluminium were extremely high, for example, there were values in excess of 10μg/g tissue dry wt. in 5 of the 12 individuals. Overall, the concentrations were higher than all previous measurements of brain aluminium except cases of known aluminium-induced encephalopathy. We have supported our quantitative analyses using a novel method of aluminium-selective fluorescence microscopy to visualise aluminium in all lobes of every brain investigated. The unique quantitative data and the stunning images of aluminium in familial Alzheimer's disease brain tissue raise the spectre of aluminium's role in this devastating disease.

  8. Memory binding and white matter integrity in familial Alzheimer's disease.

    PubMed

    Parra, Mario A; Saarimäki, Heini; Bastin, Mark E; Londoño, Ana C; Pettit, Lewis; Lopera, Francisco; Della Sala, Sergio; Abrahams, Sharon

    2015-05-01

    Binding information in short-term and long-term memory are functions sensitive to Alzheimer's disease. They have been found to be affected in patients who meet criteria for familial Alzheimer's disease due to the mutation E280A of the PSEN1 gene. However, only short-term memory binding has been found to be affected in asymptomatic carriers of this mutation. The neural correlates of this dissociation are poorly understood. The present study used diffusion tensor magnetic resonance imaging to investigate whether the integrity of white matter structures could offer an account. A sample of 19 patients with familial Alzheimer's disease, 18 asymptomatic carriers and 21 non-carrier controls underwent diffusion tensor magnetic resonance imaging, neuropsychological and memory binding assessment. The short-term memory binding task required participants to detect changes across two consecutive screens displaying arrays of shapes, colours, or shape-colour bindings. The long-term memory binding task was a Paired Associates Learning Test. Performance on these tasks were entered into regression models. Relative to controls, patients with familial Alzheimer's disease performed poorly on both memory binding tasks. Asymptomatic carriers differed from controls only in the short-term memory binding task. White matter integrity explained poor memory binding performance only in patients with familial Alzheimer's disease. White matter water diffusion metrics from the frontal lobe accounted for poor performance on both memory binding tasks. Dissociations were found in the genu of corpus callosum which accounted for short-term memory binding impairments and in the hippocampal part of cingulum bundle which accounted for long-term memory binding deficits. The results indicate that white matter structures in the frontal and temporal lobes are vulnerable to the early stages of familial Alzheimer's disease and their damage is associated with impairments in two memory binding functions known to

  9. The ANKH gene and familial calcium pyrophosphate dihydrate deposition disease.

    PubMed

    Netter, Patrick; Bardin, Thomas; Bianchi, Arnaud; Richette, Pascal; Loeuille, Damien

    2004-09-01

    Familial calcium pyrophosphate dihydrate deposition (CPPD) disease is a chronic condition in which CPPD microcrystals deposit in the joint fluid, cartilage, and periarticular tissues. Two forms of familial CPPD disease have been identified: CCAL1 and CCAL2. The CCAL1 locus is located on the long arm of chromosome 8 and is associated with CPPD and severe osteoarthritis. The CCAL2 locus has been mapped to the short arm of chromosome 5 and identified in families from the Alsace region of France and the United Kingdom. The ANKH protein is involved in pyrophosphate metabolism and, more specifically, in pyrophosphate transport from the intracellular to the extracellular compartment. Numerous ANKH gene mutations cause familial CCAL2; they enhance ANKH protein activity, thereby elevating extracellular pyrophosphate levels and promoting the formation of pyrophosphate crystals, which produce the manifestations of the disease. Recent studies show that growth factors and cytokines can modify the expression of the normal ANKH protein. These results suggest a role for ANKH in sporadic CPPD disease and in CPPD associated with degenerative disease.

  10. Copy Number Variation in Familial Parkinson Disease

    PubMed Central

    Pankratz, Nathan; Dumitriu, Alexandra; Hetrick, Kurt N.; Sun, Mei; Latourelle, Jeanne C.; Wilk, Jemma B.; Halter, Cheryl; Doheny, Kimberly F.; Gusella, James F.; Nichols, William C.; Myers, Richard H.; Foroud, Tatiana; DeStefano, Anita L.

    2011-01-01

    Copy number variants (CNVs) are known to cause Mendelian forms of Parkinson disease (PD), most notably in SNCA and PARK2. PARK2 has a recessive mode of inheritance; however, recent evidence demonstrates that a single CNV in PARK2 (but not a single missense mutation) may increase risk for PD. We recently performed a genome-wide association study for PD that excluded individuals known to have either a LRRK2 mutation or two PARK2 mutations. Data from the Illumina370Duo arrays were re-clustered using only white individuals with high quality intensity data, and CNV calls were made using two algorithms, PennCNV and QuantiSNP. After quality assessment, the final sample included 816 cases and 856 controls. Results varied between the two CNV calling algorithms for many regions, including the PARK2 locus (genome-wide p = 0.04 for PennCNV and p = 0.13 for QuantiSNP). However, there was consistent evidence with both algorithms for two novel genes, USP32 and DOCK5 (empirical, genome-wide p-values<0.001). PARK2 CNVs tended to be larger, and all instances that were molecularly tested were validated. In contrast, the CNVs in both novel loci were smaller and failed to replicate using real-time PCR, MLPA, and gel electrophoresis. The DOCK5 variation is more akin to a VNTR than a typical CNV and the association is likely caused by artifact due to DNA source. DNA for all the cases was derived from whole blood, while the DNA for all controls was derived from lymphoblast cell lines. The USP32 locus contains many SNPs with low minor allele frequency leading to a loss of heterozygosity that may have been spuriously interpreted by the CNV calling algorithms as support for a deletion. Thus, only the CNVs within the PARK2 locus could be molecularly validated and associated with PD susceptibility. PMID:21829596

  11. FYI: Services to Poor Families; Controlling Infectious Diseases; Parent Groups.

    ERIC Educational Resources Information Center

    Children Today, 1987

    1987-01-01

    Discusses services and resources available for families, parents, and child care providers. Describes a National Resource Center for Children in Poverty; a guide for controlling infectious diseases among young children in day care; a directory of parent support groups; and reports of a link between household pesticides and childhood leukemia. (BB)

  12. Linkage analysis of familial Alzheimer disease, using chromosome 21 markers

    PubMed Central

    Schellenberg, Gerard D.; Pericak-Vance, Margaret A.; Wijsman, Ellen M.; Moore, Deborah K.; Gaskell, Perry C.; Yamaoka, Larry A.; Bebout, Jacqueline L.; Anderson, Leojean; Welsh, Kathleen A.; Clark, Christopher M.; Martin, George M.; Roses, Allen D.; Bird, Thomas D.

    1991-01-01

    Chromosome 21 markers were tested for linkage to familial Alzheimer disease (FAD) in 48 kindreds. These families had multiple cases of Alzheimer disease (AD) in 2 or more generations with family age-at-onset means (M) ranging from 41 to 83 years. Included in this group are seven Volga German families which are thought to be genetically homogeneous with respect to FAD. Autopsy documentation of AD was available for 32 families. Linkage to the 21 q11-q21 region was tested using D21S16, D21S13, D21S110, D21S1/S11, and the APP gene as genetic markers. When linkage results for all the families were summed, the LOD scores for these markers were consistently negative and the entire region was formally excluded. Linkage results were also summed for the following family groups; late-onset (M > 60), early-onset (M ≤ 60), Volga Germans (M = 56), and early-onset non–Volga Germans (M ≤ 60). For the first three groups, LOD scores were negative for this region. For the early-onset non–Volga German group (six families), small positive LOD scores of Zmax = 0.78 (recombination fraction θ = .15), Zmax = 0.27 (θ = .15), and Zmax = 0.64 (θ = .0), were observed for D21S13, D21S16, and D21S110, respectively. The remainder of the long arm of chromosome 21 was tested for linkage to FAD using seven markers spanning the q22 region. Results for these markers were also predominantly negative. Thus it is highly unlikely that a chromosome 21 gene is responsible for late-onset FAD and at least some forms of early-onset FAD represented by the Volga German kindreds. PMID:1998342

  13. Familial Mediterranean fever in two Bedouin families: mutation analysis and disease severity.

    PubMed

    Press, J; Shinar, Y; Langevitz, P; Livneh, A; Pras, M; Buskila, D

    2000-06-05

    Familial Mediterranean fever (FMF) is an autosomal recessive disease prevalent among non-Ashkenazi Jews, Armenians, Arabs, and Turks. The Bedouin are nomad Arab tribes residing in desert margins of the Middle East and Arabia. FMF is quite rare in Bedouins, and here we report on two Bedouin families from southern Israel suffering from this disorder. The MEFV mutations found in the Bedouin patients M694I, V726A, and E148Q are consistent with their Arab origin. The disease severity score showed a mild to moderate severity disease in six patients. The Bedouins, leading a unique nomadic life, may prove instrumental in unraveling the role of environmental factors in the course and severity of FMF.

  14. Elucidation of endemic neurodegenerative diseases--a commentary.

    PubMed

    Nishida, Yuzo

    2003-01-01

    Recent investigations of scrapie, Creutzfeldt-Jakob disease (CJD), and chronic wasting disease (CWD) clusters in Iceland, Slovakia and Colorado, respectively, have indicated that the soil in these regions is low in copper and higher in manganese, and it has been well-known that patients of ALS or Parkinson's disease were collectively found in the New Guinea and Papua islands, where the subterranean water (drinking water) contains much Al3+ and Mn2+ ions. Above facts suggest that these neurodegenerative diseases are closely related with the function of a metal ion. We have investigated the chemical functions of the metal ions in detail and established the unique mechanism of the oxygen activation by the transition metal ions such as iron and copper, and pointed out the notable difference in the mechanism among iron, aluminum and manganese ions. Based on these results, it has become apparent that the incorporation of Al(III) or Mn(II) in the cells induces the "iron-overload syndrome", which is mainly due to the difference in an oxygen activation mechanism between the iron ion and Al(III) or the Mn(II) ion. This syndrome highly promotes formation of hydrogen peroxide, and hydrogen peroxide thus produced can be a main factor to cause serious damages to DNA and proteins (oxidative stress), yielding a copper(II)- or manganese(II)-peptide complex and its peroxide adduct, which are the serious agents to induce the structural changes from the normal prion protein (PrP(c)) to abnormal disease-causing isoforms, PrP(Sc), or the formation of PrP 27-30 (abnormal cleavage at site 90 of the prion protein). It seems reasonable to consider that the essential origin for the transmissible spongiform encephalopathies (TSEs) should be the incorporation and accumulation of Al(III) and Mn(II) ions in the cells, and the sudden and explosive increase of scrapie and bovine spongiform encephalopathy (BSE) in the last decade may be partially due to "acid rain", because the acid rain makes Al

  15. Familial associations of lymphoma and myeloma with autoimmune diseases

    PubMed Central

    Hemminki, K; Försti, A; Sundquist, K; Sundquist, J; Li, X

    2017-01-01

    Many B-cell neoplasms are associated with autoimmune diseases (AIDs) but most evidence is based on a personal rather than a family history of AIDs. Here we calculated risks for non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL) and multiple myeloma (MM) when family members were diagnosed with any of 44 different AIDs, or, independently, risk for AIDs when family members were diagnosed with a neoplasm. A total of 64 418 neoplasms and 531 155 AIDs were identified from Swedish nationwide health care records. NHL was associated with a family history of five AIDs, all increasing the risk, HL was associated with one AID increasing and three AIDs decreasing the risk while MM had no association. A family history of NHL was associated with eight, HL with seven and MM with seven different AIDs, nine increasing and 13 decreasing the risk. The present family data on B-cell neoplasms and AIDs show an approximately equal number of associations for risk increase and risk decrease, suggesting that inherited genes or gene-environment interactions may increase the risk or be protective. These results differed from published data on personal history of AID, which only report increased risks, often vastly higher and for different AIDs compared with the present data. PMID:28157190

  16. Familial aggregation of schizophrenia-like symptoms in Huntington's disease.

    PubMed

    Tsuang, D; DiGiacomo, L; Lipe, H; Bird, T D

    1998-07-10

    An increased incidence of schizophrenia-like symptoms in Huntington's disease (HD) has been well-documented in the past. The reasons for this association, however, have never been explained. At the University of Washington Medical Genetics Clinic, we had the opportunity to evaluate a unique juvenile-onset HD proband who had schizophrenia-like symptoms. This patient was referred to our clinic because of new onset of somatic delusions and command auditory hallucinations early in the course of her illness. Since we had already evaluated other affected individuals in her family, we selected another family with a nonpsychotic juvenile-onset proband for comparison. Using these two families in a small case-control study, we investigated the following hypotheses which could explain the association between schizophrenia-like symptoms and HD: first, schizophrenia-like symptoms may be related to the number of CAG repeats in the HD gene; second, schizophrenia-like symptoms may segregate in certain HD families, for unknown reasons; and third, there may coincidentally be an unrelated gene for schizophrenia in certain HD families. Comparisons of clinical characteristics and the HD genotype showed that family history of schizophrenia-like symptoms segregated with the HD gene; however, age of onset of HD, size of CAG repeat, and sex of the transmitting parent were not associated with psychotic symptoms. Further genetic and neurobiological studies are necessary to investigate the potential mechanism underlying this association.

  17. Familial associations of lymphoma and myeloma with autoimmune diseases.

    PubMed

    Hemminki, K; Försti, A; Sundquist, K; Sundquist, J; Li, X

    2017-01-06

    Many B-cell neoplasms are associated with autoimmune diseases (AIDs) but most evidence is based on a personal rather than a family history of AIDs. Here we calculated risks for non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL) and multiple myeloma (MM) when family members were diagnosed with any of 44 different AIDs, or, independently, risk for AIDs when family members were diagnosed with a neoplasm. A total of 64 418 neoplasms and 531 155 AIDs were identified from Swedish nationwide health care records. NHL was associated with a family history of five AIDs, all increasing the risk, HL was associated with one AID increasing and three AIDs decreasing the risk while MM had no association. A family history of NHL was associated with eight, HL with seven and MM with seven different AIDs, nine increasing and 13 decreasing the risk. The present family data on B-cell neoplasms and AIDs show an approximately equal number of associations for risk increase and risk decrease, suggesting that inherited genes or gene-environment interactions may increase the risk or be protective. These results differed from published data on personal history of AID, which only report increased risks, often vastly higher and for different AIDs compared with the present data.

  18. Mutations in DJ-1 are rare in familial Parkinson disease

    PubMed Central

    Pankratz, Nathan; Pauciulo, Michael W.; Elsaesser, Veronika E.; Marek, Diane K.; Halter, Cheryl A.; Wojcieszek, Joanne; Rudolph, Alice; Shults, Clifford W.; Foroud, Tatiana; Nichols Ph.D., William C.

    2006-01-01

    Mutations in DJ-1 (PARK7) are one cause of early-onset autosomal-recessive parkinsonism. We screened for DJ-1 mutations in 93 affected individuals from the 64 multiplex Parkinson disease (PD) families in our sample that had the highest family-specific multipoint LOD scores at the DJ-1 locus. In addition to sequencing all coding exons for alterations, we used multiplex ligation-dependent probe amplification (MLPA) to examine the genomic copy number of DJ-1 exons. A known polymorphism (R98Q) was found in five PD subjects, once as a homozygote and in the other four cases as heterozygotes. No additional missense mutations and no exon deletions or duplications were detected. Our results, in combination with those of previous studies, suggest that alterations in DJ-1 are not a common cause of familial PD. PMID:16997464

  19. Chromosome 14 and late-onset familial alzheimer disease (FAD)

    SciTech Connect

    Schellenberg, G.D.; Anderson, L.; Nemens, E.; Bird, T.D.; Wijsman, E.M.; Martin, G.M.; Payami, H.; Orr, H.T.; White, J.A.; Alonso, M.E.

    1993-09-01

    Familial Alzheimer disease (FAD) is genetically heterogeneous. Two loci responsible for early-onset FAD have been identified: the amyloid precursor protein gene on chromosome 21 and the as-yet-unidentified locus on chromosome 14. The genetics of late-onset FAD is unresolved. Maximum-likelihood, affected-pedigree-member (APM), and sib-pair analysis were used, in 49 families with a mean age at onset [>=]60 years, to determine whether the chromosome 14 locus is responsible for late-onset FAD. The markers used were D14S53, D14S43, and D14S52. The LOD score method was used to test for linkage of late-onset FAD to the chromosome 14 markers, under three different models: age-dependent penetrance, an affected-only analysis, and age-dependent penetrance with allowance for possible age-dependent sporadic cases. No evidence for linkage was obtained under any of these conditions for the late-onset kindreds, and strong evidence against linkage (LOD score [>=]2.0) to this region was obtained. Heterogeneity tests of the LOD score results for the combined group of families (early onset, Volga Germans, and late onset) favored the hypothesis of linkage to chromosome 14 with genetic heterogeneity. The positive results are primarily from early-onset families. APM analysis gave significant evidence for linkage of D14S43 and D14S52 to FAD in early-onset kindreds (P<.02). No evidence for linkage was found for the entire late-onset family group. Significant evidence for linkage to D14S52, however, was found for a subgroup of families of intermediate age at onset (mean age at onset [>=]60 years and <70 years). These results indicate that the chromosome 14 locus is not responsible for Alzheimer disease in most late-onset FAD kindreds but could play a role in a subset of these kindreds. 37 refs., 1 fig., 6 tabs.

  20. Chromosome 14 and late-onset familial Alzheimer disease (FAD)

    PubMed Central

    Schellenberg, Gerard D.; Payami, Haydeh; Wijsman, Ellen M.; Orr, Harry T.; Goddard, Katrina A. B.; Anderson, Leojean; Nemens, Ellen; White, June A.; Alonso, M. Elisa; Ball, Melvyn J.; Kaye, Jeffrey; Morris, John C.; Chui, Helena; Sadovnick, A. Dessa; Heston, Leonard L.; Martin, George M.; Bird, Thomas D.

    1993-01-01

    Familial Alzheimer disease (FAD) is genetically heterogeneous. Two loci responsible for early-onset FAD have been identified: the amyloid precursor protein gene on chromosome 21 and the as-yet-unidentified locus on chromosome 14. The genetics of late-onset FAD is unresolved. Maximum-likelihood, affected-pedigree-member (APM), and sib-pair analyses were used, in 49 families with a mean age at onset ≥60 years, to determine whether the chromosome 14 locus is responsible for late-onset FAD. The markers used were D14S53, D14S43, and D14S52. The LOD score method was used to test for linkage of late-onset FAD to the chromosome 14 markers, under three different models: age-dependent penetrance, an affected-only analysis, and age-dependent penetrance with allowance for possible age-dependent sporadic cases. No evidence for linkage was obtained under any of these conditions for the late-onset kindreds, and strong evidence against linkage (LOD score ≤ –2.0) to this region was obtained. Heterogeneity tests of the LOD score results for the combined group of families (early onset, Volga Germans, and late onset) favored the hypothesis of linkage to chromosome 14 with genetic heterogeneity. The positive results are primarily from early-onset families. APM analysis gave significant evidence for linkage of D14S43 and D14S52 to FAD in early-onset kindreds (P < .02). No evidence for linkage was found for the entire late-onset family group. Significant evidence for linkage to D14S52, however, was found for a subgroup of families of intermediate age at onset (mean age at onset ≥60 years and <70 years). These results indicate that the chromosome 14 locus is not responsible for Alzheimer disease in most late-onset FAD kindreds but could play a role in a subset of these kindreds. PMID:8352272

  1. IL-1 family cytokines trigger sterile inflammatory disease

    PubMed Central

    Lukens, John R.; Gross, Jordan M.; Kanneganti, Thirumala-Devi

    2012-01-01

    Inflammation plays vital roles in protective responses against pathogens and tissue repair, however, improper resolution of inflammatory networks is centrally involved in the pathogenesis of many acute and chronic diseases. Extensive advances have been made in recent years to define the inflammatory processes that are required for pathogen clearance, however, in comparison, less is known about the regulation of inflammation in sterile settings. Over the past decade non-communicable chronic diseases that are potentiated by sterile inflammation have replaced infectious diseases as the major threat to global human health. Thus, improved understanding of the sterile inflammatory process has emerged as one of the most important areas of biomedical investigation during our time. In this review we highlight the central role that interleukin-1 family cytokines play in sterile inflammatory diseases. PMID:23087690

  2. Family Stress with Chronic Childhood Illness: Cystic Fibrosis, Neuromuscular Disease, and Renal Disease.

    ERIC Educational Resources Information Center

    Holroyd, Jean; Guthrie, Donald

    1986-01-01

    Parents of children with neuromuscular disease, cystic fibrosis, and renal disease were compared with parents of control subjects matched by age to the clinical cases. The three clinical groups exhibited different patterns of stressful response, consistent with the nature of their illnesses and the requirements for care imposed on the families.…

  3. Calcified Granulomatous Disease: Occupational Associations and Lack of Familial Aggregation

    PubMed Central

    Reed, Robert M.; Amoroso, Anthony; Hashmi, Salman; Kligerman, Seth; Shuldiner, Alan R.; Mitchell, Braxton D.; Netzer, Giora

    2014-01-01

    Purpose The acute host response to histoplasma capsulatum infection varies according to exposure and susceptibility. Late sequelae include calcifications in the lung, thoracic lymphatics, and spleen. Determinants of calcified granuloma formation are poorly studied and may differ from those affecting acute response. We examined the occupational associations and familial aggregation of radiographic calcified granulomatous disease to characterize the determinants of calcified granuloma formation. Methods We analyzed prospectively collected cross-sectional data including computed tomograms from 872 adult members of the Old Order Amish of Lancaster County. Results Granulomas were present in 71 % of participants. Granulomas were present in the lung of 57 % of participants, in the hilar or mediastinal lymph nodes of 55 % of participants, and in the spleen of 29 % of participants. No significant differences were observed in the presence of granulomas between men and women. Each year of age was associated with 4 % higher odds of splenic calcifications, and a primary occupation of farming was associated with an 84 % higher odds of splenic calcifications. A compelling pattern of familial aggregation was not observed. Conclusions Calcified granulomatous disease does not appear to aggregate in families. Determinants influencing patterns of granulomatous disease include occupation, age, and geographic location. PMID:25038755

  4. Mononucleated Blood Cell Populations Display Different Abilities To Transmit Prion Disease by the Transfusion Route

    PubMed Central

    Douet, Jean-Yves; Lacroux, Caroline; Litaise, Claire; Lugan, Séverine; Corbière, Fabien; Arnold, Mark; Simmons, Hugh; Aron, Naima; Costes, Pierrette; Tillier, Cécile; Cassard, Hervé

    2016-01-01

    ABSTRACT Previous experiments carried out in a sheep scrapie model demonstrated that the transfusion of 200 μl of prion-infected whole blood has an apparent 100% efficacy for disease transmission. These experiments also indicated that, despite the apparent low infectious titer, the intravenous administration of white blood cells (WBC) resulted in efficient disease transmission. In the study presented here, using the same transmissible spongiform encephalopathy (TSE) animal model, our aim was to determine the minimal number of white blood cells and the specific abilities of mononucleated cell populations to transmit scrapie by the transfusion route. Our results confirmed that the transfusion of 100 μl, but not 10 μl, of fresh whole blood collected in asymptomatic scrapie-infected donor sheep can transmit the disease. The data also show that the intravenous administration of 105 WBCs is sufficient to cause scrapie in recipient sheep. Cell-sorted CD45R+ (predominantly B lymphocytes), CD4+/CD8+ (T lymphocytes), and CD14+ (monocytes/macrophages) blood cell subpopulations all were shown to contain prion infectivity by bioassays in ovine PrP transgenic mice. However, while the intravenous administration of 106 CD45+ or CD4+/8+ living cells was able to transmit the disease, similar numbers of CD14+ cells failed to infect the recipients. These data support the contention that mononucleated blood cell populations display different abilities to transmit TSE by the transfusion route. They also represent an important input for the risk assessment of blood-borne prion disease transmission and for refining the target performance of leukoreduction processes that currently are applied to mitigate the transmission risk in transfusion medicine. IMPORTANCE Interindividual variant Creutzfeldt-Jakob disease (vCJD) transmission through blood and blood-derived products is considered a major public health issue in transfusion medicine. Over the last decade, TSE in sheep has emerged as a

  5. NDP gene mutations in 14 French families with Norrie disease.

    PubMed

    Royer, Ghislaine; Hanein, Sylvain; Raclin, Valérie; Gigarel, Nadine; Rozet, Jean-Michel; Munnich, Arnold; Steffann, Julie; Dufier, Jean-Louis; Kaplan, Josseline; Bonnefont, Jean-Paul

    2003-12-01

    Norrie disease is a rare X-inked recessive condition characterized by congenital blindness and occasionally deafness and mental retardation in males. This disease has been ascribed to mutations in the NDP gene on chromosome Xp11.1. Previous investigations of the NDP gene have identified largely sixty disease-causing sequence variants. Here, we report on ten different NDP gene allelic variants in fourteen of a series of 21 families fulfilling inclusion criteria. Two alterations were intragenic deletions and eight were nucleotide substitutions or splicing variants, six of them being hitherto unreported, namely c.112C>T (p.Arg38Cys), c.129C>G (p.His43Gln), c.133G>A (p.Val45Met), c.268C>T (p.Arg90Cys), c.382T>C (p.Cys128Arg), c.23479-1G>C (unknown). No NDP gene sequence variant was found in seven of the 21 families. This observation raises the issue of misdiagnosis, phenocopies, or existence of other X-linked or autosomal genes, the mutations of which would mimic the Norrie disease phenotype.

  6. Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases.

    PubMed

    Kabir, M Enamul; Safar, Jiri G

    2014-01-01

    There is a growing body of evidence indicating that number of human neurodegenerative diseases, including Alzheimer disease, Parkinson disease, fronto-temporal dementias, and amyotrophic lateral sclerosis, propagate in the brain via prion-like intercellular induction of protein misfolding. Prions cause lethal neurodegenerative diseases in humans, the most prevalent being sporadic Creutzfeldt-Jakob disease (sCJD); they self-replicate and spread by converting the cellular form of prion protein (PrP(C)) to a misfolded pathogenic conformer (PrP(Sc)). The extensive phenotypic heterogeneity of human prion diseases is determined by polymorphisms in the prion protein gene, and by prion strain-specific conformation of PrP(Sc). Remarkably, even though informative nucleic acid is absent, prions may undergo rapid adaptation and evolution in cloned cells and upon crossing the species barrier. In the course of our investigation of this process, we isolated distinct populations of PrP(Sc) particles that frequently co-exist in sCJD. The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability. Exposed to mutant substrate, the winning PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability. Thus, the evolution and adaptation of human prions is enabled by a dynamic collection of distinct populations of particles, whose evolution is governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. This fundamental biological mechanism may explain the drug resistance that some prions gained after exposure to compounds targeting PrP(Sc). Whether the phenotypic heterogeneity of other neurodegenerative diseases caused by protein misfolding is determined by the spectrum of misfolded conformers (strains) remains to be established. However, the prospect that these conformers may evolve and

  7. Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years

    PubMed Central

    Jaunmuktane, Zane; Adlard, Peter; Bjurstrom, Nina; Caine, Diana; Lowe, Jessica; Norsworthy, Penny; Hummerich, Holger; Druyeh, Ron; Wadsworth, Jonathan D. F.; Brandner, Sebastian; Hyare, Harpreet; Mead, Simon; Collinge, John

    2015-01-01

    Patients with iatrogenic Creutzfeldt-Jakob disease due to administration of cadaver-sourced growth hormone during childhood are still being seen in the UK 30 years after cessation of this treatment. Of the 77 patients who have developed iatrogenic Creutzfeldt-Jakob disease, 56 have been genotyped. There has been a marked change in genotype profile at polymorphic codon 129 of the prion protein gene (PRNP) from predominantly valine homozygous to a mixed picture of methionine homozygous and methionine-valine heterozygous over time. The incubation period of iatrogenic Creutzfeldt-Jakob disease is significantly different between all three genotypes. This experience is a striking contrast with that in France and the USA, which may relate to contamination of different growth hormone batches with different strains of human prions. We describe the clinical, imaging, molecular and autopsy features in 22 of 24 patients who have developed iatrogenic Creutzfeldt-Jakob disease in the UK since 2003. Mean age at onset of symptoms was 42.7 years. Gait ataxia and lower limb dysaesthesiae were the most frequent presenting symptoms. All had cerebellar signs, and the majority had myoclonus and lower limb pyramidal signs, with relatively preserved cognitive function, when first seen. There was a progressive decline in neurological and cognitive function leading to death after 5–32 (mean 14) months. Despite incubation periods approaching 40 years, the clinical duration in methionine homozygote patients appeared to be shorter than that seen in heterozygote patients. MRI showed restricted diffusion in the basal ganglia, thalamus, hippocampus, frontal and the paracentral motor cortex and cerebellar vermis. The electroencephalogram was abnormal in 15 patients and cerebrospinal fluid 14-3-3 protein was positive in half the patients. Neuropathological examination was conducted in nine patients. All but one showed synaptic prion deposition with numerous kuru type plaques in the basal ganglia

  8. Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years.

    PubMed

    Rudge, Peter; Jaunmuktane, Zane; Adlard, Peter; Bjurstrom, Nina; Caine, Diana; Lowe, Jessica; Norsworthy, Penny; Hummerich, Holger; Druyeh, Ron; Wadsworth, Jonathan D F; Brandner, Sebastian; Hyare, Harpreet; Mead, Simon; Collinge, John

    2015-11-01

    Patients with iatrogenic Creutzfeldt-Jakob disease due to administration of cadaver-sourced growth hormone during childhood are still being seen in the UK 30 years after cessation of this treatment. Of the 77 patients who have developed iatrogenic Creutzfeldt-Jakob disease, 56 have been genotyped. There has been a marked change in genotype profile at polymorphic codon 129 of the prion protein gene (PRNP) from predominantly valine homozygous to a mixed picture of methionine homozygous and methionine-valine heterozygous over time. The incubation period of iatrogenic Creutzfeldt-Jakob disease is significantly different between all three genotypes. This experience is a striking contrast with that in France and the USA, which may relate to contamination of different growth hormone batches with different strains of human prions. We describe the clinical, imaging, molecular and autopsy features in 22 of 24 patients who have developed iatrogenic Creutzfeldt-Jakob disease in the UK since 2003. Mean age at onset of symptoms was 42.7 years. Gait ataxia and lower limb dysaesthesiae were the most frequent presenting symptoms. All had cerebellar signs, and the majority had myoclonus and lower limb pyramidal signs, with relatively preserved cognitive function, when first seen. There was a progressive decline in neurological and cognitive function leading to death after 5-32 (mean 14) months. Despite incubation periods approaching 40 years, the clinical duration in methionine homozygote patients appeared to be shorter than that seen in heterozygote patients. MRI showed restricted diffusion in the basal ganglia, thalamus, hippocampus, frontal and the paracentral motor cortex and cerebellar vermis. The electroencephalogram was abnormal in 15 patients and cerebrospinal fluid 14-3-3 protein was positive in half the patients. Neuropathological examination was conducted in nine patients. All but one showed synaptic prion deposition with numerous kuru type plaques in the basal ganglia

  9. Asbestos disease in family contacts of shipyard workers

    SciTech Connect

    Kilburn, K.H.; Lilis, R.; Anderson, H.A.; Boylen, C.T.; Einstein, H.E.; Johnson, S.J.; Warshaw, R.

    1985-06-01

    Radiologic signs of pulmonary asbestos disease were found in 11.3 per cent of 274 wives of shipyard workers who were 20 or more years from initial hiring-on in shipyards in Los Angeles County. Asbestosis was also found in 7.6 per cent of 79 sons and 2.1 per cent of 140 daughters of these workers. The wives, sons, and daughters were without occupational exposure. Comparable radiographic signs were not found in comparison groups. It is probable that asbestos exposure in the household places these family members at risk for mesothelioma and lung cancer.

  10. A family living with Alzheimer's disease: The communicative challenges.

    PubMed

    Jones, Danielle

    2015-09-01

    Alzheimer's disease irrevocably challenges a person's capacity to communicate with others. Earlier research on these challenges focused on the language disorders associated with the condition and situated language deficit solely in the limitations of a person's cognitive and semantic impairments. This research falls short of gaining insight into the actual interactional experiences of a person with Alzheimer's and their family. Drawing on a UK data set of 70 telephone calls recorded over a two-and-a-half year period (2006-2008) between one elderly woman with Alzheimer's disease, and her daughter and son-in-law, this paper explores the role which communication (and its degeneration) plays in family relationships. Investigating these interactions, using a conversation analytic approach, reveals that there are clearly communicative difficulties, but closer inspection suggests that they arise due to the contingencies that are generated by the other's contributions in the interaction. That being so, this paper marks a departure from the traditional focus on language level analysis and the assumption that deficits are intrinsic to the individual with Alzheimer's, and instead focuses on the collaborative communicative challenges that arise in the interaction itself and which have a profound impact on people's lives and relationships.

  11. [Investigation of the clinical course and treatment of prion disease patients in the akinetic mutism state in Japan].

    PubMed

    Iwasaki, Yasushi; Mori, Keiko; Ito, Masumi

    2012-01-01

    Twelve cases (one Gerstmann-Sträussler-Scheinker syndrome (P102L; definite), one genetic Creutzfeldt-Jakob disease (CJD) (V180I; definite) and ten sporadic CJD (7 MM1-type definite, 3 probable)), who reached the akinetic mutism state, were investigated with regard to their clinical course and treatment. They were hospitalized for a total of 3,968 days in the akinetic mutism state. In the nine definite cases, the median period from the akinetic mutism state to death was 22 months (average: 27.0 ± 23.3 months, range: 3-80 months) and median total disease duration was 27 months (average: 34.2 ± 30.1 months, range: 5-102 months). In the seven definite sporadic CJD cases, the median period from akinetic mutism to death was 21 months (average: 17.0 ± 9.6 months, range 3-28 months), and median total disease duration was 24 months (average: 20.6 ± 10.0 months, range: 5-31 months). Nasal-tube feeding was performed in all cases. Symptomatic treatments such as parenteral nutrition and antibiotic drugs were administered for complications such as respitory and urinary tract infections and digestive symptoms. Patients received rehabilitation and hot spring therapy regularly until death. Gastrostomy and/or tracheotomy was not performed in any case, the patients were not intubated nor was mechanical ventilation (including non-invasive positive pressure ventilation) applied. Vasoactive drugs were not administered. Clonazepam was administered for myoclonus in four patients but not in another three when myoclonus appeared. It is unclear whether the treatment influenced the duration of myoclonus. Our observations indicate that the extended survival period among Japanese prion disease patients is likely due to the management procedures implemented for prion disease in Japan, which are usually continued after the patients reach the akinetic mutism state. We speculate that nasal-tube feeding is the crucial factor that results in the prolonged disease duration of prion disease

  12. Association of Peripheral Arterial and Cardiovascular Diseases in Familial Hypercholesterolemia

    PubMed Central

    Pereira, Carolina; Miname, Marcio; Makdisse, Marcia; Kalil, Roberto; Santos, Raul D.

    2014-01-01

    Background Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by an elevation in the serum levels of total cholesterol and of low-density lipoproteins (LDL- c). Known to be closely related to the atherosclerotic process, FH can determine the development of early obstructive lesions in different arterial beds. In this context, FH has also been proposed to be a risk factor for peripheral arterial disease (PAD). Objective This observational cross-sectional study assessed the association of PAD with other manifestations of cardiovascular disease (CVD), such as coronary artery and cerebrovascular disease, in patients with heterozygous FH. Methods The diagnosis of PAD was established by ankle-brachial index (ABI) values ≤ 0.90. This study assessed 202 patients (35% of men) with heterozygous FH (90.6% with LDL receptor mutations), mean age of 51 ± 14 years and total cholesterol levels of 342 ± 86 mg /dL. Results The prevalences of PAD and previous CVD were 17% and 28.2 %, respectively. On multivariate analysis, an independent association between CVD and the diagnosis of PAD was observed (OR = 2.50; 95% CI: 1.004 - 6.230; p = 0.049). Conclusion Systematic screening for PAD by use of ABI is feasible to assess patients with FH, and it might indicate an increased risk for CVD. However, further studies are required to determine the role of ABI as a tool to assess the cardiovascular risk of those patients. PMID:25029472

  13. Cows for fear: is BSE a threat to human health? Bovine spongiform encephalopathy.

    PubMed Central

    Josephson, J

    1998-01-01

    In 1996, a new variant of Creutzfeldt-Jakob disease (vCJD)-a disease that causes lack of coordination, muscle twitching or jerking, dementia, and, eventually, death-suddenly appeared in Great Britain. It is believed that the victims contracted the disease from eating the beef of cattle stricken with bovine spongiform encephalopathy (BSE), or mad cow disease. As of December 1997, at least 25 people in the United Kingdom and France have contracted vCJD. PMID:9485478

  14. 'Essential tremor' or 'the essential tremors': is this one disease or a family of diseases?

    PubMed

    Louis, Elan D

    2014-01-01

    There is accumulating evidence that the entity referred to as 'essential tremor' (ET) is not a single disease. It may be a family of diseases better referred to as 'the ETs'. This review will summarize the following evidence: (1) the presence of etiological heterogeneity; (2) the heterogeneity of findings in postmortem studies, thus suggesting several diseases; (3) the recent discussion that age of onset may be an important marker of disease heterogeneity; (4) the clinical expansion of the concept of ET in recent years to include a broader range of tremor phenomenology, other motor features (gait ataxia), other involuntary movements (dystonia), and nonmotor features (cognitive problems, psychiatric problems), some of which could be primary; (5) the heterogeneity of pharmacological response profiles and clinical progression, and (6) the association of ET with Parkinson's disease, Alzheimer's disease, and possibly progressive supranuclear palsy, with the possibility that some ET patients are more predisposed to develop one of these. © 2013 S. Karger AG, Basel.

  15. Assessing family history of chronic disease in primary care

    PubMed Central

    Carroll, June C.; Campbell-Scherer, Denise; Permaul, Joanne A.; Myers, Jesse; Manca, Donna P.; Meaney, Christopher; Moineddin, Rahim; Grunfeld, Eva

    2017-01-01

    Abstract Objective To assess the proportion of primary care patients who report a family history (FH) of type 2 diabetes, coronary artery disease, breast cancer, or colorectal cancer (CRC); assess concordance of FH information derived from the electronic medical record (EMR) compared with patient-completed health questionnaires; and assess whether appropriate screening was informed by risk based solely on FH. Design Data from the BETTER (Building on Existing Tools to Improve Chronic Disease Prevention and Screening in Primary Care) trial were used. Patients were mailed questionnaires. Baseline FH and screening data were obtained for enrolled patients from the EMR and health questionnaires. Setting Ontario and Alberta. Participants Randomly selected patients from 8 family practices. Main outcome measures Agreement on FH between the EMR and questionnaire was determined; logistic regression was used to assess significant predictors of screening. Results In total, 775 of 789 (98%) patients completed the health questionnaire. The mean age of participants was 52.5 years and 72% were female. A minimum of 12% of patients (range 12% to 36%) had a reported FH of 1 of 4 chronic diseases. Among patients with positive FH, the following proportions of patients had that FH recorded in the EMR compared with the questionnaire: diabetes, 24% in the EMR versus 36% on the questionnaire, κ = 0.466; coronary artery disease, 35% in the EMR versus 22% on the questionnaire, κ = 0.225; breast cancer, 21% in the EMR versus 22% on the questionnaire, κ = 0.241; and CRC, 12% in the EMR versus 14% on the questionnaire, κ = 0.510. There was moderate agreement for diabetes and CRC. The presence of FH was a significant predictor of CRC screening (odds ratio 1.9, 95% CI 1.1 to 3.1). Conclusion A moderate prevalence of FH was found for 4 conditions for which screening recommendations vary with risk based on FH. Having patients self-complete an FH was thought to be feasible; however, questions

  16. Transplantation of Cadaver Tissues and Organs. Part 15. Chapter 338

    DTIC Science & Technology

    1984-01-09

    AG, Streeten B, Cowen D: Possible "p~rson-to-person transmission of Creutzfeldt - Jakob disease . N Engl J Med 290:692-693, 1974. 5. Friediaender GE... Jakob disease following corneal transplantation (4,7), as well as the virus of hepatitis transmitted through allogeneic bone (15). Aseptic procurement...iwperatives: to care for the patient whose brain is devastated by trauma or disease ; and when efforts at reversing the In- exorable course of cerebral

  17. Prion Transport to Secondary Lymphoreticular System Tissues

    DTIC Science & Technology

    2007-06-01

    Desbruslais, M., Luthert, P.J., & Collinge, J. (2001). Tissue Distribution of protease resistant prion protein in variant Creutzfeldt - Jakob disease ...examine the disease development of a prion strain (DY TME) that does not replicate in the spleen of hamsters. This system will provide details into the...gender specific responses to intraperitoneal DY TME inoculation. 15. SUBJECT TERMS Prion diseases , macrophage, complement 16. SECURITY

  18. Diagnosis and Evaluation of a Patient with Rapidly Progressive Dementia

    PubMed Central

    Bucelli, Robert C.; Ances, Beau M.

    2014-01-01

    While the most common dementia is Alzheimer’s disease (AD), a detailed history is needed to rule out rapidly progressive dementias (RPDs). RPDs are less than two years in duration and have a rate of progression faster typical neurodegenerative diseases. Identification of RPDs is important as some are treatable. This review focuses on the spectrum of RPDs, with special emphasis on paraneoplastic disorders and Creutzfeldt-Jakob disease (CJD). PMID:24279195

  19. Cortical sensory loss in a patient with posterior cortical atrophy: a case report.

    PubMed

    Hsu, Jung-Lung; Chen, Wei-Hung; Chiu, Hou-Chang

    2004-02-01

    Patients with posterior cortical atrophy (PCA) who present with initial symptoms of higher visual function deficits eventually develop alexia, aphasia, and components of Balint's syndrome or Gerstmann's syndrome. Recently, pathological findings were reported for these patients that are generally suggestive of Alzheimer's disease even though Creutzfeldt-Jakob disease (CJD) was presumed as an alternative cause of some autopsy-diagnosed PCA cases. Here, we report a case with a four-year progression of cognitive and higher visual function deterioration, and with features not described in previously reported PCA cases (i.e., a distinct sensory complaint and early frontal lobe involvement). To summarize, this case belongs to perceptual-motor syndrome of asymmetric cortical degeneration and the underlying neuropathology is more suggestive of Alzheimer's disease than of Creutzfeldt-Jakob disease.

  20. Neurochemistry changes associated with mutations in familial Parkinson's disease.

    PubMed

    Siddique, M M; Tan, E K

    2010-01-01

    Parkinson's disease (PD), a common neurodegenerative disease, is characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies and neurites. The exact role of genetic and environmental factors in the pathogenesis of PD has frequently been debated. The association of MPTP (methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine) and toxins (such as rotenone) with parkinsonism highlights the potential etiologic role of environmental toxins in disease causation. The recent discoveries of monogenic (such as α-synuclein, Parkin, UCHL1, PINK1, DJ-1, LRRK2) forms of PD have provided considerable insights into its pathophysiology. Parkin, an ubiquitin protein ligase assists in the degradation of toxic substrates via the ubiquitin proteasome system. It can also mediate a nondegradative form of ubiquitination. PINK1 and LRRK2 are possibly involved in the phosphorylation of substrates important for various cellular functions. Some toxins could interact with α-synuclein, an endogenous protein that is implicated in pathology of PD. Increasing in vitro and in vivo studies suggest that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system dysfunction underpin the pathogenesis of sporadic and familial forms of PD. Elucidation of the functions of the proteins encoded by the diseasecausing genes will provide an opportunity for identification of specific pathways that could be targeted in neurotherapeutics.

  1. The Family of Crumbs Genes and Human Disease

    PubMed Central

    Slavotinek, Anne M.

    2016-01-01

    The family of vertebrate Crumbs proteins, homologous to Drosophila Crumbs (Crb), share large extracellular domains with epidermal growth factor-like repeats and laminin-globular domains, a single transmembrane domain, and a short intracellular C-terminus containing a single membrane proximal 4.1/ezrin/radixin/moesin-binding domain and PSD-95/Discs large/ZO-1-binding motifs. There are 3 Crb genes in humans - Crumbs homolog-1 (CRB1), Crumbs homolog-2 (CRB2), and Crumbs homolog-3 (CRB3). Bilallelic loss-of-function mutations in CRB1 cause visual impairment, with Leber's congenital amaurosis and retinitis pigmentosa, whereas CRB2 mutations are associated with raised maternal serum and amniotic fluid alpha feto-protein levels, ventriculomegaly/hydrocephalus, and renal disease, ranging from focal segmental glomerulosclerosis to congenital Finnish nephrosis. CRB3 has not yet been associated with human disease. In this review, we summarize the phenotypic findings associated with deleterious sequence variants in CRB1 and CRB2. We discuss the mutational spectrum, animal models of loss of function for both genes and speculate on the likely mechanisms of disease. PMID:27867342

  2. Motor–Language Coupling in Huntington’s Disease Families

    PubMed Central

    Kargieman, Lucila; Herrera, Eduar; Baez, Sandra; García, Adolfo M.; Dottori, Martin; Gelormini, Carlos; Manes, Facundo; Gershanik, Oscar; Ibáñez, Agustín

    2014-01-01

    Traditionally, Huntington’s disease (HD) has been known as a movement disorder, characterized by motor, psychiatric, and cognitive impairments. Recent studies have shown that motor and action–language processes are neurally associated. The cognitive mechanisms underlying this interaction have been investigated through the action compatibility effect (ACE) paradigm, which induces a contextual coupling of ongoing motor actions and verbal processing. The present study is the first to use the ACE paradigm to evaluate action–word processing in HD patients (HDP) and their families. Specifically, we tested three groups: HDP, healthy first-degree relatives (HDR), and non-relative healthy controls. The results showed that ACE was abolished in HDP as well as HDR, but not in controls. Furthermore, we found that the processing deficits were primarily linguistic, given that they did not correlate executive function measurements. Our overall results underscore the role of cortico-basal ganglia circuits in action–word processing and indicate that the ACE task is a sensitive and robust early biomarker of HD and familial vulnerability. PMID:24971062

  3. Mechanisms of disease: genetic causes of familial hypercholesterolemia.

    PubMed

    Soutar, Anne K; Naoumova, Rossi P

    2007-04-01

    Familial hypercholesterolemia (FH) is characterized by raised serum LDL cholesterol levels, which result in excess deposition of cholesterol in tissues, leading to accelerated atherosclerosis and increased risk of premature coronary heart disease. FH results from defects in the hepatic uptake and degradation of LDL via the LDL-receptor pathway, commonly caused by a loss-of-function mutation in the LDL-receptor gene (LDLR) or by a mutation in the gene encoding apolipoprotein B (APOB). FH is primarily an autosomal dominant disorder with a gene-dosage effect. An autosomal recessive form of FH caused by loss-of-function mutations in LDLRAP1, which encodes a protein required for clathrin-mediated internalization of the LDL receptor by liver cells, has also been documented. The most recent addition to the database of genes in which defects cause FH is one encoding a member of the proprotein convertase family, PCSK9. Rare dominant gain-of-function mutations in PCSK9 cosegregate with hypercholesterolemia, and one mutation is associated with a particularly severe FH phenotype. Expression of PCSK9 normally downregulates the LDL-receptor pathway by indirectly causing degradation of LDL-receptor protein, and loss-of-function mutations in PCSK9 result in low plasma LDL levels. Thus, PCSK9 is an attractive target for new drugs aimed at lowering serum LDL cholesterol, which should have additive lipid-lowering effects to the statins currently used.

  4. Maternal inheritance and mitochondrial DNA variants in familial Parkinson's disease

    PubMed Central

    2010-01-01

    Background Mitochondrial function is impaired in Parkinson's disease (PD) and may contribute to the pathogenesis of PD, but the causes of mitochondrial impairment in PD are unknown. Mitochondrial dysfunction is recapitulated in cell lines expressing mitochondrial DNA (mtDNA) from PD patients, implicating mtDNA variants or mutations, though the role of mtDNA variants or mutations in PD risk remains unclear. We investigated the potential contribution of mtDNA variants or mutations to the risk of PD. Methods We examined the possibility of a maternal inheritance bias as well as the association between mitochondrial haplogroups and maternal inheritance and disease risk in a case-control study of 168 multiplex PD families in which the proband and one parent were diagnosed with PD. 2-tailed Fisher Exact Tests and McNemar's tests were used to compare allele frequencies, and a t-test to compare ages of onset. Results The frequency of affected mothers of the proband with PD (83/167, 49.4%) was not significantly different from the frequency of affected females of the proband generation (115/259, 44.4%) (Odds Ratio 1.22; 95%CI 0.83 - 1.81). After correcting for multiple tests, there were no significant differences in the frequencies of mitochondrial haplogroups or of the 10398G complex I gene polymorphism in PD patients compared to controls, and no significant associations with age of onset of PD. Mitochondrial haplogroup and 10398G polymorphism frequencies were similar in probands having an affected father as compared to probands having an affected mother. Conclusions These data fail to demonstrate a bias towards maternal inheritance in familial PD. Consistent with this, we find no association of common haplogroup-defining mtDNA variants or for the 10398G variant with the risk of PD. However, these data do not exclude a role for mtDNA variants in other populations, and it remains possible that other inherited mitochondrial DNA variants, or somatic mDNA mutations, contribute

  5. Clinical correlates of depressive symptoms in familial Parkinson's disease.

    PubMed

    Pankratz, Nathan; Marder, Karen S; Halter, Cheryl A; Rudolph, Alice; Shults, Cliff W; Nichols, William C; Foroud, Tatiana

    2008-11-15

    Depression is one of the most common nonmotor complications of Parkinson's disease (PD) and has a major impact on quality of life. Although several clinical factors have been associated with depression in PD, the relationship between depression and stage of illness as well as between depression and degree of disability remains controversial. We have collected clinical data on 1,378 PD cases from 632 families, using the Unified Parkinson's Disease Rating Scale (UPDRS) Parts II (activities of daily living) & III (motor), the Mini-Mental State Exam, the Geriatric Depression Scale (GDS), and the Blessed Functional Activity Scale (Blessed). Analyses were performed using the 840 individuals with verified PD and without evidence of cognitive decline. Logistic regression was used to identify study variables that individually and collectively best predicted the presence of depressive symptoms (GDS >or= 10). After correcting for multiple tests, depressive symptoms were significantly associated with Hoehn and Yahr stage and other clinical measures but not with any genetic variant (parkin, LRRK2, APOE). The Blessed score, education, presence of a first degree relative with signs of depression, and UPDRS Part II were found to best predict depressive symptomatology (R(2) = 0.33; P = 4 x 10(-48)). Contrary to several reports, the results from this large study indicate that stage of illness, motor impairment, and functional disability are strongly correlated with depressive symptoms.

  6. An event-based model for disease progression and its application in familial Alzheimer's disease and Huntington's disease.

    PubMed

    Fonteijn, Hubert M; Modat, Marc; Clarkson, Matthew J; Barnes, Josephine; Lehmann, Manja; Hobbs, Nicola Z; Scahill, Rachael I; Tabrizi, Sarah J; Ourselin, Sebastien; Fox, Nick C; Alexander, Daniel C

    2012-04-15

    Understanding the progression of neurological diseases is vital for accurate and early diagnosis and treatment planning. We introduce a new characterization of disease progression, which describes the disease as a series of events, each comprising a significant change in patient state. We provide novel algorithms to learn the event ordering from heterogeneous measurements over a whole patient cohort and demonstrate using combined imaging and clinical data from familial Alzheimer's and Huntington's disease cohorts. Results provide new detail in the progression pattern of these diseases, while confirming known features, and give unique insight into the variability of progression over the cohort. The key advantage of the new model and algorithms over previous progression models is that they do not require a priori division of the patients into clinical stages. The model and its formulation extend naturally to a wide range of other diseases and developmental processes and accommodate cross-sectional and longitudinal input data.

  7. Family history in public health practice: a genomic tool for disease prevention and health promotion.

    PubMed

    Valdez, Rodolfo; Yoon, Paula W; Qureshi, Nadeem; Green, Ridgely Fisk; Khoury, Muin J

    2010-01-01

    Family history is a risk factor for many chronic diseases, including cancer, cardiovascular disease, and diabetes. Professional guidelines usually include family history to assess health risk, initiate interventions, and motivate behavioral changes. The advantages of family history over other genomic tools include a lower cost, greater acceptability, and a reflection of shared genetic and environmental factors. However, the utility of family history in public health has been poorly explored. To establish family history as a public health tool, it needs to be evaluated within the ACCE framework (analytical validity; clinical validity; clinical utility; and ethical, legal, and social issues). Currently, private and public organizations are developing tools to collect standardized family histories of many diseases. Their goal is to create family history tools that have decision support capabilities and are compatible with electronic health records. These advances will help realize the potential of family history as a public health tool.

  8. Uptake and Degradation of Protease-Sensitive and -Resistant Forms of Abnormal Human Prion Protein Aggregates by Human Astrocytes

    PubMed Central

    Choi, Young Pyo; Head, Mark W.; Ironside, James W.; Priola, Suzette A.

    2015-01-01

    Sporadic Creutzfeldt-Jakob disease is the most common of the human prion diseases, a group of rare, transmissible, and fatal neurologic diseases associated with the accumulation of an abnormal form (PrPSc) of the host prion protein. In sporadic Creutzfeldt-Jakob disease, disease-associated PrPSc is present not only as an aggregated, protease-resistant form but also as an aggregated protease-sensitive form (sPrPSc). Although evidence suggests that sPrPSc may play a role in prion pathogenesis, little is known about how it interacts with cells during prion infection. Here, we show that protease-sensitive abnormal PrP aggregates derived from patients with sporadic Creutzfeldt-Jakob disease are taken up and degraded by immortalized human astrocytes similarly to abnormal PrP aggregates that are resistant to proteases. Our data suggest that relative proteinase K resistance does not significantly influence the astrocyte's ability to degrade PrPSc. Furthermore, the cell does not appear to distinguish between sPrPSc and protease-resistant PrPSc, suggesting that sPrPSc could contribute to prion infection. PMID:25280631

  9. Nosocomial viral infections: III. Guidelines for prevention and control of exanthematous viruses, gastroenteritis viruses, picornaviruses, and uncommonly seen viruses.

    PubMed

    Valenti, W M; Hruska, J F; Menegus, M A; Freeburn, M J

    1981-01-01

    This communication is the third in a four-part series on nosocomial viral infections from the Strong Memorial Hospital. This third article discusses guidelines for prevention and control of exanthematous viruses, gastroenteritis, viruses, adenoviruses and the picornaviruses other than rhinoviruses. Several uncommonly seen viruses, such as the virus of Creutzfeldt-Jakob disease and Marburg, Ebola, and Lassa fever viruses, also are reviewed briefly.

  10. Effects of Hydrazines upon Cyclic Nucleotide Regulated Neuronal Processes

    DTIC Science & Technology

    1987-07-30

    of adenylate cyclase, however, Creutzfeldt-Jakob disease (CJD) is a slow, infec- in neuronal membranes this enzyme can be tious, progressive...61102F 2312 UPONI CYFCLIC NECLEOTIDE REGULATED NEURONAL RESP+SES 12. PORSONAIL AUTMORIS) Mark MI. Rasenick, Ph.D. 934L TYPE OF REPORT 131m. Time...CT TERMI AS Icon hN.. on powe"~ 4f mete~up *ad Idendfy by. Week mum Imr) "peLo GROUP sun. owr Neuronal Signal, Transduction, Cytoskeleton

  11. Curvature Dynamics of α-Synuclein Familial Parkinson Disease Mutants

    PubMed Central

    Perlmutter, Jason D.; Braun, Anthony R.; Sachs, Jonathan N.

    2009-01-01

    α-Synuclein remains a protein of interest due to its propensity to form fibrillar aggregates in neurodegenerative disease and its putative function in synaptic vesicle regulation. Herein, we present a series of atomistic molecular dynamics simulations of wild-type α-synuclein and three Parkinson disease familial mutants (A30P, A53T, and E46K) in two distinct environments. First, in order to match recent NMR experiments, we have simulated each protein bound to an SDS detergent micelle. Second, in order to connect more closely to the true biological environment, we have simulated the proteins bound to a 1,2-dioleoyl-sn-glycero-3-phosphoserine lipid bilayer. In the micelle-bound case, we find that the wild type and all of the variants of α-synuclein flatten the underlying micelle, decreasing its surface area. A30P is known to lessen α-synuclein/membrane affinity and, consistent with experiment, destabilizes the simulated secondary structure. In the case of A53T, our simulations reveal a range of stabilizing hydrogen bonds that form with the threonine. In both environments, the E46K mutation, which is known to increase bilayer affinity, leads to an additional hydrogen bond between the protein and either the detergent or lipid. Simulations indicate that αS and its variants are less dynamic in the bilayer than in the micelle. Furthermore, the simulations of the mutants suggest how changes in the structure and dynamics of α-synuclein may affect its biological role. PMID:19126542

  12. Autoimmune BSEP disease: disease recurrence after liver transplantation for progressive familial intrahepatic cholestasis.

    PubMed

    Kubitz, Ralf; Dröge, Carola; Kluge, Stefanie; Stross, Claudia; Walter, Nathalie; Keitel, Verena; Häussinger, Dieter; Stindt, Jan

    2015-06-01

    Severe cholestasis may result in end-stage liver disease with the need of liver transplantation (LTX). In children, about 10 % of LTX are necessary because of cholestatic liver diseases. Apart from bile duct atresia, three types of progressive familial intrahepatic cholestasis (PFIC) are common causes of severe cholestasis in children. The three subtypes of PFIC are defined by the involved genes: PFIC-1, PFIC-2, and PFIC-3 are due to mutations of P-type ATPase ATP8B1 (familial intrahepatic cholestasis 1, FIC1), the ATP binding cassette transporter ABCB11 (bile salt export pump, BSEP), or ABCB4 (multidrug resistance protein 3, MDR3), respectively. All transporters are localized in the canalicular membrane of hepatocytes and together mediate bile salt and phospholipid transport. In some patients with PFIC-2 disease, recurrence has been observed after LTX, which mimics a PFIC phenotype. It could be shown by several groups that inhibitory anti-BSEP antibodies emerge, which most likely cause disease recurrence. The prevalence of severe BSEP mutations (e.g., splice site and premature stop codon mutations) is very high in this group of patients. These mutations often result in the complete absence of BSEP, which likely accounts for an insufficient auto-tolerance against BSEP. Although many aspects of this "new" disease are not fully elucidated, the possibility of anti-BSEP antibody formation has implications for the pre- and posttransplant management of PFIC-2 patients. This review will summarize the current knowledge including diagnosis, pathomechanisms, and management of "autoimmune BSEP disease."

  13. The impact of disease on family members: a critical aspect of medical care.

    PubMed

    Golics, Catherine Jane; Basra, Mohammad Khurshid Azam; Finlay, Andrew Yule; Salek, Sam

    2013-10-01

    Most existing health-related quality of life research concerns the impact of disease on patients. However, in several medical specialties including dermatology, oncology, and physical and mental disability, studies have been carried out investigating the impact of disease on the lives of families of patients. The aim of this paper is to review the literature which relates to the impact of disease on family members of patients. The OVIDSP Medline was selected as the primary database, Searches were limited to sources published in English. 158 papers were identified for review. The definition of "family" varied across the literature, and a broad definition was accepted in this review. This review shows that a wide variety of aspects of family members' lives can be affected, including emotional, financial, family relationships, education and work, leisure time, and social activities. Many of these themes are linked to one another, with themes including financial impact and social impact being linked to emotional impact. Some positive aspects were also identified from the literature, including family relationships growing stronger. Several instruments exist to measure the impact of illness on the family, and most are disease or specialty- specific. The impact of disease on families of patients is often unrecognised and underestimated. Taking into account the quality of life of families as well as patients can offer the clinician a unique insight into issues such as family relationships and the effect of treatment decisions on the patient's close social group of partner and family.

  14. Family Health History Communication Networks of Older Adults: Importance of Social Relationships and Disease Perceptions

    ERIC Educational Resources Information Center

    Ashida, Sato; Kaphingst, Kimberly A.; Goodman, Melody; Schafer, Ellen J.

    2013-01-01

    Older individuals play a critical role in disseminating family health history (FHH) information that can facilitate disease prevention among younger family members. This study evaluated the characteristics of older adults and their familial networks associated with two types of communication ("have shared" and "intend to share…

  15. Family Aggregation of Human T-Lymphotropic Virus 1-Associated Diseases: A Systematic Review

    PubMed Central

    Alvarez, Carolina; Gotuzzo, Eduardo; Vandamme, Anne-Mieke; Verdonck, Kristien

    2016-01-01

    Human T-lymphotropic virus 1 (HTLV-1) is a retrovirus that produces a persistent infection. Two transmission routes (from mother to child and via sexual intercourse) favor familial clustering of HTLV-1. It is yet unknown why most HTLV-1 carriers remain asymptomatic while about 10% of them develop complications. HTLV-1 associated diseases were originally described as sporadic entities, but familial presentations have been reported. To explore what is known about family aggregation of HTLV-1-associated diseases we undertook a systematic review. We aimed at answering whether, when, and where family aggregation of HTLV-1-associated diseases was reported, which relatives were affected and which hypotheses were proposed to explain aggregation. We searched MEDLINE, abstract books of HTLV conferences and reference lists of selected papers. Search terms used referred to HTLV-1 infection, and HTLV-1-associated diseases, and family studies. HTLV-1-associated diseases considered are adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV-1-associated uveitis, and infective dermatitis. Seventy-four records reported HTLV-1-associated diseases in more than one member of the same family and were included. Most reports came from HTLV-1-endemic countries, mainly Japan (n = 30) and Brazil (n = 10). These reports described a total of 270 families in which more than one relative had HTLV-1-associated diseases. In most families, different family members suffered from the same disease (n = 223). The diseases most frequently reported were ATLL (115 families) and HAM/TSP (102 families). Most families (n = 144) included two to four affected individuals. The proportion of ATLL patients with family history of ATLL ranged from 2 to 26%. The proportion of HAM/TSP patients with family history of HAM/TSP ranged from 1 to 48%. The predominant cluster types for ATLL were clusters of siblings and parent-child pairs and for HAM/TSP, an affected

  16. Ancestral origins of the prion protein gene D178N mutation in the Basque Country.

    PubMed

    Rodríguez-Martínez, Ana B; Barreau, Christian; Coupry, Isabelle; Yagüe, Jordi; Sánchez-Valle, Raquel; Galdós-Alcelay, Luis; Ibáñez, Agustín; Digón, Antón; Fernández-Manchola, Ignacio; Goizet, Cyril; Castro, Azucena; Cuevas, Nerea; Alvarez-Alvarez, Maite; de Pancorbo, Marian M; Arveiler, Benoît; Zarranz, Juan J

    2005-06-01

    Fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD) are familial prion diseases with autosomal dominant inheritance of the D178N mutation. FFI has been reported in at least 27 pedigrees around the world. Twelve apparently unrelated FFI and fCJD pedigrees with the characteristic D178N mutation have been reported in the Prion Diseases Registry of the Basque Country since 1993. The high incidence of familial prion diseases in this region may reflect a unique ancestral origin of the chromosome carrying this mutation. In order to investigate this putative founder effect, we developed "happy typing", a new approach to the happy mapping method, which consists of the physical isolation of large haploid genomic DNA fragments and their analysis by the Polymerase Chain Reaction in order to perform haplotypic analysis instead of pedigree analysis. Six novel microsatellite markers, located in a 150-kb genomic segment flanking the PRNP gene were characterized for typing haploid DNA fragments of 285 kb in size. A common haplotype was found in patients from the Basque region, strongly suggesting a founder effect. We propose that "happy typing" constitutes an efficient method for determining disease-associated haplotypes, since the analysis of a single affected individual per pedigree should provide sufficient evidence.

  17. Selective surgical management of progressive familial intrahepatic cholestasis (Byler's disease).

    PubMed

    Emond, J C; Whitington, P F

    1995-12-01

    Progressive familial intrahepatic cholestasis (PFIC) presents in early childhood with pruritus, jaundice, hepatomegaly, and growth failure. Medical therapy is unsuccessful, with progression from cholestasis to hepatic fibrosis, cirrhosis, and ultimately death before the age of 10 years. Because of evidence that biliary diversion can arrest or reverse progression to hepatic fibrosis, we have used partial biliary diversion (PBD) as primary therapy in PFIC, reserving orthotopic liver transplantation (OLT) for children who have progressive disease or established cirrhosis. Seventeen children with PFIC (aged 2 months to 19 years) have been treated. PBD was performed in eight cases. In these procedures, a 10-cm properistaltic jejunal segment was anastomosed to the side of the gallbladder, terminating as an end stoma for the collection and discard of bile. Eleven patients with hepatic insufficiency (or end-stage cirrhosis) received OLT using standard techniques, at the average age of 4 years. Six of the eight children treated with PBD had complete resolution of clinical symptoms and remain well 1 to 13 years postoperatively. These six patients have conjugated bilirubin values of less than 0.3 mg/dL, normal transaminases, and a serum bile salt concentration of less than 10 nmol/mL. All have had either reversal or no progression of the hepatic fibrosis. Postoperative bleeding complications occurred in two (25%), which required reoperation. One patient had an adhesive intestinal obstruction that was managed surgically 9 months postoperatively. Two patients had no benefit from PBD, and all of them had severe bridging fibrosis (1) or cirrhosis (3). These and nine others with cirrhosis at the time of presentation received orthotopic liver transplantation; of these, eight are alive (1 to 5 years postoperatively). These results show the importance of establishing a correct diagnosis in children with cholestasis. Clinical symptoms often are severe in children with PFIC before the

  18. Mutational analysis of PKD1 gene in a Chinese family with autosomal dominant polycystic kidney disease

    PubMed Central

    Liu, Jingyan; Li, Lanrong; Liu, Qingmin

    2015-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease and common renal disease. Mutations of PKD genes are responsible for this disease. We analyzed a large Chinese family with ADPKD using Sanger sequencing to identify the mutation responsible for this disease. The family comprised 27 individuals including 10 ADPKD patients. These ADPKD patients had severe renal disease and most of them died very young. We analyzed 6 survival patients gene and found they all had C10529T mutation in exon 35 of PKD1 gene. We did not found gene mutation in any unaffected relatives or 300 unrelated controls. These findings suggested that the C10529T mutation in PKD1 gene might be the pathogenic mutation responsible for the disease in this family. PMID:26722532

  19. Mutational analysis of PKD1 gene in a Chinese family with autosomal dominant polycystic kidney disease.

    PubMed

    Liu, Jingyan; Li, Lanrong; Liu, Qingmin

    2015-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease and common renal disease. Mutations of PKD genes are responsible for this disease. We analyzed a large Chinese family with ADPKD using Sanger sequencing to identify the mutation responsible for this disease. The family comprised 27 individuals including 10 ADPKD patients. These ADPKD patients had severe renal disease and most of them died very young. We analyzed 6 survival patients gene and found they all had C10529T mutation in exon 35 of PKD1 gene. We did not found gene mutation in any unaffected relatives or 300 unrelated controls. These findings suggested that the C10529T mutation in PKD1 gene might be the pathogenic mutation responsible for the disease in this family.

  20. Family History of Alzheimer's Disease and Cortical Thickness in Patients With Dementia.

    PubMed

    Ganske, Steffi; Haussmann, Robert; Gruschwitz, Antonia; Werner, Annett; Osterrath, Antje; Baumgaertel, Johanna; Lange, Jan; Donix, Katharina L; Linn, Jennifer; Donix, Markus

    2016-08-01

    A first-degree family history of Alzheimer's disease reflects genetic risks for the neurodegenerative disorder. Recent imaging data suggest localized effects of genetic risks on brain structure in healthy people. It is unknown whether this association can also be found in patients who already have dementia. Our aim was to investigate whether family history risk modulates regional medial temporal lobe cortical thickness in patients with Alzheimer's disease. We performed high-resolution magnetic resonance imaging and cortical unfolding data analysis on 54 patients and 53 nondemented individuals. A first-degree family history of Alzheimer's disease was associated with left hemispheric cortical thinning in the subiculum among patients and controls. The contribution of Alzheimer's disease family history to regional brain anatomy changes independent of cognitive impairment may reflect genetic risks that modulate onset and clinical course of the disease.

  1. Higher prevalence of autoimmune diseases and longer spells of vertigo in patients affected with familial Ménière's disease: A clinical comparison of familial and sporadic Ménière's disease.

    PubMed

    Hietikko, Elina; Sorri, Martti; Männikkö, Minna; Kotimäki, Jouko

    2014-06-01

    PURPOSE This study compared clinical features, predisposing factors, and concomitant diseases between sporadic and familial Ménière's disease (MD). METHOD Retrospective chart review and postal questionnaire were used. Participants were 250 definite patients with MD (sporadic, n =149; familial, n = 101) who fulfilled the American Academy of Otorhinolaryngology-Head and Neck Surgery (1995) criteria. RESULTS On average, familial patients were affected 5.6 years earlier than sporadic patients, and they suffered from significantly longer spells of vertigo (p = .007). The prevalence of rheumatoid arthritis (p = .002) and other autoimmune diseases (p = .046) was higher among the familial patients, who also had more migraine (p = .036) and hearing impairment (p = .002) in their families. CONCLUSION The clinical features of familial and sporadic MD are very similar in general, but some differences do exist. Familial MD patients are affected earlier and suffer from longer spells of vertigo.

  2. Finnish type of familial amyloidosis: cosegregation of Asp187----Asn mutation of gelsolin with the disease in three large families.

    PubMed Central

    Hiltunen, T; Kiuru, S; Hongell, V; Heliö, T; Palo, J; Peltonen, L

    1991-01-01

    Familial amyloidosis of Finnish type (FAF) is one of the familial amyloidotic polyneuropathy (FAP) syndromes, a group of inherited disorders characterized by extracellular accumulation of amyloid and by clinical symptoms and signs of polyneuropathy. FAF, an autosomal dominant trait, belongs to those rare monogenic disorders which occur with increased frequency in the Finnish population: only single FAF cases have been reported from other populations. In most types of FAP syndromes the accumulating protein is a transthyretin variant. However, recent evidence has suggested that the amyloid peptides in FAF are related to gelsolin, an actin modulating protein. The gelsolin fragments isolated from at least one patient with amyloidosis have been reported to have an amino acid substitution, with asparagine replacing aspartic acid at position 187 of the plasma gelsolin. In this study allele-specific oligonucleotides were used to analyze three large FAF families with multiple affected individuals as well as healthy family members. We found the corresponding G-A mutation in nucleotide 654 of the plasma gelsolin gene to cosegregate with the disease. The result was confirmed by sequencing and strongly suggests that the mutation has caused all the FAF cases of these families. Since the disease is clustered in restricted areas on the southern coast of Finland, this mutation most probably causes the majority, if not all, of FAF cases in Finland. Images Figure 2 PMID:1652889

  3. Role of stress granules and RNA-binding proteins in neurodegeneration: a mini-review.

    PubMed

    Vanderweyde, Tara; Youmans, Katie; Liu-Yesucevitz, Liqun; Wolozin, Benjamin

    2013-01-01

    The eukaryotic stress response involves translational suppression of non-housekeeping proteins and the sequestration of unnecessary mRNA transcripts into stress granules (SGs). This process is dependent on mRNA-binding proteins (RBPs) that interact with capped mRNA transcripts through RNA recognition motifs, and exhibit reversible aggregation through hydrophobic polyglycine domains, some of which are homologous to yeast prion proteins. The activity and aggregation of RBPs appears to be important in the context of unfolded protein diseases. The discovery that mutations in these RBPs can cause familial motoneuron diseases and familial dementias indicates the importance of these genes to neuronal degeneration. Some disorders linked to mutations in RBPs include: amyotrophic lateral sclerosis, frontotemporal dementia and spinal muscular atrophy. These RBPs also associate with pathological structures in other neurodegenerative diseases, including Huntington's chorea, Creutzfeldt-Jakob disease, and Alzheimer's disease. Interestingly, protein levels of RBPs change across the aging spectrum and may be linked to other age-related disorders, such as type 2 diabetes. The link between SG pathways and proteins linked to neurodegenerative diseases suggests a potential role for common pathways in both processes, such as those involved in translational control, and highlights potentially novel targets for therapeutic intervention in neurodegenerative diseases.

  4. Converging approaches to understanding early onset familial Alzheimer disease: A First Nation study

    PubMed Central

    Cabrera, Laura Y; Beattie, B Lynn; Dwosh, Emily; Illes, Judy

    2015-01-01

    Objectives: In 2007, a novel pathogenic genetic mutation associated with early onset familial Alzheimer disease was identified in a large First Nation family living in communities across British Columbia, Canada. Building on a community-based participatory study with members of the Nation, we sought to explore the impact and interplay of medicalization with the Nation’s knowledge and approaches to wellness in relation to early onset familial Alzheimer disease. Methods: We performed a secondary content analysis of focus group discussions and interviews with 48 members of the Nation between 2012 and 2013. The analysis focused specifically on geneticization, medicalization, and traditional knowledge of early onset familial Alzheimer disease, as these themes were prominent in the primary analysis. Results: We found that while biomedical explanations of disease permeate the knowledge and understanding of early onset familial Alzheimer disease, traditional concepts about wellness are upheld simultaneously. Conclusion: The analysis brings the theoretical framework of “two-eyed seeing” to the case of early onset familial Alzheimer disease for which the contributions of different ways of knowing are embraced, and in which traditional and western ways complement each other on the path of maintaining wellness in the face of progressive neurologic disease. PMID:27092264

  5. Rare deleterious mutations are associated with disease in bipolar disorder families

    PubMed Central

    Rao, Aliz R; Yourshaw, Michael; Christensen, Bryce; Nelson, Stanley F; Kerner, Berit

    2016-01-01

    Bipolar disorder (BD) is a common, complex, and heritable psychiatric disorder characterized by episodes of severe mood swings. The identification of rare, damaging genomic mutations in families with BD could inform about disease mechanisms and lead to new therapeutic interventions. To determine whether rare, damaging mutations shared identity-by-descent in families with BD could be associated with disease, exome sequencing was performed in multigenerational families of the NIMH BD Family Study followed by in silico functional prediction. Disease association and disease specificity was determined using 5 090 exomes from the Sweden-Schizophrenia (SZ) Population-Based Case-Control Exome Sequencing study. We identified 14 rare and likely deleterious mutations in 14 genes that were shared identity-by-descent among affected family members. The variants were associated with BD (p<0.05 after Bonferroni correction) and disease specificity was supported by the absence of the mutations in patients with SZ. In addition, we found rare, functional mutations in known causal genes for neuropsychiatric disorders including holoprosencephaly and epilepsy. Our results demonstrate that exome sequencing in multigenerational families with BD is effective in identifying rare genomic variants of potential clinical relevance and also disease modifiers related to coexisting medical conditions. Replication of our results and experimental validation are required before disease causation could be assumed. PMID:27725659

  6. Clinical Decision Support for Vascular Disease in Community Family Practice

    PubMed Central

    Keshavjee, K; Holbrook, AM; Lau, E; Esporlas-Jewer, I; Troyan, S

    2006-01-01

    The COMPETE III Vascular Disease Tracker (C3VT) is a personalized, Web-based, clinical decision support tool that provides patients and physicians access to a patient’s 16 individual vascular risk markers, specific advice for each marker and links to best practices in vascular disease management. It utilizes the chronic care model1 so that physicians can better manage patients with chronic diseases. Over 1100 patients have been enrolled into the COMPETE III study to date.

  7. Experiences of Supporting People with Down Syndrome and Alzheimer's Disease in Aged Care and Family Environments

    ERIC Educational Resources Information Center

    Carling-Jenkins, Rachel; Torr, Jennifer; Iacono, Teresa; Bigby, Christine

    2012-01-01

    Background: Research addressing the experiences of families of adults with Down syndrome and Alzheimer's disease in seeking diagnosis and gaining support is limited. The aim of this study was to gain a greater understanding of these processes by exploring the experiences of families and carers in supporting people with Down syndrome and…

  8. Using Picture Books to Help Children Cope with a Family Member's Alzheimer's Disease

    ERIC Educational Resources Information Center

    Holland, Marna

    2005-01-01

    A diagnosis of Alzheimer's disease (AD) and the resulting behavioral changes in a loved one can cause intense emotional reactions from all family members, including children. Sharing and discussing relevant picture books can be an effective strategy to help the children in such families understand and deal with their emotions. Picture books can…

  9. [Chronic disease, the chronic patient and his family. Psychosocial impact of diabetes mellitus].

    PubMed

    Rebelo, L

    1992-07-01

    Concerning a revision about the mutual influence between the diabetes, the diabetic and his family, the author reviews the literature about the psychosocial area of the Family Physician content's work. It is also confirmed the high prevalency of the chronic disease and the importance of the family ecosystem, not only as support but also as problem to the bearing person of such type of disease. Studies of chronic disease indicate that family dysfunction is associated with poor health outcomes. The areas which more and better have been studied in this scope are reviewed. Thus, having as backdrop the diabetes management, the family's diabetic influence in general is reviewed, as well as the parental attitudes, the family organization and the family life events. Finally, the health care team role is reviewed and particulary the role of the family physician in the management of this type of patients. It is pointed out, as example of the Family Medicine specific contribution, the improving cooperation with medical treatment from the diabetic.

  10. The effect of chronic disease family history on healthcare provider practice and patient behavior among Oregonians.

    PubMed

    Zlot, A I; Cox, S L; Silvey, K; Leman, R

    2012-01-01

    Family history is an independent risk factor for many chronic conditions. Therefore, efforts to prevent these diseases among asymptomatic people at high familial risk are justified to reduce the health burden of these chronic conditions. We analyzed 2006-2009 Oregon Behavioral Risk Factor Surveillance System data to examine associations between family history of diabetes, cardiovascular disease (CVD), colorectal cancer (CRC), breast cancer (BC), and: (1) patient-reported clinician recommendations, (2) adoption of preventive and screening behaviors, and (3) chronic disease risk factors among respondents without a personal history of the condition. A positive family history was associated with a higher likelihood of reported discussion by clinicians of CRC and BC screening and a greater likelihood of respondents having cholesterol and CRC screening. The combination of family history and clinician recommendations significantly increased the odds of CRC and BC screening compared to family history alone. A positive family history was also associated with respondents reporting lifestyle changes to prevent diabetes, CVD, and CRC, but not BC. Awareness of family history prompts clinicians to recommend screening and may motivate patients to be screened. Understanding positive family history may also motivate patients to adopt healthy lifestyles.

  11. [Focal epithelial hyperplasia (Heck's disease) in a Turkish family].

    PubMed

    Weidner, F

    1996-12-01

    A 31-year-old Turkish patient and some family members suffered from multiple hyperplastic oral mucosal papules. Intralesional papilloma virus was not found but the patient had elevated levels of CD8 lymphocytes in his peripheral blood. We diagnosed focal epithelial hyperplasia of Heck.

  12. Family Stigma and Caregiver Burden in Alzheimer's Disease

    ERIC Educational Resources Information Center

    Werner, Perla; Mittelman, Mary S.; Goldstein, Dovrat; Heinik, Jeremia

    2012-01-01

    Purpose: The stigma experienced by the family members of an individual with a stigmatized illness is defined by 3 dimensions: caregiver stigma, lay public stigma, and structural stigma. Research in the area of mental illness suggests that caregivers' perception of stigma is associated with increased burden. However, the effect of stigma on…

  13. EXPLORING PARENT-SIBLING COMMUNICATION IN FAMILIES OF CHILDREN WITH SICKLE CELL DISEASE

    PubMed Central

    Graff, J. Carolyn; Hankins, Jane S.; Hardy, Belinda T.; Hall, Heather R.; Roberts, Ruth J.; Neely-Barnes, Susan L.

    2011-01-01

    Focus group interviews were conducted with parents of children with sickle cell disease to explore parent-sibling communication about sickle cell disease. Communication was influenced by attributes and behaviors of the parent, the child with sickle cell disease, and the sibling; extended family, neighbors, friends, and church members or social networks; and available, accessible resources related to the child’s health, child’s school, and parent employment. Outcomes that influenced and were influenced by factors within and outside the parent-sibling dyad and nuclear family included parent satisfaction, parent roles, family intactness, and status attainment. These findings support previous research with African American families and expand our views of the importance of educating parents, family members, and others about sickle cell disease. The findings suggest a need to explore sibling perception of this communication, parent and sibling perception of the impact of frequent hospitalizations and clinic visits on the sibling and family, and variations within families of children with sickle cell disease. PMID:20384476

  14. Tristetraprolin family proteins may prevent and treat cardiovascular diseases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cardiovascular disease (CVD) is the most deadly disease in the U. S., according to the American Heart Association statistics. CVD have been consistently ranked the No. 1 killer since 1900 (except 1918), accounted for 38.5% of all deaths in 2001, and was estimated to cost $368.4 billion in 2004 in t...

  15. Instruments measuring the disease-specific quality of life of family carers of people with neurodegenerative diseases: a systematic review

    PubMed Central

    Page, Thomas E; Farina, Nicolas; Brown, Anna; Daley, Stephanie; Bowling, Ann; Basset, Thurstine; Livingston, Gill; Knapp, Martin; Murray, Joanna; Banerjee, Sube

    2017-01-01

    Objective Neurodegenerative diseases, such as dementia, have a profound impact on those with the conditions and their family carers. Consequently, the accurate measurement of family carers' quality of life (QOL) is important. Generic measures may miss key elements of the impact of these conditions, so using disease-specific instruments has been advocated. This systematic review aimed to identify and examine the psychometric properties of disease-specific outcome measures of QOL of family carers of people with neurodegenerative diseases (Alzheimer's disease and other dementias; Huntington's disease; Parkinson's disease; multiple sclerosis; and motor neuron disease). Design Systematic review. Methods Instruments were identified using 5 electronic databases (PubMed, PsycINFO, Web of Science, Scopus and the International Bibliography of the Social Sciences (IBSS)) and lateral search techniques. Only studies which reported the development and/or validation of a disease-specific measure for adult family carers, and which were written in English, were eligible for inclusion. The methodological quality of the included studies was evaluated using the COnsensus based Standards for the selection of health Measurement Instruments (COSMIN) checklist. The psychometric properties of each instrument were examined. Results 676 articles were identified. Following screening and lateral searches, a total of 8 articles were included; these reported 7 disease-specific carer QOL measures. Limited evidence was available for the psychometric properties of the 7 instruments. Psychometric analyses were mainly focused on internal consistency, reliability and construct validity. None of the measures assessed either criterion validity or responsiveness to change. Conclusions There are very few measures of carer QOL that are specific to particular neurodegenerative diseases. The findings of this review emphasise the importance of developing and validating psychometrically robust disease

  16. Impact of MS genetic loci on familial aggregation, clinical phenotype, and disease prediction

    PubMed Central

    Esposito, Federica; Guaschino, Clara; Sorosina, Melissa; Clarelli, Ferdinando; Ferre', Laura; Mascia, Elisabetta; Santoro, Silvia; Pagnesi, Matteo; Radaelli, Marta; Colombo, Bruno; Moiola, Lucia; Rodegher, Mariaemma; Stupka, Elia; Martinelli, Vittorio; Comi, Giancarlo

    2015-01-01

    Objective: To investigate the role of known multiple sclerosis (MS)-associated genetic variants in MS familial aggregation, clinical expression, and accuracy of disease prediction in sporadic and familial cases. Methods: A total of 1,443 consecutive patients were screened for MS and familial autoimmune history in a hospital-based Italian cohort. Among them, 461 sporadic and 93 familial probands were genotyped for 107 MS-associated polymorphisms. Their effect sizes were combined to calculate the weighted genetic risk score (wGRS). Results: Family history of MS was reported by 17.2% of probands, and 33.8% reported a familial autoimmune disorder, with autoimmune thyroiditis and psoriasis being the most frequent. No difference in wGRS was observed between sporadic and familial MS cases. In contrast, a lower wGRS was observed in probands with greater familial aggregation (>1 first-degree relative or >2 relatives with MS) (p = 0.03). Also, female probands of familial cases with greater familial aggregation had a lower wGRS than sporadic cases (p = 0.0009) and male probands of familial cases (p = 0.04). An inverse correlation between wGRS and age at onset was observed (p = 0.05). The predictive performance of the genetic model including all known MS variants was modest but greater in sporadic vs familial cases (area under the curve = 0.63 and 0.57). Conclusions: Additional variants outside the known MS-associated loci, rare variants, and/or environmental factors may explain disease occurrence within families; in females, hormonal and epigenetic factors probably have a predominant role in explaining familial aggregation. The inclusion of these additional factors in future versions of aggregated genetic measures could improve their predictive ability. PMID:26185776

  17. Cardiovascular disease mortality in patients with genetically verified familial hypercholesterolemia in Norway during 1992-2013.

    PubMed

    Mundal, Liv; Igland, Jannicke; Ose, Leiv; Holven, Kirsten B; Veierød, Marit B; Leren, Trond P; Retterstøl, Kjetil

    2017-01-01

    Background Patients with familial hypercholesterolemia have increased cardiovascular disease mortality but the magnitude of the increased risk is uncertain. The primary aim of this study was to investigate all causes of death and place and manner of deaths in a large sample of genotyped familial hypercholesterolemia patients. Design, methods and results In this registry study data on 5518 patients with genotyped familial hypercholesterolemia were linked to the Norwegian Cause of Death Registry during 1992-2013. Standardized mortality ratios and 95% confidence intervals (CIs) were estimated. There were in total 189 deaths. Cardiovascular disease was the most common cause of death (42.3%). Mean age at cardiovascular disease death was 64.5 years (range 33-91). Cardiovascular disease mortality including all cardiovascular disease deaths mentioning any place on the death certificate was significantly higher in familial hypercholesterolemia patients compared to the general Norwegian population under 70 years of age. Standardized mortality ratio (95% CI) was highest in the 20-39 years age group; 4.12 (1.85-9.18) decreasing to 0.77 (0.50-1.19) for those over 80 years. For total cardiovascular disease deaths occurring out of hospital, standardized mortality ratio was 12.35 (5.14-29.70) for those aged 20-39 years. Conclusion Familial hypercholesterolemia patients under 70 years of age have significantly higher cardiovascular disease mortality compared to the general Norwegian population. For those aged 20-39 years the risk of cardiovascular disease deaths occurring out of hospital was increased 12-fold. In spite of genotyped familial hypercholesterolemia and premature cardiovascular disease deaths, the majority of all death certificates did not include familial hypercholesterolemia among any of the contributing causes of death.

  18. Analysis of the prion protein gene in multiple system atrophy.

    PubMed

    Chelban, Viorica; Manole, Andreea; Pihlstrøm, Lasse; Schottlaender, Lucia; Efthymiou, Stephanie; OConnor, Emer; Meissner, Wassilios G; Holton, Janice L; Houlden, Henry

    2017-01-01

    Neurodegenerative diseases are a very diverse group of disorders but they share some common mechanisms such as abnormally misfolded proteins with prion-like propagation and aggregation. Creutzfeldt-Jakob disease (CJD) is the most prevalent prion disease in humans. In the sporadic form of CJD the only known risk factor is the codon 129 polymorphism. Recent reports suggested that α-synuclein in multiple system atrophy (MSA) has similar pathogenic mechanisms as the prion protein. Here we present 1 Italian family with MSA and prion disease. Also, cases of concurrent MSA and prion pathology in the same individual or family suggest the possibility of molecular interaction between prion protein and α-synuclein in the process of protein accumulation and neurodegeneration, warranting further investigations. We assessed the PRNP gene by whole-exome sequencing in 264 pathologically confirmed MSA cases and 462 healthy controls to determine whether the 2 diseases share similar risk factors. We then analyzed codon 129 polymorphism by Sanger sequencing and compared with previously published results in sporadic CJD. Homozygosity at codon 129 was present in 50% of pathologically confirmed MSA cases and in 58% of normal controls (odds ratio, 0.7 (95% confidence interval of 0.5-0.9)) compared with 88.2% in sporadic CJD. Our data show that the homozygous state of position 129 in the PRNP is not a risk factor for MSA. No other variants in the PRNP gene were associated with increased risk for MSA.

  19. High prevalence of diabetes mellitus in a five-generation Chinese family with Huntington's disease.

    PubMed

    Hu, Yueqing; Liang, Jingyao; Yu, Shengyuan

    2014-01-01

    Huntington's disease (HD) is associated with diabetes mellitus (DM) in population studies, but no case has been reported in a large HD family. We report a case of a five-generation Chinese family who is afflicted by both HD and DM. The prevalence of DM in HD of this family was high (72.7%). The diagnosis of HD in 11 family members was confirmed by the genetic test of the proband who had 42 CAG repeats. Furthermore, the proband's daughter had abnormal locus at G3460T in MT-ND1 among mtDNA genome. Our case report suggests a genetic link between HD and DM.

  20. Study designs for identification of rare disease variants in complex diseases: the utility of family-based designs.

    PubMed

    Ionita-Laza, Iuliana; Ottman, Ruth

    2011-11-01

    The recent progress in sequencing technologies makes possible large-scale medical sequencing efforts to assess the importance of rare variants in complex diseases. The results of such efforts depend heavily on the use of efficient study designs and analytical methods. We introduce here a unified framework for association testing of rare variants in family-based designs or designs based on unselected affected individuals. This framework allows us to quantify the enrichment in rare disease variants in families containing multiple affected individuals and to investigate the optimal design of studies aiming to identify rare disease variants in complex traits. We show that for many complex diseases with small values for the overall sibling recurrence risk ratio, such as Alzheimer's disease and most cancers, sequencing affected individuals with a positive family history of the disease can be extremely advantageous for identifying rare disease variants. In contrast, for complex diseases with large values of the sibling recurrence risk ratio, sequencing unselected affected individuals may be preferable.

  1. Using family history information to promote healthy lifestyles and prevent diseases; a discussion of the evidence

    PubMed Central

    2010-01-01

    Background A family history, reflecting genetic susceptibility as well as shared environmental and behavioral factors, is an important risk factor for common chronic multifactorial diseases such as cardiovascular diseases, type 2 diabetes and many cancers. Discussion The purpose of the present paper is to discuss the evidence for the use of family history as a tool for primary prevention of common chronic diseases, in particular for tailored interventions aimed at promoting healthy lifestyles. The following questions are addressed: (1) What is the value of family history information as a determinant of personal disease risk?; (2)How can family history information be used to motivate at-risk individuals to adopt and maintain healthy lifestyles in order to prevent disease?; and (3) What additional studies are needed to assess the potential value of family history information as a tool to promote a healthy lifestyle? Summary In addition to risk assessment, family history information can be used to personalize health messages, which are potentially more effective in promoting healthy lifestyles than standardized health messages. More research is needed on the evidence for the effectiveness of such a tool. PMID:20465810

  2. Heart-Healthy Families. Helping Your Kids Stay Fit Could Prevent Heart Disease in Their Futures.

    ERIC Educational Resources Information Center

    Vagnini, Frederic J.; Malone, Mary Jo

    1994-01-01

    The conditions and habits that lead to heart disease begin early in life. Obesity is the predecessor of a host of cardiovascular-related diseases; childhood obesity poses serious physical and psychological roadblocks for youngsters as they mature. The article suggests how families can adopt fitter lifestyles and instill good eating and exercise…

  3. 76 FR 13621 - Disease, Disability, and Injury Prevention and Control Special Emphasis Panel (SEP): Family...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-14

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention Disease, Disability, and Injury Prevention and Control Special Emphasis Panel (SEP): Family History and Diamond Blackfan Anemia, DD11- 010,...

  4. Familial Analysis of Seropositivity to Trypanosoma cruzi and of Clinical Forms of Chagas Disease

    PubMed Central

    Silva-Grecco, Roseane L.; Balarin, Marly A. S.; Correia, Dalmo; Prata, Aluízio; Rodrigues, Virmondes

    2010-01-01

    A cross-sectional study was carried out in Água Comprida, MG, Brazil, a region previously endemic to Chagas disease whose vectorial transmission was interrupted around 20 year ago. A total of 998 individuals were examined for anti-Trypanosoma cruzi antibodies. Seropositivity was observed in 255 subjects (25.5%), and 743 subjects were negative. Forty-one families with 5–80 individuals with similar environmental conditions were selected for familial analysis. In 15 families, seropositivity to T. cruzi was observed in > 50% of individuals. The segregation analysis confirmed family aggregation for the seropositivity to the T. cruzi. Heart commitment was the major clinical form observed, and in six families, > 50% of the individuals display cardiopathy that may be attributed to T. cruzi infection. Our results support the hypothesis that there is a family aggregation for the seropositivity but without the effect of one major gene. PMID:20064994

  5. Prions in Variably Protease-Sensitive Prionopathy: An Update

    PubMed Central

    Zou, Wen-Quan; Gambetti, Pierluigi; Xiao, Xiangzhu; Yuan, Jue; Langeveld, Jan; Pirisinu, Laura

    2013-01-01

    Human prion diseases, including sporadic, familial, and acquired forms such as Creutzfeldt-Jakob disease (CJD), are caused by prions in which an abnormal prion protein (PrPSc) derived from its normal cellular isoform (PrPC) is the only known component. The recently-identified variably protease-sensitive prionopathy (VPSPr) is characterized not only by an atypical clinical phenotype and neuropathology but also by the deposition in the brain of a peculiar PrPSc. Like other forms of human prion disease, the pathogenesis of VPSPr also currently remains unclear. However, the findings of the peculiar features of prions from VPSPr and of the possible association of VPSPr with a known genetic prion disease linked with a valine to isoleucine mutation at residue 180 of PrP reported recently, may be of great importance in enhancing our understanding of not only this atypical human prion disease in particular, but also other prion diseases in general. In this review, we highlight the physicochemical and biological properties of prions from VPSPr and discuss the pathogenesis of VPSPr including the origin and formation of the peculiar prions. PMID:25437202

  6. Familial Prion Disease with Alzheimer Disease-Like Tau Pathology and Clinical Phenotype

    PubMed Central

    Jayadev, Suman; Nochlin, David; Poorkaj, Parvoneh; Steinbart, Ellen J.; Mastrianni, James A.; Montine, Thomas J.; Ghetti, Bernardino; Schellenberg, Gerard D.; Bird, Thomas D.; Leverenz, James B.

    2011-01-01

    Objective To describe the Alzheimer disease (AD)-like clinical and pathological features, including marked neurofibrillary tangle (NFT) pathology, of a familial prion disease due to a rare nonsense mutation of the prion gene (PRNP). Methods Longitudinal clinical assessments were available for the proband and her mother. After death, both underwent neuropathological evaluation. PRNP was sequenced after failure to find immunopositive Aβ deposits in the proband and the documentation of prion protein (PrP) immunopositive pathology. Results The proband presented at age 42 years with a 3-year history of progressive short-term memory impairment and depression. Neuropsychological testing found impaired memory performance, with relatively preserved attention and construction. She was diagnosed with AD and died at age 47 years. Neuropathologic evaluation revealed extensive limbic and neocortical NFT formation and neuritic plaques consistent with a Braak stage of VI. The NFTs were immunopositive, with multiple tau antibodies, and electron microscopy revealed paired helical filaments. However, the neuritic plaques were immunonegative for Aβ, whereas immunostaining for PrP was positive. The mother of the proband had a similar presentation, including depression, and had been diagnosed clinically and pathologically as AD. Reevaluation of her brain tissue confirmed similar tau and PrP immunostaining findings. Genetic analysis revealed that both the proband and her mother had a rare PRNP mutation (Q160X) that resulted in the production of truncated PrP. Interpretation We suggest that PRNP mutations that result in a truncation of PrP lead to a prolonged clinical course consistent with a clinical diagnosis of AD and severe AD-like NFTs. PMID:21416485

  7. Observations on Patient and Family Coping with Huntington's Disease.

    ERIC Educational Resources Information Center

    Falek, Arthur

    1979-01-01

    Huntington's disease is an autosomal dominantly inherited disorder. No definitive method for the preclinical detection of carriers is known. The consequences of this diagnosis are discussed. The significance of genetic counseling and a description of the phases in psychological coping is presented to enable informed decision making by family…

  8. Benzothiazole aniline tetra(ethylene glycol) and 3-amino-1,2,4-triazole inhibit neuroprotection against amyloid peptides by catalase overexpression in vitro.

    PubMed

    Chilumuri, Amrutha; Odell, Mark; Milton, Nathaniel G N

    2013-11-20

    Alzheimer's disease, Familial British dementia, Familial Danish dementia, Type 2 diabetes mellitus, plus Creutzfeldt-Jakob disease are associated with amyloid fibril deposition and oxidative stress. The antioxidant enzyme catalase is a neuroprotective amyloid binding protein. Herein the effects of catalase overexpression in SH-SY5Y neuronal cells on the toxicity of amyloid-β (Aβ), amyloid-Bri (ABri), amyloid-Dan (ADan), amylin (IAPP), and prion protein (PrP) peptides were determined. Results showed catalase overexpression was neuroprotective against Aβ, ABri, ADan, IAPP, and PrP peptides. The catalase inhibitor 3-amino-1,2,4-triazole (3-AT) and catalase-amyloid interaction inhibitor benzothiazole aniline tetra(ethylene glycol) (BTA-EG4) significantly enhanced neurotoxicity of amyloid peptides in catalase overexpressing neuronal cells. This suggests catalase neuroprotection involves breakdown of hydrogen peroxide (H2O2) plus a direct binding interaction between catalase and the Aβ, ABri, ADan, IAPP, and PrP peptides. Kisspeptin 45-50 had additive neuroprotective actions against the Aβ peptide in catalase overexpressing cells. The effects of 3-AT had an intracellular site of action, while catalase-amyloid interactions had an extracellular component. These results suggest that the 3-AT and BTA-EG4 compounds may be able to inhibit endogenous catalase mediated neuroprotection. Use of BTA-EG4, or compounds that inhibit catalase binding to amyloid peptides, as potential therapeutics for Neurodegenerative diseases may therefore result in unwanted effects.

  9. Symmetrical corticobasal syndrome caused by a novel C.314dup progranulin mutation.

    PubMed

    Dopper, Elise G P; Seelaar, Harro; Chiu, Wang Zheng; de Koning, Inge; van Minkelen, Rick; Baker, Matthew C; Rozemuller, Annemieke J M; Rademakers, Rosa; van Swieten, John C

    2011-11-01

    Corticobasal syndrome (CBS) is characterised by asymmetrical parkinsonism and cognitive impairment. The underlying pathology varies between corticobasal degeneration, progressive supranuclear palsy, Alzheimer's disease, Creutzfeldt-Jakob disease and frontotemporal lobar degeneration sometimes in association with GRN mutations. A 61-year-old male underwent neurological examination, neuropsychological assessment, MRI, and HMPAO-SPECT at our medical centre. After his death at the age of 63, brain autopsy, genetic screening and mRNA expression analysis were performed. The patient presented with slow progressive walking disabilities, non-fluent language problems, behavioural changes and forgetfulness. His family history was negative. He had primitive reflexes, rigidity of his arms and postural instability. Later in the disease course he developed dystonia of his left leg, pathological crying, mutism and dysphagia. Neuropsychological assessment revealed prominent ideomotor and ideational apraxia, executive dysfunction, non-fluent aphasia and memory deficits. Neuroimaging showed symmetrical predominant frontoparietal atrophy and hypoperfusion. Frontotemporal lobar degeneration (FTLD)-TDP type 3 pathology was found at autopsy. GRN sequencing revealed a novel frameshift mutation c.314dup, p.Cys105fs and GRN mRNA levels showed a 50% decrease. We found a novel GRN mutation in a patient with an atypical (CBS) presentation with symmetric neuroimaging findings. GRN mutations are an important cause of CBS associated with FTLD-TDP type 3 pathology, sometimes in sporadic cases. Screening for GRN mutations should also be considered in CBS patients without a positive family history.

  10. State-of-the-art review of goat TSE in the European Union, with special emphasis on PRNP genetics and epidemiology

    PubMed Central

    Vaccari, Gabriele; Panagiotidis, Cynthia H.; Acin, Cristina; Peletto, Simone; Barillet, Francis; Acutis, Pierluigi; Bossers, Alex; Langeveld, Jan; van Keulen, Lucien; Sklaviadis, Theodoros; Badiola, Juan J.; Andréoletti, Olivier; Groschup, Martin H.; Agrimi, Umberto; Foster, James; Goldmann, Wilfred

    2009-01-01

    Scrapie is a fatal, neurodegenerative disease of sheep and goats. It is also the earliest known member in the family of diseases classified as transmissible spongiform encephalopathies (TSE) or prion diseases, which includes Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy (BSE), and chronic wasting disease in cervids. The recent revelation of naturally occurring BSE in a goat has brought the issue of TSE in goats to the attention of the public. In contrast to scrapie, BSE presents a proven risk to humans. The risk of goat BSE, however, is difficult to evaluate, as our knowledge of TSE in goats is limited. Natural caprine scrapie has been discovered throughout Europe, with reported cases generally being greatest in countries with the highest goat populations. As with sheep scrapie, susceptibility and incubation period duration of goat scrapie are most likely controlled by the prion protein (PrP) gene (PRNP). Like the PRNP of sheep, the caprine PRNP shows significantly greater variability than that of cattle and humans. Although PRNP variability in goats differs from that observed in sheep, the two species share several identical alleles. Moreover, while the ARR allele associated with enhancing resistance in sheep is not present in the goat PRNP, there is evidence for the existence of other PrP variants related to resistance. This review presents the current knowledge of the epidemiology of caprine scrapie within the major European goat populations, and compiles the current data on genetic variability of PRNP. PMID:19505422

  11. A population-based study of familial Alzheimer disease: Linkage to chromosomes 14, 19, and 21

    SciTech Connect

    Duijn, C.M. van; Hofman, A.; Hendriks, L.; Cruts, M.; Van Broeckhoven, C.; Backhovens, H.; Wehnert, A. |; Farrer, L.A.

    1994-10-01

    Linkage of Alzheimer disease (AD) to DNA markers on chromosomes 14, 19, and 21 was studied in 10 families in which the disease was apparently inherited as an autosomal dominant trait. Families were derived from a Dutch population-based epidemiologic study of early-onset AD. Although in all probands the onset of AD was at or before age 65 years, the mean age at onset was after age 65 years in four families (referred to as {open_quotes}LOAD{close_quotes}). Among the six families with early-onset AD (referred to as {open_quotes}EOAD,{close_quotes} i.e., mean age of onset of AD of relatives was at or before age 65 years), conclusive linkage to 14q24.3 was found in one family with a very early onset (around 47 years), while linkage to the same region was excluded in two other families. For the LOAD families, predominantly negative lod scores were obtained, and the overall lod score excluded linkage to chromosome 14. The results with markers on chromosome 19 and chromosome 21 were not conclusive for EOAD and LOAD. The findings of our study confirm genetic heterogeneity within familial EOAD. 50 refs., 7 figs., 2 tabs.

  12. Characteristics of familial aggregation in early-onset Alzheimer`s disease: Evidence of subgroups

    SciTech Connect

    Campion, D.; Martinez, M.; Babron, M.C.

    1995-06-19

    Characteristics of familial aggregation of Alzheimer`s Disease were studied in 92 families ascertained through a clinically diagnosed proband with an onset below age 60 years. In each family data were systematically collected on the sibships of the proband, of his father, and of his mother. A total of 926 relatives were included and 81% of the living relatives (i.e., 251 individuals) were directly examined. The estimated cumulative risk among first degree relatives was equal to 35% by age 89 years (95% confidence interval 22 to 47%). This result does not support the hypothesis that an autosomal dominant gene, fully penetrant by age 90 years, is segregating within all these pedigrees. Despite the fact that all probands were selected for an onset before age 60 years it was shown that two types of families could be delineated with respect to age at onset among affected relatives: all secondary cases with an onset below age 60 years were contributed by a particular group of families (type 1 families), whereas all secondary cases with an onset after age 60 years were contributed by another group of families (type 2 families). Although genetic interpretation of these findings is not straightforward, they support the hypothesis of etiologic heterogeneity in the determinism of early-onset Alzheimer`s disease. 58 refs., 5 figs., 2 tabs.

  13. Relevance of Chronic Lyme Disease to Family Medicine as a Complex Multidimensional Chronic Disease Construct: A Systematic Review

    PubMed Central

    Goderis, Geert

    2014-01-01

    Lyme disease has become a global public health problem and a prototype of an emerging infection. Both treatment-refractory infection and symptoms that are related to Borrelia burgdorferi infection remain subject to controversy. Because of the absence of solid evidence on prevalence, causes, diagnostic criteria, tools and treatment options, the role of autoimmunity to residual or persisting antigens, and the role of a toxin or other bacterial-associated products that are responsible for the symptoms and signs, chronic Lyme disease (CLD) remains a relatively poorly understood chronic disease construct. The role and performance of family medicine in the detection, integrative treatment, and follow-up of CLD are not well studied either. The purpose of this paper is to describe insights into the complexity of CLD as a multidimensional chronic disease construct and its relevance to family medicine by means of a systematic literature review. PMID:25506429

  14. [Lafora disease presentation, two cases in a Mexican family].

    PubMed

    González-De la Rosa, María Guadalupe; Alva-Moncayo, Edith

    2017-01-01

    Myoclonic epilepsy, described in 1911 by Lafora and Glueck, is an autosomal recessive hereditary clinical-pathological entity, which begins at the end of childhood or during adolescence, presents atypical absences, generalized and atonic tonic-clonic seizures, which can evolve to the epileptic state. The diagnosis is confirmed trough the skin biopsy or trough determination of the protein laforine. In this paper we present the initial case of a patient in whom we confirm the diagnosis of progressive myoclonic epilepsy and in particular the Lafora disease, which due to the symptomatology and the knowledge of the case we were able to detect her sister's disease. Skin biopsies are reported with high sensitivity and specificity, observing inclusion bodies, and neurophysiological and electroencephalographic studies are undoubtedly non-specific. The article reports on the cases of two sisters, who were definitively confirmed their diagnosis, which allowed us to focus on the early detection of the other case.

  15. Family history and disease outcomes in patients with Crohn’s disease: A comparison between China and the United States

    PubMed Central

    Wang, Pei-Qi; Hu, Jun; Al Kazzi, Elie S; Akhuemonkhan, Eboselume; Zhi, Min; Gao, Xiang; de Paula Pessoa, Raquel Holand; Ghazaleh, Sami; Cornelius, Tuhina; Sabunwala, Suhel Abbas; Ghadermarzi, Shadi; Tripathi, Kartikeya; Lazarev, Mark; Hu, Pin-Jin; Hutfless, Susan

    2016-01-01

    AIM To investigate the differences in family history of inflammatory bowel disease (IBD) and clinical outcomes among individuals with Crohn’s disease (CD) residing in China and the United States. METHODS We performed a survey-based cross-sectional study of participants with CD recruited from China and the United States. We compared the prevalence of IBD family history and history of ileal involvement, CD-related surgeries and IBD medications in China and the United States, adjusting for potential confounders. RESULTS We recruited 49 participants from China and 145 from the United States. The prevalence of family history of IBD was significantly lower in China compared with the United States (China: 4.1%, United States: 39.3%). The three most commonly affected types of relatives were cousin, sibling, and parent in the United States compared with child and sibling in China. Ileal involvement (China: 63.3%, United States: 63.5%) and surgery for CD (China: 51.0%, United States: 49.7%) were nearly equivalent in the two countries. CONCLUSION The lower prevalence of familial clustering of IBD in China may suggest that the etiology of CD is less attributed to genetic background or a family-shared environment compared with the United States. Despite the potential difference in etiology, surgery and ileal involvement were similar in the two countries. Examining the changes in family history during the continuing rise in IBD may provide further insight into the etiology of CD. PMID:27867689

  16. Polyphenols as Modulators of Aquaporin Family in Health and Disease.

    PubMed

    Fiorentini, Diana; Zambonin, Laura; Dalla Sega, Francesco Vieceli; Hrelia, Silvana

    2015-01-01

    Polyphenols are bioactive molecules widely distributed in fruits, vegetables, cereals, and beverages. Polyphenols in food sources are extensively studied for their role in the maintenance of human health and in the protection against development of chronic/degenerative diseases. Polyphenols act mainly as antioxidant molecules, protecting cell constituents against oxidative damage. The enormous number of polyphenolic compounds leads to huge different mechanisms of action not fully understood. Recently, some evidence is emerging about the role of polyphenols, such as curcumin, pinocembrin, resveratrol, and quercetin, in modulating the activity of some aquaporin (AQP) isoforms. AQPs are integral, small hydrophobic water channel proteins, extensively expressed in many organs and tissues, whose major function is to facilitate the transport of water or glycerol over cell plasma membranes. Here we summarize AQP physiological functions and report emerging evidence on the implication of these proteins in a number of pathophysiological processes. In particular, this review offers an overview about the role of AQPs in brain, eye, skin diseases, and metabolic syndrome, focusing on the ability of polyphenols to modulate AQP expression. This original analysis can contribute to elucidating some peculiar effects exerted by polyphenols and can lead to the development of an innovative potential preventive/therapeutic strategy.

  17. Clinical features of early onset, familial Alzheimer`s disease linked to chromosome 14

    SciTech Connect

    Mullan, M.; Bennett, C.; Figueredo, C.; Crawford, F.

    1995-02-27

    Early onset familial Alzheimer`s disease (AD) has an autosomal dominant mode of inheritance. Two genes are responsible for the majority of cases of this subtype of AD. Mutations in the {beta}-amyloid precursor protein ({beta}APP) gene on chromosome 21 have been shown to completely cosegregate with the disease. We and others have previously described the clinical features of families with {beta}APP mutations at the codon 717 locus in an attempt to define the phenotype associated with a valine to isoleucine (Val {r_arrow} Ile) or a valine to glycine (Val {r_arrow} Gly) change. More recently, a second locus for very early onset disease has been localized to chromosome 14. The results of linkage studies in some families suggesting linkage to both chromosomes have been explained by the suggestion of a second (centromeric) locus on chromosome 21. Here we report the clinical features and genetic analysis of a British pedigree (F74) with early onset AD in which neither the {beta}APP locus nor any other chromosome 21 locus segregates with the disease, but in which good evidence is seen for linkage on the long arm of chromosome 14. In particular we report marker data suggesting that the chromosome 14 disease locus is close to D14S43 and D14S77. Given the likelihood that F74 represents a chromosome 14 linked family, we describe the clinical features and make a limited clinical comparison with the {beta}APP717 Val {r_arrow} Ile and {beta}APP717 Val {r_arrow} Gly encoded families that have been previously described. We conclude that although several previously reported clinical features occur to excess in early onset familial AD, no single clinical feature demarcates either the chromosome 14 or {beta}APP codon 717 mutated families except mean age of onset. 52 refs., 2 figs., 5 tabs.

  18. Intrafamilial phenotypic variability in four families with Anderson-Fabry disease.

    PubMed

    Rigoldi, M; Concolino, D; Morrone, A; Pieruzzi, F; Ravaglia, R; Furlan, F; Santus, F; Strisciuglio, P; Torti, G; Parini, R

    2014-09-01

    We analysed the clinical history of 16 hemizygous males affected by Anderson-Fabry Disease, from four families, to verify their intrafamilial phenotypic variability. Seven male patients, ranging from 26 to 61 years of age, died, whereas nine (age range 23-55) are alive. Eleven patients have undergone enzyme replacement therapy (ERT) for a period of 5-10 years. We have found a wide range of intrafamilial phenotypic variability in these families, both in terms of target-organs and severity of the disease. Overall, our findings confirm previous data from the literature showing a high degree of intrafamilial phenotypic variability in patients carrying the same mutation. Furthermore, our results underscore the difficulty in giving accurate prognostic information to patients during genetic counselling, both in terms of rate of disease progression and involvement of different organs, when such prognosis is solely based on the patient's family history.

  19. The impact of Juvenile Huntington's Disease on the family: the case of a rare childhood condition.

    PubMed

    Brewer, Helen M; Eatough, Virginia; Smith, Jonathan A; Stanley, Cath A; Glendinning, Neil W; Quarrell, Oliver W J

    2008-01-01

    There has been little research into the impact of Juvenile Huntington's Disease (JHD) on the family, and the issues facing this group are poorly understood. The study reported here is part of larger project that aimed to address this. Ten semi-structured interviews with the main carer were carried out, and were analysed using Interpretative Phenomenological Analysis (IPA). This article reports three themes arising from the study relating to the psychosocial impact of JHD on the family: (1) dealing with something so different; (2) lack of understanding (3) isolation. This information is useful in developing appropriate services for families affected by JHD, as well as being of relevance to other childhood conditions.

  20. The APOE locus advances disease progression in late onset familial Alzheimer`s disease but is not causative

    SciTech Connect

    Crawford, F.; Bennett, C.; Osborne, A.

    1994-09-01

    An association has been observed in several independent data sets between late onset Alzheimer`s disease (AD) and the APOE locus on chromosomes 19. We have examined the genotype in family history positive (FHP) and family history negative (FHN) cases and find a distortion of the APOE allele frequencies in accord with previous studies. However, when we examined the allele distribution of the at-risk siblings of the FHP group we found an excess of the {epsilon}4 allele which also differs significantly from historic controls but not from the affected siblings. The age distribution of the affected and unaffected siblings was similar, suggesting that the allelic frequency distortion in the unaffected siblings was not due to their being below the mean age of onset. Lod score linkage analysis, with age dependent onset and nonstringent specification of the genetic parameters, did not suggest linkage to the APOE locus. Furthermore, an analysis of variance of the age of disease-free survival suggested that APOE genotype contributes a small fraction of the total variance, indicating that the APOE locus is a poor predictor of disease-free survival time within late onset families. We suggest that the APOE locus enhances the rate of progression of the disease in otherwise predisposed individuals and that variation at this locus is not able in and of itself to cause this disease.

  1. Supernumerary nipples in association with Hailey-Hailey disease in a Tunisian family.

    PubMed

    Benmously-Mlika, R; Deghais, S; Bchetnia, M; Charfeddine, C; Mokni, M; Kassar, S; Haouet, S; Boubaker, S; Mokhtar, I; Abdelhak, S; Dhahri, A Ben Osman

    2008-06-15

    Supernumerary nipples (SNs) or polythelia are developmental abnormalities of breast tissue. They are located along the embryonic mammary lines. Polythelia usually occurs as a sporadic abnormality, although familial aggregation has been occasionally reported. Hailey-Hailey disease is a rare autosomal genodermatosis characterized by disturbed keratinocyte adhesion. These cutaneous disorders have been described in correlation with many other abnormalities. We report here the association of Hailey-Hailey disease and supernumerary nipples in a Northern Tunisian family. To our knowledge, this is the first report of such a clinical association.

  2. Comorbidity in patients with chronic obstructive pulmonary disease in family practice: a cross sectional study

    PubMed Central

    2013-01-01

    Background Chronic obstructive pulmonary disease (COPD) is frequent and often coexists with other diseases. The aim of this study was to quantify the prevalence of COPD and related chronic comorbidity among patients aged over 40 years visiting family practices in an area of Madrid. Methods An observational, descriptive, cross-sectional study was conducted in a health area of the Madrid Autonomous Region (Comunidad Autónoma de Madrid). The practice population totalled 198,670 persons attended by 129 Family Physicians (FPs), and the study population was made up of persons over the age of 40 years drawn from this practice population. Patients were deemed to have COPD if this diagnosis appeared on their clinical histories. Prevalence of COPD; prevalence of a further 25 chronic diseases in patients with COPD; and standardised prevalence ratios, were calculated. Results Prevalence of COPD in family medicine was 3.2% (95% CI 3.0–3.3) overall, 5.3% among men and 1.4% among women; 90% of patients presented with comorbidity, with a mean of 4 ± 2.04 chronic diseases per patient, with the most prevalent related diseases being arterial hypertension (52%), disorders of lipid metabolism (34%), obesity (25%), diabetes (20%) and arrhythmia (15%). After controlling for age and sex, the observed prevalence of the following ten chronic diseases was higher than expected: heart failure; chronic liver disease; asthma; generalised artherosclerosis; osteoporosis; ischaemic heart disease; thyroid disease; anxiety/depression; arrhythmia; and obesity. Conclusions Patients with COPD, who are frequent in family practice, have a complex profile and pose a clinical and organisational challenge to FPs. PMID:23324308

  3. Germline mutation screening and predictive testing in families with von Hippel-Lindau disease

    SciTech Connect

    Brauch, H.; Glavac, D.; Pausch, F.

    1994-09-01

    von Hippel-Lindau (VHL) disease is an autosomal inheritable disease that predisposes gene carriers to develop tumors in the eyes, central nervous system, kidney, adrenal gland, pancreas and epididymis. VHL type 1 is without phenochromocytoma (P); VHL type 2 is with P. Screening for germline mutations and preclinical diagnosis in families with VHL disease has become feasible since the VHL gene was isolated. We applied Southern blotting and hybridization with g7cDNA to detect rearrangements, PCR-SSCP and sequencing to detect missense, nonsense and splice mutations, and primer-specified restriction map modification to detect a P-specific missense mutation. In 48 apparently unrelated VHL families mainly from Germany, we identified 20/48 (42%) VHL mutations: 7 (14.5%) rearrangements, 9/48 (19%) missense mutations affecting nt505, 1/48 (2%) splice site mutation, 2/48 (4%) other missense mutations, and 1/48 (2%) nonsense mutation. The predominance of the nt505 mutation in 9 German families with VHL type 2 suggests that this genotype expresses the VHL/P disease pattern. Predictive testing for VHL gene carriers in families with specific mutations identified 7 asymptomatic gene carriers. VHL manifestations have been confirmed by clinical examination in two individuals. Early molecular diagnosis may result in a successful management of VHL disease and prolong survival of VHL patients.

  4. Alcoholic patients' response to their disease: perspective of patients and family

    PubMed Central

    Lima-Rodríguez, Joaquín Salvador; Guerra-Martín, María Dolores; Domínguez-Sánchez, Isabel; Lima-Serrano, Marta

    2015-01-01

    Objective: to know the perspective of alcoholic patients and their families about the behavioral characteristics of the disease, identifying the issues to modify the addictive behavior and seek rehabilitation. Method: ethnographic research using interpretative anthropology, via participant observation and a detailed interview with alcoholic patients and their families, members of Alcoholics Anonymous (AA) and Alanon in Spain. Results: development of disease behavior in alcoholism is complex due to the issues of interpreting the consumption model as a disease sign. Patients often remain long periods in the pre-contemplation stage, delaying the search for assistance, which often arrives without them accepting the role of patient. This constrains the recovery and is related to the social thought on alcoholism and self-stigma on alcoholics and their families, leading them to deny the disease, condition of the patient, and help. The efforts of self-help groups and the involvement of health professionals is essential for recovery. Conclusion: understanding how disease behavior develops, and the change process of addictive behavior, it may be useful for patients, families and health professionals, enabling them to act in a specific way at each stage. PMID:26626009

  5. HDR: a statistical two-step approach successfully identifies disease genes in autosomal recessive families.

    PubMed

    Imai, Atsuko; Kohda, Masakazu; Nakaya, Akihiro; Sakata, Yasushi; Murayama, Kei; Ohtake, Akira; Lathrop, Mark; Okazaki, Yasushi; Ott, Jurg

    2016-11-01

    In the search for sequence variants underlying disease, commonly applied filtering steps usually result in a number of candidate variants that cannot further be narrowed down. In autosomal recessive families, disease usually occurs only in one generation so that genetic linkage analysis is unlikely to help. Because homozygous recessive mutations tend to be inherited together with flanking homozygous variants, we developed a statistical method to detect pathogenic variants in autosomal recessive families: We look for differences in patterns of homozygosity around candidate variants between patients and control individuals and expect that such differences are greater for pathogenic variants than random candidate variants. In six autosomal recessive mitochondrial disease families, in which pathogenic homozygous variants have already been identified, our approach succeeded in prioritizing pathogenic mutations. Our method is applicable to single patients from recessive families with at least a few dozen control individuals from the same population; it is easy to use and is highly effective for detecting causative mutations in autosomal recessive families.

  6. Linkage analyses of chromosome 6 loci, including HLA, in familial aggregations of Crohn disease

    SciTech Connect

    Hugot, J.P.; Laurent-Puig, P.; Gower-Rousseau, C.; Caillat-Zueman, S.; Beaugerie, L.; Dupas, J.L.; Van Gossum, A.; Bonaiti-Pellie, C.; Cortot, A.

    1994-08-15

    Segregation analyses of familial aggregations of Crohn disease have provided consistent results pointing to the involvement of a predisposing gene with a recessive mode of inheritance. Although extensively investigated, the role played by human leucocyte antigen (HLA) genes in this inflammatory bowel disease remains elusive and the major histocompatibility complex is a candidate region for the mapping of the Crohn disease susceptibility gene. A total of 25 families with multiple cases of Crohn disease was genotyped for HLA DRB1 and for 16 highly polymorphic loci evenly distributed on chromosome 6. The data were subjected to linkage analysis using the lod score method. Neither individual nor combined lod scores for any family and for any locus tested reached values suggesting linkage or genetic heterogeneity. The Crohn disease predisposing locus was excluded from the whole chromosome 6 with lod scores less than -2. It was excluded from the major histocompatibility complex and from 91% of the chromosome 6 genetic map with lod scores less than -4. The major recessive gene involved in genetic predisposition to Crohn disease does not reside on the major histocompatibility complex nor on any locus mapping to chromosome 6. 37 refs., 2 figs., 2 tabs.

  7. The Rh protein family: gene evolution, membrane biology, and disease association.

    PubMed

    Huang, Cheng-Han; Ye, Mao

    2010-04-01

    The Rh (Rhesus) genes encode a family of conserved proteins that share a structural fold of 12 transmembrane helices with members of the major facilitator superfamily. Interest in this family has arisen from the discovery of Rh factor's involvement in hemolytic disease in the fetus and newborn, and of its homologs widely expressed in epithelial tissues. The Rh factor and Rh-associated glycoprotein (RhAG), with epithelial cousins RhBG and RhCG, form four subgroups conferring upon vertebrates a genealogical commonality. The past decade has heralded significant advances in understanding the phylogenetics, allelic diversity, crystal structure, and biological function of Rh proteins. This review describes recent progress on this family and the molecular insights gleaned from its gene evolution, membrane biology, and disease association. The focus is on its long evolutionary history and surprising structural conservation from prokaryotes to humans, pointing to the importance of its functional role, related to but distinct from ammonium transport proteins.

  8. Genome-wide Linkage Screen in Familial Parkinson Disease Identifies Loci on Chromosomes 3 and 18

    PubMed Central

    Gao, Xiaoyi; Martin, Eden R.; Liu, Yutao; Mayhew, Gregory; Vance, Jeffery M.; Scott, William K.

    2009-01-01

    Parkinson disease (PD) is a complex, multifactorial neurodegenerative disease with substantial evidence for genetic risk factors. We conducted a genome-wide linkage screen of 5824 single-nucleotide polymorphisms in 278 families of European, non-Hispanic descent to localize regions that harbor susceptibility loci for PD. By using parametric and nonparametric linkage analyses and allowing for genetic heterogeneity among families, we found two loci for PD. Significant evidence for linkage was detected on chromosome 18q11 (maximum lod score [MLOD] = 4.1) and suggestive evidence for linkage was obtained on chromosome 3q25 (MLOD = 2.5). These results were strongest in families not previously screened for linkage, and simulation studies suggest that these findings are likely due to locus heterogeneity rather than random statistical error. The finding of two loci (one highly statistically significant) suggests that additional PD susceptibility genes might be identified through targeted candidate gene studies in these regions. PMID:19327735

  9. [Family and religious traditions present in medical discourses by medical professionals about children with genetic diseases].

    PubMed

    Martins, Antilia Januária; Cardoso, Maria Helena Cabral de Almeida; Llerena, Juan Clinton; Moreira, Martha Cristina Nunes

    2012-02-01

    This study explores the influences of cultural traditions rooted in the tone of medical discourse at the Instituto Fernandes Figueira/ Fundação Oswaldo Cruz by physicians regarding children with genetic diseases involving malformations and mental retardation, as well as reflections upon the professional care for these children. Data were collected using oral interviews (in the form of conversational narratives) and were submitted to semiotic analysis. The results pointed to four main cultural traditions present in medical discourse: the norm, the reason, the family and the Jewish-Christian religiosity. This article, however, focuses on the latter two, emphasizing how the notion of the family, mainly the mythification of the mother, can make the child with a genetic disease 'invisible,' in addition to contributing towards womanhood being underestimated when contrasted with motherhood. Such concepts overlap with those brought by the religious traditions and directly influence the medical perceptions towards patients and their families.

  10. [Unverricht-Lündborg disease: clinical and electrophysiologic study of 19 Maghreb families].

    PubMed

    Gouider, R; Ibrahim, S; Fredj, M; Gargouri, A; Saïdi, H; Ouezzani, R; Malafosse, A; Yahiaoui, M; Grid, D; Mrabet, A

    1998-07-01

    We describe clinical, electrophysiological and genetic features in 44 patients with Unverricht-Lündborg disease from 19 families living in North African countries (Tunisia, Algeria and Morocco). The mean age of patients was 25.3 years; mean age was at onset 11.3 years. The disease began more frequently with seizures (91 per cent) or myoclonus (80 p. 100) than ataxia (16 p. 100). Subsequently myoclonus and generalized seizures were present in all patients, cerebellar signs were absent in four cases. EEG findings included normal background activity (90 p. 100), spontaneous fast generalized spikes (93 p. 100) and photosensitivity (70 p. 100). Antiepileptic polytherapy (clonazepam and/or phenobarbital and/or valporic acid) was used in 84 per cent of cases. Antiepileptic drugs were more effective in controlling epileptic seizures (less than one seizure/month in 60 p. 100) than myocloni which persisted daily in 64 p. 100 of cases. Mean duration of the disease was 13.5 years. One patient died of status epilepticus. Consanguinity was noted in 17 families (first degree in 15 families). Linkage to chromosome 21q 22.3 was confirmed in 11 families. We noted an inter and intrafamilial variability of clinical signs and disease course.

  11. Feasibility of recruiting families into a heart disease prevention program based on dietary patterns

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Offspring of parents with a history of cardiovascular disease (CVD) inherit a similar genetic profile and share diet and lifestyle behaviors. This study aimed to evaluate the feasibility of recruiting families at risk of CVD to a dietary prevention program, determine the changes in diet achieved, an...

  12. The role of family in a dietary risk reduction intervention for cardiovascular disease

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Diet is an essential strategy for the prevention of primary and secondary cardiovascular disease (CVD) events. The objectives were to examine: how families at increased risk of CVD perceived personal risk, their motivations to make dietary changes, their understanding of diet, and the influence of o...

  13. Family History

    MedlinePlus

    Your family history includes health information about you and your close relatives. Families have many factors in common, including their genes, ... as heart disease, stroke, and cancer. Having a family member with a disease raises your risk, but ...

  14. Relationship of lipoprotein(a) levels to physical activity and family history of coronary heart disease.

    PubMed Central

    Martín, S; Elosua, R; Covas, M I; Pavesi, M; Vila, J; Marrugat, J

    1999-01-01

    OBJECTIVES: This study evaluated the association of physical activity with serum lipoprotein(a) [La(a)] levels in individuals according to whether they had a family history of coronary heart disease (CHD). METHODS: Lp(a) levels in 332 healthy Spanish men aged 20 to 60 years were measured. Physical activity and family history of CHD were assessed. RESULTS: For men with a family history of CHD, the odds ratio for Lp(a) levels above the median value was 0.13 (95% confidence interval = 0.03, 0.50) in very active men (energy expended in physical activity > 300 kcal/day) compared with active men (energy expended in physical activity < 300 kcal/day). CONCLUSIONS: Regular daily physical activity in individuals with a family history of CHD could be useful for controlling Lp(a) levels. PMID:10076490

  15. Family health history communication networks of older adults: importance of social relationships and disease perceptions.

    PubMed

    Ashida, Sato; Kaphingst, Kimberly A; Goodman, Melody; Schafer, Ellen J

    2013-10-01

    Older individuals play a critical role in disseminating family health history (FHH) information that can facilitate disease prevention among younger family members. This study evaluated the characteristics of older adults and their familial networks associated with two types of communication (have shared and intend to share new FHH information with family members) to inform public health efforts to facilitate FHH dissemination. Information on 970 social network members enumerated by 99 seniors (aged 57 years and older) at 3 senior centers in Memphis, Tennessee, through face-to-face interviews was analyzed. Participants shared FHH information with 27.5% of the network members; 54.7% of children and 24.4% of siblings. Two-level logistic regression models showed that participants had shared FHH with those to whom they provided emotional support (odds ratio [OR] = 1.836) and felt close to (OR = 1.757). Network-members were more likely to have received FHH from participants with a cancer diagnosis (OR = 2.617) and higher familiarity with (OR = 1.380) and importance of sharing FHH with family (OR = 1.474). Participants intended to share new FHH with those who provide tangible support to (OR = 1.804) and were very close to them (OR = 2.112). Members with whom participants intend to share new FHH were more likely to belong to the network of participants with higher perceived severity if family members encountered heart disease (OR = 1.329). Many first-degree relatives were not informed of FHH. Perceptions about FHH and disease risk as well as quality of social relationships may play roles in whether seniors communicate FHH with their families. Future studies may consider influencing these perceptions and relationships.

  16. A novel approach for identifying causal models of complex diseases from family data.

    PubMed

    Park, Leeyoung; Kim, Ju H

    2015-04-01

    Causal models including genetic factors are important for understanding the presentation mechanisms of complex diseases. Familial aggregation and segregation analyses based on polygenic threshold models have been the primary approach to fitting genetic models to the family data of complex diseases. In the current study, an advanced approach to obtaining appropriate causal models for complex diseases based on the sufficient component cause (SCC) model involving combinations of traditional genetics principles was proposed. The probabilities for the entire population, i.e., normal-normal, normal-disease, and disease-disease, were considered for each model for the appropriate handling of common complex diseases. The causal model in the current study included the genetic effects from single genes involving epistasis, complementary gene interactions, gene-environment interactions, and environmental effects. Bayesian inference using a Markov chain Monte Carlo algorithm (MCMC) was used to assess of the proportions of each component for a given population lifetime incidence. This approach is flexible, allowing both common and rare variants within a gene and across multiple genes. An application to schizophrenia data confirmed the complexity of the causal factors. An analysis of diabetes data demonstrated that environmental factors and gene-environment interactions are the main causal factors for type II diabetes. The proposed method is effective and useful for identifying causal models, which can accelerate the development of efficient strategies for identifying causal factors of complex diseases.

  17. Family Based Whole Exome Sequencing Reveals the Multifaceted Role of Notch Signaling in Congenital Heart Disease

    PubMed Central

    Chetaille, Philippe; Prince, Andrea; Godard, Beatrice; Leclerc, Severine; Sobreira, Nara; Ling, Hua; Awadalla, Philip; Thibeault, Maryse; Khairy, Paul; Samuels, Mark E.; Andelfinger, Gregor

    2016-01-01

    Left-ventricular outflow tract obstructions (LVOTO) encompass a wide spectrum of phenotypically heterogeneous heart malformations which frequently cluster in families. We performed family based whole-exome and targeted re-sequencing on 182 individuals from 51 families with multiple affected members. Central to our approach is the family unit which serves as a reference to identify causal genotype-phenotype correlations. Screening a multitude of 10 overlapping phenotypes revealed disease associated and co-segregating variants in 12 families. These rare or novel protein altering mutations cluster predominantly in genes (NOTCH1, ARHGAP31, MAML1, SMARCA4, JARID2, JAG1) along the Notch signaling cascade. This is in line with a significant enrichment (Wilcoxon, p< 0.05) of variants with a higher pathogenicity in the Notch signaling pathway in patients compared to controls. The significant enrichment of novel protein truncating and missense mutations in NOTCH1 highlights the allelic and phenotypic heterogeneity in our pediatric cohort. We identified novel co-segregating pathogenic mutations in NOTCH1 associated with left and right-sided cardiac malformations in three independent families with a total of 15 affected individuals. In summary, our results suggest that a small but highly pathogenic fraction of family specific mutations along the Notch cascade are a common cause of LVOTO. PMID:27760138

  18. The Role of Family in a Dietary Risk Reduction Intervention for Cardiovascular Disease

    PubMed Central

    Schumacher, Tracy L.; Burrows, Tracy L.; Thompson, Deborah I.; Callister, Robin; Spratt, Neil J.; Collins, Clare E.

    2016-01-01

    Diet is an essential strategy for the prevention of primary and secondary cardiovascular disease (CVD) events. The objectives were to examine: how families at increased risk of CVD perceived personal risk, their motivations to make dietary changes, their understanding of diet, and the influence of other family members. Individuals (>18 years) who completed an Australian family-based CVD risk reduction program were invited to a semi-structured telephone interview. Responses were recorded, transcribed verbatim and analysed using a systematic deductive approach with coding derived from key concepts developed as part of the interview structure. Seventeen participants from eight families were interviewed (aged 18–70 years, 47% male, five with CVD diagnosis). Key themes indicated both intrinsic and extrinsic motivations to improve heart health, variations in risk perception, recognition of the role diet plays in heart health, and the extent of family influences on eating patterns. Discrepancies between perceived and actual CVD risk perception impacted on perceived “need” to modify current dietary patterns towards heart health recommendations. Therefore, strategies not reliant on risk perception are needed to engage those with low risk perception. This could involve identifying and accessing the family “ringleader” to influence involvement and capitalising on personal accountability to other family members. PMID:27706027

  19. The Role of Family in a Dietary Risk Reduction Intervention for Cardiovascular Disease.

    PubMed

    Schumacher, Tracy L; Burrows, Tracy L; Thompson, Deborah I; Callister, Robin; Spratt, Neil J; Collins, Clare E

    2016-09-30

    Diet is an essential strategy for the prevention of primary and secondary cardiovascular disease (CVD) events. The objectives were to examine: how families at increased risk of CVD perceived personal risk, their motivations to make dietary changes, their understanding of diet, and the influence of other family members. Individuals (>18 years) who completed an Australian family-based CVD risk reduction program were invited to a semi-structured telephone interview. Responses were recorded, transcribed verbatim and analysed using a systematic deductive approach with coding derived from key concepts developed as part of the interview structure. Seventeen participants from eight families were interviewed (aged 18-70 years, 47% male, five with CVD diagnosis). Key themes indicated both intrinsic and extrinsic motivations to improve heart health, variations in risk perception, recognition of the role diet plays in heart health, and the extent of family influences on eating patterns. Discrepancies between perceived and actual CVD risk perception impacted on perceived "need" to modify current dietary patterns towards heart health recommendations. Therefore, strategies not reliant on risk perception are needed to engage those with low risk perception. This could involve identifying and accessing the family "ringleader" to influence involvement and capitalising on personal accountability to other family members.

  20. PKD1 and PKD2 mutations in Slovenian families with autosomal dominant polycystic kidney disease

    PubMed Central

    Vouk, Katja; Strmecki, Lana; Stekrova, Jitka; Reiterova, Jana; Bidovec, Matjaz; Hudler, Petra; Kenig, Anton; Jereb, Simona; Zupanic-Pajnic, Irena; Balazic, Joze; Haarpaintner, Guido; Leskovar, Bostjan; Adamlje, Anton; Skoflic, Antun; Dovc, Reina; Hojs, Radovan; Komel, Radovan

    2006-01-01

    Background Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder caused by mutations in at least two different loci. Prior to performing mutation screening, if DNA samples of sufficient number of family members are available, it is worthwhile to assign the gene involved in disease progression by the genetic linkage analysis. Methods We collected samples from 36 Slovene ADPKD families and performed linkage analysis in 16 of them. Linkage was assessed by the use of microsatellite polymorphic markers, four in the case of PKD1 (KG8, AC2.5, CW3 and CW2) and five for PKD2 (D4S1534, D4S2929, D4S1542, D4S1563 and D4S423). Partial PKD1 mutation screening was undertaken by analysing exons 23 and 31–46 and PKD2 . Results Lod scores indicated linkage to PKD1 in six families and to PKD2 in two families. One family was linked to none and in seven families linkage to both genes was possible. Partial PKD1 mutation screening was performed in 33 patients (including 20 patients from the families where linkage analysis could not be performed). We analysed PKD2 in 2 patients where lod scores indicated linkage to PKD2 and in 7 families where linkage to both genes was possible. We detected six mutations and eight polymorphisms in PKD1 and one mutation and three polymorphisms in PKD2. Conclusion In our study group of ADPKD patients we detected seven mutations: three frameshift, one missense, two nonsense and one putative splicing mutation. Three have been described previously and 4 are novel. Three newly described framesfift mutations in PKD1 seem to be associated with more severe clinical course of ADPKD. Previously described nonsense mutation in PKD2 seems to be associated with cysts in liver and milder clinical course. PMID:16430766

  1. The impact of a child with sickle cell disease on family dynamics.

    PubMed

    Burlew, A K; Evans, R; Oler, C

    1989-01-01

    This paper has reviewed research and other papers that have furthered our understanding of the impact of the presence of a child with sickle cell disease on the family. The research suggests that the primary parent in such a family experiences additional emotional strain much like primary parents of children with other chronic illnesses have been found to exhibit. The research also suggests that the ill child's presence influences interpersonal relationships within the family. Specifically, there is some evidence that the relationship between the parents and the relationship between the parent and other offspring may be affected adversely. The only evidence for an adverse impact on the relationship between the parent and the chronically ill child was in our research when considering only single-parent families. The research also suggests that the family environment is affected. In particular, the research suggests that the level of conflict and organization within the family was less favorable than within the control families. Moreover, the research suggests that the child's presence reduces the ability of the primary parent to participate in social activities outside of the family. Secondary parents, on the other hand, report less satisfaction with the extent to which their own individual needs are being met within the family. The available research also suggests that other factors mediate the impact of the child's illness on the family. In particular, parents with more knowledge about the illness and more social support available appear to cope more favorably with the illness. Moreover, the available research also suggests that the family also impacts on how the patient responds to the illness. Specifically, the more psychosocial stressors within the family, the less effectively the patient copes with the illness. In addition, the more social support available to the patient from the family and other significant others, the more likely the patient is to comply

  2. Host-microbiome interaction in Crohn's disease: A familiar or familial issue?

    PubMed

    Michielan, Andrea; D'Incà, Renata

    2015-11-15

    An impaired interaction between the gut and the intestinal microbiome is likely to be the key element in the pathogenesis of Crohn's disease (CD). Family studies have provided invaluable information on CD pathogenesis and on its etiology. Relatives share the same genetic risk of developing the disease as affected subjects. Relatives also exhibit similar features relating to their host-microbiome interaction, namely genetic variants in loci involved in detecting bacteria, a greater sero-reactivity to microbial components, and an impaired intestinal permeability. The burden of environmental factors such as cigarette smoking and dysbiosis also seems to be particularly relevant in these genetically predisposed subjects. Diet is emerging as an important factor and could account for the changing epidemiology of CD in recent years. Despite the pivotal role of genetics in the disease's pathogenesis (especially in familial CD), screening tests in healthy relatives cannot be recommended.

  3. Analysis of POFUT1 Gene Mutation in a Chinese Family with Dowling-Degos Disease

    PubMed Central

    Chen, Mingfei; Li, Yi; Liu, Hong; Fu, Xi'an; Yu, Yiongxiang; Yu, Gongqi; Wang, Chuan; Bao, Fangfang; Liany, Herty; Wang, Zhenzhen; Shi, Zhongxiang; Zhang, Dizhan; Zhou, Guizhi; Liu, Jianjun; Zhang, Furen

    2014-01-01

    Dowling-Degos disease (DDD) is an autosomal dominant genodermatosis characterized by reticular pigmented anomaly mainly affecting flexures. Though KRT5 has been identified to be the causal gene of DDD, the heterogeneity of this disease was displayed: for example, POFUT1 and POGLUT1 were recently identified and confirmed to be additional pathogenic genes of DDD. To identify other DDD causative genes, we performed genome-wide linkage and exome sequencing analyses in a multiplex Chinese DDD family, in which the KRT5 mutation was absent. Only a novel 1-bp deletion (c.246+5delG) in POFUT1 was found. No other novel mutation or this deletion was detected in POFUT1 in a second DDD family and a sporadic DDD case by Sanger Sequencing. The result shows the genetic-heterogeneity and complexity of DDD and will contribute to the further understanding of DDD genotype/phenotype correlations and to the pathogenesis of this disease. PMID:25157627

  4. Analysis of POFUT1 gene mutation in a Chinese family with Dowling-Degos disease.

    PubMed

    Chen, Mingfei; Li, Yi; Liu, Hong; Fu, Xi'an; Yu, Yiongxiang; Yu, Gongqi; Wang, Chuan; Bao, Fangfang; Liany, Herty; Wang, Zhenzhen; Shi, Zhongxiang; Zhang, Dizhan; Zhou, Guizhi; Liu, Jianjun; Zhang, Furen

    2014-01-01

    Dowling-Degos disease (DDD) is an autosomal dominant genodermatosis characterized by reticular pigmented anomaly mainly affecting flexures. Though KRT5 has been identified to be the causal gene of DDD, the heterogeneity of this disease was displayed: for example, POFUT1 and POGLUT1 were recently identified and confirmed to be additional pathogenic genes of DDD. To identify other DDD causative genes, we performed genome-wide linkage and exome sequencing analyses in a multiplex Chinese DDD family, in which the KRT5 mutation was absent. Only a novel 1-bp deletion (c.246+5delG) in POFUT1 was found. No other novel mutation or this deletion was detected in POFUT1 in a second DDD family and a sporadic DDD case by Sanger Sequencing. The result shows the genetic-heterogeneity and complexity of DDD and will contribute to the further understanding of DDD genotype/phenotype correlations and to the pathogenesis of this disease.

  5. Transmission and age-at-onset patterns in familial Alzheimer's disease: evidence for heterogeneity.

    PubMed

    Farrer, L A; Myers, R H; Cupples, L A; St George-Hyslop, P H; Bird, T D; Rossor, M N; Mullan, M J; Polinsky, R; Nee, L; Heston, L

    1990-03-01

    We evaluated age at onset and lifetime risk for Alzheimer's disease (AD) in 70 kindreds with familial AD (designated FAD) composed of 541 affected and 1,066 unaffected offspring of demented parents who were identified retrospectively. Using a survival analysis method which takes into account affected persons with unknown onset ages and unaffected persons with unknown censoring ages, we found lifetime risk of AD among at-risk offspring by age 87 to be 64%. Analysis of age at onset among kindreds showed evidence for a bimodal distribution: in this sample, families with a mean onset age of less than 58 years were designated as having early-onset, while late-onset families had a mean onset age greater than 58 years. At-risk offspring in early-onset families had an estimated lifetime risk for dementia of 53%, which is significantly less than the risk of 86% that was estimated for offspring in late-onset families. Men and women in early-onset families had equivalent risk of dementia. In late-onset families, the risk to female offspring was somewhat higher than to male offspring but this difference was marginally significant. Lifetime risk of dementia in early-onset FAD kindreds is consistent with an autosomal dominant inheritance model. Our results may suggest that late-onset FAD has at least 2 etiologies; AD in some families may be transmitted as a dominant trait, whereas a proportion of cases in these and other late-onset families may be caused by other genetic or shared environmental factors.

  6. Ethical issues involved in establishing a registry for familial Alzheimer's disease.

    PubMed

    Godard, B; Knoppers, B M; Glass, K; Grenon, M; Bouchard, R; Bouvier, M; Goulet, J; Gauvreau, D

    1994-01-01

    In January 1992, the IMAGE Project extended the establishment of its registry of familial Alzheimer cases to all areas of the province of Quebec, for collection of epidemiological and clinical data, as well as biological samples. The aim is to study genetic transmission patterns of Alzheimer's disease (AD) and to provide a sampling framework for further etiologic and risk factor studies. The IMAGE registry already includes data of a population-based study in the Saguenay-Lac-St-Jean area; the project to collect data on familial AD (FAD) cases across the province of Quebec is known as the ALGENE Initiative. The registry is thus a collection of "AD families" for both familial and sporadic cases. The establishment of the registry involves several steps in the field work: recruitment and selection of families; collection of information on family medical history; selection of informative families and genetic testing for AD/FAD by linkage analysis. As AD is not homogeneous in its etiology and since we do not know if, in the event that genetics is involved in AD whether or not penetrance of the gene(s) is high, we must be aware of the "genetic horizons" of AD in collecting and conserving data on families of cases, and in the genetic testing for AD/FAD by linkage analysis. Families who choose genetic testing must be aware of the implications of our undertaking, assured of the confidentiality of the test and, at the same time, they must understand its limitations. The experimental nature of our research project raises ethical dilemmas. This article examines these initial considerations of the field work involved in developing a registry pertaining to genetic testing for AD/FAD by linkage analysis and offers some preliminary observations on the experience of the first year of this project.

  7. Burden and associated pathologies in family caregivers of Alzheimer’s disease patients in Spain

    PubMed Central

    Cotelo, Natalia Vérez; Rodríguez, N. Floro Andrés; PÉREZ, José A. Fornos; Iglesias, J. Carlos Andrés; Lago, Marcos Ríos

    2014-01-01

    Objectives: To evaluate the profile of family caregivers of Alzheimer’s disease patients, identify any signs of psychopathology, quantify the level of perceived burden on the caregiver, and determine the caregiver’s relationship with their pharmacist. Methods: A cross-sectional study was conducted at a community pharmacy in Pontevedra, Spain. Demographic variables were collected, and the following questionnaires were administered: the Beck Depression Inventory-II, STAI-Anxiety Questionnaire, Zarit Burden Scale, family APGAR scale, and the Duke-UNC questionnaire. Results: The typical caregiver profile consists of a 55-year old first degree relative (mostly daughters) with a primary education who belongs to a functional or mildly dysfunctional family. Nearly one quarter (24%) of caregivers had a high perception of burden, with anxiety in 20% of caregivers and symptoms of depression in 20%. Family caregivers usually went to the same pharmacy as the patients (96%), were treated with psychotropic drugs (68%), and interacted with the pharmacist (92%). Conclusion: This study confirmed that psychological distress and burden is present among family caregivers. Care for caregivers should be integrated into patient care as part of a national plan, including grants and subsidies, which will result in better care of Alzheimer’s patients. Pharmacists are the most accessible health care professionals and can provide information about Alzheimer’s disease management to caregivers to ease the burden of care. PMID:26131040

  8. Role of interleukin-12 family cytokines in the cellular response to mycobacterial disease.

    PubMed

    Méndez-Samperio, Patricia

    2010-05-01

    Interleukin (IL)-12 is a multifunctional cytokine acting as a key regulator of cell-mediated immune responses through the differentiation of naïve CD4+ T cells into type 1 helper T cells (Th1) producing interferon-gamma. As our knowledge of IL-12 family members is rapidly growing, it will be important to specify their involvement in the regulation of mycobacterial infection. This article is a review of the current knowledge regarding the functions of the IL-12 family cytokines in the immune host defense system against mycobacteria. Specifically, this review aims to describe recent scientific evidence concerning the protective role of some members of the IL-12 family cytokines for the control of mycobacterial infection, as well as to summarize knowledge of the potential use of the IL-12 family members as potent adjuvants in the prevention and treatment of mycobacterial infectious diseases. In addition, recent data supporting the importance of the IL-12 family members in mycobacterial diseases in relation to Th17 function are discussed. This examination will help to improve our understanding of the immune response to mycobacterial infection and also improve vaccine design and immunotherapeutic intervention against tuberculosis.

  9. Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease

    PubMed Central

    Luzón-Toro, Berta; Gui, Hongsheng; Ruiz-Ferrer, Macarena; Sze-Man Tang, Clara; Fernández, Raquel M.; Sham, Pak-Chung; Torroglosa, Ana; Kwong-Hang Tam, Paul; Espino-Paisán, Laura; Cherny, Stacey S.; Bleda, Marta; Enguix-Riego, María del Valle; Dopazo, Joaquín; Antiñolo, Guillermo; García-Barceló, María-Mercé; Borrego, Salud

    2015-01-01

    Hirschsprung disease (HSCR; OMIM 142623) is a developmental disorder characterized by aganglionosis along variable lengths of the distal gastrointestinal tract, which results in intestinal obstruction. Interactions among known HSCR genes and/or unknown disease susceptibility loci lead to variable severity of phenotype. Neither linkage nor genome-wide association studies have efficiently contributed to completely dissect the genetic pathways underlying this complex genetic disorder. We have performed whole exome sequencing of 16 HSCR patients from 8 unrelated families with SOLID platform. Variants shared by affected relatives were validated by Sanger sequencing. We searched for genes recurrently mutated across families. Only variations in the FAT3 gene were significantly enriched in five families. Within-family analysis identified compound heterozygotes for AHNAK and several genes (N = 23) with heterozygous variants that co-segregated with the phenotype. Network and pathway analyses facilitated the discovery of polygenic inheritance involving FAT3, HSCR known genes and their gene partners. Altogether, our approach has facilitated the detection of more than one damaging variant in biologically plausible genes that could jointly contribute to the phenotype. Our data may contribute to the understanding of the complex interactions that occur during enteric nervous system development and the etiopathology of familial HSCR. PMID:26559152

  10. Clinical Studies in Familial VCP Myopathy Associated With Paget Disease of Bone and Frontotemporal Dementia

    PubMed Central

    Kimonis, Virginia. E.; Mehta, Sarju G.; Fulchiero, Erin C.; Thomasova, Dana; Pasquali, Marzia; Boycott, Kym; Neilan, Edward G.; Kartashov, Alex; Forman, Mark S.; Tucker, Stuart; Kimonis, Katerina; Mumm, Steven; Whyte, Michael P.; Smith, Charles D.; Watts, Giles D. J.

    2008-01-01

    Inclusion body myopathy with Paget disease of the bone (PDB) and/or frontotemporal dementia (IBMPFD, OMIM 167320), is a progressive autosomal dominant disorder caused by mutations in the Valousin-containing protein (VCP, p97 or CDC48) gene. IBMPFD can be difficult to diagnose. We assembled data on a large set of families to illustrate the number and type of misdiagnoses that occurred. Clinical analysis of 49 affected individuals in nine families indicated that 42 (87%) of individuals had muscle disease. The majority were erroneously diagnosed with limb girdle muscular dystrophy (LGMD), facioscapular muscular dystrophy, peroneal muscular dystrophy, late adult onset distal myopathy, spinal muscular atrophy, scapuloperoneal muscular dystrophy, or amyotrophic lateral sclerosis (ALS) among others. Muscle biopsies showed rimmed vacuoles characteristic of an inclusion body myopathy in 7 of 18 patients (39%), however, inclusion body myopathy was correctly diagnosed among individuals in only families 5 and 15. Frontotemporal dementia (FTD) was diagnosed in 13 individuals (27%) at a mean age of 57 years (range 48.9–60.2 years); however, several individuals had been diagnosed with Alzheimer disease. Histopathological examination of brains of three affected individuals revealed a pattern of ubiquitin positive neuronal intranuclear inclusions and dystrophic neurites. These families expand the clinical phenotype in IBMPFD, a complex disorder caused by mutations in VCP. The presence of PDB in 28 (57%) individuals suggests that measuring serum alkaline phosphatase (ALP) activity may be a useful screen for IBMPFD in patients with myopathy. PMID:18260132

  11. Defining the ends of Parkin exon 4 deletions in two different families with Parkinson's disease.

    PubMed

    Clarimon, Jordi; Johnson, Janel; Dogu, Okan; Horta, Wagner; Khan, Naheed; Lees, Andrew J; Hardy, John; Singleton, Andrew

    2005-02-05

    Autosomal recessive juvenile parkinsonism (AR-JP, PARK2) is characterized by an early onset parkinsonism, often presenting with dystonia as an early feature. Mutations in Parkin are a relatively common cause of AR-JP and are estimated to be present in approximately 30% of familial young onset Parkinson disease (PD) [Abbas et al. (1999); Hum Mol Genet 8:567-574]. These mutations include exon rearrangements (deletions and duplications), point mutations, and small deletions. Similar genomic mutations have been described in unrelated patients, thereby indicating independent mutational events or ancient founder effects. We have identified homozygous deletion mutations of exon 4 in Parkin in two unrelated families, one from Brazil and the other from Turkey [Dogu et al. (2004); Mov Dis 9:812-816; Khan et al., Mov Dis, in press]. We have performed molecular analysis of the deletion breakpoints and this data indicates these mutations originated independently. We present here data demonstrating that the mutation responsible for disease in the Brazilian kindred consists of two separate deletions (1,069 and 1,750 bp) surrounding and including exon 4. The deletion removing parkin exon 4 identified in the Turkish family extended 156,203 bp. In addition to demonstrating that disease in these families is not caused by a single founder mutation, these data show that there is no common fragile site between these mutational events.

  12. Cerebrospinal Fluid Biomarkers in Familial Forms of Alzheimer's Disease and Frontotemporal Dementia.

    PubMed

    Rostgaard, Nina; Waldemar, Gunhild; Nielsen, Jørgen Erik; Simonsen, Anja Hviid

    2015-01-01

    As dementia is a fast-growing health care problem, it is becoming an increasingly urgent need to provide an early diagnosis in order to offer patients the best medical treatment and care. Validated biomarkers which reflect the pathology and disease progression are essential for diagnosis and are important when developing new therapies. Today, the core protein biomarkers amyloid-β42, total tau and phosphorylated tau in the cerebrospinal fluid (CSF) are used to diagnose Alzheimer's disease (AD), because these biomarkers have shown to reflect the underlying amyloid and tau pathology. However, the biomarkers have proved insufficient predictors of dementias with a different pathology, e.g. frontotemporal dementia (FTD); furthermore, the biomarkers are not useful for early AD diagnosis. Familial dementias with a known disease-causing mutation can be extremely valuable to study; yet the biomarker profiles in patients with familial dementias are not clear. This review summarizes CSF biomarker findings from studies on symptomatic and presymptomatic individuals carrying a mutation in one of the genes known to cause early-onset familial AD or FTD. In conclusion, the biomarker profile of inherited AD is quite similar between carriers of different mutations as well as similar to the profile found in sporadic AD, whereas familial FTD does not seem to have a clear biomarker profile. Hence, new biomarkers are needed for FTD.

  13. Amyotrophic lateral sclerosis in a patient with a family history of huntington disease: genetic counseling challenges.

    PubMed

    Smith, Andrea L; Teener, James W; Callaghan, Brian C; Harrington, Jack; Uhlmann, Wendy R

    2014-10-01

    Amyotrophic lateral sclerosis (ALS) and Huntington disease (HD) are generally considered to be distinct and easily differentiated neurologic conditions. However, there are case reports of the co-occurrence of ALS with HD. We present a 57-year-old male with a clinical diagnosis of sporadic ALS in the context of a family history of HD. This case adds to the limited literature regarding individuals with a family history of HD who present with features of ALS. There were several genetic counseling challenges in counseling this patient including the diagnostic consideration of two fatal conditions, complex risk information, the personal and familial implications, and the patient's inability to communicate verbally or through writing due to disease progression. DNA banking effectively preserved the right of our patient and his wife not to learn his HD genetic status during a stressful time of disease progression while providing the option for family members to learn this information in the future if desired. We present lessons learned and considerations for other clinical genetics professionals who are presented with similar challenging issues.

  14. [Viral safety: European and French directives].

    PubMed

    Rossi, F; Legras, J F

    2000-05-01

    The viral safety of IVIg is defined by transposition of European Directives. Directive 89/381/CEE defines plasma-derived medicinal products (pd-MP) which should be registred through a Marketing Authorization (75/318/CEE) and requires specific criteria for donation acceptability and fractionation processing. Recommendations and Notes for Guidance are prepared by the "Biotechnology Working Party" (BWP), Committee for Proprietary Medicinal Products (CPMP) ad hoc group. "Note for Guidance on Virus Validation Studies: CPMP/BWP/268/95" defines, for conventional viruses, the validation study as regards viral elimination /inactivation steps (relevant virus, scale reduction system and statistical interpretation of the results). "Note for Guidance on 'blood products'- CPMP/BWP/269/95" defines the key issues of viral safety: starting material, viral elimination /inactivation steps within the fractionation processing and in process controls. Pd-MP used as excipients are also covered. BWP/CPMP recommends that exclusion criteria only be considered for sporadic, familial or iatrogenic Creutzfeldt-Jakob disease (CJD), while withdrawal should be undertaken, according to the precaution principle, when a donor is suffering from nv-CJD (February 1998). Also, screening tests currently under development for transmissible spongiform encephalopathies are encouraged to be introduced for fractionation products (January 1999). Some donor exclusion criteria for conventional viruses and prions are specific to France. In conclusion, measures taken to ensure pd-MP viral safety are constantly changing. Its evaluation can only be done when considering numerous parameters within a global context.

  15. TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy.

    PubMed

    Theis, Jeanne L; Zimmermann, Michael T; Larsen, Brandon T; Rybakova, Inna N; Long, Pamela A; Evans, Jared M; Middha, Sumit; de Andrade, Mariza; Moss, Richard L; Wieben, Eric D; Michels, Virginia V; Olson, Timothy M

    2014-11-01

    Locus mapping has uncovered diverse etiologies for familial atrial fibrillation (AF), dilated cardiomyopathy (DCM), and mixed cardiac phenotype syndromes, yet the molecular basis for these disorders remains idiopathic in most cases. Whole-exome sequencing (WES) provides a powerful new tool for familial disease gene discovery. Here, synergistic application of these genomic strategies identified the pathogenic mutation in a familial syndrome of atrial tachyarrhythmia, conduction system disease (CSD), and DCM vulnerability. Seven members of a three-generation family exhibited the variably expressed phenotype, three of whom manifested CSD and clinically significant arrhythmia in childhood. Genome-wide linkage analysis mapped two equally plausible loci to chromosomes 1p3 and 13q12. Variants from WES of two affected cousins were filtered for rare, predicted-deleterious, positional variants, revealing an unreported heterozygous missense mutation disrupting the highly conserved kinase domain in TNNI3K. The G526D substitution in troponin I interacting kinase, with the most deleterious SIFT and Polyphen2 scores possible, resulted in abnormal peptide aggregation in vitro and in silico docking models predicted altered yet energetically favorable wild-type mutant dimerization. Ventricular tissue from a mutation carrier displayed histopathological hallmarks of DCM and reduced TNNI3K protein staining with unique amorphous nuclear and sarcoplasmic inclusions. In conclusion, mutation of TNNI3K, encoding a heart-specific kinase previously shown to modulate cardiac conduction and myocardial function in mice, underlies a familial syndrome of electrical and myopathic heart disease. The identified substitution causes a TNNI3K aggregation defect and protein deficiency, implicating a dominant-negative loss of function disease mechanism.

  16. The hnRNP family: insights into their role in health and disease.

    PubMed

    Geuens, Thomas; Bouhy, Delphine; Timmerman, Vincent

    2016-08-01

    Heterogeneous nuclear ribonucleoproteins (hnRNPs) represent a large family of RNA-binding proteins (RBPs) that contribute to multiple aspects of nucleic acid metabolism including alternative splicing, mRNA stabilization, and transcriptional and translational regulation. Many hnRNPs share general features, but differ in domain composition and functional properties. This review will discuss the current knowledge about the different hnRNP family members, focusing on their structural and functional divergence. Additionally, we will highlight their involvement in neurodegenerative diseases and cancer, and the potential to develop RNA-based therapies.

  17. [Chronic obstructive pulmonary disease: sense of coherence and family support versus anxiety and depression].

    PubMed

    Tselebis, A; Bratis, D; Pachi, A; Moussas, G; Karkanias, A; Harikiopoulou, M; Theodorakopoulou, E; Kosmas, E; Ilias, I; Siafakas, N; Vgontzas, A; Tzanakis, N

    2013-01-01

    Chronic Obstructive Pulmonary Disease (COPD) is mainly related to smoking habit and is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Worldwide and in Greece, COPD constitutes a major epidemiological issue. Incidence of depression and anxiety is high in the COPD population. Most studies on depression and anxiety in COPD deal with factors that are positively correlated with both of these comorbidities. The aim of our study was to assess whether two variables, sense of coherence (SOC) and perception of family support (FS), are negatively correlated with depressive and anxiety symptoms in outpatients with COPD. According to Aaron Antonovsky, sense of coherence refers to the ability of individuals to make sense of and manage events. Studies in other diseases suggest that sense of family support has a significant impact on the course and outcome of the disease, yet a limited number of reports across literature addresses the role of family support in COPD patients. In our present study one hundred twenty two (98 men and 24 women) outpatients with pure COPD were included. Age and years of education were recorded. Severity of COPD was assessed with spirometry before and after bronchodilation. All patients replied to self- administered questionnaires on depression (Beck Depression Inventory, BDI), anxiety (Spielberger State-Trait Anxiety Scale, STAI), family support (Family Support Scale, FSS-13) and sense of coherence (Sense of Coherence Scale, SOC). According to our results the mean BDI depression score was 11.65 (SD 7.35), mean trait anxiety score was 40.69 (SD 11.19), mean SOC score was 54.62 (SD 7.40) and mean FS score was 64.58 (SD 11.63). Women patients had higher anxiety scores and lower sense of family support compared to men. Significant negative correlations were evidenced between depression and

  18. Feasibility of Recruiting Families into a Heart Disease Prevention Program Based on Dietary Patterns

    PubMed Central

    Schumacher, Tracy L.; Burrows, Tracy L.; Thompson, Deborah I.; Spratt, Neil J.; Callister, Robin; Collins, Clare E.

    2015-01-01

    Offspring of parents with a history of cardiovascular disease (CVD) inherit a similar genetic profile and share diet and lifestyle behaviors. This study aimed to evaluate the feasibility of recruiting families at risk of CVD to a dietary prevention program, determine the changes in diet achieved, and program acceptability. Families were recruited into a pilot parallel group randomized controlled trial consisting of a three month evidence-based dietary intervention, based on the Mediterranean and Portfolio diets. Feasibility was assessed by recruitment and retention rates, change in diet by food frequency questionnaire, and program acceptability by qualitative interviews and program evaluation. Twenty one families were enrolled over 16 months, with fourteen families (n = 42 individuals) completing the study. Post-program dietary changes in the intervention group included small daily increases in vegetable serves (0.8 ± 1.3) and reduced usage of full-fat milk (−21%), cheese (−12%) and meat products (−17%). Qualitative interviews highlighted beneficial changes in food purchasing habits. Future studies need more effective methods of recruitment to engage families in the intervention. Once engaged, families made small incremental improvements in their diets. Evaluation indicated that feedback on diet and CVD risk factors, dietetic counselling and the resources provided were appropriate for a program of this type. PMID:26308048

  19. Feasibility of Recruiting Families into a Heart Disease Prevention Program Based on Dietary Patterns.

    PubMed

    Schumacher, Tracy L; Burrows, Tracy L; Thompson, Deborah I; Spratt, Neil J; Callister, Robin; Collins, Clare E

    2015-08-21

    Offspring of parents with a history of cardiovascular disease (CVD) inherit a similar genetic profile and share diet and lifestyle behaviors. This study aimed to evaluate the feasibility of recruiting families at risk of CVD to a dietary prevention program, determine the changes in diet achieved, and program acceptability. Families were recruited into a pilot parallel group randomized controlled trial consisting of a three month evidence-based dietary intervention, based on the Mediterranean and Portfolio diets. Feasibility was assessed by recruitment and retention rates, change in diet by food frequency questionnaire, and program acceptability by qualitative interviews and program evaluation. Twenty one families were enrolled over 16 months, with fourteen families (n = 42 individuals) completing the study. Post-program dietary changes in the intervention group included small daily increases in vegetable serves (0.8 ± 1.3) and reduced usage of full-fat milk (-21%), cheese (-12%) and meat products (-17%). Qualitative interviews highlighted beneficial changes in food purchasing habits. Future studies need more effective methods of recruitment to engage families in the intervention. Once engaged, families made small incremental improvements in their diets. Evaluation indicated that feedback on diet and CVD risk factors, dietetic counselling and the resources provided were appropriate for a program of this type.

  20. Regressive logistic models for familial diseases: a formulation assuming an underlying liability model.

    PubMed Central

    Demenais, F M

    1991-01-01

    Statistical models have been developed to delineate the major-gene and non-major-gene factors accounting for the familial aggregation of complex diseases. The mixed model assumes an underlying liability to the disease, to which a major gene, a multifactorial component, and random environment contribute independently. Affection is defined by a threshold on the liability scale. The regressive logistic models assume that the logarithm of the odds of being affected is a linear function of major genotype, phenotypes of antecedents and other covariates. An equivalence between these two approaches cannot be derived analytically. I propose a formulation of the regressive logistic models on the supposition of an underlying liability model of disease. Relatives are assumed to have correlated liabilities to the disease; affected persons have liabilities exceeding an estimable threshold. Under the assumption that the correlation structure of the relatives' liabilities follows a regressive model, the regression coefficients on antecedents are expressed in terms of the relevant familial correlations. A parsimonious parameterization is a consequence of the assumed liability model, and a one-to-one correspondence with the parameters of the mixed model can be established. The logits, derived under the class A regressive model and under the class D regressive model, can be extended to include a large variety of patterns of family dependence, as well as gene-environment interactions. PMID:1897524

  1. Refined phenotyping identifies links between preeclampsia and related diseases in a Norwegian preeclampsia family cohort

    PubMed Central

    Thomsen, Liv Cecilie V.; Melton, Phillip E.; Tollaksen, Kjersti; Lyslo, Ingvill; Roten, Linda T.; Odland, Maria L.; Strand, Kristin M.; Nygård, Ottar; Sun, Chen; Iversen, Ann-Charlotte; Austgulen, Rigmor; Moses, Eric K.; Bjørge, Line

    2015-01-01

    Objective: Preeclampsia is a complex genetic disease of pregnancy with a heterogenous presentation, unknown cause and potential severe outcomes for both mother and child. Preeclamptic women have increased risk for atherothrombotic cardiovascular disease. We aimed to identify heritabilities and phenotypic correlations of preeclampsia and related conditions in the Norwegian Preeclampsia Family Biobank. Methods: By applying a variance components model, a total of 493 individuals (from 138 families with increased occurrence of preeclampsia) were classified according to 30 disease-related phenotypes. Results: Of parous women, 75.7% (263/338) had experienced preeclampsia and 35.7% of women with and 22.4% without preeclampsia delivered children small for gestational age (SGA). We identified 11 phenotypes as heritable. The increased occurrence of preeclampsia was reflected by the presence [heritability (H2r) = 0.60)] and severity (H2r = 0.15) of preeclampsia and being born in a preeclamptic pregnancy (H2r = 0.25). Other heritable phenotypes identified included SGA (H2r = 0.40), chronic hypertension (H2r = 0.57), severity of atherothrombotic cardiovascular disease (H2r = 0.31), BMI (H2r = 0.60) and pulmonary disease (H2r = 0.91). The heritable phenotype preeclampsia overlapped with SGA (P = 0.03), whereas pulmonary disease was phenotypically correlated with atherothrombotic cardiovascular disease (P < 0.01), SGA (P = 0.02) and BMI (P = 0.02). Conclusion: This is the first study identifying the H2r of a range of health-related conditions in preeclamptic families. Our study demonstrates how refinement of phenotypes leads to better H2r estimation and the identification of a biological relationship between preeclampsia and related traits. PMID:26259119

  2. Sleep Pattern in Charcot-Marie-Tooth Disease Type 2: Report of Family Case Series

    PubMed Central

    Souza, Cynthia C.; Hirotsu, Camila; Neves, Eduardo L.A.; Santos, Lidiane C.L.; Costa, Iandra M.P.F.; Garcez, Catarina A.; Nunes, Paula S.; Araujo, Adriano A.S.

    2015-01-01

    Objectives: Charcot-Marie-Tooth (CMT) disease is the most prevalent hereditary motor and sensory polyneuropathy, and a condition in which sleep has rarely been studied, particularly in relation to the type 2 (CMT2). Thus, we aimed to characterize the sleep patterns of a family affected by CMT2 disease. Methods: Sixteen volunteers with CMT2 from the same multigenerational family agreed to participate in the study (refusal rate = 31%). All participants answered sleep questionnaires and came to the sleep laboratory to perform a diagnostic polysomnography (PSG). Clinical manifestation and severity of the disease were also evaluated. Results: 56% of the sample were male and 44% female, with a mean age of 32 ± 17 years, of normal weight (body mass index 21 ± 3 kg/m2); 64% presented moderate to severe CMT2. Regarding subjective sleep, 31% had excessive daytime sleepiness and 75% reported poor sleep quality. The PSG results revealed that CMT2 patients had an increase in stage N3 and a reduction in REM sleep, in addition to a high arousal index. Although 81% of the sample were snorers, only 13% had an apnea-hypopnea index (AHI) > 5. However, a positive correlation was found between the severity of disease and the AHI. Conclusions: Taken together, these data show that CMT2 disease is characterized by important changes in sleep architecture, probably due to sleep fragmentation. Although these alterations may worsen with disease severity, it seems that they are not related to sleep breathing or movement disorders. Citation: Souza CC, Hirotsu C, Neves EL, Santos LC, Costa IM, Garcez CA, Nunes PS, Araujo AA. Sleep pattern in charcot-marie-tooth disease type 2: report of family case series. J Clin Sleep Med 2015;11(3):205–211. PMID:25515278

  3. Family history of chronic disease and meeting public health guidelines for physical activity: the cooper center longitudinal study.

    PubMed

    Shuval, Kerem; Chiu, Chung-Yi; Barlow, Carolyn E; Gabriel, Kelley Pettee; Kendzor, Darla E; Businelle, Michael S; Skinner, Celette Sugg; Balasubramanian, Bijal A

    2013-06-01

    We aimed to assess whether a family history of coronary heart disease, diabetes, or cancer is linked to meeting public health guidelines for health-promoting physical activity. To achieve this objective, we analyzed data on 29,513 adults who came to the Cooper Clinic (Dallas, Texas) between January 1, 1990, and December 31, 2010, for a preventive medicine visit. Patients completed a comprehensive medical survey including information on family medical history, physical activity, and other lifestyle behaviors. Bivariate and multivariate logistic regression were used to examine the relationship between having a family history of chronic disease and meeting physical activity guidelines. The results indicated that individuals with a family history of disease had reduced odds for meeting or exceeding physical activity guidelines. For example, participants with a family history of 3 diseases were 36% less likely to meet or exceed physical activity guidelines than their counterparts without a family history of disease (odds ratio, 0.64; 95% CI, 0.58-0.72), while controlling for covariates. Among this large sample of adults, those with a family history of chronic disease were less inclined to regularly engage in physical activity. Thus, targeted programs encouraging adoption and maintenance of health-promoting physical activity might be warranted, specifically targeting individuals with familial history of disease.

  4. [Identifying different susceptibility loci associated with early onset diabetes and cardiovascular disease in Mexican families].

    PubMed

    Canizales-Quinteros, Samuel; Huertas-Vázquez, Adriana; Riba-Ramírez, Laura; Monroy-Guzmán, Adriana; Domínguez-López, Aarón; Romero-Hidalgo, Sandra; Aguilar-Salinas, Carlos; Rodríguez-Torres, Maribel; Ramírez-Jiménez, Salvador; Tusié-Luna, María Teresa

    2005-01-01

    Coronary artery disease and diabetes mellitus are among the primary mortality and morbidity causes in Mexico. Genetic factors play a fundamental role in the development of these entities. In the past few years due to the recognition and study of families with monogenic forms of diabetes and dislipidemias associated with development of atherosclerosis, several genes and loci have been associated with these conditions through genetic linkage studies. These studies have provided evidence of the genetic heterogeneity that exists and the type of genes involved in different ethnic groups. The study of Mexican families with early-onset diabetes and combined familial hyperlipidemia showed the participation of different genetic loci associated with these conditions in the Mexican population. These findings show the value of gene mapping strategies in the identification of the genetic component in these entities in our population.

  5. HLA is unlikely to be a major component of risk in familial inflammatory bowl disease

    SciTech Connect

    Mathew, C.G.; Naom, I.S.; Hodgson, S.V.

    1994-09-01

    Inflammatory bowel disease (IBD) is a chronic inflammation of the bowel which is confined to the colon in ulcerative colitis (UC) or may affect any part of the gastrointestinal tract in Crohn`s disease (CD). The cause of IBD is unknown, but a genetic component is suggested by a 10-fold increase in risk to first degree relatives, and a higher concordance of disease in MZ versus DZ twins. Distinct associations of HLA DR2 with UC and DR1/DQw5 with CD have been reported. We are searching for susceptibility genes in IBD by linkage analysis in a panel of 43 families with 3 or more living affected members, which includes 12 families with CD, 17 with UC and 14 {open_quotes}mixed{close_quotes} families with UC and CD. In view of the reported HLA associations in IBD, we have analyzed 5 microsatellite markers from the major histocompatibility complex for linkage to IBD using both parametric and nonparametric methods. LOD scores were calculated for 4 different genetic models, including both dominant and recessive inheritance, and haplotype sharing was analyzed in affected siblings. LOD scores for the MHC locus were negative in the full data set, and in the 3 classes of family (UC,CD,mixed). Haplotype sharing in affected sibs was very close to that expected if no linkage was present. We conclude that genes from the HLA region are unlikely to be a major component of risk in familial IBD. Linkage analysis of genes which cause chronic colitis when disrupted in transgenic mice is in progress.

  6. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region

    SciTech Connect

    Kamino, K.; Anderson, L.; O'dahl, S.; Nemens, E.; Bird, T.D.; Schellenberg, G.D.; Wijsman, E.M.; Kukall, W.; Larson, E. ); Heston, L.L.

    1992-11-01

    A large number of familial Alzheimer disease (FAD) kindreds were examined to determine whether mutations in the amyloid precursor protein (APP) gene could be responsible for the disease. Previous studies have identified three mutations at APP codon 717 which are pathogenic for Alzheimer disease (AD). Samples from affected subjects were examined for mutations in exons 16 and 17 of the APP gene. A combination of direct sequencing and single-strand conformational polymorphism analysis was used. Sporadic AD and normal controls were also examined by the same methods. Five sequence variants were identified. One variant at APP codon 693 resulted in a Glu[yields]Gly change. This is the same codon as the hereditary cerebral hemorrhage with amyloidosis-Dutch type Glu[yields]Gln mutation. Another single-base change at APP codon 708 did not alter the amino acid encoded at this site. Two point mutations and a 6-bp deletion were identified in the intronic sequences surrounding exon 17. None of the variants could be unambigously determined to be responsible for FAD. The larger families were also analyzed by testing for linkage of FAD to a highly polymorphic short tandem repeat marker (D21S210) that is tightly linked to APP. Highly negative LOD scores were obtained for the family groups tested, and linkage was formally excluded beyond [theta] = .10 for the Volga German kindreds, [theta] = .20 for early-onset non-Volga Germans, and [theta] = .10 for late-onset families. LOD scores for linkage of FAD to markers centromeric to APP (D21S1/S11, D21S13, and D21S215) were also negative in the three family groups. These studies show that APP mutations account for AD in only a small fraction of FAD kindreds. 49 refs., 6 figs., 4 tabs.

  7. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region

    PubMed Central

    Kamino, Kouzin; Orr, Harry T.; Payami, Haydeh; Wijsman, Ellen M.; Alonso, Ma. Elisa; Pulst, Stefan M.; Anderson, Leojean; O'dahl, Sheldon; Nemens, Ellen; White, June A.; Sadovnick, Adele D.; Ball, Melvyn J.; Kaye, Jeffery; Warren, Andrew; McInnis, Melvin; Antonarakis, Stylianos E.; Korenberg, Julie R.; Sharma, Vikram; Kukull, Walter; Larson, Eric; Heston, Leonard L.; Martin, George M.; Bird, Thomas D.; Schellenberg, Gerard D.

    1992-01-01

    A large number of familial Alzheimer disease (FAD) kindreds were examined to determine whether mutations in the amyloid precursor protein (APP) gene could be responsible for the disease. Previous studies have identified three mutations at APP codon 717 which are pathogenic for Alzheimer disease (AD). Samples from affected subjects were examined for mutations in exons 16 and 17 of the APP gene. A combination of direct sequencing and single-strand conformational polymorphism analysis was used. Sporadic AD and normal controls were also examined by the same methods. Five sequence variants were identified. One variant at APP codon 693 resulted in a Glu→Gly change. This is the same codon as the hereditary cerebral hemorrhage with amyloidosis–Dutch type Glu→Gln mutation. Another single-base change at APP codon 708 did not alter the amino acid encoded at this site. Two point mutations and a 6-bp deletion were identified in the intronic sequences surrounding exon 17. None of the variants could be unambiguously determined to be responsible for FAD. The larger families were also analyzed by testing for linkage of FAD to a highly polymorphic short tandem repeat marker (D21S210) that is tightly linked to APP. Highly negative LOD scores were obtained for the family groups tested, and linkage was formally excluded beyond θ = .10 for the Volga German kindreds, θ = .20 for early-onset non-Volga Germans, and θ = .10 for late-onset families. LOD scores for linkage of FAD to markers centromeric to APP (D21S1/S11, D21S13, and D21S215) were also negative in the three family groups. These studies show that APP mutations account for AD in only a small fraction of FAD kindreds. ImagesFigure 4p1009-a PMID:1415269

  8. Dying with motor neurone disease, what can we learn from family caregivers?

    PubMed Central

    Ray, Robin A.; Brown, Janice; Street, Annette F.

    2012-01-01

    Abstract Background  Increasingly, people with neurodegenerative illness are cared for at home until close to death. Yet, discussing the reality of dying remains a social taboo. Objective  To examine the ways, family caregivers of people living with motor neurone disease (MND) experienced the dying of their relative and to identify how health practitioners can better prepare families for end‐of‐life care. Design  Secondary analysis was undertaken on data sets generated from two longitudinal qualitative studies employing similar data collection and analysis methods. Combining data sets increased participant numbers in a low incidence disease group. Setting and participants  Primary studies were undertaken with family caregivers in England and Australia. Interview and observational data were collected mostly in home. Participants who discussed dying and death formed the sample for secondary analysis. Results  Combined data revealed four major themes: planning for end of life, unexpected dying, dignity in the dying body and positive end to MND. Despite short survival predictions, discussions among family members about dying were often sporadic and linked to loss of hope. Effective planning for death assisted caregivers to manage the final degenerative processes of dying. When plans were not effectively communicated or enacted, capacity to preserve personhood was reduced. Discussion and Conclusion  Returning death and dying to social discourse will raise the level of community awareness and normalize conversations about end‐of‐life care. Strategies for on‐going, effective communication that facilitates advance care planning among patients, their families and practitioners are essential to improve dying and death for people with MND and their family caregivers. PMID:22512686

  9. The Effectiveness of a Liver Disease Education Class for Providing Information to Patients and Their Families

    PubMed Central

    Kadokawa, Yukio; Katayama, Kazuhiro; Takahashi, Kozo; Fukushima, Nobuhisa; Tanaka, Setsu; Taniguchi, Yuko; Nawa, Takatoshi; Sakakibara, Mitsuru; Ohkawa, Kazuyoshi

    2017-01-01

    Background We have been conducting liver disease education classes regularly in our hospital for the purpose of providing health information to patients and their families. Methods In order to evaluate the effectiveness of these classes, we conducted a questionnaire survey of patients and family members who attended the classes held three times in 2012. The cumulative total number of participants was 80 (49 patients, 26 family members, and five others). The classes focused on the following areas: 1) prevention of hepatic cancer; 2) treatment of hepatic cancer; 3) iron restriction diet for hepatitis C patients; and 4) importance of branched-chain amino acid preparations. Self-evaluation of knowledge in these areas was based on a four-point scale. Results A comparison of knowledge levels between the patients and their family members revealed no statistically significant differences. Therefore, subsequent analyses were performed by combining the patients and their families into one group. The knowledge level of the participants increased with the number of class attendances; that is, the more often they attended, the more they accumulated knowledge (Kruskal-Wallis test: P < 0.0001; P = 0.0368; P = 0.0021; and P < 0.0001). In addition, the results of the questionnaire administered immediately before and after the education class showed significant improvement in the knowledge level for each area. Conclusion The results of this study indicate the liver disease education class to be effective for improving the knowledge of patients and their families. The importance of repeated information provision was also demonstrated. PMID:28179968

  10. Host-microbiome interaction in Crohn’s disease: A familiar or familial issue?

    PubMed Central

    Michielan, Andrea; D’Incà, Renata

    2015-01-01

    An impaired interaction between the gut and the intestinal microbiome is likely to be the key element in the pathogenesis of Crohn’s disease (CD). Family studies have provided invaluable information on CD pathogenesis and on its etiology. Relatives share the same genetic risk of developing the disease as affected subjects. Relatives also exhibit similar features relating to their host-microbiome interaction, namely genetic variants in loci involved in detecting bacteria, a greater sero-reactivity to microbial components, and an impaired intestinal permeability. The burden of environmental factors such as cigarette smoking and dysbiosis also seems to be particularly relevant in these genetically predisposed subjects. Diet is emerging as an important factor and could account for the changing epidemiology of CD in recent years. Despite the pivotal role of genetics in the disease’s pathogenesis (especially in familial CD), screening tests in healthy relatives cannot be recommended. PMID:26600974

  11. [Dopaminergic treatment in Parkinson's disease: what has each therapeutic family got to offer?].

    PubMed

    Pagonabarraga, Javier; Kulisevsky, Jaume

    2014-01-01

    Different families of dopaminergic agents have allowed to increase the availability of dopamine within the central nervous system by different mechanisms of action. Each drug family has specific efficacious properties, as well as a different profile of adverse events. The knowledge in detail of these specificities is mandatory to avoid severe systemic or neuropsychiatric complications. Despite these limitations, the development of new drugs within the past 20 years has prolonged survival in Parkinson's disease, increasing the time with preserved daily day functionality compared with the levodopa era, when this drug was the only dopaminergic drug available. The correct combination of dopaminergic drugs with different mechanisms of action allows the management of Parkinson's disease motor symptoms within safety dose ranges, and up to day, this appears as the best algorithm to maintain functionality for longer periods of time.

  12. Hospitalizations for cardiovascular diseases and the coverage by the family health strategy 1

    PubMed Central

    Lentsck, Maicon Henrique; Mathias, Thais Aidar de Freitas

    2015-01-01

    Abstract Objective: to verify the correlation between the rates of hospitalization for primary care-sensitive cardiovascular diseases and the coverage by the Family Health Strategy of residents of the State of Paraná, by regional health divisions, from 2000 to 2011. Method: ecological study developed from data of the Hospital Information System of the Brazilian Unified Health System (SUS) and the Department of Primary Care of the Ministry of Health. The rates of hospitalization for cardiovascular diseases were correlated with the annual coverage by the Family Health Strategy using Pearson's and Spearman's correlation coefficients. Result: there was a strong and negative correlation in the State of Paraná (r=-0.91; p <0.001) and in most regional health divisions, with the highest correlations observed in the Metropolitan and Toledo (r =-0.93; p<0.001) and Paranaguá (r=-0.92, p<0.001) regional health divisions. Conclusion: the results suggest that the increase in the coverage by the Family Health Strategy was an important factor for decrease in the hospitalizations for cardiovascular conditions among residents of the State of Paraná and in most regional health divisions. Other studies should be performed to analyze the factors and causes in regional health divisions where there was no correlation with increase in the Family Health Strategy. PMID:26444162

  13. MicroRNA208 family in cardiovascular diseases: therapeutic implication and potential biomarker.

    PubMed

    Huang, Ying; Li, Jun

    2015-09-01

    Cardiovascular disease remains to be a severe and yet unsolved health problem that has become a leading threat to human health. It is urgent to explore early diagnostic biomarker and innovative therapeutic strategy to prevent the progression of cardiovascular diseases. MicroRNAs (miRNAs) are conserved endogenous, non-coding small RNAs that are essential modulators of gene expression by inhibiting translation or promoting degradation of messenger RNAs (mRNAs). A large range of functions has been attributed to miRNAs, such as cell proliferation, differentiation, apoptosis, and invasion. So far, miRNAs have shown characteristic changes in expression during the process of cardiovascular disease that may act as potential biomarkers. A series of studies have clearly discovered that the miR-208 family is closely associated with the development of cardiac diseases, such as myocardial hypertrophy, cardiac fibrosis, myocardial infarction, arrhythmia, and heart failure. In this review, we will highlight novel insights into miR-208 family functions and discuss it as potential biomarker and therapeutic target in cardiovascular diseases.

  14. A prion primer

    PubMed Central

    Cashman, N R

    1997-01-01

    By biological and medical criteria, prions are infectious agents; however, many of their properties differ profoundly from those of conventional microbes. Prions are "encoded" by alterations in protein conformation rather than in nucleic acid or amino acid sequence. New epidemic prion diseases (bovine spongiform encephalopathy and new variant Creutzfeldt-Jakob disease) have recently emerged under the active surveillance of the modern world. The risk of contracting prion disease from blood products or other biologicals is now a focus of worldwide concern. Much has been discovered about prions and prion diseases, but much remains to be done. PMID:9371069

  15. Personal Factors Associated with Reported Benefits of Huntington Disease Family History or Genetic Testing

    PubMed Central

    Williams, Janet K.; Erwin, Cheryl; Juhl, Andrew; Mills, James; Brossman, Bradley

    2010-01-01

    Aims: A family history of Huntington disease (HD) or receiving results of HD predictive genetic testing can influence individual well-being, family relationships, and social interactions in positive and negative ways. The aim of this study was to examine benefits reported by people with an HD family history or those who have undergone predictive HD testing, as well as the personal variables associated with perceived benefits. Methods: Seventy-four of 433 people completing the International Response of a Sample Population to HD risk (I-RESPOND-HD) survey reported benefits. Knowledge and understanding was perceived as the most common benefit from participants in both groups. The next most frequent perceived benefits from a family history were connecting with others and achieving life meaning and insights. The next most common perceived benefits from genetic testing were life planning and social support. The least common perceived benefit for both groups was renewed hope and optimism. Older age and spirituality were significantly associated with benefits in both groups. Conclusions: Perceptions of benefit may not be as likely until later years in people with prodromal HD. A developed sense of spirituality is identified as a personal resource associated with the perception of benefit from genetic testing for HD. Associations among spirituality, perceived benefits, and other indicators of personal and family well-being may be useful in genetic counseling and health care of people with prodromal HD. PMID:20722493

  16. High Variability of Fabry Disease Manifestations in an Extended Italian Family

    PubMed Central

    Cammarata, Giuseppe; Fatuzzo, Pasquale; Rodolico, Margherita Stefania; Colomba, Paolo; Sicurella, Luigi; Iemolo, Francesco; Zizzo, Carmela; Bartolotta, Caterina; Duro, Giovanni

    2015-01-01

    Fabry disease (FD) is an inherited metabolic disorder caused by partial or full inactivation of the lysosomal hydrolase α-galactosidase A (α-GAL). The impairment of α-GAL results in the accumulation of undegraded glycosphingolipids in lysosomes and subsequent cell and microvascular dysfunctions. This study reports the clinical, biochemical, and molecular characterization of 15 members of the same family. Eight members showed the exonic mutation M51I in the GLA gene, a disease-causing mutation associated with the atypical phenotype. The clinical history of this family highlights a wide phenotypic variability, in terms of involved organs and severity. The phenotypic variability of two male patients is not related to differences in α-GAL enzymatic activity: though both have no enzymatic activity, the youngest shows severe symptoms, while the eldest is asymptomatic. It is noticeable that for two female patients with the M51I mutation the initial clinical diagnosis was different from FD. One of them was diagnosed with Familial Mediterranean Fever, the other with Multiple Sclerosis. Overall, this study confirms that the extreme variability of the clinical manifestations of FD is not entirely attributable to different mutations in the GLA gene and emphasizes the need to consider other factors or mechanisms involved in the pathogenesis of Fabry Disease. PMID:25977923

  17. Hereditary ring sideroblastic anaemia and Christmas disease in a Swedish family.

    PubMed

    Hast, R; Miale, T; Westin, J; Birgegård, G; Möller, E; Reizenstein, P; Teger-Nilsson, A C; Wetterberg, L

    1983-05-01

    The association of hereditary ring sideroblastic anaemia with Christmas disease in a Swedish family is described. We have studied the transmission of the sideroblastic trait, in relation to HLA groups and Christmas disease, and also evaluated the erythrocyte morphology, uroporphyrinogen-I-synthetase activity and S-ferritin for the detection of latent cases of ring sideroblastic anaemia. The proband had ring sideroblastic anaemia, Christmas disease and haemochromatosis. 3 cases of ring sideroblastic anaemia were found among the 12 family members studied. Using the factor IX deficiency as a marker of the X chromosome, it appeared that autosomal transmission of the sideroblastic trait was most likely. The sideroblastic trait did not seem to be linked to HLA-A3-alloantigen. Erythrocyte morphology was normal in all non-anaemic subjects. S-ferritin was found to be increased in all 3 cases of sideroblastic anaemia as well as in 1 non-anaemic relative. Erythrocyte uroporphyrinogen-I-synthetase was elevated in 10 of the 12 family members; those with sideroblastic anaemia had the highest values indicating that uroporphyrinogen-I-synthetase is of importance in the disturbed haem-synthesis of ring sideroblastic anaemia. This interpretation is supported by the positive correlation between S-ferritin values and the uroporphyrinogen-I-synthetase activity.

  18. Score test for familial aggregation in probands studies: application to Alzheimer's disease.

    PubMed

    Commenges, D; Jacqmin, H; Letenneur, L; Van Duijn, C M

    1995-06-01

    When studying familial aggregation of a disease, the following two-stage design is often used: first select index subjects (cases and controls); then record data on their relatives. The likelihood corresponding to this design is derived and a score test of homogeneity is proposed for testing the hypothesis of no-aggregation. This test takes into account the selection procedure and allows adjustment to be made for explanatory variables. It appears as the sum of three terms: a pure test of homogeneity, a test of comparison of observed minus expected cases in the two groups, and a term which adjusts for the possible unequal probabilities of disease of the index subjects. Asymptotic efficiency and a simulation study show that the proposed test is superior to either the pure homogeneity test or tests based on the comparison of numbers of affected in the two groups. The test statistic, which has an asymptotically standard normal distribution, is applied to a study of familial aggregation of early-onset Alzheimer's disease for which a highly significant value (9.46) is obtained: this is the highest value among the three tests compared, in agreement with the simulation study. A logistic normal model is fitted to the data, taking account of the selection procedure: it allows to estimate the regression parameters and the variance of the random effect; the likelihood ratio test for familial aggregation seems less powerful than the score test.

  19. Renal outcomes in children with lupus and a family history of autoimmune disease.

    PubMed

    Apenteng, T; Kaplan, B; Meyers, K

    2006-01-01

    Genetic factors play an important role in systemic lupus erythematosus (SLE) susceptibility and development of lupus nephritis (LN). The significance, however, of a positive family history of autoimmune disease on renal outcome in SLE patients is unknown. This retrospective study of 64 children with LN investigates whether children with LN and a family history of AID (autoimmune disease; 34 patients) had worse renal outcomes when compared with children who did not have a family history (26 patients) of AID. In four patients the family history was unknown. The primary endpoint was doubling of serum creatinine (sCr) and the secondary endpoint was requiring dialysis or transplant (ESRD). Demographic variables for family history + versus mean age in years (range) at onset of LN were 13.5 (7.4-15.9) versus 13.2 (6.4-19.7); female 26: 34 (76%) versus 24: 26 (92%), P = 0.097; race Black 23 (68%), Caucasian 7 (21%), Asian 1 (2%), Hispanic 3(9%) versus Black 14 (54%), Caucasian 6 (23%), Asian 2 (8%), Hispanic 4 (15%). Three patients died (1.6%); sCr doubled in 6/34 (17.6%) versus 2/26 (7.7%), P = 0.45, followed for 2.8 years (0.8-5.8) and 1.8 years (1.8-1.9), respectively, P = 0.24; sCr doubled plus ESRD in 10/34 (29%) versus 6/26 (23%), P = 0.77, followed for 2.7 years (0.8-5.8) and 2.0 years (0.7-4.1) respectively, P = 0.29. In the family history + group, more Black versus non-Black patients doubled their sCr or reached ESRD, 8/23 (35%) versus 2/11 (18%), P = 0.44. More males and Black patients with LN had a positive family history for AID and were more likely to double their sCr or reach ESRD. These results suggest that a family history of AID impacts on renal outcome in children with SLE.

  20. Clinical presentation and mutation analysis of VHL disease in a large Chinese family.

    PubMed

    Zhang, Qing; Li, De-Ling; Kang, Peng; Ji, Nan; Yang, Jun; Liu, Wei-Ming; Zhang, Li-Wei; Jia, Gui-Jun

    2015-11-01

    Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited neoplastic disorder characterized by marked phenotypic variability and age-dependent penetrance. This disease is caused by germline mutations in the VHL tumor suppressor gene. Systematic physical examinations, imaging assessments and molecular genetic tests for the VHL gene were performed in a large Chinese VHL family. The examined Chinese VHL family, which has 25 members from four generations, including 7 diagnosed VHL patients and 2 asymptomatic mutation carriers. The average ages of first onset for generations I, II, and III were 37, 30 and 16, respectively. The male:female ratio among VHL patients was 6:1. Molecular genetic investigations detected the c.433C>T [p.Q145X] nonsense mutation in the VHL gene. Molecular modeling of the VHL-ElonginC- ElonginB-HIF-1α complex predicted that the p.Q145X mutation markedly alters the L7 loop structure of the β-domain of the VHL protein (pVHL), destabilizes the VHL-HIF-1αcomplex, and induces the truncation of pVHL. We speculate that the p.Q145X nonsense mutation leads to relatively obvious familial aggregation. This mutation causes the type I phenotype of VHL disease and is associated with a high risk of retinal and central nervous system (CNS) hemangioblastomas (HGBs) and visceral cysts, but a low risk of renal cell carcinoma. Moreover, within a VHL family, the average ages of first onset became younger in successive generations, and the CNS HGBs are more likely to occur in male patients.

  1. Transactive Response DNA-Binding Protein 43 Burden in Familial Alzheimer Disease and Down Syndrome

    PubMed Central

    Lippa, Carol F.; Rosso, Andrea L.; Stutzbach, Lauren D.; Neumann, Manuela; Lee, Virginia M.-Y.; Trojanowski, John Q.

    2010-01-01

    Objective To assess the transactive response DNA-binding protein 43 (TDP-43) burden in familial forms of Alzheimer disease (FAD) and Down syndrome (DS) to determine whether TDP-43 inclusions are also present. Design Using standard immunohistochemical techniques, we examined brain tissue samples from 42 subjects with FAD and 14 with DS. Results We found pathological TDP-43 aggregates in 14.0% of participants (6 of 42 and 2 of 14 participants with FAD and DS, respectively). In both FAD and DS, TDP-43 immunoreactivity did not colocalize with neurofibrillary tangles. Occasionally participants with FAD or DS had TDP-43–positive neuropil threads or dots. Overall, the amygdala was most commonly affected, followed by the hippocampus, with no TDP-43 pathology in neocortical regions. A similar distribution of TDP-43 inclusions is seen in sporadic Alzheimer disease, but it differs from that seen in amyotrophic lateral sclerosis and frontotemporal dementia. Conclusions Transactive response DNA-binding protein 43 pathology occurs in FAD and DS, similar to that observed in sporadic Alzheimer disease. Thus, pathological TDP-43 may contribute the cognitive impairments in familial and sporadic forms of Alzheimer disease. PMID:20008652

  2. Clinical and genetic investigation of a Brazilian family with Huntington’s disease

    PubMed Central

    de Andrade Agostinho, Luciana; Spitz, Mariana; Pereira, João Santos; Paiva, Carmen Lucia Antão

    2016-01-01

    Summary The aim of this study was to investigate a Brazilian family carrying full penetrance alleles for Huntington’s disease (HD) in order to correlate each member’s genetic and clinical features. To this end, the following scales were administered in each patient: the Beck Depression Inventory, the Mini-Mental State Examination (MMSE) and the Unified Huntington’s Disease Rating Scale (UHDRS). The patterns of CAG and CCG polymorphic regions in the HTT gene were determined, the disease burden score was calculated, and genotypes were correlated with phenotypes within this family. We suggest that HD duration, the number of years of formal education, and UHDRS status variables can explain 96.6% of the MMSE variability in HD patients. A strong significant correlation was found between the disease burden score and the UHDRS (r = 0.76; p-value = 0.049) and the MMSE (r = −0.90; p-value = 0.006). The correlations between CAG allele size and the three clinical evaluations performed in the HD patients were not statistically significant. PMID:27678206

  3. Machine learning amplifies the effect of parental family history of Alzheimer's disease on list learning strategy.

    PubMed

    Chang, Timothy S; Coen, Michael H; La Rue, Asenath; Jonaitis, Erin; Koscik, Rebecca L; Hermann, Bruce; Sager, Mark A

    2012-05-01

    Identification of preclinical Alzheimer's disease (AD) is an essential first step in developing interventions to prevent or delay disease onset. In this study, we examine the hypothesis that deeper analyses of traditional cognitive tests may be useful in identifying subtle but potentially important learning and memory differences in asymptomatic populations that differ in risk for developing Alzheimer's disease. Subjects included 879 asymptomatic higher-risk persons (middle-aged children of parents with AD) and 355 asymptotic lower-risk persons (middle-aged children of parents without AD). All were administered the Rey Auditory Verbal Learning Test at baseline. Using machine learning approaches, we constructed a new measure that exploited finer differences in memory strategy than previous work focused on serial position and subjective organization. The new measure, based on stochastic gradient descent, provides a greater degree of statistical separation (p = 1.44 × 10-5) than previously observed for asymptomatic family history and non-family history groups, while controlling for apolipoprotein epsilon 4, age, gender, and education level. The results of our machine learning approach support analyzing memory strategy in detail to probe potential disease onset. Such distinct differences may be exploited in asymptomatic middle-aged persons as a potential risk factor for AD.

  4. Family history of cardiovascular disease is associated with cardiovascular responses to stress in healthy young men and women.

    PubMed

    Wright, Caroline E; O'Donnell, Katie; Brydon, Lena; Wardle, Jane; Steptoe, Andrew

    2007-03-01

    Heightened cardiovascular stress responsivity is associated with cardiovascular disease, but the origins of heightened responsivity are unclear. The present study investigated whether disturbances in cardiovascular responsivity were evident in individuals with a family history of cardiovascular disease risk. Data were collected from 60 women and 31 men with an average age of 21.4 years. Family history of cardiovascular disease risk was defined by the presence of coronary heart disease, hypertension, diabetes or high cholesterol in participants' parents and grandparents; 75 participants had positive, and 16 had negative family histories. Systolic and diastolic blood pressure (BP), heart rate and heart rate variability were measured continuously for 5 min periods at baseline, during two mental stress tasks (Stroop and speech task) and at 10-15 min, 25-30 min and 40-45 min post-stress. Individuals with a positive family history exhibited significantly greater diastolic BP reactivity and poorer systolic and diastolic BP recovery from the stressors in comparison with family history negative individuals. In addition, female participants with a positive family history had heightened heart rate and heart rate variability reactivity to stressors. These effects were independent of baseline cardiovascular activity, body mass index, waist to hip ratio and smoking status. Family history of hypertension alone was not associated with stress responsivity. The findings indicate that a family history of cardiovascular disease risk influences stress responsivity which may in turn contribute to risk of future cardiovascular disorders.

  5. Identification of genetic modifiers of age-at-onset for familial Parkinson’s disease

    PubMed Central

    Hill-Burns, Erin M.; Ross, Owen A.; Wissemann, William T.; Soto-Ortolaza, Alexandra I.; Zareparsi, Sepideh; Siuda, Joanna; Lynch, Timothy; Wszolek, Zbigniew K.; Silburn, Peter A.; Mellick, George D.; Ritz, Beate; Scherzer, Clemens R.; Zabetian, Cyrus P.; Factor, Stewart A.; Breheny, Patrick J.; Payami, Haydeh

    2016-01-01

    Parkinson’s disease (PD) is the most common cause of neurodegenerative movement disorder and the second most common cause of dementia. Genes are thought to have a stronger effect on age-at-onset of PD than on risk, yet there has been a phenomenal success in identifying risk loci but not age-at-onset modifiers. We conducted a genome-wide study for age-at-onset. We analysed familial and non-familial PD separately, per prior evidence for strong genetic effect on age-at-onset in familial PD. GWAS was conducted in 431 unrelated PD individuals with at least one affected relative (familial PD) and 1544 non-familial PD from the NeuroGenetics Research Consortium (NGRC); an additional 737 familial PD and 2363 non-familial PD were used for replication. In familial PD, two signals were detected and replicated robustly: one mapped to LHFPL2 on 5q14.1 (PNGRC = 3E-8, PReplication = 2E-5, PNGRC + Replication = 1E-11), the second mapped to TPM1 on 15q22.2 (PNGRC = 8E-9, PReplication = 2E-4, PNGRC + Replication = 9E-11). The variants that were associated with accelerated onset had low frequencies (<0.02). The LHFPL2 variant was associated with earlier onset by 12.33 [95% CI: 6.2; 18.45] years in NGRC, 8.03 [2.95; 13.11] years in replication, and 9.79 [5.88; 13.70] years in the combined data. The TPM1 variant was associated with earlier onset by 15.30 [8.10; 22.49] years in NGRC, 9.29 [1.79; 16.79] years in replication, and 12.42 [7.23; 17.61] years in the combined data. Neither LHFPL2 nor TPM1 was associated with age-at-onset in non-familial PD. LHFPL2 (function unknown) is overexpressed in brain tumours. TPM1 encodes a highly conserved protein that regulates muscle contraction, and is a tumour-suppressor gene. PMID:27402877

  6. A psychometric evaluation of the PedsQL™ Family Impact Module in parents of children with sickle cell disease

    PubMed Central

    Panepinto, Julie A; Hoffmann, Raymond G; Pajewski, Nicholas M

    2009-01-01

    Background Caring for a child with a chronic condition, such as sickle cell disease, can have a significant impact on parents and families. In order to provide comprehensive care and support to these families, psychometrically sound instruments are needed as an initial step in measuring the impact of chronic diseases on parents and families. We sought to evaluate the psychometric properties of the PedsQL™ Family Impact Module in populations of children with and without sickle cell disease. In addition, we sought to determine the correlation between parent's well being and their proxy report of their child's health-related quality of life (HRQL). Methods We conducted a cross-sectional study of parents of children with and without sickle cell disease who presented to an urban hospital-based sickle cell disease clinic and an urban primary care clinic. We assessed the HRQL and family functioning of both groups of parents utilizing the PedsQL™ Family Impact Module. The reliability, validity and factor structure of the instrument were determined and scores from the instrument were correlated with scores from parent-proxy report of their child's HRQL using the PedsQL™ 4.0 Generic Core Scales. Results Parents of 170 children completed the module (97 parents of children with sickle cell disease and 73 parents of children without sickle cell disease). The Family Impact Module had high ceiling effects but was reliable (Cronbach's alpha > 0.80 in all scales). The empirical factor structure was generally consistent with the theoretical factor structure and supported construct validity. The Family Impact Module discriminated between parents of children with severe sickle cell disease from parents of children with mild disease or no disease in the areas of communication and worry. There were no significant differences across any of the subscales between parents of children with mild sickle cell disease and those with no disease. Parents with higher scores, representing

  7. A familial form of parkinsonism, dementia, and motor neuron disease: a longitudinal study

    PubMed Central

    Fujioka, Shinsuke; Boeve, Bradley F.; Parisi, Joseph E.; Tacik, Pawel; Aoki, Naoya; Strongosky, Audrey J.; Baker, Matt; Ross, Owen A.; Rademakers, Rosa; Sossi, Vesna; Dickson, Dennis W.; Stoessl, A. Jon; Wszolek, Zbigniew K.

    2014-01-01

    Objective To describe clinical, positron emission tomography (PET), pathological, and genetic findings of a large kindred with progressive neurodegenerative phenotypes in which the proband had autopsy-confirmed corticobasal degeneration (CBD). Methods Five family members, including the proband, were examined neurologically. Clinical information from the other family members was collected by questionnaires. Three individuals underwent PET with 11C-dihydrotetrabenazine and 18F-fludeoxyglucose. The proband was examined post-mortem. Genetic studies were performed. Results The pedigree contains 64 individuals, including 8 affected patients. The inheritance is likely autosomal dominant with reduced penetrance. The proband developed progressive speech and language difficulties at the age of 64 years. Upon examination at the age of 68 years, she showed non-fluent aphasia, word-finding difficulties, circumlocution, frontal release signs, and right-sided bradykinesia, rigidity, and pyramidal signs. She died 5 years after disease onset. The neuropathology was consistent with CBD, including many cortical and subcortical astrocytic plaques. Other family members had progressive neurodegenerative phenotypes – two were diagnosed with parkinsonism and behavioral problems, two with parkinsonism alone, one with amyotrophic lateral sclerosis alone, one with dementia, and one with progressive gait and speech problems. PET on three potentially affected individuals showed no significant pathology. Genetic sequencing of DNA from the proband excluded mutations in known neurodegenerative-related genes including MAPT, PGRN, LRRK2, and C9ORF72. Conclusions Families with such complex phenotypes rarely occur. They are usually associated with MAPT mutations; however, in this family, MAPT mutations have been excluded, implicating another causative gene or genes. Further genetic studies on this family may eventually disclose the etiology. PMID:25175602

  8. The TNF-family cytokine TL1A: from lymphocyte costimulator to disease co-conspirator

    PubMed Central

    Richard, Arianne C.; Ferdinand, John R.; Meylan, Françoise; Hayes, Erika T.; Gabay, Odile; Siegel, Richard M.

    2015-01-01

    Originally described in 2002 as a T cell-costimulatory cytokine, the tumor necrosis factor family member TNF-like factor 1A (TL1A), encoded by the TNFSF15 gene, has since been found to affect multiple cell lineages through its receptor, death receptor 3 (DR3, encoded by TNFRSF25) with distinct cell-type effects. Genetic deficiency or blockade of TL1A-DR3 has defined a number of disease states that depend on this cytokine-receptor pair, whereas excess TL1A leads to allergic gastrointestinal inflammation through stimulation of group 2 innate lymphoid cells. Noncoding variants in the TL1A locus are associated with susceptibility to inflammatory bowel disease and leprosy, predicting that the level of TL1A expression may influence host defense and the development of autoimmune and inflammatory diseases. PMID:26188076

  9. Activating chronic kidney disease patients and family members through the Internet to promote integration of care

    PubMed Central

    Trisolini, Michael; Roussel, Amy; Zerhusen, Eileen; Schatell, Dorian; Harris, Shelly; Bandel, Karen; Salib, Philip; Klicko, Kristi

    2004-01-01

    Abstract Purpose To describe the potential role of the Internet as a vehicle for improving integration of care through activating chronic kidney disease patients and their family members. Also, to describe how that potential is being developed through a website sponsored by the Medicare program in the United States. Background The Internet is expanding at a rapid rate, and health-related websites are one of its most popular features. Efforts to promote integration of care have focused mainly on providers up to now, and more emphasis is needed on the potential roles of patients. Chronically ill patients have particular needs for improved education about their conditions and enhanced involvement in care planning and treatment decisions. Medicare developed the Dialysis Facility Compare website to serve those goals for people with chronic kidney disease. Methods We conducted qualitative research with 140 chronic kidney disease patients and family members, and 130 renal care professionals to evaluate and improve the Dialysis Facility Compare website. A series of 19 focus groups, 13 triads (small focus groups), and 56 individual interviews were conducted in four regions of the United States and by telephone. Results We found that the Dialysis Facility Compare website has the potential to improve integration of care for people with chronic kidney disease in at least three ways. First: by expanding the roles of patients as members of the multi-disciplinary team of caregivers treating their disease. Second: through better integration of the informal care provided in the home and community with the formal care provided by health professionals. Third: by improving coordination of between care provided in the pre-dialysis and dialysis phases of the disease. Discussion We developed recommendations for revising and enhancing the Dialysis Facility Compare website in a number of ways to better promote patient activation and integration of care. The unique features of the Internet

  10. The choline transporter-like family SLC44: properties and roles in human diseases.

    PubMed

    Traiffort, Elisabeth; O'Regan, Seana; Ruat, Martial

    2013-01-01

    The Na(+)-independent, high affinity choline carrier system proposed to supply choline for the synthesis of cell membrane phospholipids was recently associated with SLC44 family members (SLC44A1-5) also called choline-like transporter family. SLC44A1 is widely expressed throughout the nervous system in both neurons and oligodendrocytes, while SLC44A2-4 are mainly detected in peripheral tissues. The subcellular localization of the proteins was mainly addressed for SLC44A1 through the development of specific antibodies. SLC44A1 is detected in both the plasma and mitochondrial membranes where the protein is able to transport choline at high affinity and in a Na(+)-independent manner. The physiological relevance of SLC44A1 as a choline carrier is indicated by its likely involvement in membrane synthesis for cell growth or repair, and also by its role in phospholipid production for the generation of lung surfactant. Moreover, an autoimmune disease has been related to the blockade of SLC44A2 function, which results in the alteration of hair cells in the inner ear and leads to autoimmune hearing loss. In the alloimmune syndrome called transfusion-related acute lung injury, antibodies to SLC44A2 cause a deleterious aggregation of granulocytes. Therefore transporters of the SLC44 family represent attractive and promising targets for therapeutic and diagnostic applications regarding both immune and degenerative diseases.

  11. Conveying a probabilistic genetic test result to families with an inherited heart disease.

    PubMed

    Ingles, Jodie; Semsarian, Christopher

    2014-06-01

    The evolution of genetic testing in the past few years has been astounding. In a matter of only a few years, we now have comprehensive gene tests comprising vast panels of "cardiac" genes, whole exome sequencing (the entire coding region) and even whole genome sequencing (the entire genome). Making the call as to whether a DNA variant is causative or benign is difficult and the focus of intense research efforts. In most cases, the final answer will not be a simple yes/no outcome but rather a graded continuum of pathogenicity. This allows classification of variants in a more probabilistic way. How we convey this to a patient is the challenge, and certainly shines a spotlight on the important skills of the cardiac genetic counselor. This is an exciting step forward, but the overwhelming complexity of the information generated from these tests means our current practices of conveying genetic information to the family must be carefully considered. Despite the challenges, a genetic diagnosis in a family has great benefit both in reassuring unaffected family members and removing the need for lifetime clinical surveillance. The multidisciplinary specialized clinic model, incorporating genetic counselors, cardiologists and geneticists, provides the ideal framework for ensuring the best possible care for genetic heart disease families.

  12. Case-control association mapping by proxy using family history of disease.

    PubMed

    Liu, Jimmy Z; Erlich, Yaniv; Pickrell, Joseph K

    2017-03-01

    Collecting cases for case-control genetic association studies can be time-consuming and expensive. In some situations (such as studies of late-onset or rapidly lethal diseases), it may be more practical to identify family members of cases. In randomly ascertained cohorts, replacing cases with their first-degree relatives enables studies of diseases that are absent (or nearly absent) in the cohort. We refer to this approach as genome-wide association study by proxy (GWAX) and apply it to 12 common diseases in 116,196 individuals from the UK Biobank. Meta-analysis with published genome-wide association study summary statistics replicated established risk loci and yielded four newly associated loci for Alzheimer's disease, eight for coronary artery disease and five for type 2 diabetes. In addition to informing disease biology, our results demonstrate the utility of association mapping without directly observing cases. We anticipate that GWAX will prove useful in future genetic studies of complex traits in large population cohorts.

  13. Teneurins and Alzheimer's disease: a suggestive role for a unique family of proteins.

    PubMed

    Bastías-Candia, Sussy; Braidy, Nady; Zolezzi, Juan M; Inestrosa, Nibaldo C

    2015-04-01

    Alzheimer's disease is a debilitating age-related disorder characterized by distinct pathological hallmarks, such as progressive memory loss and cognitive impairment. During the last few years, several cellular signaling pathways have been associated with the pathogenesis of Alzheimer's disease, such as Notch, mTOR and Wnt. However, the potential factors that modulate these pathways and novel molecular mechanisms that might account for the pathogenesis of Alzheimer's disease or for therapy against this disease are still matters of intense research. Teneurins are members of a unique protein system that has recently been proposed as a novel and highly conserved regulatory signaling system in the vertebrate brain, so far related with neurite outgrowth and neuronal matching. The similitude in structure and function of teneurins with other cellular signaling pathways, suggests that they may play a critical role in Alzheimer's disease, either through the modulation of transcription factors due to the nuclear translocation of the teneurins intracellular domain, or through the activity of the corticotrophin releasing factor (CRF)-like peptide sequence, called teneurin C-terminal associated peptide. Moreover, the presence of Ca(2+)-binding motifs within teneurins structure and the Zic2-mediated Wnt/β-catenin signaling modulation, allows hypothesize a potential crosslink between teneurins and the Wnt signaling pathway, particularly. Herein, we aim to highlight the main characteristics of teneurins and propose, based on current knowledge of this family of proteins, an interesting review of their potential involvement in Alzheimer's disease.

  14. Preventing a Mass Disease: The Case of Gallstones Disease: Role and Competence for Family Physicians.

    PubMed

    Portincasa, Piero; Di Ciaula, Agostino; Grattagliano, Ignazio

    2016-07-01

    Gallstone formation is the result of a complex interaction between genetic and nongenetic factors. We searched and reviewed the available literature to define how the primary prevention of gallstones (cholesterol gallstones in particular) could be applied in general practice. Electronic bibliographical databases were searched. Prospective and retrospective cohort studies and case-controlled studies were analyzed and graded for evidence quality. The epidemiological data confirmed that genetic factors are estimated to account for only approximately 25% of the overall risk of gallstones, while metabolic/environmental factors are at least partially modifiable in stone-free risk groups, and are thus modifiable by primary prevention measures related to diet, lifestyle, and environmental factors (i.e., rapid weight loss, bariatric surgery, somatostatin or analogues therapy, transient gallbladder stasis, and hormone therapy). There is no specific recommendation for the secondary prevention of recurrent gallstones. Family physicians can contribute to preventing gallstones due to their capability to identify and effectively manage several risk factors discussed in this study. Although further studies are needed to better elucidate the involvement of epigenetic factors that may regulate the effect of environment and lifestyle on gene expression in the primary prevention of gallstone formation, preventive interventions are feasible and advisable in the general practice setting.

  15. Preventing a Mass Disease: The Case of Gallstones Disease: Role and Competence for Family Physicians

    PubMed Central

    Di Ciaula, Agostino; Grattagliano, Ignazio

    2016-01-01

    Gallstone formation is the result of a complex interaction between genetic and nongenetic factors. We searched and reviewed the available literature to define how the primary prevention of gallstones (cholesterol gallstones in particular) could be applied in general practice. Electronic bibliographical databases were searched. Prospective and retrospective cohort studies and case–controlled studies were analyzed and graded for evidence quality. The epidemiological data confirmed that genetic factors are estimated to account for only approximately 25% of the overall risk of gallstones, while metabolic/environmental factors are at least partially modifiable in stone-free risk groups, and are thus modifiable by primary prevention measures related to diet, lifestyle, and environmental factors (i.e., rapid weight loss, bariatric surgery, somatostatin or analogues therapy, transient gallbladder stasis, and hormone therapy). There is no specific recommendation for the secondary prevention of recurrent gallstones. Family physicians can contribute to preventing gallstones due to their capability to identify and effectively manage several risk factors discussed in this study. Although further studies are needed to better elucidate the involvement of epigenetic factors that may regulate the effect of environment and lifestyle on gene expression in the primary prevention of gallstone formation, preventive interventions are feasible and advisable in the general practice setting. PMID:27468338

  16. Kuru: A Journey Back in Time from Papua New Guinea to the Neanderthals’ Extinction

    PubMed Central

    Liberski, Pawel P.

    2013-01-01

    Kuru, the first human transmissible spongiform encephalopathy was transmitted to chimpanzees by D. Carleton Gajdusek (1923–2008). In this review, I briefly summarize the history of this seminal discovery along its epidemiology, clinical picture, neuropathology and molecular genetics. The discovery of kuru opened new windows into the realms of human medicine and was instrumental in the later transmission of Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease as well as the relevance that bovine spongiform encephalopathy had for transmission to humans. The transmission of kuru was one of the greatest contributions to biomedical sciences of the 20th century. PMID:25437203

  17. Assessing family caregiver skill in managing behavioral symptoms of Alzheimer’s disease

    PubMed Central

    Farran, Carol J.; Fogg, Louis G.; McCann, Judith J.; Etkin, Caryn; Dong, Xinqi; Barnes, Lisa L.

    2011-01-01

    Objectives This measurement study operationalized family caregiver skill in managing behavioral symptoms associated with Alzheimer’s disease (AD) by testing a Caregiver Assessment of Behavioral Skill-Self Report measure (CAB-SR). Method A cross-sectional design was used. Caregivers had a family member with possible/probable AD, resided at home with the care recipient and provided the majority of care (N=82). The mail-administered assessment included the CAB-SR and other care recipient and caregiver measures. Results Preliminary CAB-SR reliability and validity were determined, using reliability, factor analytic and correlational procedures. Conclusion This measure provides a preliminary assessment of caregiver skill in managing behavioral symptoms of AD and shows promise for use in research and clinical intervention settings. PMID:21500018

  18. The mammalian START domain protein family in lipid transport in health and disease.

    PubMed

    Clark, Barbara J

    2012-03-01

    Lipid transfer proteins of the steroidogenic acute regulatory protein-related lipid transfer (START) domain family are defined by the presence of a conserved ∼210 amino acid sequence that folds into an α/β helix-grip structure forming a hydrophobic pocket for ligand binding. The mammalian START proteins bind diverse ligands, such as cholesterol, oxysterols, phospholipids, sphingolipids, and possibly fatty acids, and have putative roles in non-vesicular lipid transport, thioesterase enzymatic activity, and tumor suppression. However, the biological functions of many members of the START domain protein family are not well established. Recent research has focused on characterizing the cell-type distribution and regulation of the START proteins, examining the specificity and directionality of lipid transport, and identifying disease states associated with dysregulation of START protein expression. This review summarizes the current concepts of the proposed physiological and pathological roles for the mammalian START domain proteins in cholesterol and lipid trafficking.

  19. Using Family Health History for Chronic Disease Prevention in the Age of Genomics: Translation to Health Education Practice

    ERIC Educational Resources Information Center

    Hanson, Carl; Novilla, Lelinneth; Barnes, Michael; De La Cruz, Natalie; Meacham, Aaron

    2007-01-01

    Advances in the field of human genomics have important implications for the prevention of chronic disease. In response to these advancements, public health professionals--including health educators--must become competent in the principles underlying the interface between genomics and the use of family health history. Family health history captures…

  20. Exploring Spirituality in Family Caregivers of Patients With Primary Malignant Brain Tumors Across the Disease Trajectory

    PubMed Central

    Newberry, Alyssa G.; Jean Choi, Chien-Wen; Donovan, Heidi S.; Schulz, Richard; Bender, Catherine; Given, Barbara; Sherwood, Paula

    2013-01-01

    Purpose/Objectives To determine whether the perceived level of spirituality in family caregivers of patients with primary malignant brain tumors (PMBTs) changes across the disease trajectory. Design Ongoing descriptive, longitudinal study. Setting Southwestern Pennsylvania. Sample 50 family caregivers of patients with PMBT. Methods Caregivers and care recipients were recruited at time of diagnosis. Participants were interviewed at two subse-quent time points, four and eight months following diagnosis. Main Research Variables Care recipients’ symptoms, neuro-psychologic status, and physical function, as well as caregiver social support. Findings Results showed no significant difference in spirituality scores reported at baseline and eight months (p = 0.8), suggesting that spirituality may be a stable trait across the disease trajectory. Conclusions Spirituality remains relatively stable along the course of the disease trajectory. Reports of caregiver depressive symptoms and anxiety were lower when paired with higher reports of spirituality. Implications for Nursing Clinicians can better identify caregivers at risk for negative outcomes by identifying those who report lower levels of spirituality. Future interventions should focus on the development and implementation of interventions that provide protective buffers such as increased social support. Knowledge Translation Spirituality is a relatively stable trait. High levels of spirituality can serve as a protective buffer from negative mental health outcomes. Caregivers with low levels of spirituality may be at risk for greater levels of burden, anxiety, and stress. PMID:23615145

  1. Neuropsychiatric symptoms of the elderly with Alzheimer's disease and the family caregivers' distress 1

    PubMed Central

    Storti, Luana Baldin; Quintino, Débora Teles; Silva, Natália Michelato; Kusumota, Luciana; Marques, Sueli

    2016-01-01

    ABSTRACT Objective: to analyze the relationship between the distress of the family caregiver and the presence of neuropsychiatric symptoms in elderly patients with Alzheimer's disease or mixed dementia. Method: a descriptive, cross-sectional study conducted in the Geriatric and Dementias Clinic of a general tertiary hospital, with 96 elderly people with Alzheimer's disease or mixed dementia and their family caregivers. Questionnaires to characterize the elderly and caregivers, and the Neuropsychiatric Inventory were used. Descriptive statistics and Pearson correlation test were performed. Results: 68.7% of the elderly were women, average age 80.8 years, 56.2% had Alzheimer's disease and 43.7%, mixed dementia. Among caregivers, 90.6% were women, average age 56, 70.8% took care of parents and 64.6% lived with the elderly. There was a strong (r = 0.82) and significant (p <0.01) correlation between the total score on the Neuropsychiatric Inventory and the total score on the Neuropsychiatric Inventory-Distress and strong (r = 0.80) and significant (p <0 01) correlation between the total score on the Neuropsychiatric Inventory Distress and the number of neuropsychiatric symptoms, i.e., the higher the number, frequency and severity of these symptoms in the elderly, the more intense is the caregiver distress. Conclusion: the presence of neuropsychiatric symptoms in the elderly was related to increased distress in caregivers. PMID:27533264

  2. A Novel Missense Mutation of GATA4 in a Chinese Family with Congenital Heart Disease

    PubMed Central

    Wang, Bo; Chen, Sun; Fu, Qihua; Sun, Kun

    2016-01-01

    Background Congenital heart disease (CHD) is the most prevalent type of birth defect in human, with high morbidity in infant. Several genes essential for heart development have been identified. GATA4 is a pivotal transcription factor that can regulate the cardiac development. Many GATA4 mutations have been identified in patients with different types of CHD. Aims In this study, the NKX2-5, HAND1 and GATA4 coding regions were sequenced in a family spanning three generations in which seven patients had CHD. Disease-causing potential variation in this family was evaluated by bioinformatics programs and the transcriptional activity of mutant protein was analyzed by the dual luciferase reporter assay. Results A novel GATA4 mutation, c.C931T (p.R311W), was identified and co-segregated with the affected patients in this family. The bioinformatics programs predicted this heterozygous mutation to be deleterious and the cross-species alignment of GATA4 sequences showed that the mutation occurred within a highly conserved amino acid. Even though it resided in the nuclear localization signal domain, the mutant protein didn’t alter its intracellular distribution. Nevertheless, further luciferase reporter assay demonstrated that the p.R311W mutation reduced the ability of GATA4 to activate its downstream target gene. Conclusions Our study identified a novel mutation in GATA4 that likely contributed to the CHD in this family. This finding expanded the spectrum of GATA4 mutations and underscored the pathogenic correlation between GATA4 mutations and CHD. PMID:27391137

  3. Idiopathic hemochromotosis and alpha-1-antitrypsin deficiency: coexistence in a family with progressive liver disease in the proband.

    PubMed

    Anand, S; Schade, R R; Bendetti, C; Kelly, R; Rabin, B S; Krause, J; Starzl, T E; Iwatsuki, S; Van Thiel, D H

    1983-01-01

    A patient with coexistent hemochromatosis and alpha-1-antitrypsin deficiency which led to cirrhosis and death despite adequate therapy for hemochromatosis is reported. Evaluation of the family revealed first degree relatives with iron overload and others with alpha-1-antitrypsin deficiency but none with both conditions. The role of family studies in the early recognition and possible prevention of overt clinical disease in individuals with either of these two genetic diseases is discussed.

  4. Idiopathic Hemochromotosis and Alpha-1-Antitrypsin Deficiency: Coexistence in a Family with Progressive Liver Disease in the Proband

    PubMed Central

    Anand, Suri; Schade, Robert R.; Bendetti, Carlos; Kelly, Robert; Rabin, Bruce S.; Krause, John; Starzl, Thomas E.; Iwatsuki, Shunzaburo; Van Thiel, David H.

    2010-01-01

    A patient with coexistent hemochromatosis and alpha-1-antitrypsin deficiency which led to cirrhosis and death despite adequate therapy for hemochromatosis is reported. Evaluation of the family revealed first degree relatives with iron overload and others with alpha-1-antitrypsin deficiency but none with both conditions. The role of family studies in the early recognition and possible prevention of overt clinical disease in individuals with either of these two genetic diseases is discussed. PMID:6604688

  5. Genetic polymorphism of MMP family and coronary disease susceptibility: a meta-analysis.

    PubMed

    Li, Min; Shi, Jingpu; Fu, Lingyu; Wang, Hailong; Zhou, Bo; Wu, Xiaomei

    2012-03-01

    The issue that genetic polymorphism of matrix metalloproteinase (MMP) family is in association with coronary disease is controversial. So we did a meta-analysis to clarify it clearly. We made a literature search of PubMed, the Web of Science, and Cochrane Collaboration's database to identify eligible reports. The methodological quality of each included studies was assessed. We calculated the pooled ORs with their 95%CI for each genetic polymorphism in STATA 11 software. Separate analysis was performed to address the consistency of results across the subgroup with different continents. A total of 39 studies were included, with a sample of 42269 individuals. This meta-analysis provided evidence that genetic polymorphism of MMP1-1607 1G/2G, MMP3-Gly45lys, MMP3-376 G/C, MMP3-1171 5A/6A, MMP9-1562 C/T and MMP9-R279Q have a small to medium effect on incidence of coronary disease. There was no evidence that MMP1-519 A/G, MMP1-340 T/C and MMP2-1306 C/T polymorphism could increase risk of coronary disease. Results from subgroup analysis supported a relation between MMP3-1711 5A allele, MMP9-1562 C allele and coronary disease especially in Asian population. The results provide moderate association between the six common genetic polymorphism of matrix metalloproteinase family and coronary disease. However, the challenge for researcher is identifying separate effect on different races.

  6. The Role of Cardiovascular Risk Factors and Stroke in Familial Alzheimer Disease

    PubMed Central

    Tosto, Giuseppe; Bird, Thomas D.; Bennett, David A.; Boeve, Bradley F.; Brickman, Adam M.; Cruchaga, Carlos; Faber, Kelley; Foroud, Tatiana M.; Farlow, Martin; Goate, Alison M.; Graff-Radford, Neill R.; Lantigua, Rafael; Manly, Jennifer; Ottman, Ruth; Rosenberg, Roger; Schaid, Daniel J.; Schupf, Nicole; Stern, Yaakov; Sweet, Robert A.; Mayeux, Richard

    2016-01-01

    Importance The contribution of cardiovascular disease (CV) and cerebrovascular disease to the risk for late-onset Alzheimer disease (LOAD) has been long debated. Investigations have shown that antecedent CV risk factors increase the risk for LOAD, although other investigations have failed to validate this association. Objective To study the contribution of CV risk factors (type 2 diabetes, hypertension, and heart disease) and the history of stroke to LOAD in a data set of large families multiply affected by LOAD. Design, Setting, and Participants The National Institute on Aging Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease family study (hereinafter referred to as NIA-LOAD study) is a longitudinal study of families with multiple members affected with LOAD. A multiethnic community-based longitudinal study (Washington Heights–Inwood Columbia Aging Project [WHICAP]) was used to replicate findings. The 6553 participants in the NIA-LOAD study were recruited from 23 US Alzheimer disease centers with ongoing data collection since 2003; the 5972 WHICAP participants were recruited at Columbia University with ongoing data collection since 1992. Data analysis was performed from 2003 to 2015. Main Outcomes and Measures Generalized mixed logistic regression models tested the association of CV risk factors (primary association) with LOAD. History of stroke was used for the secondary association. A secondary model adjusted for the presence of an apolipoprotein E (APOE) ε4 allele. A genetic risk score, based on common variants associated with LOAD, was used to account for LOAD genetic risk beyond the APOE ε4 effect. Mediation analyses evaluated stroke as a mediating factor between the primary association and LOAD. Results A total of 6553 NIA-LOAD participants were included in the analyses (4044 women [61.7%]; 2509 men [38.3%]; mean [SD] age, 77.0 [9] years), with 5972 individuals from the WHICAP study included in the replication sample (4072 women

  7. The health-disease process and the family health strategy: the user's perspective1

    PubMed Central

    Santos, Débora de Souza; Tenório, Elainey de Albuquerque; Brêda, Mércia Zeviane; Mishima, Silvana Martins

    2014-01-01

    OBJECTIVE: to analyze the meanings Primary Health Care users attribute to their health-disease process and the services used. METHODS: this qualitative research uses the focus group technique to interview two groups of users the service monitors. The first is a group of elderly people and the second of pregnant women. To analyze the meanings, the discourse analysis technique and the reference framework of health promotion are used. RESULTS: the group of elderly, being mostly female arterial hypertension and diabetes mellitus patients, visualizes the health-disease process as the evolution of human existence controlled by divine power, signifying the health service as a blessing in the control of the disease. The Group of young pregnant women signified health as the ability for self-care and disease as the disability for that purposes, considering the Primary Health Care service as responsible for the recovery of individual and family health. FINAL CONSIDERATIONS: the users demonstrated dissatisfaction with bureaucratic and vertical relations present at the health services. In each group, it was observed that the meanings for health and disease and meanings of the health service the users elaborated can be related. PMID:25591086

  8. Familial Adult-onset Alexander Disease: Clinical and Neuroradiological Findings of Three Cases

    PubMed Central

    ELMALI, Ayşe Deniz; ÇETİNÇELİK, Ümran; IŞLAK, Civan; UZUN ADATEPE, Nurten; KARAALİ SAVRUN, Feray; YALÇINKAYA, Cengiz

    2016-01-01

    The adult-onset Alexander disease (AOAD) dramatically differs from the early onset AD with respect to clinical and neuroradiological findings. Herein we report the detailed clinical and neuroradiological findings of a Turkish family with AOAD. In all three cases, magnetic resonance imaging revealed marked atrophy of the mesencephalon, bulbus, and cervical spinal cord accompanied with signal abnormalities in the same regions along with supratentorial white matter. Basal ganglia were affected in two cases. Molecular genetic analysis revealed heterozygous mutation in the 8th exon of the glial fibrillary acidic protein gene M451I (c.1245G>A), leading to the diagnosis of AOAD in all cases. PMID:28360791

  9. Chronic kidney disease in an adolescent with hyperuricemia: familial juvenile hyperuricemic nephropathy.

    PubMed

    Alaygut, Demet; Torun-Bayram, Meral; Soylu, Alper; Kasap, Belde; Türkmen, Mehmet; Kavukçu, Salih

    2013-01-01

    Chronic kidney disease (CKD) is a life-long condition associated with substantial morbidity and premature death due to complications from a progressive decrease in kidney function. Especially in children, early diagnosis and detection of the etiologic factors are important to improve their health outcomes. Familial juvenile hyperuricemic nephropathy (FJHN) is a rare autosomal-dominant disorder characterized by hyperuricemia with renal uric acid under-excretion and CKD. Genetic studies have revealed mutations in the uromodulin (UMOD) gene. Highlighting the importance of CKD in children, a 14-year-old girl with the rare diagnosis of FJHN is reported herein.

  10. Evidence of abnormality of lymphocyte uroporphyrinogen synthase in family members of patients with lymphoproliferative diseases.

    PubMed

    Lahav, M; Epstein, O; Schoenfeld, N; Nemesh, L; Shaklai, M; Atsmon, A

    1985-01-01

    Patients with active lymphoproliferative diseases (LPD) were shown to have high activity of lymphocyte uroporphyrinogen synthase (L-UROS), the enzyme which converts porphobilinogen to uroporphyrinogen. The mean L-UROS activity of 64 first-degree relatives of patients with LPD was significantly higher than that of a control group and 45% of these relatives had pathological values of L-UROS. L-UROS activity was also determined in the spouses of 2 patients and was pathologically elevated in both. The pattern of pathological values among family members may indicate the presence of a communicable agent.

  11. Whole Exome Sequence Analysis Implicates Rare Il17REL Variants In Familial And Sporadic Inflammatory Bowel Disease

    PubMed Central

    Sasaki, Mark M; Skol, Andrew D; Hungate, Eric A; Bao, Riyue; Huang, Lei; Kahn, Stacy A; Allan, James M; Brant, Steven R; McGovern, Dermot PB; Peter, Inga; Silverberg, Mark S; Cho, Judy H; Kirschner, Barbara S; Onel, Kenan

    2015-01-01

    Background Rare variants (<1%) likely contribute significantly to risk for common diseases such as inflammatory bowel disease (IBD) in specific patient subsets, such as those with high familiality. They are, however, extraordinarily challenging to identify. Methods To discover candidate rare variants associated with IBD, we performed whole exome sequencing (WES) on six members of a pediatric-onset IBD family with multiple affected individuals. To determine whether the variants discovered in this family are also associated with non-familial IBD, we investigated their influence on disease in two large case-control (CC) series. Results We identified two rare variants, rs142430606 and rs200958270, both in the established IBD-susceptibility gene IL17REL, carried by all four affected family members and their obligate-carrier parents. We then demonstrated that both variants are associated with sporadic ulcerative colitis (UC) in two independent datasets. For UC in CC 1: rs142430606 (OR=2.99, Padj=0.028; MAFcases=0.0063, MAFcontrols=0.0021); rs200958270 (OR=2.61, Padj=0.082; MAFcases=0.0045, MAFcontrols=0.0017). For UC in CC 2: rs142430606 (OR=1.94, P=0.0056; MAFcases=0.0071, MAFcontrols=0.0045); rs200958270 (OR=2.08, P=0.0028; MAFcases=0.0071, MAFcontrols=0.0042). Conclusions We discover in a family and replicate in two CC datasets two rare susceptibility variants for IBD, both in IL17REL. Our results illustrate that WES performed on disease-enriched families to guide association testing can be an efficient strategy for the discovery of rare disease-associated variants. We speculate that rare variants identified in families and confirmed in the general population may be important modifiers of disease risk for patients with a family history, and that genetic testing of these variants may be warranted in this patient subset. PMID:26480299

  12. Specific deficit of colour-colour short-term memory binding in sporadic and familial Alzheimer's disease.

    PubMed

    Parra, Mario A; Sala, Sergio Della; Abrahams, Sharon; Logie, Robert H; Méndez, Luis Guillermo; Lopera, Francisco

    2011-06-01

    Short-term memory binding of visual features which are processed across different dimensions (shape-colour) is impaired in sporadic Alzheimer's disease, familial Alzheimer's disease, and in asymptomatic carriers of familial Alzheimer's disease. This study investigated whether Alzheimer's disease also impacts on within-dimension binding processes. The study specifically explored whether visual short-term memory binding of features of the same type (colour-colour) is sensitive to Alzheimer's disease. We used a neuropsychological battery and a short-term memory binding task to assess patients with sporadic Alzheimer's disease (Experiment 1), familial Alzheimer's disease (Experiment 2) due to the mutation E280A of the Presenilin-1 gene and asymptomatic carriers of the mutation. The binding task assessed change detection within arrays of unicoloured objects (Colour Only) or bicoloured objects the colours of which had to be remembered separately (Unbound Colours) or together (Bound Colours). Performance on the Bound Colours condition (1) explained the largest proportion of variance between patients (sporadic and familial Alzheimer's disease), (2) combined more sensitivity and specificity for the disease than other more traditional neuropsychological tasks, (3) identified asymptomatic carriers of the mutation even when traditional neuropsychological measures and other measures of short-term memory did not and, (4) contrary to shape-colour binding, correlated with measures of hippocampal functions. Colour-colour binding and shape-colour binding both appear to be sensitive to AD even though they seem to rely on different brain mechanisms.

  13. [The symptoms in family medicine are not symptoms of disease, they are symptoms of life].

    PubMed

    Turabián, José Luis; Pérez Franco, Benjamín; Turabián Fernández, José Luis; Pérez Franco, Benjamin

    2012-04-01

    The symptoms in family medicine are not signs of disease, but "signs of life"; in the consultation "all patient life comes together with him". Every consultation is primarily a biopsicosocial problem: the person perceives a dysfunction or alteration in relation with himself and his context. To do a diagnosis only with physical symptoms, can be a mistake because these do not identify the real problem. The different types of symptoms are "entangled" or chained some in others: the symptoms can be fitted or inevitable; to be expressions of biochemical alterations, symbols for the patient, group context expressions, or kinds of facing the facts; and they depend on the previous psychological patient performance, the severity of the deficit of the psychological function associated with the disease, the residual skills, the adjustment and the confrontation of the functional limitations, the relation doctor-patient, as well as on the influence of the context.

  14. Panvascular Disease in Familial Hypercholesterolaemia Treated with Endovascular Simultaneous Bilateral Carotid Stenting

    PubMed Central

    Alurkar, Anand; Shah, Shripal; Mare, Pandurang

    2016-01-01

    Familial Hypercholesterolaemia (FH) is a monogenic autosomal dominant disorder affecting 1 in 500 individuals. We report a case of 32-year-old female with FH, previously not on any treatment, who presented with recurrent bilateral Middle Cerebral Artery (MCA) territory strokes and dyspnoea on exertion due to severe panvascualar disease involving descending aorta, innominate, subclavian, common carotid, internal carotid and coronary vessels. Her complete clinical work up was done and was started on lipid lowering drug treatment and low calorie diet. She underwent simultaneous bilateral carotid stenting followed by coronary artery bypass surgery at a later date. In the present scenario we want to emphasize the importance of early detection and treatment of individuals with FH, failing of which results in premature and accelerated atherosclerosis causing multisystemic vascular disease with significant morbidity and mortality. Screening of first degree relatives is important owing to the autosomal dominant inheritance pattern of the FH. PMID:27891422

  15. Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer's disease.

    PubMed

    Shinohara, Mitsuru; Fujioka, Shinsuke; Murray, Melissa E; Wojtas, Aleksandra; Baker, Matthew; Rovelet-Lecrux, Anne; Rademakers, Rosa; Das, Pritam; Parisi, Joseph E; Graff-Radford, Neill R; Petersen, Ronald C; Dickson, Dennis W; Bu, Guojun

    2014-05-01

    Recent studies suggest that subcortical structures, including striatum, are vulnerable to amyloid-β accumulation and other neuropathological features in familial Alzheimer's disease due to autosomal dominant mutations. We explored differences between familial and sporadic Alzheimer's disease that might shed light on their respective pathogenic mechanisms. To this end, we analysed 12 brain regions, including neocortical, limbic and subcortical areas, from post-mortem brains of familial Alzheimer's disease (n = 10; age at death: 50.0 ± 8.6 years) with mutations in amyloid precursor protein (APP) or presenilin 1 (PSEN1), sporadic Alzheimer's disease (n = 19; age at death: 84.7 ± 7.8 years), neurologically normal elderly without amyloid-β accumulation (normal ageing; n = 13, age at death: 82.9 ± 10.8 years) and neurologically normal elderly with extensive cortical amyloid-β deposits (pathological ageing; n = 15; age at death: 92.7 ± 5.9 years). The levels of amyloid-β₄₀, amyloid-β₄₂, APP, apolipoprotein E, the synaptic marker PSD95 (now known as DLG4), the astrocyte marker GFAP, other molecules related to amyloid-β metabolism, and tau were determined by enzyme-linked immunosorbent assays. We observed that familial Alzheimer's disease had disproportionate amyloid-β₄₂ accumulation in subcortical areas compared with sporadic Alzheimer's disease, whereas sporadic Alzheimer's disease had disproportionate amyloid-β₄₂ accumulation in cortical areas compared to familial Alzheimer's disease. Compared with normal ageing, the levels of several proteins involved in amyloid-β metabolism were significantly altered in both sporadic and familial Alzheimer's disease; however, such changes were not present in pathological ageing. Among molecules related to amyloid-β metabolism, the regional distribution of PSD95 strongly correlated with the regional pattern of amyloid-β₄₂ accumulation in sporadic Alzheimer's disease and pathological ageing, whereas the

  16. Complex Inheritance of ABCA4 Disease: Four Mutations in a Family with Multiple Macular Phenotypes

    PubMed Central

    Lee, Winston; Xie, Yajing (Angela); Zernant, Jana; Yuan, Bo; Bearelly, Srilaxmi; Tsang, Stephen H.; Lupski, James R.; Allikmets, Rando

    2015-01-01

    Over 800 mutations in the ABCA4 gene cause autosomal recessive Stargardt disease. Due to extensive genetic heterogeneity, observed variant-associated phenotypes can manifest tremendous variability of expression. Furthermore, the high carrier frequency of pathogenic ABCA4 alleles in the general population (~1:20) often results in pseudo-dominant inheritance patterns further complicating the diagnosis and characterization of affected individuals. This study describes a genotype/phenotype analysis of an unusual family with multiple macular disease phenotypes spanning across two generations and segregating four distinct ABCA4 mutant alleles. Complete sequencing of ABCA4 discovered two known missense mutations, p.C54Y and p.G1961E. Array comparative genomic hybridization revealed a large novel deletion combined with a small insertion, c.6148-698_c.6670del/insTGTGCACCTCCCTAG, and complete sequencing of the entire ABCA4 genomic locus uncovered a new deep intronic variant, c.302+68C>T. Patients with the p.G1961E mutation had the mildest, confined maculopathy phenotype with peripheral flecks while those with all other mutant allele combinations exhibited a more advanced stage of generalized retinal and choriocapillaris atrophy. This family epitomizes the clinical and genetic complexity of ABCA4-associated diseases. It contained variants from all classes of mutations, in the coding region, deep intronic, both single nucleotide variants (SNV) and copy number variants (CNV) that accounted for varying phenotypes segregating in an apparent dominant fashion. Unequivocally defining disease-associated alleles in the ABCA4 locus requires a multifaceted approach that includes advanced mutation detection methods and a thorough analysis of clinical phenotypes. PMID:26527198

  17. Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer's Disease.

    PubMed

    Potter, Huntington; Granic, Antoneta; Caneus, Julbert

    2016-01-01

    Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and increased beta-amyloid (Aβ) peptide production underlie the universal development of Alzheimer's disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy 21 and other forms of aneuploidy also arise among neurons and peripheral cells in both sporadic and familial AD and in mouse and cell models thereof, reinforcing the conclusion that AD and DS are two sides of the same coin. The demonstration that 90% of the neurodegeneration in AD can be attributed to the selective loss of aneuploid neurons generated over the course of the disease indicates that aneuploidy is an essential feature of the pathogenic pathway leading to the depletion of neuronal cell populations. Trisomy 21 mosaicism also occurs in neurons and other cells from patients with Niemann-Pick C1 disease and from patients with familial or sporadic frontotemporal lobar degeneration (FTLD), as well as in their corresponding mouse and cell models. Biochemical studies have shown that Aβ induces mitotic spindle defects, chromosome mis-segregation, and aneuploidy in cultured cells by inhibiting specific microtubule motors required for mitosis. These data indicate that neuronal trisomy 21 and other types of aneuploidy characterize and likely contribute to multiple neurodegenerative diseases and are a valid target for therapeutic intervention. For example, reducing extracellular calcium or treating cells with lithium chloride (LiCl) blocks the induction of trisomy 21 by Aβ. The latter finding is relevant in light of recent reports of a lowered risk of dementia in bipolar patients treated with LiCl and in the stabilization of cognition in AD patients treated with LiCl.

  18. Machado–Joseph disease in a Nigerian family: mutational origin and review of the literature

    PubMed Central

    Ogun, Shamsideen Abayomi; Martins, Sandra; Adebayo, Philip B; Dawodu, Clara O; Sequeiros, Jorge; Finkel, Michael F

    2015-01-01

    Machado–Joseph disease (MJD) has been described in Africans, but no cases have been reported from Nigeria. Current MJD global distribution results from both the ancestral populations-of-origin and the founder effects of mutations, some as a consequence of the Portuguese sea travels in the 15th to 16th century. Two main ancestral haplotypes have been identified: the Machado lineage, which is more recent, predominant in families of Portuguese extraction, and the Joseph lineage, which is much older and worldwide spread, postulated to have an Asian origin. We report a Nigerian family with MJD from Calabar, once settled by Portuguese slave traders, and assessed its mutational origin. The proband was a 33-year-old man with progressive unsteady gait, weakness of all limbs, dysphagia, dysarthria, urinary frequency and diaphoresis. He had end-of-gaze nystagmus, spastic quadriparesis and atrophic small muscles of the hand. He showed fibrillation potentials on EMG, and nerve conduction studies suggested a central axonopathy without demyelination. This family bears the Joseph haplotype, which has a founder effect in the island of Flores, in the Azores (and their descendants in North-America), but is also the most common in non-Portuguese populations worldwide, with an estimated mutation age of around 7000 years. PMID:24781759

  19. A Yoga and Compassion Meditation Program Reduces Stress in Familial Caregivers of Alzheimer's Disease Patients

    PubMed Central

    Danucalov, M. A. D.; Kozasa, E. H.; Ribas, K. T.; Galduróz, J. C. F.; Garcia, M. C.; Verreschi, I. T. N.; Oliveira, K. C.; Romani de Oliveira, L.; Leite, J. R.

    2013-01-01

    Familial caregivers of patients with Alzheimer's disease exhibit reduced quality of life and increased stress levels. The aim of this study was to investigate the effects of an 8-week yoga and compassion meditation program on the perceived stress, anxiety, depression, and salivary cortisol levels in familial caregivers. A total of 46 volunteers were randomly assigned to participate in a stress-reduction program for a 2-month period (yoga and compassion meditation program—YCMP group) (n = 25) or an untreated group for the same period of time (control group) (n = 21). The levels of stress, anxiety, depression, and morning salivary cortisol of the participants were measured before and after intervention. The groups were initially homogeneous; however, after intervention, the groups diverged significantly. The YCMP group exhibited a reduction of the stress (P < 0.05), anxiety (P < 0.000001), and depression (P < 0.00001) levels, as well as a reduction in the concentration of salivary cortisol (P < 0.05). Our study suggests that an 8-week yoga and compassion meditation program may offer an effective intervention for reducing perceived stress, anxiety, depression, and salivary cortisol in familial caregivers. PMID:23690846

  20. Machado-Joseph disease in a Nigerian family: mutational origin and review of the literature.

    PubMed

    Ogun, Shamsideen Abayomi; Martins, Sandra; Adebayo, Philip B; Dawodu, Clara O; Sequeiros, Jorge; Finkel, Michael F

    2015-02-01

    Machado-Joseph disease (MJD) has been described in Africans, but no cases have been reported from Nigeria. Current MJD global distribution results from both the ancestral populations-of-origin and the founder effects of mutations, some as a consequence of the Portuguese sea travels in the 15th to 16th century. Two main ancestral haplotypes have been identified: the Machado lineage, which is more recent, predominant in families of Portuguese extraction, and the Joseph lineage, which is much older and worldwide spread, postulated to have an Asian origin. We report a Nigerian family with MJD from Calabar, once settled by Portuguese slave traders, and assessed its mutational origin. The proband was a 33-year-old man with progressive unsteady gait, weakness of all limbs, dysphagia, dysarthria, urinary frequency and diaphoresis. He had end-of-gaze nystagmus, spastic quadriparesis and atrophic small muscles of the hand. He showed fibrillation potentials on EMG, and nerve conduction studies suggested a central axonopathy without demyelination. This family bears the Joseph haplotype, which has a founder effect in the island of Flores, in the Azores (and their descendants in North-America), but is also the most common in non-Portuguese populations worldwide, with an estimated mutation age of around 7000 years.

  1. Medicinal and other products and human and animal transmissible spongiform encephalopathies: memorandum from a WHO meeting.

    PubMed Central

    1997-01-01

    The report in March 1996 of 10 human cases of a novel from of Creutzfeldt-Jakob disease in the United Kingdom, and its possible link to the agent that causes bovine spongiform encephalopathy (BSE), raises many questions about the safety of animal-derived products and by-products entering the food chain or being used in medicine. This Memorandum updates the preventive measures put forward in 1991 to minimize the risks associated with the use of bovine-derived materials in medicinal products and medical devices. PMID:9509622

  2. Toward fluorescence detection of protein residues on surgical instruments

    NASA Astrophysics Data System (ADS)

    Richardson, Patricia R.; Jones, Anita C.; Baxter, Robert L.; Baxter, Helen C.; Whittaker, A. Gavin; Campbell, Gaynor A.

    2004-06-01

    Prion proteins are the infectious agents that cause Creutzfeldt-Jakob Disease (CJD) in humans. These proteins are particularly resistant to normal sterilization procedures, and the theoretical risk of prion transmission via surgical instruments is of current public and professional concern. We are currently investigating fluorescence methods for the detection of proteins on surfaces, with a view to developing an optical-fiber-based system for routine, online monitoring of residual protein contamination on surgical instruments, in hospital sterilization departments. This paper presents preliminary results on the detection of femtomole amounts of fluorescently labelled protein on surgical steel and discusses some of the problems involved in the detection of fluorescence from metal samples.

  3. Highly sensitive rapid fluorescence detection of protein residues on surgical instruments

    NASA Astrophysics Data System (ADS)

    Kovalev, Valeri I.; Bartona, James S.; Richardson, Patricia R.; Jones, Anita C.

    2006-07-01

    There is a risk of contamination of surgical instruments by infectious protein residues, in particular, prions which are the agents for Creutzfeldt-Jakob Disease in humans. They are exceptionally resistant to conventional sterilization, therefore it is important to detect their presence as contaminants so that alternative cleaning procedures can be applied. We describe the development of an optimized detection system for fluorescently labelled protein, suitable for in-hospital use. We show that under optimum conditions the technique can detect ~10 attomole/cm2 with a scan speed of ~3-10 cm2/s of the test instrument's surface. A theoretical analysis and experimental measurements will be discussed.

  4. Relation Between Family History of Premature Coronary Artery Disease and the Risk of Death in Patients With Coronary Artery Disease.

    PubMed

    Abdi-Ali, Ahmed; Shaheen, AbdelAziz; Southern, Danielle; Zhang, Mei; Knudtson, Merril; White, James; Graham, Michelle; James, Mathew T; Wilton, Stephen B

    2016-02-01

    Family history (FHx) of premature coronary artery disease (CAD) is a risk factor for development of incident cardiovascular disease. However the association between FHx and outcomes in patients with established CAD is unclear. We followed 84,373 patients with angiographic CAD enrolled in the inclusive Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease registry between April 2002 and March 2013. Overall, 25,566 (30%) self-reported an FHx of CAD, defined as a first-degree relative with premature CAD (men, age <55 years; women, age <65 years). We tested the association between FHx and all-cause mortality using multivariable Cox proportional hazards regression. After adjusting for baseline differences in clinical characteristics, indication, and extent of CAD, FHx was associated with reduced all-cause mortality over a median 5.6 years in follow-up (hazard ratio [HR] 0.77 [95% CI 0.73 to 0.80]). The magnitude of this protective association was weaker in those with versus without a previous myocardial infarction (HR 0.87 [95% CI 0.81 to 0.93] versus 0.72 [0.69 to 0.76], interaction p <0.0001) and slightly stronger in those presenting with versus without an acute coronary syndrome (HR 0.74 [0.70 to 0.79] versus 0.80 [0.75 to 0.85], interaction p = 0.08). There was attenuation of association with increasing age, but FHx remained protective even in those aged older than 80 years (HR 0.86 [0.77 to 0.95]). In conclusion, in patients with angiographic CAD, self-reported FHx of premature CAD is associated with improved long-term survival rate, independent of clinical characteristics, mode of presentation, and extent of disease. Further investigation of potential patient- and system-level mediators of this seemingly paradoxical relation is required.

  5. New mutations in the GLA gene in Brazilian families with Fabry disease.

    PubMed

    Turaça, Lauro Thiago; Pessoa, Juliana Gilbert; Motta, Fabiana Louise; Muñoz Rojas, Maria Verônica; Müller, Karen Barbosa; Lourenço, Charles Marques; Junior Marques, Wilson; D'Almeida, Vania; Martins, Ana Maria; Pesquero, João Bosco

    2012-06-01

    Fabry disease (FD) is an X-linked inborn error of glycosphingolipid catabolism that results from mutations in the alpha-galactosidase A (GLA) gene. Evaluating the enzymatic activity in male individuals usually performs the diagnosis of the disease, but in female carriers the diagnosis based only on enzyme assays is often inconclusive. In this work, we analyzed 568 individuals from 102 families with suspect of FD. Overall, 51 families presented 38 alterations in the GLA gene, among which 19 were not previously reported in literature. The alterations included 17 missense mutations, 7 nonsense mutations, 7 deletions, 6 insertions and 1 in the splice site. Six alterations (R112C, R118C, R220X, R227X, R342Q and R356W) occurred at CpG dinucleotides. Five mutations not previously described in the literature (A156D, K237X, A292V, I317S, c.1177_1178insG) were correlated with low GLA enzyme activity and with prediction of molecular damages. From the 13 deletions and insertions, 7 occurred in exons 6 or 7 (54%) and 11 led to the formation of a stop codon. The present study highlights the detection of new genomic alterations in the GLA gene in the Brazilian population, facilitating the selection of patients for recombinant enzyme-replacement trials and offering the possibility to perform prenatal diagnosis.

  6. Reproductive options for prospective parents in families with Huntington's disease: clinical, psychological and ethical reflections.

    PubMed

    de Die-Smulders, C E M; de Wert, G M W R; Liebaers, I; Tibben, A; Evers-Kiebooms, G

    2013-01-01

    BACKGROUND Huntington's disease (HD) is an autosomal dominant neurodegenerative late onset disorder. This review of reproductive options aims to increase reproductive confidence and to prevent suffering in relation to family planning around HD and possibly other late onset neurodegenerative disorders. METHODS Selected relevant literature and own views and experiences as clinical geneticists, psychologists and ethicists have been used. RESULTS Possible options, with emphasis on prenatal diagnosis (PD) and preimplantation genetic diagnosis (PGD) to prevent the transmission of HD to the next generation, are described and discussed. They are formally presented in a decision tree, taking into account the presence or absence of a fully penetrant allele (FPA), a reduced penetrant allele (RPA) or an intermediate allele (IA). A table compares invasive and non-invasive PD and PGD. From a psychological perspective, the complex process of counselling and decision-making regarding reproductive options is discussed. Special attention is paid to the decision to avoid the transmission of the mutation and to the confrontation and coping of a mutation-free child growing up with a parent developing disease symptoms. From an ethical point of view, reflections on both PD and PGD are brought forward taking into account the difference between FPA, RPA and IA, direct testing or exclusion testing and taking into account the welfare of the child in the context of medically assisted reproduction. CONCLUSION Recommendations and suggestions for good clinical practice in the reproductive care for HD families are formulated.

  7. Spectral Analysis of EEG in Familial Alzheimer's Disease with E280A Presenilin-1 Mutation Gene

    PubMed Central

    Rodriguez, Rene; Lopera, Francisco; Alvarez, Alfredo; Fernandez, Yuriem; Galan, Lidice; Quiroz, Yakeel; Bobes, Maria Antonieta

    2014-01-01

    To evaluate the hypothesis that quantitative EEG (qEEG) analysis is susceptible to detect early functional changes in familial Alzheimer's disease (AD) preclinical stages. Three groups of subjects were selected from five extended families with hereditary AD: a Probable AD group (18 subjects), an asymptomatic carrier (ACr) group (21 subjects), with the mutation but without any clinical symptoms of dementia, and a normal group of 18 healthy subjects. In order to reveal significant differences in the spectral parameter, the Mahalanobis distance (D2) was calculated between groups. To evaluate the diagnostic efficiency of this statistic D2, the ROC models were used. The ROC curve was summarized by accuracy index and standard deviation. The D2 using the parameters of the energy in the fast frequency bands shows accurate discrimination between normal and ACr groups (area ROC = 0.89) and between AD probable and ACr groups (area ROC = 0.91). This is more significant in temporal regions. Theses parameters could be affected before the onset of the disease, even when cognitive disturbance is not clinically evident. Spectral EEG parameter could be firstly used to evaluate subjects with E280A Presenilin-1 mutation without impairment in cognitive function. PMID:24551475

  8. Deadly outbreak of iron storage disease (ISD) in Italian birds of the family Turdidae.

    PubMed

    Pavone, Silvia; Salamida, Sonia; Pecorelli, Ivan; Rossi, Elisabetta; Manuali, Elisabetta

    2014-09-01

    A widespread deadly outbreak occurred in captive birds belonging to the family Turdidae in Italy. The present study was performed on 46 dead birds coming from 3 small decoy-bird breeders in central Italy. Only Turdus pilaris, Turdus iliacus, Turdus philomelos and Turdus merula were affected. No other species of bird held by these breeders died. A change of diet before the hunting season was reported from all breeders. Full necropsy of the animals and histological investigations of representative tissue samples were performed. Microscopical examination showed marked iron deposits in liver samples. Bacteriological investigations and molecular analysis to exclude bacterial and viral diseases were carried out. Contamination of food pellet samples by mycotoxins and analysis to detect heavy metal contaminants in food pellet samples were considered. An interesting result was the high iron content found in food pellets. It was higher than that considered suitable for birds, especially for species susceptible to development iron storage disease (ISD). Taken together, the results suggested an outbreak of ISD caused by the high iron content of food given to the birds before the hunting season. The high mortality recorded only in species belonging to the family Turdidae suggests a genetic predisposition in the affected birds.

  9. Deadly Outbreak of Iron Storage Disease (ISD) in Italian Birds of the Family Turdidae

    PubMed Central

    PAVONE, Silvia; SALAMIDA, Sonia; PECORELLI, Ivan; ROSSI, Elisabetta; MANUALI, Elisabetta

    2014-01-01

    ABSTRACT A widespread deadly outbreak occurred in captive birds belonging to the family Turdidae in Italy. The present study was performed on 46 dead birds coming from 3 small decoy-bird breeders in central Italy. Only Turdus pilaris, Turdus iliacus, Turdus philomelos and Turdus merula were affected. No other species of bird held by these breeders died. A change of diet before the hunting season was reported from all breeders. Full necropsy of the animals and histological investigations of representative tissue samples were performed. Microscopical examination showed marked iron deposits in liver samples. Bacteriological investigations and molecular analysis to exclude bacterial and viral diseases were carried out. Contamination of food pellet samples by mycotoxins and analysis to detect heavy metal contaminants in food pellet samples were considered. An interesting result was the high iron content found in food pellets. It was higher than that considered suitable for birds, especially for species susceptible to development iron storage disease (ISD). Taken together, the results suggested an outbreak of ISD caused by the high iron content of food given to the birds before the hunting season. The high mortality recorded only in species belonging to the family Turdidae suggests a genetic predisposition in the affected birds. PMID:24920545

  10. The kindlin family: functions, signaling properties and implications for human disease.

    PubMed

    Rognoni, Emanuel; Ruppert, Raphael; Fässler, Reinhard

    2016-01-01

    The kindlin (or fermitin) family of proteins comprises three members (kindlin-1,-2 and -3) of evolutionarily conserved focal adhesion (FA) proteins, whose best-known task is to increase integrin affinity for a ligand (also referred as integrin activation) through binding of β-integrin tails. The consequence of kindlin-mediated integrin activation and integrin-ligand binding is cell adhesion, spreading and migration, assembly of the extracellular matrix (ECM), cell survival, proliferation and differentiation. Another hallmark of kindlins is their involvement in disease. Mutations in the KINDLIN-1 (also known as FERMT1) gene cause Kindler syndrome (KS)--in which mainly skin and intestine are affected, whereas mutations in the KINDLIN-3 (also known as FERMT3) gene cause leukocyte adhesion deficiency type III (LAD III), which is characterized by impaired extravasation of blood effector cells and severe, spontaneous bleedings. Also, aberrant expression of kindlins in various forms of cancer and in tissue fibrosis has been reported. Although the malfunctioning of integrins represent a major cause leading to kindlin-associated diseases, increasing evidence also point to integrin-independent functions of kindlins that play an important role in the pathogenesis of certain disease aspects. Furthermore, isoform-specific kindlin functions have been discovered, explaining, for example, why loss of kindlins differentially affects tissue stem cell homeostasis or tumor development. This Commentary focuses on new and isoform-specific kindlin functions in different tissues and discusses their potential role in disease development and progression.