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Sample records for acquired genetic disorders

  1. Role of Radiologic Imaging in Genetic and Acquired Neuromuscular Disorders

    PubMed Central

    Zanato, Riccardo; Coran, Alessandro; Beltrame, Valeria; Stramare, Roberto

    2015-01-01

    Great technologic and clinical progress have been made in the last two decades in identifying genetic defects of several neuromuscular diseases, as Spinal Muscular Atrophy, genetic muscular dystrophies and other genetic myopathies. The diagnosis is usually challenging, due to great variability in genetic abnormalities and clinical phenotypes and the poor specificity of complementary analyses, i.e., serum creatine kinase (CK) and electrophysiology. Muscle biopsy represents the gold standard for the diagnosis of genetic neuromuscular diseases, but clinical imaging of muscle tissue is an important diagnostic tool to identify and quantifyies muscle damage. Radiologic imaging is, indeed, increasingly used as a diagnostic tool to describe patterns and the extent of muscle involvement, thanks to modern techniques that enable to definethe definition of degrees of muscle atrophy and changes in connective tissue. They usually grade the severity of the disease process with greater accuracy than clinical scores. Clinical imaging is more than complementary to perform muscle biopsy, especially as ultrasound scans are often mandatory to identify the muscle to be biopsied. We will here detail and provideWe will herein provide detailed examples of the radiologic methods that can be used in genetic and acquired neuromuscular disorders, stressing pros and cons. Key Words: Muscle Imaging, MRI, CT, genetic muscle disorders, myopathies, dystrophies PMID:26913153

  2. Genetic Disorders

    MedlinePlus

    ... Management Education & Events Advocacy For Patients About ACOG Genetic Disorders Home For Patients Search FAQs Genetic Disorders ... Spanish Genetic Disorders FAQ094, April 2014 PDF Format Genetic Disorders Pregnancy What are genes? What are chromosomes? ...

  3. Update on iron metabolism and molecular perspective of common genetic and acquired disorder, hemochromatosis.

    PubMed

    Yun, Seongseok; Vincelette, Nicole D

    2015-07-01

    Iron is an essential component of erythropoiesis and its metabolism is tightly regulated by a variety of internal and external cues including iron storage, tissue hypoxia, inflammation and degree of erythropoiesis. There has been remarkable improvement in our understanding of the molecular mechanisms of iron metabolism past decades. The classical model of iron metabolism with iron response element/iron response protein (IRE/IRP) is now extended to include hepcidin model. Endogenous and exogenous signals funnel down to hepcidin via wide range of signaling pathways including Janus Kinase/Signal Transducer and Activator of Transcription 3 (JAK/STAT3), Bone Morphogenetic Protein/Hemojuvelin/Mothers Against Decapentaplegic Homolog (BMP/HJV/SMAD), and Von Hippel Lindau/Hypoxia-inducible factor/Erythropoietin (VHL/HIF/EPO), then relay to ferroportin, which directly regulates intra- and extracellular iron levels. The successful molecular delineation of iron metabolism further enhanced our understanding of common genetic and acquired disorder, hemochromatosis. The majority of the hereditary hemochromatosis (HH) patients are now shown to have mutations in the genes coding either upstream or downstream proteins of hepcidin, resulting in iron overload. The update on hepcidin centered mechanisms of iron metabolism and their clinical perspective in hemochromatosis will be discussed in this review.

  4. Genetic Disorders

    MedlinePlus

    ... This can cause a medical condition called a genetic disorder. You can inherit a gene mutation from ... during your lifetime. There are three types of genetic disorders: Single-gene disorders, where a mutation affects ...

  5. Inherited or acquired metabolic disorders.

    PubMed

    Eichler, Florian; Ratai, Eva; Carroll, Jason J; Masdeu, Joseph C

    2016-01-01

    This chapter starts with a description of imaging of inherited metabolic disorders, followed by a discussion on imaging of acquired toxic-metabolic disorders of the adult brain. Neuroimaging is crucial for the diagnosis and management of a number of inherited metabolic disorders. Among these, inherited white-matter disorders commonly affect both the nervous system and endocrine organs. Magnetic resonance imaging (MRI) has enabled new classifications of these disorders that have greatly enhanced both our diagnostic ability and our understanding of these complex disorders. Beyond the classic leukodystrophies, we are increasingly recognizing new hereditary leukoencephalopathies such as the hypomyelinating disorders. Conventional imaging can be unrevealing in some metabolic disorders, but proton magnetic resonance spectroscopy (MRS) may be able to directly visualize the metabolic abnormality in certain disorders. Hence, neuroimaging can enhance our understanding of pathogenesis, even in the absence of a pathologic specimen. This review aims to present pathognomonic brain MRI lesion patterns, the diagnostic capacity of proton MRS, and information from clinical and laboratory testing that can aid diagnosis. We demonstrate that applying an advanced neuroimaging approach enhances current diagnostics and management. Additional information on inherited and metabolic disorders of the brain can be found in Chapter 63 in the second volume of this series.

  6. [Acquired disorders of color vision].

    PubMed

    Lascu, Lidia; Balaş, Mihaela

    2002-01-01

    This article is a general view of acquired disorders of color vision. The revision of the best known methods and of the etiopathogenic classification is not very important in ophthalmology but on the other hand, the detection of the blue defect advertise and associated ocular pathology. There is a major interest in serious diseases as multiple sclerosis, AIDS, diabetes melitus, when the first ocular sign can be a defect in the color vision.

  7. Specific Genetic Disorders

    MedlinePlus

    ... of Genetic Terms Definitions for genetic terms Specific Genetic Disorders Many human diseases have a genetic component. ... Condition in an Adult The Undiagnosed Diseases Program Genetic Disorders Achondroplasia Alpha-1 Antitrypsin Deficiency Antiphospholipid Syndrome ...

  8. Genetic Brain Disorders

    MedlinePlus

    A genetic brain disorder is caused by a variation or a mutation in a gene. A variation is a different form ... mutation is a change in a gene. Genetic brain disorders affect the development and function of the ...

  9. Genetics of bipolar disorder.

    PubMed

    Escamilla, Michael A; Zavala, Juan M

    2008-01-01

    Bipolar disorder especially the most severe type (type I), has a strong genetic component. Family studies suggest that a small number of genes of modest effect are involved in this disorder. Family-based studies have identified a number of chromosomal regions linked to bipolar disorder, and progress is currently being made in identifying positional candidate genes within those regions. A number of candidate genes have also shown evidence of association with bipolar disorder, and genome-wide association studies are now under way, using dense genetic maps. Replication studies in larger or combined datasets are needed to definitively assign a role for specific genes in this disorder. This review covers our current knowledge of the genetics of bipolar disorder, and provides a commentary on current approaches used to identify the genes involved in this complex behavioral disorder.

  10. Clinicopathological correlation of acquired hyperpigmentary disorders.

    PubMed

    Patel, Anisha B; Kubba, Raj; Kubba, Asha

    2013-01-01

    Acquired pigmentary disorders are group of heterogenous entities that share single, most significant, clinical feature, that is, dyspigmentation. Asians and Indians, in particular, are mostly affected. Although the classic morphologies and common treatment options of these conditions have been reviewed in the global dermatology literature, the value of histpathological evaluation has not been thoroughly explored. The importance of accurate diagnosis is emphasized here as the underlying diseases have varying etiologies that need to be addressed in order to effectively treat the dyspigmentation. In this review, we describe and discuss the utility of histology in the diagnostic work of hyperpigmentary disorders, and how, in many cases, it can lead to targeted and more effective therapy. We focus on the most common acquired pigmentary disorders seen in Indian patients as well as a few uncommon diseases with distinctive histological traits. Facial melanoses, including mimickers of melasma, are thoroughly explored. These diseases include lichen planus pigmentosus, discoid lupus erythematosus, drug-induced melanoses, hyperpigmentation due to exogenous substances, acanthosis nigricans, and macular amyloidosis.

  11. Stereotypic movement disorder after acquired brain injury.

    PubMed

    McGrath, Cynthia M; Kennedy, Richard E; Hoye, Wayne; Yablon, Stuart A

    2002-05-01

    Stereotypic movement disorder (SMD) consists of repetitive, non-functional motor behaviour that interferes with daily living or causes injury to the person. It is most often described in patients with mental retardation. However, recent evidence indicates that this condition is common among otherwise normal individuals. This case study describes a patient with new-onset SMD occurring after subdural haematoma and brain injury. SMD has rarely been reported after acquired brain injury, and none have documented successful treatment. The current psychiatric literature regarding neurochemistry, neuroanatomy, and treatment of SMD are reviewed with particular application to one patient. Treatment options include serotonin re-uptake inhibitors, opioid antagonists and dopamine antagonists. SMD has been under-appreciated in intellectually normal individuals, and may also be unrecognized after brain injury. Further investigation is needed in this area, which may benefit other individuals with SMD as well.

  12. Genetics Home Reference: bipolar disorder

    MedlinePlus

    ... Me Understand Genetics Home Health Conditions bipolar disorder bipolar disorder Enable Javascript to view the expand/collapse boxes. ... bipolar affective psychosis bipolar spectrum disorder depression, bipolar manic depressive illness Related Information How are genetic conditions and genes ...

  13. Frequently Asked Questions about Genetic Disorders

    MedlinePlus

    ... used on this page Frequently Asked Questions About Genetic Disorders What are genetic disorders? A genetic disorder is a disease caused ... significant risk of developing the disease. . Geneticists group genetic disorders into three categories: Monogenetic disorders are caused ...

  14. Low vision due to cerebral visual impairment: differentiating between acquired and genetic causes

    PubMed Central

    2014-01-01

    Background To gain more insight into genetic causes of cerebral visual impairment (CVI) in children and to compare ophthalmological findings between genetic and acquired forms of CVI. Methods The clinical data of 309 individuals (mainly children) with CVI, and a visual acuity ≤0.3 were analyzed for etiology and ocular variables. A differentiation was made between acquired and genetic causes. However, in persons with West syndrome or hydrocephalus, it might be impossible to unravel whether CVI is caused by the seizure disorder or increased intracranial pressure or by the underlying disorder (that in itself can be acquired or genetic). In two subgroups, individuals with ‘purely’ acquired CVI and with ‘purely’ genetic CVI, the ocular variables (such as strabismus, pale optic disc and visual field defects) were compared. Results It was possible to identify a putative cause for CVI in 60% (184/309) of the cohort. In the remaining 40% the etiology could not be determined. A ‘purely’ acquired cause was identified in 80 of the patients (26%). West syndrome and/or hydrocephalus was identified in 21 patients (7%), and in 17 patients (6%) both an acquired cause and West and/or hydrocephalus was present. In 66 patients (21%) a genetic diagnosis was obtained, of which 38 (12%) had other possible risk factor (acquired, preterm birth, West syndrome or hydrocephalus), making differentiation between acquired and genetic not possible. In the remaining 28 patients (9%) a ‘purely’ genetic cause was identified. CVI was identified for the first time in several genetic syndromes, such as ATR-X, Mowat-Wilson, and Pitt Hopkins syndrome. In the subgroup with ‘purely’ acquired causes (N = 80) strabismus (88% versus 64%), pale optic discs (65% versus 27%) and visual field defects (72% versus 30%) could be observed more frequent than in the subgroup with ‘purely’ genetic disorders (N = 28). Conclusions We conclude that CVI can be part of a genetic syndrome and

  15. Imaging genetics of mood disorders

    PubMed Central

    Scharinger, Christian; Rabl, Ulrich; Sitte, Harald H.; Pezawas, Lukas

    2015-01-01

    Mood disorders are highly heritable and have been linked to brain regions of emotion processing. Over the past few years, an enormous amount of imaging genetics studies has demonstrated the impact of risk genes on brain regions and systems of emotion processing in vivo in healthy subjects as well as in mood disorder patients. While sufficient evidence already exists for several monaminergic genes as well as for a few nonmonoaminergic genes, such as brain-derived neurotrophic factor (BDNF) in healthy subjects, many others only have been investigated in single studies so far. Apart from these studies, the present review also covers imaging genetics studies applying more complex genetic disease models of mood disorders, such as epistasis and gene–environment interactions, and their impact on brain systems of emotion processing. This review attempts to provide a comprehensive overview of the rapidly growing field of imaging genetics studies in mood disorder research. PMID:20156570

  16. [Acquired platelet function disorders: pathogenesis, classification, frequency, diagnosis, clinical management].

    PubMed

    Scharf, R E

    2008-12-01

    Given the high consumption of pharmacological agents in western societies, it is not surprising at all that drugs represent the most common cause of acquired platelet dysfunction. While acetylsalicylic acid, clopigogrel and integrin alphaIIbbeta3 (GPIIb-IIIa) receptor antagonists are well-known as prototypes of antiplatelet drugs, other widely used agents including non-steroidal anti-inflammatory drugs, antibiotics, serotonin reuptake inhibitors, and volume expanders can also impair platelet function and cause or aggravate haemorrhages. Besides pharmacological agents, certain clinical conditions are often associated with qualitative platelet disorders and bleeding diathesis. Consequently, in contrast to inherited platelet disorders, acquired platelet function defects are much more frequent in clinical practice and deserve special attention. Their pathogenesis is widespread and heterogeneous with various, sometimes overlapping abnormalities. Moreover, acquired platelet dysfunctions can occur at any age and range in severity from mild to life-threatening haemorrhages. Due to their heterogeneity, acquired platelet function disorders will be classified and discussed according to the underlying clinical setting or disease.

  17. Genetic factors in anxiety disorders.

    PubMed

    Domschke, Katharina; Maron, Eduard

    2013-01-01

    Presently available clinical genetic studies point to a considerable heritability of anxiety disorders (30-67%), with multiple vulnerability genes such as 5-HT1A, 5-HTT, MAO-A, COMT, CCK-B, ADORA2A, CRHR1, FKBP5, ACE, RGS2/7 and NPSR1 suggested by molecular genetic association studies. These genes have been shown to partially interact with each other as well as with environmental factors to shape the overall disease risk in a complex genetic model. Additionally, recent studies have pointed out the crucial role of epigenetic signatures such as methylation patterns in modifying environmental influences as well as in driving the functional impact of anxiety disorder risk genes. On a systems level, vulnerability genes of anxiety disorders seem to confer some of the disease risk via intermediate phenotypes like behavioral inhibition, anxiety sensitivity or several neurobiological traits such as increased startle reactivity or dysfunctional corticolimbic activity during emotional processing. Finally, first pharmaco- and psychotherapy-genetic studies provide evidence for certain risk genes to confer interindividual variability in response to a pharmacological or psychotherapeutic intervention in anxiety disorders. Genetic research in anxiety disorders will be discussed regarding its potential to foster innovative and individually tailored therapeutic approaches for patients with anxiety disorders.

  18. Acquired aphasia with convulsive disorder: course and prognosis.

    PubMed

    Mantovani, J F; Landau, W M

    1980-05-01

    Acquired aphasia with convulsive disorder is an unusual condition in childhood, characterized by loss of language function associated with a paroxysmal electroencephalogram. To determine the course and outcome of this disorder, we evaluated nine patients 10 to 28 years after the onset of aphasia. Four patients had recovered fully, one had mild language dysfunction, and four had moderate language disability. Four of the five patients with the best outcome had decreased visuoperceptive function as measured by the Revised Benton Visual Retention Test (RBVRT), whereas the three tested patients with moderate language dysfunction had normal RBVRT scores.

  19. Community-Acquired Pneumonia Hospitalization among Children with Neurologic Disorders

    PubMed Central

    Millman, Alexander J.; Finelli, Lyn; Bramley, Anna M.; Peacock, Georgina; Williams, Derek J.; Arnold, Sandra R.; Grijalva, Carlos G.; Anderson, Evan J.; McCullers, Jonathan A.; Ampofo, Krow; Pavia, Andrew T.; Edwards, Kathryn M.; Jain, Seema

    2016-01-01

    Objective To describe and compare the clinical characteristics, outcomes, and etiology of pneumonia among children hospitalized with community-acquired pneumonia (CAP) with neurologic disorders, non-neurologic underlying conditions, and no underlying conditions. Study design Children <18 years old hospitalized with clinical and radiographic CAP were enrolled at 3 US children’s hospitals. Neurologic disorders included cerebral palsy, developmental delay, Down syndrome, epilepsy, non-Down syndrome chromosomal abnormalities, and spinal cord abnormalities. We compared the epidemiology, etiology, and clinical outcomes of CAP in children with neurologic disorders with those with non-neurologic underlying conditions, and those with no underlying conditions using bivariate, age-stratified, and multivariate logistic regression analyses. Results From January 2010–June 2012, 2358 children with radiographically confirmed CAP were enrolled; 280 (11.9%) had a neurologic disorder (52.1% of these individuals also had non-neurologic underlying conditions), 934 (39.6%) had non-neurologic underlying conditions only, and 1144 (48.5%) had no underlying conditions. Children with neurologic disorders were older and more likely to require intensive care unit (ICU) admission than children with non-neurologic underlying conditions and children with no underlying conditions; similar proportions were mechanically ventilated. In age-stratified analysis, children with neurologic disorders were less likely to have a pathogen detected than children with non-neurologic underlying conditions. In multivariate analysis, having a neurologic disorder was associated with ICU admission for children ≥2 years of age. Conclusions Children with neurologic disorders hospitalized with CAP were less likely to have a pathogen detected and more likely to be admitted to the ICU than children without neurologic disorders. PMID:27017483

  20. Imaging genetics and psychiatric disorders.

    PubMed

    Hashimoto, R; Ohi, K; Yamamori, H; Yasuda, Y; Fujimoto, M; Umeda-Yano, S; Watanabe, Y; Fukunaga, M; Takeda, M

    2015-01-01

    Imaging genetics is an integrated research method that uses neuroimaging and genetics to assess the impact of genetic variation on brain function and structure. Imaging genetics is both a tool for the discovery of risk genes for psychiatric disorders and a strategy for characterizing the neural systems affected by risk gene variants to elucidate quantitative and mechanistic aspects of brain function implicated in psychiatric disease. Early studies of imaging genetics included association analyses between brain morphology and single nucleotide polymorphisms whose function is well known, such as catechol-Omethyltransferase (COMT) and brain-derived neurotrophic factor (BDNF). GWAS of psychiatric disorders have identified genes with unknown functions, such as ZNF804A, and imaging genetics has been used to investigate clues of the biological function of these genes. The difficulty in replicating the findings of studies with small sample sizes has motivated the creation of largescale collaborative consortiums, such as ENIGMA, CHARGE and IMAGEN, to collect thousands of images. In a genome-wide association study, the ENIGMA consortium successfully identified common variants in the genome associated with hippocampal volume at 12q24, and the CHARGE consortium replicated this finding. The new era of imaging genetics has just begun, and the next challenge we face is the discovery of small effect size signals from large data sets obtained from genetics and neuroimaging. New methods and technologies for data reduction with appropriate statistical thresholds, such as polygenic analysis and parallel independent component analysis (ICA), are warranted. Future advances in imaging genetics will aid in the discovery of genes and provide mechanistic insight into psychiatric disorders.

  1. Imaging Genetics and Psychiatric Disorders

    PubMed Central

    Hashimoto, R; Ohi, K; Yamamori, H; Yasuda, Y; Fujimoto, M; Umeda-Yano, S; Watanabe, Y; Fukunaga, M; Takeda, M

    2015-01-01

    Imaging genetics is an integrated research method that uses neuroimaging and genetics to assess the impact of genetic variation on brain function and structure. Imaging genetics is both a tool for the discovery of risk genes for psychiatric disorders and a strategy for characterizing the neural systems affected by risk gene variants to elucidate quantitative and mechanistic aspects of brain function implicated in psychiatric disease. Early studies of imaging genetics included association analyses between brain morphology and single nucleotide polymorphisms whose function is well known, such as catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF). GWAS of psychiatric disorders have identified genes with unknown functions, such as ZNF804A, and imaging genetics has been used to investigate clues of the biological function of these genes. The difficulty in replicating the findings of studies with small sample sizes has motivated the creation of large-scale collaborative consortiums, such as ENIGMA, CHARGE and IMAGEN, to collect thousands of images. In a genome-wide association study, the ENIGMA consortium successfully identified common variants in the genome associated with hippocampal volume at 12q24, and the CHARGE consortium replicated this finding. The new era of imaging genetics has just begun, and the next challenge we face is the discovery of small effect size signals from large data sets obtained from genetics and neuroimaging. New methods and technologies for data reduction with appropriate statistical thresholds, such as polygenic analysis and parallel independent component analysis (ICA), are warranted. Future advances in imaging genetics will aid in the discovery of genes and provide mechanistic insight into psychiatric disorders. PMID:25732148

  2. The etiology of primary femoroacetabular impingement: genetics or acquired deformity?

    PubMed

    Packer, Jonathan D; Safran, Marc R

    2015-10-01

    The etiology of primary femoroacetabular impingement (FAI) remains controversial. Both genetic and acquired causes have been postulated and studied. While recent studies suggest that genetic factors may have a role in the development of FAI, there is no conclusive evidence that FAI is transmitted genetically. Currently, the most popular theory for the development of cam-type deformities is that a repetitive injury to the proximal femoral physis occurs during a critical period of development. There is a correlation between a high volume of impact activities during adolescence and the development of cam-type deformities. Multiple studies have found a high prevalence of FAI in elite football, ice hockey, basketball and soccer players. In this article, we review the current literature relating to the etiology of primary FAI.

  3. Molecular Genetics of Mitochondrial Disorders

    ERIC Educational Resources Information Center

    Wong, Lee-Jun C.

    2010-01-01

    Mitochondrial respiratory chain (RC) disorders (RCDs) are a group of genetically and clinically heterogeneous diseases because of the fact that protein components of the RC are encoded by both mitochondrial and nuclear genomes and are essential in all cells. In addition, the biogenesis, structure, and function of mitochondria, including DNA…

  4. Telerehabilitation, Virtual Therapists, and Acquired Neurologic Speech and Language Disorders

    PubMed Central

    Cherney, Leora R.; van Vuuren, Sarel

    2013-01-01

    Telerehabilitation (telererehab) offers cost effective services that potentially can improve access to care for those with acquired neurologic communication disorders. However, regulatory issues including licensure, reimbursement, and threats to privacy and confidentiality hinder the routine implementation of telerehab services into the clinical setting. Despite these barriers, rapid technological advances and a growing body of research regarding the use of telerehab applications support its use. This article reviews the evidence related to acquired neurologic speech and language disorders in adults, focusing on studies that have been published since 2000. Research studies have used telerehab systems to assess and treat disorders including dysarthria, apraxia of speech, aphasia, and mild Alzheimer’s disease. They show that telerehab is a valid and reliable vehicle for delivering speech and language services. The studies represent a progression of technological advances in computing, Internet, and mobile technologies. They range on a continuum from working synchronously (in real-time) with a speech-language pathologist to working asynchronously (offline) with a stand-in virtual therapist. One such system that uses a virtual therapist for the treatment of aphasia, the Web-ORLA™ (Rehabilitation Institute of Chicago, Chicago, IL) system, is described in detail. Future directions for the advancement of telerehab for clinical practice are discussed. PMID:22851346

  5. Telerehabilitation, virtual therapists, and acquired neurologic speech and language disorders.

    PubMed

    Cherney, Leora R; van Vuuren, Sarel

    2012-08-01

    Telerehabilitation (telerehab) offers cost-effective services that potentially can improve access to care for those with acquired neurologic communication disorders. However, regulatory issues including licensure, reimbursement, and threats to privacy and confidentiality hinder the routine implementation of telerehab services into the clinical setting. Despite these barriers, rapid technological advances and a growing body of research regarding the use of telerehab applications support its use. This article reviews the evidence related to acquired neurologic speech and language disorders in adults, focusing on studies that have been published since 2000. Research studies have used telerehab systems to assess and treat disorders including dysarthria, apraxia of speech, aphasia, and mild Alzheimer disease. They show that telerehab is a valid and reliable vehicle for delivering speech and language services. The studies represent a progression of technological advances in computing, Internet, and mobile technologies. They range on a continuum from working synchronously (in real-time) with a speech-language pathologist to working asynchronously (offline) with a stand-in virtual therapist. One such system that uses a virtual therapist for the treatment of aphasia, the Web-ORLA™ (Rehabilitation Institute of Chicago, Chicago, IL) system, is described in detail. Future directions for the advancement of telerehab for clinical practice are discussed.

  6. Genetic disorders of nuclear receptors.

    PubMed

    Achermann, John C; Schwabe, John; Fairall, Louise; Chatterjee, Krishna

    2017-04-03

    Following the first isolation of nuclear receptor (NR) genes, genetic disorders caused by NR gene mutations were initially discovered by a candidate gene approach based on their known roles in endocrine pathways and physiologic processes. Subsequently, the identification of disorders has been informed by phenotypes associated with gene disruption in animal models or by genetic linkage studies. More recently, whole exome sequencing has associated pathogenic genetic variants with unexpected, often multisystem, human phenotypes. To date, defects in 20 of 48 human NR genes have been associated with human disorders, with different mutations mediating phenotypes of varying severity or several distinct conditions being associated with different changes in the same gene. Studies of individuals with deleterious genetic variants can elucidate novel roles of human NRs, validating them as targets for drug development or providing new insights into structure-function relationships. Importantly, human genetic discoveries enable definitive disease diagnosis and can provide opportunities to therapeutically manage affected individuals. Here we review germline changes in human NR genes associated with "monogenic" conditions, including a discussion of the structural basis of mutations that cause distinctive changes in NR function and the molecular mechanisms mediating pathogenesis.

  7. Genetic Determinism and the Innate-Acquired Distinction in Medicine

    PubMed Central

    2009-01-01

    This article illustrates in which sense genetic determinism is still part of the contemporary interactionist consensus in medicine. Three dimensions of this consensus are discussed: kinds of causes, a continuum of traits ranging from monogenetic diseases to car accidents, and different kinds of determination due to different norms of reaction. On this basis, this article explicates in which sense the interactionist consensus presupposes the innate–acquired distinction. After a descriptive Part 1, Part 2 reviews why the innate–acquired distinction is under attack in contemporary philosophy of biology. Three arguments are then presented to provide a limited and pragmatic defense of the distinction: an epistemic, a conceptual, and a historical argument. If interpreted in a certain manner, and if the pragmatic goals of prevention and treatment (ideally specifying what medicine and health care is all about) are taken into account, then the innate–acquired distinction can be a useful epistemic tool. It can help, first, to understand that genetic determination does not mean fatalism, and, second, to maintain a system of checks and balances in the continuing nature–nurture debates. PMID:20234831

  8. Genetic Determinism and the Innate-Acquired Distinction in Medicine.

    PubMed

    Kronfeldner, Maria E

    2009-06-01

    This article illustrates in which sense genetic determinism is still part of the contemporary interactionist consensus in medicine. Three dimensions of this consensus are discussed: kinds of causes, a continuum of traits ranging from monogenetic diseases to car accidents, and different kinds of determination due to different norms of reaction. On this basis, this article explicates in which sense the interactionist consensus presupposes the innate-acquired distinction. After a descriptive Part 1, Part 2 reviews why the innate-acquired distinction is under attack in contemporary philosophy of biology. Three arguments are then presented to provide a limited and pragmatic defense of the distinction: an epistemic, a conceptual, and a historical argument. If interpreted in a certain manner, and if the pragmatic goals of prevention and treatment (ideally specifying what medicine and health care is all about) are taken into account, then the innate-acquired distinction can be a useful epistemic tool. It can help, first, to understand that genetic determination does not mean fatalism, and, second, to maintain a system of checks and balances in the continuing nature-nurture debates.

  9. A Platelet Acquired Storage Pool Disorder Associated with Tamoxifen Therapy

    PubMed Central

    Nayak, Lalitha; Schmaier, Alvin H.

    2012-01-01

    The antiestrogenic drug tamoxifen, used in patients with breast cancer, is associated with an increase in arterial and venous thrombotic events, the mechanism of which is not clearly understood. We report a case of a lady who presented with new bruising and prolonged bleeding following a tooth extraction 4–6 weeks after starting tamoxifen. Investigations were consistent with an acquired platelet storage pool disorder. Repeat platelet function analysis was normal, performed 3 months after discontinuation of tamoxifen. We present a previously clinically unreported effect of tamoxifen on platelet function. PMID:23326738

  10. Genetic disorders of thyroid metabolism and brain development.

    PubMed

    Kurian, Manju A; Jungbluth, Heinz

    2014-07-01

    Normal thyroid metabolism is essential for human development, including the formation and functioning of the central and peripheral nervous system. Disorders of thyroid metabolism are increasingly recognized within the spectrum of paediatric neurological disorders. Both hypothyroid and hyperthyroid disease states (resulting from genetic and acquired aetiologies) can lead to characteristic neurological syndromes, with cognitive delay, extrapyramidal movement disorders, neuropsychiatric symptoms, and neuromuscular manifestations. In this review, the neurological manifestations of genetic disorders of thyroid metabolism are outlined, with particular focus on Allan-Herndon-Dudley syndrome and benign hereditary chorea. We report in detail the clinical features, major neurological and neuropsychiatric manifestations, molecular genetic findings, disease mechanisms, and therapeutic strategies for these emerging genetic 'brain-thyroid' disorders.

  11. Genetic disorders of thyroid metabolism and brain development

    PubMed Central

    Kurian, Manju A; Jungbluth, Heinz

    2014-01-01

    Normal thyroid metabolism is essential for human development, including the formation and functioning of the central and peripheral nervous system. Disorders of thyroid metabolism are increasingly recognized within the spectrum of paediatric neurological disorders. Both hypothyroid and hyperthyroid disease states (resulting from genetic and acquired aetiologies) can lead to characteristic neurological syndromes, with cognitive delay, extrapyramidal movement disorders, neuropsychiatric symptoms, and neuromuscular manifestations. In this review, the neurological manifestations of genetic disorders of thyroid metabolism are outlined, with particular focus on Allan-Herndon-Dudley syndrome and benign hereditary chorea. We report in detail the clinical features, major neurological and neuropsychiatric manifestations, molecular genetic findings, disease mechanisms, and therapeutic strategies for these emerging genetic ‘brain-thyroid’ disorders. PMID:24665922

  12. Drug induced phospholipidosis: an acquired lysosomal storage disorder.

    PubMed

    Shayman, James A; Abe, Akira

    2013-03-01

    There is a strong association between lysosome enzyme deficiencies and monogenic disorders resulting in lysosomal storage disease. Of the more than 75 characterized lysosomal proteins, two thirds are directly linked to inherited diseases of metabolism. Only one lysosomal storage disease, Niemann-Pick disease, is associated with impaired phospholipid metabolism. However, other phospholipases are found in the lysosome but remain poorly characterized. A recent exception is lysosomal phospholipase A2 (group XV phospholipase A2). Although no inherited disorder of lysosomal phospholipid metabolism has yet been associated with a loss of function of this lipase, this enzyme may be a target for an acquired form of lysosomal storage, drug induced phospholipidosis. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.

  13. Basics on Genes and Genetic Disorders

    MedlinePlus

    ... Healthy Breakfasts Shyness The Basics on Genes and Genetic Disorders KidsHealth > For Teens > The Basics on Genes ... repair" the gene change. previous continue What Are Genetic Disorders? Researchers have identified more than 4,000 ...

  14. Gene Therapy for Diseases and Genetic Disorders

    MedlinePlus

    ... notable advancements are the following: Gene Therapy for Genetic Disorders Severe Combined Immune Deficiency (ADA-SCID) ADA- ... in preclinical animal models of this disease. Other genetic disorders After many years of laboratory and preclinical ...

  15. Genetic engineering and therapy for inherited and acquired cardiomyopathies.

    PubMed

    Day, Sharlene; Davis, Jennifer; Westfall, Margaret; Metzger, Joseph

    2006-10-01

    The cardiac myofilaments consist of a highly ordered assembly of proteins that collectively generate force in a calcium-dependent manner. Defects in myofilament function and its regulation have been implicated in various forms of acquired and inherited human heart disease. For example, during cardiac ischemia, cardiac myocyte contractile performance is dramatically downregulated due in part to a reduced sensitivity of the myofilaments to calcium under acidic pH conditions. Over the last several years, the thin filament regulatory protein, troponin I, has been identified as an important mediator of this response. Mutations in troponin I and other sarcomere genes are also linked to several distinct inherited cardiomyopathic phenotypes, including hypertrophic, dilated, and restrictive cardiomyopathies. With the cardiac sarcomere emerging as a central player for such a diverse array of human heart diseases, genetic-based strategies that target the myofilament will likely have broad therapeutic potential. The development of safe vector systems for efficient gene delivery will be a critical hurdle to overcome before these types of therapies can be successfully applied. Nonetheless, studies focusing on the principles of acute genetic engineering of the sarcomere hold value as they lay the essential foundation on which to build potential gene-based therapies for heart disease.

  16. Genetic aspects of dental disorders.

    PubMed

    Townsend, G C; Aldred, M J; Bartold, P M

    1998-08-01

    This paper reviews past and present applications of quantitative and molecular genetics to dental disorders. Examples are given relating to craniofacial development (including malocclusion), oral supporting tissues (including periodontal diseases) and dental hard tissues (including defects of enamel and dentine as well as dental caries). Future developments and applications to clinical dentistry are discussed. Early investigations confirmed genetic bases to dental caries, periodontal diseases and malocclusion, but research findings have had little impact on clinical practice. The complex multifactorial aetiologies of these conditions, together with methodological problems, have limited progress until recently. Present studies are clarifying previously unrecognized genetic and phenotypic heterogeneities and attempting to unravel the complex interactions between genes and environment by applying new statistical modelling approaches to twin and family data. Linkage studies using highly polymorphic DNA markers are providing a means of locating candidate genes, including quantitative trait loci (QTL). In future, as knowledge increases; it should be possible to implement preventive strategies for those genetically-predisposed individuals who are identified to be at risk.

  17. Mouse models of neurological disorders--a comparison of heritable and acquired traits.

    PubMed

    Harper, Alex

    2010-10-01

    Human neurological disorders include a wide range of illnesses which have a disproportionately high prevalence in the increasingly populous geriatric community. Any research effort directed at discovering the aetiology of neurological disease is greatly enhanced with in vivo models of the disease of interest. Scientific research incorporating the use of mice has advanced rapidly in the last three decades. Relatively simple to breed, maintain and train, mice have many advantages over other species for use in research. More than a century of selective breeding has provided investigators with a rich gene pool and sub-strain diversity from which to choose for their research. Thus the dramatic increase in genetic screening and gene engineering that has occurred in research in recent decades has enabled the generation of a multitude of mouse models. This review discusses the relative utility of mouse models in which a heritable or non-heritable (acquired) manipulation has been used to model a specified trait of a human neurological disorder. The techniques used in deriving useful genetic alterations or modifications and in generating acquired mouse models are outlined with examples of each provided.

  18. Genetics of obsessive-compulsive disorder and related disorders.

    PubMed

    Browne, Heidi A; Gair, Shannon L; Scharf, Jeremiah M; Grice, Dorothy E

    2014-09-01

    Twin and family studies support a significant genetic contribution to obsessive-compulsive disorder (OCD) and related disorders, such as chronic tic disorders, trichotillomania, skin-picking disorder, body dysmorphic disorder, and hoarding disorder. Recently, population-based studies and novel laboratory-based methods have confirmed substantial heritability in OCD. Genome-wide association studies and candidate gene association studies have provided information on specific gene variations that may be involved in the pathobiology of OCD, though a substantial portion of the genetic risk architecture remains unknown.

  19. Genetics of hereditary neurological disorders in children.

    PubMed

    Huang, Yue; Yu, Sui; Wu, Zhanhe; Tang, Beisha

    2014-04-01

    Hereditary neurological disorders (HNDs) are relatively common in children compared to those occurring in adulthood. Recognising clinical manifestations of HNDs is important for the selection of genetic testing, genetic testing results interpretation, and genetic consultation. Meanwhile, advances in next generation sequencing (NGS) technologies have significantly enabled the discovery of genetic causes of HNDs and also challenge paediatricians on applying genetic investigation. Combination of both clinical information and advanced technologies will enhance the genetic test yields in clinical setting. This review summarises the clinical presentations as well as genetic causes of paediatric neurological disorders in four major areas including movement disorders, neuropsychiatric disorders, neuron peripheral disorders and epilepsy. The aim of this review is to help paediatric neurologists not only to see the clinical features but also the complex genetic aspect of HNDs in order to utilise genetic investigation confidently in their clinical practice. A smooth transition from research based to clinical use of comprehensive genetic testing in HNDs in children could be foreseen in the near future while genetic testing, genetic counselling and genetic data interpretation are in place appropriately.

  20. Genetics of hereditary neurological disorders in children

    PubMed Central

    Yu, Sui; Wu, Zhanhe; Tang, Beisha

    2014-01-01

    Hereditary neurological disorders (HNDs) are relatively common in children compared to those occurring in adulthood. Recognising clinical manifestations of HNDs is important for the selection of genetic testing, genetic testing results interpretation, and genetic consultation. Meanwhile, advances in next generation sequencing (NGS) technologies have significantly enabled the discovery of genetic causes of HNDs and also challenge paediatricians on applying genetic investigation. Combination of both clinical information and advanced technologies will enhance the genetic test yields in clinical setting. This review summarises the clinical presentations as well as genetic causes of paediatric neurological disorders in four major areas including movement disorders, neuropsychiatric disorders, neuron peripheral disorders and epilepsy. The aim of this review is to help paediatric neurologists not only to see the clinical features but also the complex genetic aspect of HNDs in order to utilise genetic investigation confidently in their clinical practice. A smooth transition from research based to clinical use of comprehensive genetic testing in HNDs in children could be foreseen in the near future while genetic testing, genetic counselling and genetic data interpretation are in place appropriately. PMID:26835329

  1. Genetic Relationships Between Schizophrenia, Bipolar Disorder, and Schizoaffective Disorder

    PubMed Central

    Cardno, Alastair G.

    2014-01-01

    There is substantial evidence for partial overlap of genetic influences on schizophrenia and bipolar disorder, with family, twin, and adoption studies showing a genetic correlation between the disorders of around 0.6. Results of genome-wide association studies are consistent with commonly occurring genetic risk variants, contributing to both the shared and nonshared aspects, while studies of large, rare chromosomal structural variants, particularly copy number variants, show a stronger influence on schizophrenia than bipolar disorder to date. Schizoaffective disorder has been less investigated but shows substantial familial overlap with both schizophrenia and bipolar disorder. A twin analysis is consistent with genetic influences on schizoaffective episodes being entirely shared with genetic influences on schizophrenic and manic episodes, while association studies suggest the possibility of some relatively specific genetic influences on broadly defined schizoaffective disorder, bipolar subtype. Further insights into genetic relationships between these disorders are expected as studies continue to increase in sample size and in technical and analytical sophistication, information on phenotypes beyond clinical diagnoses are increasingly incorporated, and approaches such as next-generation sequencing identify additional types of genetic risk variant. PMID:24567502

  2. Mental disorders and thwarted belongingness, perceived burdensomeness, and acquired capability for suicide.

    PubMed

    Silva, Caroline; Ribeiro, Jessica D; Joiner, Thomas E

    2015-03-30

    Nearly all mental disorders increase suicide risk; however, some better predict ideation versus attempts. The interpersonal theory of suicide provides a framework to understand these relationships, via the constructs of thwarted belongingness, perceived burdensomeness, and acquired capability. The current study examined the relationships between various mental disorders and theory constructs among 997 adult outpatients, controlling for sex and age. Disorders generally symptomatically associated with social withdrawal or potential liability to others (i.e., depressive and bipolar disorders, social phobia, borderline personality disorder, schizophrenia and other psychotic disorders, certain drug dependence) were uniquely positively associated with thwarted belongingness and perceived burdensomeness. Disorders associated with potential exposure to painful and provocative events (i.e., posttraumatic stress disorder, schizophrenia and other psychotic disorders, certain drug use) were associated with increased acquired capability. Notably, alcohol use disorders, attention-deficit/hyperactivity disorder subtypes, and panic/agoraphobia were negatively associated with thwarted belongingness or perceived burdensomeness; avoidant personality disorder, and certain anxiety disorders and drug use disorders, were associated with decreased acquired capability. Importantly, disorders associated with both thwarted belongingness and perceived burdensomeness may place individuals at greatest risk for suicide if acquired capability develops. Implications for comorbidity and suicide risk assessment and treatment are discussed.

  3. Risks of reproducing with a genetic disorder.

    PubMed

    Byler, Melissa Ciano; Lebel, Robert Roger

    2013-07-01

    Male-factor infertility is the cause of reproductive issues in many couples. For approximately 15% of these men, the origin of the infertility is genetic. These causes include both chromosomal and single-gene disorders frequently impacting spermatogenesis. By identifying the genetic mechanism behind the infertility, we determine the ability of the couple to use assisted reproduction technologies. Use of these methods has ignited a new spectrum of concerns for the genetic competence of the offspring. By knowing what specific genetic risks exist for the offspring of men with these particular disorders, we are able to use preimplantation genetic diagnosis to detect these problems.

  4. Genetic testing for paediatric neurological disorders.

    PubMed

    Valente, Enza Maria; Ferraris, Alessandro; Dallapiccola, Bruno

    2008-12-01

    Paediatric neurological disorders encompass a large group of clinically heterogeneous diseases, of which some are known to have a genetic cause. Over the past few years, advances in nosological classifications and in strategies for molecular testing have substantially improved the diagnosis, genetic counselling, and clinical management of many patients, and have facilitated the possibility of prenatal diagnoses for future pregnancies. However, the increasing availability of genetic tests for paediatric neurological disorders is raising important questions with regard to the appropriateness, choice of protocols, interpretation of results, and ethical and social concerns of these services. In this Review, we discuss these topics and how these concerns affect genetic counselling.

  5. Mechanisms of Non-Genetic Inheritance and Psychiatric Disorders

    PubMed Central

    Toth, Miklos

    2015-01-01

    Inheritance is typically associated with the Mendelian transmission of information from parents to offspring by alleles (DNA sequence). However, empirical data clearly suggest that traits can be acquired from ancestors by mechanisms that do not involve genetic alleles, referred to as non-genetic inheritance. Information that is non-genetically transmitted across generations includes parental experience and exposure to certain environments, but also parental mutations and polymorphisms, because they can change the parental ‘intrinsic' environment. Non-genetic inheritance is not limited to the first generation of the progeny, but can involve the grandchildren and even further generations. Non-genetic inheritance has been observed for multiple traits including overall development, cardiovascular risk and metabolic symptoms, but this review will focus on the inheritance of behavioral abnormalities pertinent to psychiatric disorders. Multigenerational non-genetic inheritance is often interpreted as the transmission of epigenetic marks, such as DNA methylation and chromatin modifications, via the gametes (transgenerational epigenetic inheritance). However, information can be carried across generations by a large number of bioactive substances, including hormones, cytokines, and even microorganisms, without the involvement of the gametes. We reason that this broader definition of non-genetic inheritance is more appropriate, especially in the context of psychiatric disorders, because of the well-recognized role of parental and early life environmental factors in later life psychopathology. Here we discuss the various forms of non-genetic inheritance in humans and animals, as well as rodent models of psychiatric conditions to illustrate possible mechanisms. PMID:24889369

  6. Mechanisms of non-genetic inheritance and psychiatric disorders.

    PubMed

    Toth, Miklos

    2015-01-01

    Inheritance is typically associated with the Mendelian transmission of information from parents to offspring by alleles (DNA sequence). However, empirical data clearly suggest that traits can be acquired from ancestors by mechanisms that do not involve genetic alleles, referred to as non-genetic inheritance. Information that is non-genetically transmitted across generations includes parental experience and exposure to certain environments, but also parental mutations and polymorphisms, because they can change the parental 'intrinsic' environment. Non-genetic inheritance is not limited to the first generation of the progeny, but can involve the grandchildren and even further generations. Non-genetic inheritance has been observed for multiple traits including overall development, cardiovascular risk and metabolic symptoms, but this review will focus on the inheritance of behavioral abnormalities pertinent to psychiatric disorders. Multigenerational non-genetic inheritance is often interpreted as the transmission of epigenetic marks, such as DNA methylation and chromatin modifications, via the gametes (transgenerational epigenetic inheritance). However, information can be carried across generations by a large number of bioactive substances, including hormones, cytokines, and even microorganisms, without the involvement of the gametes. We reason that this broader definition of non-genetic inheritance is more appropriate, especially in the context of psychiatric disorders, because of the well-recognized role of parental and early life environmental factors in later life psychopathology. Here we discuss the various forms of non-genetic inheritance in humans and animals, as well as rodent models of psychiatric conditions to illustrate possible mechanisms.

  7. Genetic Disorders: An Integrated Curriculum Project.

    ERIC Educational Resources Information Center

    Greenberg, Doug; Haynie, W. J., III

    2001-01-01

    This unit of study on genetic disorders takes an integrated approach to the study of biotechnology. Includes both technology education and science as well as links to health, social sciences, language arts, communication skills, and mathematics. (JOW)

  8. The genetic epidemiology of personality disorders

    PubMed Central

    Reichborn-Kjennerud, Ted

    2010-01-01

    Genetic epidemiologic studies indicate that all ten personality disorders (PDs) classified on the DSM-IV axis II are modestly to moderately heritable. Shared environmental and nonadditive genetic factors are of minor or no importance. No sex differences have been identified. Multivariate studies suggest that the extensive comorbidity between the PDs can be explained by three common genetic and environmental risk factors. The genetic factors do not reflect the DSM-IV cluster structure, but rather: i) broad vulnerability to PD pathology or negative emotionality; ii) high impulsivity/low agreeableness; and iii) introversion. Common genetic and environmental liability factors contribute to comorbidity between pairs or clusters of axis I and axis II disorders. Molecular genetic studies of PDs, mostly candidate gene association studies, indicate that genes linked to neurotransmitter pathways, especially in the serotonergic and dopaminergic systems, are involved. Future studies, using newer methods like genome-wide association, might take advantage of the use of endophenotypes. PMID:20373672

  9. The genetic epidemiology of personality disorders.

    PubMed

    Reichborn-Kjennerud, Ted

    2010-01-01

    Genetic epidemiologic studies indicate that all ten personality disorders (PDs) classified on the DSM-IV axis II are modestly to moderately heritable. Shared environmental and nonadditive genetic factors are of minor or no importance. No sex differences have been identified, Multivariate studies suggest that the extensive comorbidity between the PDs can be explained by three common genetic and environmental risk factors. The genetic factors do not reflect the DSM-IV cluster structure, but rather: i) broad vulnerability to PD pathology or negative emotionality; ii) high impulsivity/low agreeableness; and iii) introversion. Common genetic and environmental liability factors contribute to comorbidity between pairs or clusters of axis I and axis II disorders. Molecular genetic studies of PDs, mostly candidate gene association studies, indicate that genes linked to neurotransmitter pathways, especially in the serotonergic and dopaminergic systems, are involved. Future studies, using newer methods like genome-wide association, might take advantage of the use of endophenotypes.

  10. Metabolic, endocrine, and other genetic disorders.

    PubMed

    Dahmoush, Hisham M; Melhem, Elias R; Vossough, Arastoo

    2016-01-01

    Metabolic, endocrine, and genetic diseases of the brain include a very large array of disorders caused by a wide range of underlying abnormalities and involving a variety of brain structures. Often these disorders manifest as recognizable, though sometimes overlapping, patterns on neuroimaging studies that may enable a diagnosis based on imaging or may alternatively provide enough clues to direct further diagnostic evaluation. The diagnostic workup can include various biochemical laboratory or genetic studies. In this chapter, after a brief review of normal white-matter development, we will describe a variety of leukodystrophies resulting from metabolic disorders involving the brain, including mitochondrial and respiratory chain diseases. We will then describe various acidurias, urea cycle disorders, disorders related to copper and iron metabolism, and disorders of ganglioside and mucopolysaccharide metabolism. Lastly, various other hypomyelinating and dysmyelinating leukodystrophies, including vanishing white-matter disease, megalencephalic leukoencephalopathy with subcortical cysts, and oculocerebrorenal syndrome will be presented. In the following section on endocrine disorders, we will examine various disorders of the hypothalamic-pituitary axis, including developmental, inflammatory, and neoplastic diseases. Neonatal hypoglycemia will also be briefly reviewed. In the final section, we will review a few of the common genetic phakomatoses. Throughout the text, both imaging and brief clinical features of the various disorders will be discussed.

  11. Genetics of inherited primary arrhythmia disorders

    PubMed Central

    Spears, Danna A; Gollob, Michael H

    2015-01-01

    A sudden unexplained death is felt to be due to a primary arrhythmic disorder when no structural heart disease is found on autopsy, and there is no preceding documentation of heart disease. In these cases, death is presumed to be secondary to a lethal and potentially heritable abnormality of cardiac ion channel function. These channelopathies include congenital long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and short QT syndrome. In certain cases, genetic testing may have an important role in supporting a diagnosis of a primary arrhythmia disorder, and can also provide prognostic information, but by far the greatest strength of genetic testing lies in the screening of family members, who may be at risk. The purpose of this review is to describe the basic genetic and molecular pathophysiology of the primary inherited arrhythmia disorders, and to outline a rational approach to genetic testing, management, and family screening. PMID:26425105

  12. Genetic influences in common respiratory disorders.

    PubMed

    Workman, M Linda; Winkelman, Chris

    2008-06-01

    Respiratory disorders are common problems for adults and children in North America and generally represent the outcome of gene-environment interactions. Some problems are considered genetic in origin, such as cystic fibrosis, and others are considered environmental in origin, such as respiratory infections. Emerging information indicates that even genetic-based disorders are influenced by the environment and that environmental-based disorders are modified by personal genetic factors in individual physiologic responses. An understanding of an individual's personal risk factors for disease or health problem development can allow health care professionals to tailor health promotion strategies and treatment plans with appropriate environmental manipulation. This article explores the genetic influences that may affect the individual's physiologic responses and the consequences of environmental stimuli.

  13. Community acquired pneumonia: genetic variants influencing systemic inflammation.

    PubMed

    Ferrer Agüero, J M; Millán, S; Rodríguez de Castro, F; Martín-Loeches, I; Solé Violán, J

    2014-01-01

    The inflammatory response depends on several factors, including pathogenicity and duration of the stimulus, and also on the balance between inflammatory and antiinflammatory response. Several studies have presented evidence of the importance of genetic factors in severe infections. The innate immune response prevents the invasion and spread of pathogens during the first hours after infection. Each of the different processes involved in innate immunity may be affected by genetic polymorphisms, which can result in susceptibility or resistance to infection. The results obtained in the different studies do not irrefutably prove the role or function of a gene in the pathogenesis of respiratory infections. However, they can generate new hypotheses, suggest new candidate genes based on their role in the inflammatory response, and constitute a first step in understanding the underlying genetic factors.

  14. Human Genetic Disorders of Axon Guidance

    PubMed Central

    Engle, Elizabeth C.

    2010-01-01

    This article reviews symptoms and signs of aberrant axon connectivity in humans, and summarizes major human genetic disorders that result, or have been proposed to result, from defective axon guidance. These include corpus callosum agenesis, L1 syndrome, Joubert syndrome and related disorders, horizontal gaze palsy with progressive scoliosis, Kallmann syndrome, albinism, congenital fibrosis of the extraocular muscles type 1, Duane retraction syndrome, and pontine tegmental cap dysplasia. Genes mutated in these disorders can encode axon growth cone ligands and receptors, downstream signaling molecules, and axon transport motors, as well as proteins without currently recognized roles in axon guidance. Advances in neuroimaging and genetic techniques have the potential to rapidly expand this field, and it is feasible that axon guidance disorders will soon be recognized as a new and significant category of human neurodevelopmental disorders. PMID:20300212

  15. Endocrine disorders in Brazilian patients with acquired immune deficiency syndrome.

    PubMed

    Fontes, Rosita; Vangeloti, Andréa; Pires, Maria Lucia; Lima, Mário B C; Dimetz, Trude; Faulhaber, Marcelo; Faria, Raul; Meirelles, Ricardo M

    2003-01-01

    Acquired immunodeficiency syndrome (AIDS) was first reported in Brazil in 1980. In 1997, its incidence was 147 per million and then declined to 90 per million in 2000. Abnormalities of endocrine organ systems occur frequently in patients with AIDS. We evaluated mineralcorticoid, glucocorticoid, and thyroid hormone axes and glucose and insulin responses to a standardized oral glucose dose in healthy individuals; human immunodeficiency virus (HIV)-seropositive, asymptomatic individuals; HIV-infected patients with general lymphadenopathy, diarrhea, fever, fatigue, nocturnal sweating, and weight loss; and HIV-infected patients diagnosed with secondary infectious diseases or neoplasms. Baseline cortisol levels in the patients with AIDS were significantly higher than those in healthy control subjects. However, after adrenocorticotrophic hormone stimulation, cortisol levels were significantly lower in HIV-infected patients. Insulin concentrations were significantly higher after the glucose load in HIV-infected asymptomatic than in patients with AIDS. There were no significant differences in mineralocorticoid or thyroid function among groups.

  16. Genetic disorders of the vestibular system

    PubMed Central

    Eppsteiner, Robert W.; Smith, Richard J.H.

    2012-01-01

    Purpose of review This review highlights the current body of literature related to the genetics of inherited vestibular disorders and provides a framework for the characterization of these disorders. We emphasize peripheral causes of vestibular dysfunction and highlight recent advances in the field, point out gaps in understanding, and focus on key areas for future investigation. Recent findings The discovery of a modifier gene that leads to a more severe Usher syndrome phenotype calls into question the assumption that Usher syndrome is universally a monogenic disorder. Despite the use of several investigational approaches, the genetic basis of Menière’s disease remains poorly understood. Evidence for a vestibular phenotype associated with DFNB1 suggests that mutations in other genes causally related to nonsyndromic hearing loss also may have an unrecognized vestibular phenotype. Summary Our understanding of the genetic basis for vestibular disorders is superficial. Significant challenges include defining the genetics of inherited isolated vestibular dysfunction and understanding the pathological basis of Menière’s disease. However, improved characterization of inherited vestibular dysfunction, coupled with advanced genetic techniques such as targeted genome capture and massively parallel sequencing, provides an opportunity to investigate these diseases at the genetic level. PMID:21825995

  17. Molecular genetics of neuronal migration disorders.

    PubMed

    Liu, Judy S

    2011-04-01

    Cortical malformations associated with defects in neuronal migration result in severe developmental consequences including intractable epilepsy and intellectual disability. Genetic causes of migration defects have been identified with the advent and widespread use of high-resolution MRI and genetic techniques. Thus, the full phenotypic range of these genetic disorders is becoming apparent. Genes that cause lissencephaly, pachygyria, subcortical band heterotopia, and periventricular nodular heterotopias have been defined. Many of these genes are involved in cytoskeletal regulation including the function of microtubules (LIS1, TUBA1A,TUBB3, and DCX) and of actin (FilaminA). Thus, the molecular pathways regulating neuronal migration including the cytoskeletal pathways appear to be defined by human mutation syndromes. Basic science, including cell biology and animal models of these disorders, has informed our understanding of the pathogenesis of neuronal migration disorders and further progress depends on the continued integration of the clinical and basic sciences.

  18. Acquired Hemophilia A: A Frequently Overlooked Autoimmune Hemorrhagic Disorder

    PubMed Central

    Takeda, Tomohiro

    2014-01-01

    Acquired hemophilia A (AHA) is a rare hemorrhagic disease in which autoantibodies against coagulation factor VIII- (FVIII-) neutralizing antibodies (inhibitors) impair the intrinsic coagulation system. As the inhibitors developed in AHA are autoantibodies, the disease may have an autoimmune cause and is often associated with autoimmune disease. Although acute hemorrhage associated with AHA may be fatal and is costly to treat, AHA is often unrecognized or misdiagnosed. AHA should thus be considered in the differential diagnosis particularly in postpartum women and the elderly with bleeding tendency or prolonged activated partial thromboplastin time. Cross-mixing tests and measurement of FVIII-binding antibodies are useful to confirm AHA diagnosis. For treatment of acute hemorrhage, hemostatic therapy with bypassing agents should be provided. Unlike in congenital hemophilia A with inhibitors, in which immune tolerance induction therapy using repetitive infusions of high-dose FVIII concentrates is effective for inhibitor eradication, immune tolerance induction therapy has shown poor efficacy in treating AHA. Immunosuppressive treatment should thus be initiated to eradicate inhibitors as soon as the diagnosis of AHA is confirmed. PMID:24741588

  19. Acquired hemophilia A: a frequently overlooked autoimmune hemorrhagic disorder.

    PubMed

    Sakurai, Yoshihiko; Takeda, Tomohiro

    2014-01-01

    Acquired hemophilia A (AHA) is a rare hemorrhagic disease in which autoantibodies against coagulation factor VIII- (FVIII-) neutralizing antibodies (inhibitors) impair the intrinsic coagulation system. As the inhibitors developed in AHA are autoantibodies, the disease may have an autoimmune cause and is often associated with autoimmune disease. Although acute hemorrhage associated with AHA may be fatal and is costly to treat, AHA is often unrecognized or misdiagnosed. AHA should thus be considered in the differential diagnosis particularly in postpartum women and the elderly with bleeding tendency or prolonged activated partial thromboplastin time. Cross-mixing tests and measurement of FVIII-binding antibodies are useful to confirm AHA diagnosis. For treatment of acute hemorrhage, hemostatic therapy with bypassing agents should be provided. Unlike in congenital hemophilia A with inhibitors, in which immune tolerance induction therapy using repetitive infusions of high-dose FVIII concentrates is effective for inhibitor eradication, immune tolerance induction therapy has shown poor efficacy in treating AHA. Immunosuppressive treatment should thus be initiated to eradicate inhibitors as soon as the diagnosis of AHA is confirmed.

  20. Genetics of Huntington's disease and related disorders.

    PubMed

    Burgunder, Jean-Marc

    2014-07-01

    Huntington's disease is the most frequent form of the hereditary choreas and has a multifaceted phenotype including cognitive and psychiatric impairment. The disorder is due to a dynamic mutation, which also influences the onset age of the disorder. Other genetic modifiers of the HD phenotypes have been suggested but often not confirmed by independent studies. Several syndromes with similar presentation have different genetic backgrounds, including the neuroacanthocytoses, mainly choreoacanthocytosis and MacLeod syndrome as a result of mutations in chorein and Kell protein, respectively, but also benign hereditary chorea, owing to mutations in NKX-2-1, and paroxysmal kinesigenic dyskinesia, as a result of recently found mutations in the proline-rich transmembrane protein 2, PRRT2. Chorea can also be a major feature in other neurogenetic disorders, including the spinocerebellar ataxias and also in neurometabolic disorders.

  1. Fluency Disorders in Genetic Syndromes

    ERIC Educational Resources Information Center

    Van Borsel, John; Tetnowski, John A.

    2007-01-01

    The characteristics of various genetic syndromes have included "stuttering" as a primary symptom associated with that syndrome. Specifically, Down syndrome, fragile X syndrome, Prader-Willi syndrome, Tourette syndrome, Neurofibromatosis type I, and Turner syndrome all list "stuttering" as a characteristic of that syndrome. An extensive review of…

  2. Genetic Disorders in the Newborn Infant

    PubMed Central

    Meschino, Wendy S.; Summers, Anne M.

    1988-01-01

    Genetic disorders in the neonate should be suspected in a number of different clinical situations, ranging from that of an infant with dysmorphic features and multiple congenital malformations to that of a previously well newborn who becomes acutely ill. An approach for the primary-care physician to the initial investigation and management of these situations is outlined. In addition neonatal screening tests for metabolic disorders and congenital hypothyroidism are briefly discussed. PMID:21253098

  3. Genetically modified pig models for neurodegenerative disorders.

    PubMed

    Holm, Ida E; Alstrup, Aage Kristian Olsen; Luo, Yonglun

    2016-01-01

    Increasing incidence of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease has become one of the most challenging health issues in ageing humans. One approach to combat this is to generate genetically modified animal models of neurodegenerative disorders for studying pathogenesis, prognosis, diagnosis, treatment, and prevention. Owing to the genetic, anatomic, physiologic, pathologic, and neurologic similarities between pigs and humans, genetically modified pig models of neurodegenerative disorders have been attractive large animal models to bridge the gap of preclinical investigations between rodents and humans. In this review, we provide a neuroanatomical overview in pigs and summarize and discuss the generation of genetically modified pig models of neurodegenerative disorders including Alzheimer's diseases, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, and ataxia-telangiectasia. We also highlight how non-invasive bioimaging technologies such as positron emission tomography (PET), computer tomography (CT), and magnetic resonance imaging (MRI), and behavioural testing have been applied to characterize neurodegenerative pig models. We further propose a multiplex genome editing and preterm recloning (MAP) approach by using the rapid growth of the ground-breaking precision genome editing technology CRISPR/Cas9 and somatic cell nuclear transfer (SCNT). With this approach, we hope to shorten the temporal requirement in generating multiple transgenic pigs, increase the survival rate of founder pigs, and generate genetically modified pigs that will more closely resemble the disease-causing mutations and recapitulate pathological features of human conditions.

  4. Assessing acquired language disorders in adults via the Internet.

    PubMed

    Theodoros, Deborah; Hill, Anne; Russell, Trevor; Ward, Elizabeth; Wootton, Richard

    2008-08-01

    Aphasia, a language disturbance, frequently occurs following acquired brain impairment in adults. Because management of aphasia is often long-term, provision of ongoing and equitable access to treatment creates a significant challenge to speech-language pathologists (SLPs). This study aimed to determine the validity and reliability of assessing aphasia using standardized language assessments via an Internet-based videoconferencing system using a bandwidth of 128 kbits/sec. Thirty-two participants with aphasia due to stroke or traumatic brain injury were assessed simultaneously in either a face-to-face or online-led environment by two SLPs. Short forms of the Boston Diagnostic Aphasia Examination (BDAE-3) and the Boston Naming Test (BNT, 2nd edition) were administered. An eight-item participant satisfaction questionnaire was completed by 15 participants assigned to the online-led assessment. Results failed to identify any significant differences between the 24 subtest scores of the BDAE-3 and the BNT scores obtained in the online and face-to-face test environments (p > 0.01). Weighted kappa statistics indicated moderate to very good agreement (0.59-1.00) between the two assessors for the 24 subtests and eight rating scales of the BDAE-3, the BNT, and for aphasia diagnosis. Good to very good inter- and intra-rater reliability for the online assessment was found across the majority of assessment tasks. Participants reported high overall satisfaction, comfort level, and audio and visual quality in the online environment. This study supports the validity and reliability of delivering standardized assessments of aphasia online and provides a basis for ongoing development of telerehabilitation as an alternate mode of service delivery to persons with aphasia.

  5. Sphingolipids in Genetic and Acquired Forms of Chronic Kidney Diseases.

    PubMed

    Ueda, Norishi

    2017-01-12

    Sphingolipids (SLs) regulate apoptosis, proliferation, and stress response. SLs, including ceramide, glycosphingolipids (glucosylceramide, lactosylceramide, and gangliosides) and sphingosine-1-phosphate (S1P), play a role in the pathogenesis and progression of genetic (lysosomal storage disease, congenital nephrotic syndrome and polycystic kidney disease) and non-genetic forms of chronic kidney diseases (CKDs). SLs metabolism defects promote complications (cardiovascular events, etc.) via oxidant stress in CKDs. A balancing role of apoptotic SLs and anti-apoptotic S1P is crucial in the regulation of glomerular injury and complications associated with CKDs. Interaction between SLs, endothelial function and renin-angiotensin-aldosterone system (RAAS) plays an important role in the regulation of glomerular injury. SLs affect mitochondrial function that regulate the opening of mitochondrial permeability transition (MPT) pore, mitochondrial outer membrane permeability (MOMP), generation of reactive oxygen species (ROS), Bcl-2 family proteins, leading to cytochrome c release and caspase activation, leading to apoptosis, and regulate glomerular cell proliferation or renal fibrosis. Interaction between SLs, endothelial function and RAAS plays a role in the regulation of glomerular injury. This review article summarizes the current evidence supporting a role of SLs metabolism defects in the pathogenesis and progression of glomerular injury and discusses a role of mitochondria, including MPT pore, MOMP, ROS, Bcl-2 family proteins, interaction between SLs, endothelial function and RAAS, and SLs-induced downstream signaling events in CKDs. Crosstalk between these factors plays a role in the pathogenesis and progression of CKDs. Therapeutic strategy of targeting SLs metabolism defects for CKDs through modulation of the enzymes responsible for SLs metabolism defects are also discussed.

  6. Genetic assessment of safflower (Carthamus tinctorius L.) collection with microsatellite markers acquired via pyrosequencing method.

    PubMed

    Lee, Gi-An; Sung, Jung-Sook; Lee, Sok-Young; Chung, Jong-Wook; Yi, Jung-Yoon; Kim, Yeon-Gyu; Lee, Myung-Chul

    2014-01-01

    A genetic evaluation of safflower germplasm collections derived from different geographical regions and countries will provide useful information for sustainable conservation and the utilization of genetic diversity. However, the molecular marker information is limited for evaluation of genetic diversity of safflower germplasm. In this study, we acquired 509 putative genomic SSR markers for sufficient genome coverage using next-generation sequencing methods and characterized thirty polymorphic SSRs in safflower collection composed of 100 diverse accessions. The average allele number and expected heterozygosity were 2.8 and 0.386, respectively. Analysis of population structure and phylogeny based on thirty SSR profiles revealed genetic admixture between geographical regions contrary to genetic clustering. However, the accessions from Korea were genetically conserved in distinctive groups in contrast to other safflower gene pool. In conclusion, these new genomic SSRs will facilitate valuable studies to clarify genetic relationships as well as conduct population structure analyses, genetic map construction and association analysis for safflower.

  7. Genetic Variation in Cardiomyopathy and Cardiovascular Disorders.

    PubMed

    McNally, Elizabeth M; Puckelwartz, Megan J

    2015-01-01

    With the wider deployment of massively-parallel, next-generation sequencing, it is now possible to survey human genome data for research and clinical purposes. The reduced cost of producing short-read sequencing has now shifted the burden to data analysis. Analysis of genome sequencing remains challenged by the complexity of the human genome, including redundancy and the repetitive nature of genome elements and the large amount of variation in individual genomes. Public databases of human genome sequences greatly facilitate interpretation of common and rare genetic variation, although linking database sequence information to detailed clinical information is limited by privacy and practical issues. Genetic variation is a rich source of knowledge for cardiovascular disease because many, if not all, cardiovascular disorders are highly heritable. The role of rare genetic variation in predicting risk and complications of cardiovascular diseases has been well established for hypertrophic and dilated cardiomyopathy, where the number of genes that are linked to these disorders is growing. Bolstered by family data, where genetic variants segregate with disease, rare variation can be linked to specific genetic variation that offers profound diagnostic information. Understanding genetic variation in cardiomyopathy is likely to help stratify forms of heart failure and guide therapy. Ultimately, genetic variation may be amenable to gene correction and gene editing strategies.

  8. The Genetic Basis of Panic Disorder

    PubMed Central

    Na, Hae-Ran; Kang, Eun-Ho; Lee, Jae-Hon

    2011-01-01

    Panic disorder is one of the chronic and disabling anxiety disorders. There has been evidence for either genetic heterogeneity or complex inheritance, with environmental factor interactions and multiple single genes, in panic disorder's etiology. Linkage studies have implicated several chromosomal regions, but no research has replicated evidence for major genes involved in panic disorder. Researchers have suggested several neurotransmitter systems are related to panic disorder. However, to date no candidate gene association studies have established specific loci. Recently, researchers have emphasized genome-wide association studies. Results of two genome-wide association studies on panic disorder failed to show significant associations. Evidence exists for differences regarding gender and ethnicity in panic disorder. Increasing evidence suggests genes underlying panic disorder overlap, transcending current diagnostic boundaries. In addition, an anxious temperament and anxiety-related personality traits may represent intermediate phenotypes that predispose to panic disorder. Future research should focus on broad phenotypes, defined by comorbidity or intermediate phenotypes. Genome-wide association studies in large samples, studies of gene-gene and gene-environment interactions, and pharmacogenetic studies are needed. PMID:21655053

  9. Motives for Acquiring and Saving in Hoarding Disorder, OCD, and Community Controls

    PubMed Central

    Frost, Randy O.; Steketee, Gail; Tolin, David F.; Sinopoli, Nicole; Ruby, Dylan

    2015-01-01

    Hoarding Disorder (HD) was classified as a separate disorder in DSM-5 (APA, 2013). However, only recently has research on hoarding begun in earnest, and as of yet, very little research exists on the motivation to acquire and save the excessive volume of possessions seen in patients with this disorder. This investigation examined the frequency of four motives for acquiring and saving possessions that are often reported anecdotally by people with HD (information, emotional reasons, avoid waste, and aesthetic reasons). Comparisons in a sample of 443 participants indicated that those with HD reported higher frequencies of each of these four motives for acquiring and saving compared to OCD participants and community controls. The intention to avoid waste emerged as the most prominent motive in people with HD. Understanding waste avoidance may be key to better understanding and treating HD. PMID:25729641

  10. Suppose It Were a Genetic Disorder?

    ERIC Educational Resources Information Center

    Krugman, Richard D.

    1997-01-01

    This editorial contemplates some of the implications of the possibility that child abuse and neglect might be a genetic disorder by describing a 1996 study (Brown, et al.) that seemed to identify a nurturing gene in mice and described the symptoms of its absence. Parallels between mouse and human displays of non-nurturing behavior are discussed.…

  11. Genetic Testing for Autism Spectrum Disorders

    ERIC Educational Resources Information Center

    Bauer, Sarah C.; Msall, Michael E.

    2011-01-01

    Children with autism spectrum disorders (ASD) have unique developmental and behavioral phenotypes, and they have specific challenges with communication, social skills, and repetitive behaviors. At this time, no single etiology for ASD has been identified. However, evidence from family studies and linkage analyses suggests that genetic factors play…

  12. Molecular genetics of autism spectrum disorders.

    PubMed

    Shastry, Barkur S

    2003-01-01

    Autistic disorder belongs to a broad spectrum of pervasive developmental disorders. Autism is a clinically and genetically heterogeneous condition. It is characterized by impairment in a broad range of social interactions, communication, and repetitive patterns of behavior and interest. Although the exact etiology of the condition is not known, family and twin studies strongly support genetic factors in autism. Genome-wide scans suggest several susceptibility loci that may contain one or more predisposing genes. However, no such genes have been identified so far that predispose patients to autism. The condition is over 90% heritable, but the mode of inheritance is not clear. Moreover, it does not seem to be a single gene disorder. There is no cure for autism. Individualized structured education, family support services, and antipsychotic drugs are recommended. These may alleviate some behavioral problems. The identification of autism genes, an understanding of the neurobiology of the condition, and additional clinical studies may help to develop pharmacological interventions in the future.

  13. Mitochondrial disorders: clinical and genetic features.

    PubMed

    Simon, D K; Johns, D R

    1999-01-01

    Virtually all cells in humans depend on mitochondrial oxidative phosphorylation to generate energy, accounting for the remarkable diversity of clinical disorders associated with mitochondrial DNA mutations. However, certain tissues are particularly susceptible to mitochondrial dysfunction, resulting in recognizable clinical syndromes. Mitochondrial DNA mutations have been linked to seizures, strokes, optic atrophy, neuropathy, myopathy, cardiomyopathy, sensorineural hearing loss, diabetes mellitus, and other clinical features. Mitochondrial DNA mutations also may play an important role in aging, as well as in common age-related neurodegenerative disorders such as Parkinson's disease. Therefore, it is becoming increasingly important for clinicians to recognize the clinical syndromes suggestive of a mitochondrial disorder, and to understand the unique features of mitochondrial genetics that complicate diagnosis and genetic counseling.

  14. MR imaging of congenital/developmental and acquired disorders of the pediatric hip and pelvis.

    PubMed

    Dillon, Johanne E; Connolly, Susan A; Connolly, Leonard P; Kim, Young-Jo; Jaramillo, Diego

    2005-11-01

    This article reviews the MR imaging findings of some of the more common congenital and acquired disorders of the pediatric hip and pelvis,with the intent of increasing the awareness of radiologists and facilitating early and accurate diagnosis and treatment. The importance of MR imaging in the pediatric population is underscored by its ability to evaluate these disorders well and without the use of ionizing radiation.

  15. Developmental and genetic disorders in spermatogenesis.

    PubMed

    Diemer, T; Desjardins, C

    1999-01-01

    The most common cause of male infertility is idiopathic. Fresh insights based on genetic and molecular analysis of the human genome permit classification of formerly unexplained disorders in spermatogenesis. In this article, we review new procedures that expand diagnostic and therapeutic approaches to male infertility. Recombinant DNA technology makes it possible to detect specific chromosomal and/or genetic defects among infertile patients. The identification of genes linked to disorders in spermatogenesis and male sexual differentiation has increased exponentially in the past decade. Genetic defects leading to male factor infertility can now be explained at the molecular level, even though the germ cell profile of infertile patients is too variable to permit classification of the clinical phenotype. Increasing knowledge of genes that direct spermatogenesis provides important new information about the molecular and cellular events involved in human spermatogenesis. Molecular analysis of chromosomes and/or genes of infertile patients offers unique opportunities to uncover the aetiology of genetic disorders in spermatogenesis. Increasing numbers of cases, previously classified as idiopathic, can now be diagnosed to facilitate the treatment of infertile men. Advanced knowledge also poses ethical dilemmas, since children conceived with assisted reproductive technologies such as intracytoplasmic sperm injection (ICSI) are at risk for congenital abnormalities, unbalanced complements of chromosomes and male infertility.

  16. Study of the frequency of occurrence of genetic and acquired thrombophilia in infertile women prior IVF.

    PubMed

    Petukhova, N L; Tsaturova, K A; Vartanian, E V; Schigoleva, A V; Markin, A V

    2014-10-01

    This study of infertile women prior in vitro fertilization (IVF) is focused at the genetic and acquired thrombophilia before the IVF program, the identification of the frequency of occurrence of thrombophilia in them, the impact of thrombophilia of the offensive, the course and outcome of pregnancies, to improve the quality of cycles in terms of a pregnancy and childbirth. Forty-five women with infertility were examined. Thirty-two (71%) were identified thrombophilia: genetic thrombophilia in 32 cases (100%), among them a combination of several forms of genetic thrombophilia - 21 (63%) of them, other forms of thrombophilia (genetic and acquired) - in 5 of them (16%). In IVF 23 (72%) women became pregnant. In 87% of pregnancies ended in spontaneous birth, in 13% of cases of preterm birth.

  17. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder

    PubMed Central

    Frye, R E; Melnyk, S; MacFabe, D F

    2013-01-01

    Autism spectrum disorder (ASD) has been associated with mitochondrial disease (MD). Interestingly, most individuals with ASD and MD do not have a specific genetic mutation to explain the MD, raising the possibility of that MD may be acquired, at least in a subgroup of children with ASD. Acquired MD has been demonstrated in a rodent ASD model in which propionic acid (PPA), an enteric bacterial fermentation product of ASD-associated gut bacteria, is infused intracerebroventricularly. This animal model shows validity as it demonstrates many behavioral, metabolic, neuropathologic and neurophysiologic abnormalities associated with ASD. This animal model also demonstrates a unique pattern of elevations in short-chain and long-chain acyl-carnitines suggesting abnormalities in fatty-acid metabolism. To determine if the same pattern of biomarkers of abnormal fatty-acid metabolism are present in children with ASD, the laboratory results from a large cohort of children with ASD (n=213) who underwent screening for metabolic disorders, including mitochondrial and fatty-acid oxidation disorders, in a medically based autism clinic were reviewed. Acyl-carnitine panels were determined to be abnormal if three or more individual acyl-carnitine species were abnormal in the panel and these abnormalities were verified by repeated testing. Overall, 17% of individuals with ASD demonstrated consistently abnormal acyl-carnitine panels. Next, it was determined if specific acyl-carnitine species were consistently elevated across the individuals with consistently abnormal acyl-carnitine panels. Significant elevations in short-chain and long-chain, but not medium-chain, acyl-carnitines were found in the ASD individuals with consistently abnormal acyl-carnitine panels—a pattern consistent with the PPA rodent ASD model. Examination of electron transport chain function in muscle and fibroblast culture, histological and electron microscopy examination of muscle and other biomarkers of

  18. Mouse Genetic Models of Human Brain Disorders

    PubMed Central

    Leung, Celeste; Jia, Zhengping

    2016-01-01

    Over the past three decades, genetic manipulations in mice have been used in neuroscience as a major approach to investigate the in vivo function of genes and their alterations. In particular, gene targeting techniques using embryonic stem cells have revolutionized the field of mammalian genetics and have been at the forefront in the generation of numerous mouse models of human brain disorders. In this review, we will first examine childhood developmental disorders such as autism, intellectual disability, Fragile X syndrome, and Williams-Beuren syndrome. We will then explore psychiatric disorders such as schizophrenia and lastly, neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease. We will outline the creation of these mouse models that range from single gene deletions, subtle point mutations to multi-gene manipulations, and discuss the key behavioral phenotypes of these mice. Ultimately, the analysis of the models outlined in this review will enhance our understanding of the in vivo role and underlying mechanisms of disease-related genes in both normal brain function and brain disorders, and provide potential therapeutic targets and strategies to prevent and treat these diseases. PMID:27047540

  19. The Relationship between Body Dysmorphic Disorder Behaviors and the Acquired Capability for Suicide

    ERIC Educational Resources Information Center

    Witte, Tracy K.; Didie, Elizabeth R.; Menard, William; Phillips, Katharine A.

    2012-01-01

    In a sample of 200 individuals diagnosed with body dysmorphic disorder (BDD), we utilized the interpersonal-psychological theory for suicide as a framework to examine BDD behaviors that might be associated with suicide risk, insofar as they might increase the acquired capability for suicide. We predicted that physically painful BDD behaviors…

  20. Genetics of Sleep and Sleep disorders

    PubMed Central

    Sehgal, Amita; Mignot, Emmanuel

    2011-01-01

    Sleep remains one of the least understood phenomena in biology – even its role in synaptic plasticity remains debatable. Since sleep was recognized to be regulated genetically, intense research has launched on two fronts: the development of model organisms for deciphering the molecular mechanisms of sleep and attempts to identify genetic underpinnings of human sleep disorders. In this Review, we describe how unbiased, high-throughput screens in model organisms are uncovering sleep regulatory mechanisms and how pathways, such as the circadian clock network and specific neurotransmitter signals, have conserved effects on sleep from Drosophila to humans. At the same time, genome-wide association (GWA) studies have uncovered ~14 loci increasing susceptibility to sleep disorders, such as narcolepsy and restless leg syndrome. To conclude, we discuss how these different strategies will be critical to unambiguously defining the function of sleep. PMID:21784243

  1. Advances in gene technology: Human genetic disorders

    SciTech Connect

    Scott, W.A.; Ahmad, F.; Black, S.; Schultz, J.; Whelan, W.J.

    1984-01-01

    This book discusses the papers presented at the conference on the subject of ''advances in Gene technology: Human genetic disorders''. Molecular biology of various carcinomas and inheritance of metabolic diseases is discussed and technology advancement in diagnosis of hereditary diseases is described. Some of the titles discussed are-Immunoglobulin genes translocation and diagnosis; hemophilia; oncogenes; oncogenic transformations; experimental data on mice, hamsters, birds carcinomas and sarcomas.

  2. Genetics and Epigenetics of Eating Disorders.

    PubMed

    Yilmaz, Zeynep; Hardaway, J Andrew; Bulik, Cynthia M

    Eating disorders (EDs) are serious psychiatric conditions influenced by biological, psychological, and sociocultural factors. A better understanding of the genetics of these complex traits and the development of more sophisticated molecular biology tools have advanced our understanding of the etiology of EDs. The aim of this review is to critically evaluate the literature on the genetic research conducted on three major EDs: anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). We will first review the diagnostic criteria, clinical features, prevalence, and prognosis of AN, BN, and BED, followed by a review of family, twin, and adoption studies. We then review the history of genetic studies of EDs covering linkage analysis, candidate gene association studies, genome-wide association studies, and the study of rare variants in EDs. Our review also incorporates a translational perspective by covering animal models of ED-related phenotypes. Finally, we review the nascent field of epigenetics of EDs and a look forward to future directions for ED genetic research.

  3. Genetics and Epigenetics of Eating Disorders

    PubMed Central

    Yilmaz, Zeynep; Hardaway, J. Andrew; Bulik, Cynthia M.

    2015-01-01

    Eating disorders (EDs) are serious psychiatric conditions influenced by biological, psychological, and sociocultural factors. A better understanding of the genetics of these complex traits and the development of more sophisticated molecular biology tools have advanced our understanding of the etiology of EDs. The aim of this review is to critically evaluate the literature on the genetic research conducted on three major EDs: anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). We will first review the diagnostic criteria, clinical features, prevalence, and prognosis of AN, BN, and BED, followed by a review of family, twin, and adoption studies. We then review the history of genetic studies of EDs covering linkage analysis, candidate gene association studies, genome-wide association studies, and the study of rare variants in EDs. Our review also incorporates a translational perspective by covering animal models of ED-related phenotypes. Finally, we review the nascent field of epigenetics of EDs and a look forward to future directions for ED genetic research. PMID:27013903

  4. Genetic variants of ghrelin in metabolic disorders.

    PubMed

    Ukkola, Olavi

    2011-11-01

    An increasing understanding of the role of genes in the development of obesity may reveal genetic variants that, in combination with conventional risk factors, may help to predict an individual's risk for developing metabolic disorders. Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis and it is a reasonable candidate gene for obesity-related co-morbidities. In cross-sectional studies low total ghrelin concentrations and some genetic polymorphisms of ghrelin have been associated with obesity-associated diseases. The present review highlights many of the important problems in association studies of genetic variants and complex diseases. It is known that population-specific differences in reported associations exist. We therefore conclude that more studies on variants of ghrelin gene are needed to perform in different populations to get deeper understanding on the relationship of ghrelin gene and its variants to obesity.

  5. In Vivo NMR Studies of the Brain with Hereditary or Acquired Metabolic Disorders.

    PubMed

    Sherry, Erica B; Lee, Phil; Choi, In-Young

    2015-12-01

    Metabolic disorders, whether hereditary or acquired, affect the brain, and abnormalities of the brain are related to cellular integrity; particularly in regard to neurons and astrocytes as well as interactions between them. Metabolic disturbances lead to alterations in cellular function as well as microscopic and macroscopic structural changes in the brain with diabetes, the most typical example of metabolic disorders, and a number of hereditary metabolic disorders. Alternatively, cellular dysfunction and degeneration of the brain lead to metabolic disturbances in hereditary neurological disorders with neurodegeneration. Nuclear magnetic resonance (NMR) techniques allow us to assess a range of pathophysiological changes of the brain in vivo. For example, magnetic resonance spectroscopy detects alterations in brain metabolism and energetics. Physiological magnetic resonance imaging (MRI) detects accompanying changes in cerebral blood flow related to neurovascular coupling. Diffusion and T1/T2-weighted MRI detect microscopic and macroscopic changes of the brain structure. This review summarizes current NMR findings of functional, physiological and biochemical alterations within a number of hereditary and acquired metabolic disorders in both animal models and humans. The global view of the impact of these metabolic disorders on the brain may be useful in identifying the unique and/or general patterns of abnormalities in the living brain related to the pathophysiology of the diseases, and identifying future fields of inquiry.

  6. Teaching molecular genetics: chapter 4-positional cloning of genetic disorders.

    PubMed

    Puliti, Aldamaria; Caridi, Gianluca; Ravazzolo, Roberto; Ghiggeri, Gian Marco

    2007-12-01

    Positional cloning is the approach of choice for the identification of genetic mutations underlying the pathological development of diseases with simple Mendelian inheritance. It consists of different consecutive steps, starting with recruitment of patients and DNA collection, that are critical to the overall process. A genetic analysis of the enrolled patients and their families is performed, based on genetic recombination frequencies generated by meiotic cross-overs and on genome-wide molecular studies, to define a critical DNA region of interest. This analysis culminates in a statistical estimate of the probability that disease features may segregate in the families independently or in association with specific molecular markers located in known regions. In this latter case, a marker can be defined as being linked to the disease manifestations. The genetic markers define an interval that is a function of their recombination frequencies with the disease, in which the disease gene is localised. The identification and characterisation of chromosome abnormalities as translocations, deletions and duplications by classical cytogenetic methods or by the newly developed microarray-based comparative genomic hybridisation (array CGH) technique may define extensions and borders of the genomic regions involved. The step following the definition of a critical genomic region is the identification of candidate genes that is based on the analysis of available databases from genome browsers. Positional cloning culminates in the identification of the causative gene mutation, and the definition of its functional role in the pathogenesis of the disorder, by the use of cell-based or animal-based experiments. More often, positional cloning ends with the generation of mice with homologous mutations reproducing the human clinical phenotype. Altogether, positional cloning has represented a fundamental step in the research on genetic renal disorders, leading to the definition of several

  7. Genetics of Recurrent Vertigo and Vestibular Disorders

    PubMed Central

    Gazquez, Irene; Lopez-Escamez, Jose A

    2011-01-01

    We present recent advances in the genetics of recurrent vertigo, including familial episodic ataxias, migraneous vertigo, bilateral vestibular hypofunction and Meniere’s disease. Although several vestibular disorders are more common within families, the genetics of vestibulopathies is largely not known. Genetic loci and clinical features of familial episodic ataxias have been defined in linkage disequilibrium studies with mutations in neuronal genes KCNA1 and CACNA1A. Migrainous vertigo is a clinical disorder with a high comorbidity within families much more common in females with overlapping features with episodic ataxia and migraine. Bilateral vestibular hypofunction is a heterogeneous clinical group defined by episodes of vertigo leading to progressive loss of vestibular function which also can include migraine. Meniere’s disease is a clinical syndrome characterized by spontaneous episodes of recurrent vertigo, sensorineural hearing loss, tinnitus and aural fullness and familial Meniere’s disease in around 10-20% of cases. An international collaborative effort to define the clinical phenotype and recruiting patients with migrainous vertigo and Meniere’s disease is ongoing for genome-wide association studies. PMID:22379397

  8. Crouzon's Syndrome: A Rare Genetic Disorder.

    PubMed

    Kaushik, Anupriya; Bhatia, Hindpal; Sharma, Naresh

    2016-01-01

    Crouzon's syndrome, also known as brachial arch syndrome, is an autosomal dominant disorder with complete penetrance and variable expressivity. Described by a French neurosurgeon in 1912, it is a rare genetic disorder. Crouzon's syndrome is caused by mutation in the fibroblast growth factor receptor 2 (FGFR2) gene. Normally, the sutures in the human skull fuse after the complete growth of the brain, but if any of these sutures close early, then it may interfere with the growth of the brain. The disease is characterized by craniosynostosis, with associated dentofacial anomalies. This report describes the different clinical features in a 10-year-old male patient, with particular reference to characteristic findings of this syndrome.

  9. Genetic basis of human circadian rhythm disorders.

    PubMed

    Jones, Christopher R; Huang, Angela L; Ptáček, Louis J; Fu, Ying-Hui

    2013-05-01

    Circadian rhythm disorders constitute a group of phenotypes that usually present as altered sleep-wake schedules. Until a human genetics approach was applied to investigate these traits, the genetic components regulating human circadian rhythm and sleep behaviors remained mysterious. Steady advances in the last decade have dramatically improved our understanding of the genes involved in circadian rhythmicity and sleep regulation. Finding these genes presents new opportunities to use a wide range of approaches, including in vitro molecular studies and in vivo animal modeling, to elevate our understanding of how sleep and circadian rhythms are regulated and maintained. Ultimately, this knowledge will reveal how circadian and sleep disruption contribute to various ailments and shed light on how best to maintain and recover good health.

  10. An Overview of Mutation Detection Methods in Genetic Disorders

    PubMed Central

    Mahdieh, Nejat; Rabbani, Bahareh

    2013-01-01

    Genetic disorders are traditionally categorized into three main groups: single-gene, chromosomal, and multifactorial disorders. Single gene or Mendelian disorders result from errors in DNA sequence of a gene and include autosomal dominant (AD), autosomal recessive (AR), X-linked recessive (XR), X-linked dominant and Y-linked (holandric) disorders. Chromosomal disorders are due to chromosomal aberrations including numerical and structural damages. Molecular and cytogenetic techniques have been applied to identify genetic mutations leading to diseases. Accurate diagnosis of diseases is essential for appropriate treatment of patients, genetic counseling and prevention strategies. Characteristic features of patterns of inheritance are briefly reviewed and a short description of chromosomal disorders is also presented. In addition, applications of cytogenetic and molecular techniques and different types of mutations are discussed for genetic diagnosis of the pediatric genetic diseases. The purpose is to make pediatricians familiar with the applications of cytogenetic and molecular techniques and tools used for genetic diagnosis. PMID:24427490

  11. The genetic basis of addictive disorders.

    PubMed

    Ducci, Francesca; Goldman, David

    2012-06-01

    Addictions are common, chronic, and relapsing diseases that develop through a multistep process. The impact of addictions on morbidity and mortality is high worldwide. Twin studies have shown that the heritability of addictions ranges from 0.39 (hallucinogens) to 0.72 (cocaine). Twin studies indicate that genes influence each stage from initiation to addiction, although the genetic determinants may differ. Addictions are by definition the result of gene × environment interaction. These disorders, which are in part volitional, in part inborn, and in part determined by environmental experience, pose the full range of medical, genetic, policy, and moral challenges. Gene discovery is being facilitated by a variety of powerful approaches, but is in its infancy. It is not surprising that the genes discovered so far act in a variety of ways: via altered metabolism of drug (the alcohol and nicotine metabolic gene variants), via altered function of a drug receptor (the nicotinic receptor, which may alter affinity for nicotine but as discussed may also alter circuitry of reward), and via general mechanisms of addiction (genes such as monoamine oxidase A and the serotonin transporter that modulate stress response, emotion, and behavioral control). Addiction medicine today benefits from genetic studies that buttress the case for a neurobiologic origin of addictive behavior, and some general information on familially transmitted propensity that can be used to guide prevention. A few well-validated, specific predictors such as OPRM1, ADH1B, ALDH2, CHRNA5, and CYP26 have been identified and can provide some specific guidance, for example, to understand alcohol-related flushing and upper GI cancer risk (ADH1B and AKLDH2), variation in nicotine metabolism (CYP26), and, potentially, naltrexone treatment response (OPRM1). However, the genetic predictors available are few in number and account for only a small portion of the genetic variance in liability, and have not been integrated

  12. Medical genetics: 3. An approach to the adult with a genetic disorder

    PubMed Central

    Gilchrist, Dawna M.

    2002-01-01

    Abstract MANY GENETIC DISORDERS DO NOT MANIFEST themselves until the adult years. Such disorders often involve multiple genetic factors interacting with multiple environmental factors, over time, to produce a phenotype. This paper reviews the modes of inheritance of genetic disorders and describes the types of genetic testing that are currently available. It offers clues that should lead physicians to suspect that an adult patient might have a genetic disorder and raises issues that should be considered in counselling the patient about genetic testing. Resources for patients and their family physicians are also discussed. PMID:12403743

  13. Periodontal disease associated to systemic genetic disorders.

    PubMed

    Nualart Grollmus, Zacy Carola; Morales Chávez, Mariana Carolina; Silvestre Donat, Francisco Javier

    2007-05-01

    A number of systemic disorders increase patient susceptibility to periodontal disease, which moreover evolves more rapidly and more aggressively. The underlying factors are mainly related to alterations in immune, endocrine and connective tissue status. These alterations are associated with different pathologies and syndromes that generate periodontal disease either as a primary manifestation or by aggravating a pre-existing condition attributable to local factors. This is where the role of bacterial plaque is subject to debate. In the presence of qualitative or quantitative cellular immune alterations, periodontal disease may manifest early on a severe localized or generalized basis--in some cases related to the presence of plaque and/or specific bacteria (severe congenital neutropenia or infantile genetic agranulocytosis, Chediak-Higiashi syndrome, Down syndrome and Papillon-Lefévre syndrome). In the presence of humoral immune alterations, periodontal damage may result indirectly as a consequence of alterations in other systems. In connective tissue disorders, bacterial plaque and alterations of the periodontal tissues increase patient susceptibility to gingival inflammation and alveolar resorption (Marfan syndrome and Ehler-Danlos syndrome). The management of periodontal disease focuses on the control of infection and bacterial plaque by means of mechanical and chemical methods. Periodontal surgery and even extraction of the most seriously affected teeth have also been suggested. There are variable degrees of consensus regarding the background systemic disorder, as in the case of Chediak-Higiashi syndrome, where antibiotic treatment proves ineffective; in severe congenital neutropenia or infantile genetic agranulocytosis, where antibiotic prophylaxis is suggested; and in Papillon-Lefévre syndrome, where an established treatment protocol is available.

  14. Shared Genetic Effects Between Age at Menarche and Disordered Eating

    PubMed Central

    Baker, Jessica H.; Thornton, Laura M.; Bulik, Cynthia M.; Kendler, Kenneth S.; Lichtenstein, Paul

    2012-01-01

    Purpose An early age at menarche is associated with disordered eating in women. However, it is unclear whether they share genetic factors. The goal of the current study is to delineate the genetic correlation between age at menarche and disordered eating. Methods Participants included 427 monozygotic and 329 dizygotic 16-17 year-old female twins from the Swedish Twin Study of Child and Adolescent Development. Disordered eating was assessed with the Eating Disorder Inventory-2. Age at menarche was assessed via self-report. A bivariate correlated factors model was used to delineate the genetic correlation between age at menarche and disordered eating. Results The analysis revealed a negative genetic correlation of −.18 in the best-fit model indicating that the genetic factors that influence younger age at menarche are associated with increased liability for disordered eating. Conclusion Future research should examine possible causes for this correlation such as the estrogen system and gene-environment interactions. PMID:23084171

  15. [Genetics applied to clinical practice in neurodevelopmental disorders].

    PubMed

    Fernández-Jaén, Alberto; Cigudosa, Juan C; Martín Fernández-Mayoralas, Daniel; Suela, Javier; Fernández-Perrone, Ana L; Calleja-Pérez, Beatriz; López-Martín, Sara

    2014-02-24

    The medical literature contains a wide body of evidence supporting genetic involvement in neurodevelopmental disorders. Advances made in genetics and technology have increased the diagnostic cost-effectiveness of current studies from 3-5% to 30-40% in patients with intellectual disability or autism spectrum disorders. In this regard, chromosomal microarray studies display greater diagnostic power than conventional techniques (karyotype, subtelomeric analyses, etc.). The latest protocols in the biomedical field of the genetic study of these disorders cite chromosomal microarrays as the first-line analysis, while also recommending other specific studies depending on the patient's clinical features (fragile X syndrome, PTEN mutation, etc.). In the evaluation of other neurodevelopmental disorders (attention deficit hyperactivity disorder, learning disorders, etc.), the number of genetic tests carried out is limited and conditioned by the clinical characteristics or the patient's familial or personal history. Even in these situations, there are no genetic referral or evaluation protocols.

  16. Comprehensive Neurocognitive Endophenotyping Strategies for Mouse Models of Genetic Disorders

    PubMed Central

    Hunsaker, Michael R.

    2012-01-01

    There is a need for refinement of the current behavioral phenotyping methods for mouse models of genetic disorders. The current approach is to perform a behavioral screen using standardized tasks to define a broad phenotype of the model. This phenotype is then compared to what is known concerning the disorder being modeled. The weakness inherent in this approach is twofold: First, the tasks that make up these standard behavioral screens do not model specific behaviors associated with a given genetic mutation but rather phenotypes affected in various genetic disorders; secondly, these behavioral tasks are insufficiently sensitive to identify subtle phenotypes. An alternate phenotyping strategy is to determine the core behavioral phenotypes of the genetic disorder being studied and develop behavioral tasks to evaluate specific hypotheses concerning the behavioral consequences of the genetic mutation. This approach emphasizes direct comparisons between the mouse and human that facilitate the development of neurobehavioral biomarkers or quantitative outcome measures for studies of genetic disorders across species. PMID:22266125

  17. Iron-overload injury and cardiomyopathy in acquired and genetic models is attenuated by resveratrol therapy.

    PubMed

    Das, Subhash K; Wang, Wang; Zhabyeyev, Pavel; Basu, Ratnadeep; McLean, Brent; Fan, Dong; Parajuli, Nirmal; DesAulniers, Jessica; Patel, Vaibhav B; Hajjar, Roger J; Dyck, Jason R B; Kassiri, Zamaneh; Oudit, Gavin Y

    2015-12-07

    Iron-overload cardiomyopathy is a prevalent cause of heart failure on a world-wide basis and is a major cause of mortality and morbidity in patients with secondary iron-overload and genetic hemochromatosis. We investigated the therapeutic effects of resveratrol in acquired and genetic models of iron-overload cardiomyopathy. Murine iron-overload models showed cardiac iron-overload, increased oxidative stress, altered Ca(2+) homeostasis and myocardial fibrosis resulting in heart disease. Iron-overload increased nuclear and acetylated levels of FOXO1 with corresponding inverse changes in SIRT1 levels in the heart corrected by resveratrol therapy. Resveratrol, reduced the pathological remodeling and improved cardiac function in murine models of acquired and genetic iron-overload at varying stages of iron-overload. Echocardiography and hemodynamic analysis revealed a complete normalization of iron-overload mediated diastolic and systolic dysfunction in response to resveratrol therapy. Myocardial SERCA2a levels were reduced in iron-overloaded hearts and resveratrol therapy restored SERCA2a levels and corrected altered Ca(2+) homeostasis. Iron-mediated pro-oxidant and pro-fibrotic effects in human and murine cardiomyocytes and cardiofibroblasts were suppressed by resveratrol which correlated with reduction in iron-induced myocardial oxidative stress and myocardial fibrosis. Resveratrol represents a clinically and economically feasible therapeutic intervention to reduce the global burden from iron-overload cardiomyopathy at early and chronic stages of iron-overload.

  18. Posttraumatic Stress Disorder Symptom Clusters and Acquired Capability for Suicide: A Reexamination Using DSM-5 Criteria.

    PubMed

    Spitzer, Elizabeth G; Zuromski, Kelly L; Davis, Margaret T; Witte, Tracy K; Weathers, Frank

    2017-03-06

    This study used the interpersonal-psychological theory of suicide to explore the relationships among DSM-5 posttraumatic stress disorder (PTSD) symptom clusters derived from the six-factor anhedonia model and facets of acquired capability for suicide (ACS). In a sample of 373 trauma-exposed undergraduates, most PTSD symptom clusters were negatively associated with facets of ACS in bivariate correlations, but the anhedonia cluster was positively associated with ACS in regression models. Structure coefficients and commonality analysis indicated that anhedonia served as a suppressor variable for the other symptom clusters. Our findings further elucidate the complex relationship between specific PTSD symptom clusters and ACS.

  19. Genetic disorders coupled to ROS deficiency

    PubMed Central

    O’Neill, Sharon; Brault, Julie; Stasia, Marie-Jose; Knaus, Ulla G.

    2015-01-01

    Maintaining the redox balance between generation and elimination of reactive oxygen species (ROS) is critical for health. Disturbances such as continuously elevated ROS levels will result in oxidative stress and development of disease, but likewise, insufficient ROS production will be detrimental to health. Reduced or even complete loss of ROS generation originates mainly from inactivating variants in genes encoding for NADPH oxidase complexes. In particular, deficiency in phagocyte Nox2 oxidase function due to genetic variants (CYBB, CYBA, NCF1, NCF2, NCF4) has been recognized as a direct cause of chronic granulomatous disease (CGD), an inherited immune disorder. More recently, additional diseases have been linked to functionally altered variants in genes encoding for other NADPH oxidases, such as for DUOX2/DUOXA2 in congenital hypothyroidism, or for the Nox2 complex, NOX1 and DUOX2 as risk factors for inflammatory bowel disease. A comprehensive overview of novel developments in terms of Nox/Duox-deficiency disorders is presented, combined with insights gained from structure–function studies that will aid in predicting functional defects of clinical variants. PMID:26210446

  20. Atypical benign partial epilepsy of childhood with acquired neurocognitive, lexical semantic, and autistic spectrum disorder.

    PubMed

    Allen, Nicholas M; Conroy, Judith; Deonna, Thierry; McCreary, Dara; McGettigan, Paul; Madigan, Cathy; Carter, Imogen; Ennis, Sean; Lynch, Sally A; Shahwan, Amre; King, Mary D

    2016-01-01

    Atypical benign partial epilepsy (ABPE) of childhood or pseudo-Lennox syndrome is a form of idiopathic focal epilepsy characterized by multiple seizure types, focal and/or generalized epileptiform discharges, continuous spike-wave during sleep (CSWS), and sometimes reversible neurocognitive deficits. There are few reported cases of ABPE describing detailed correlative longitudinal follow-up of the various associated neurocognitive, language, social communicative, or motor deficits, in parallel with the epilepsy. Furthermore, the molecular inheritance pattern for ABPE and the wider spectrum of epilepsy aphasia disorders have yet to be fully elucidated. We describe the phenotype-genotype study of a boy with ABPE with follow-up from ages 5 to 13 years showing acquired oromotor and, later, a specific lexical semantic and pervasive developmental disorder. Exome sequencing identified variants in SCN9A, CPA6, and SCNM1. A direct role of the epilepsy in the pathogenesis of the oromotor and neurocognitive deficits is apparent.

  1. Genetic basis of clinical catecholamine disorders

    NASA Technical Reports Server (NTRS)

    Garland, Emily M.; Hahn, Maureen K.; Ketch, Terry P.; Keller, Nancy R.; Kim, Chun-Hyung; Kim, Kwang-Soo; Biaggioni, Italo; Shannon, John R.; Blakely, Randy D.; Robertson, David

    2002-01-01

    Norepinephrine and epinephrine are critical determinants of minute-to-minute regulation of blood pressure. Here we review the characterization of two syndromes associated with a genetic abnormality in the noradrenergic pathway. In 1986, we reported a congenital syndrome of undetectable tissue and circulating levels of norepinephrine and epinephrine, elevated levels of dopamine, and absence of dopamine-beta-hydroxylase (DBH). These patients appeared with ptosis and severe orthostatic hypotension and lacked sympathetic noradrenergic function. In two persons with DBH deficiency, we identified seven novel polymorphisms. Both patients are compound heterozygotes for a variant that affects expression of DBH protein via impairment of splicing. Patient 1 also has a missense mutation in DBH exon 2, and patient 2 carries missense mutations in exons 1 and 6. Orthostatic intolerance is a common syndrome affecting young women, presenting with orthostatic tachycardia and symptoms of cerebral hypoperfusion on standing. We tested the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to its etiology. In our proband, we found an elevated plasma norepinephrine with standing that was disproportionate to the increase in levels of dihydroxphenylglycol, as well as impaired norepinephrine clearance and tyramine resistance. Studies of NET gene structure revealed a coding mutation converting a conserved alanine residue in transmembrane domain 9 to proline. Analysis of the protein produced by the mutant cDNA demonstrated greater than 98% reduction in activity relative to normal. The finding of genetic mutations responsible for DBH deficiency and orthostatic intolerance leads us to believe that genetic causes of other autonomic disorders will be found, enabling us to design more effective therapeutic interventions.

  2. Specific Genetic Disorders and Autism: Clinical Contribution towards Their Identification

    ERIC Educational Resources Information Center

    Cohen, David; Pichard, Nadege; Tordjman, Sylvie; Baumann, Clarisse; Burglen, Lydie; Excoffier, Elsa; Lazar, Gabriela; Mazet, Philippe; Pinquier, Clement; Verloes, Alian; Heron, Delphine

    2005-01-01

    Autism is a heterogeneous disorder that can reveal a specific genetic disease. This paper describes several genetic diseases consistently associated with autism (fragile X, tuberous sclerosis, Angelman syndrome, duplication of 15q11-q13, Down syndrome, San Filippo syndrome, MECP2 related disorders, phenylketonuria, Smith-Magenis syndrome, 22q13…

  3. The starting point of eating disorders: role of genetics.

    PubMed

    Juli, Giada; Juli, Luigi

    2014-11-01

    Eating disorders are perplexing diseases of which the etiology is still unknown. Recent research has focused on the possibility that genetics plays a role in vulnerability to these pathologies. This study gives an overview of the available literature focusing on family, twin and molecular genetic studies of eating disorders.

  4. Genetics Home Reference: ALG12-congenital disorder of glycosylation

    MedlinePlus

    ... type 1G congenital disorder of glycosylation type Ig Related Information How are genetic conditions and genes named? Additional Information & Resources MedlinePlus (1 link) Health Topic: Metabolic Disorders Genetic and Rare Diseases Information Center (2 links) ALG12-CDG (CDG-Ig) ...

  5. The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

    PubMed Central

    Smoller, Jordan W

    2016-01-01

    Research into the causes of psychopathology has largely focused on two broad etiologic factors: genetic vulnerability and environmental stressors. An important role for familial/heritable factors in the etiology of a broad range of psychiatric disorders was established well before the modern era of genomic research. This review focuses on the genetic basis of three disorder categories—posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and the anxiety disorders—for which environmental stressors and stress responses are understood to be central to pathogenesis. Each of these disorders aggregates in families and is moderately heritable. More recently, molecular genetic approaches, including genome-wide studies of genetic variation, have been applied to identify specific risk variants. In this review, I summarize evidence for genetic contributions to PTSD, MDD, and the anxiety disorders including genetic epidemiology, the role of common genetic variation, the role of rare and structural variation, and the role of gene–environment interaction. Available data suggest that stress-related disorders are highly complex and polygenic and, despite substantial progress in other areas of psychiatric genetics, few risk loci have been identified for these disorders. Progress in this area will likely require analysis of much larger sample sizes than have been reported to date. The phenotypic complexity and genetic overlap among these disorders present further challenges. The review concludes with a discussion of prospects for clinical translation of genetic findings and future directions for research. PMID:26321314

  6. Genetic and Environmental Factors in Complex Neurodevelopmental Disorders

    PubMed Central

    van Loo, K.M.J; Martens, G.J.M

    2007-01-01

    Complex neurodevelopmental disorders, such as schizophrenia, autism, attention deficit (hyperactivity) disorder, (manic) depressive illness and addiction, are thought to result from an interaction between genetic and environmental factors. Association studies on candidate genes and genome-wide linkage analyses have identified many susceptibility chromosomal regions and genes, but considerable efforts to replicate association have been surprisingly often disappointing. Here, we summarize the current knowledge of the genetic contribution to complex neurodevelopmental disorders, focusing on the findings from association and linkage studies. Furthermore, the contribution of the interaction of the genetic with environmental and epigenetic factors to the aetiology of complex neurodevelopmental disorders as well as suggestions for future research are discussed. PMID:19412416

  7. [Attention deficit hyperactivity disorder (ADHD)--molecular and genetic aspects].

    PubMed

    Migdalska, Anna; Nawara, Magdalena; Bal, Jerzy; Mazurczak, Tadeusz

    2006-01-01

    Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder of childhood, affecting approximately 5-10% of children. ADHD is considered to be a multifactorial disorder because both genetic and environmental components may contribute to its progress. The etiology of attention deficit hyperactivity disorder (ADHD) is unknown, however family, twin and adoption studies have suggested that genetic factors are very important in its etiopathogenesis. The research of genetic basis of ADHD consists of linkage analysis, candidate gene approach and association studies. These analyses and also investigations on animal models of disease suggest that mutations in genes involved in dopaminergic, serotonergic and adrenergic systems are likely to be responsible for ADHD.

  8. Biology and genetics of oculocutaneous albinism and vitiligo - common pigmentation disorders in southern Africa.

    PubMed

    Manga, Prashiela; Kerr, Robyn; Ramsay, Michèle; Kromberg, Jennifer G R

    2013-07-29

    Pigmentation disorders span the genetic spectrum from single-gene autosomal recessive disorders such as oculocutaneous albinism (OCA), the autosomal dominant disorder piebaldism to X-linked ocular albinism and multifactorial vitiligo. OCA connotes a group of disorders that result in hypopigmented skin due to decreased melanin production in melanocytes and loss of visual acuity. There are four non-syndromic forms, OCA1-4, which are classified based on the gene that is mutated (tyrosinase, OCA2, tyrosinase-related protein 1 and SLC45A2, respectively). Despite the fact that multiple genes account for the various forms of OCA, the phenotypes of all four forms result from disruption in the maturation and trafficking of the enzyme tyrosinase. OCA2 is the most prevalent autosomal recessive disorder among southern African blacks, affecting 1/3 900 individuals; while OCA3, although rare, is most prevalent in southern Africa. Another common pigmentation disorder in southern Africa is vitiligo, which affects 1 - 2% of people worldwide. Vitiligo is a complex, acquired disorder in which melanocytes are destroyed due to an autoimmune response. The aetiology underlying this disorder is poorly understood, although recent genetic association studies have begun to shed light on the contributing factors. Pigmentation disorders have significant psychosocial implications and co-morbidities, yet therapies are still lacking. Recent progress in our understanding of the pathobiology of both albinism and vitiligo may herald novel treatment strategies for these disorders

  9. Etiology of Attention Disorders: A Neurological/Genetic Perspective.

    ERIC Educational Resources Information Center

    Grantham, Madeline Kay

    This paper explores the historical origins of attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD) as a neurological disorder, current neurological and genetic research concerning the etiology of ADD/ADHD, and implications for diagnosis and treatment. First, ADD/ADHD is defined and then the origins of ADD/ADHD as a…

  10. A Primer on the Genetics of Comorbid Eating Disorders and Substance Use Disorders

    PubMed Central

    Munn-Chernoff, Melissa A.; Baker, Jessica H.

    2016-01-01

    Eating disorders (EDs) and substance use disorders (SUDs) frequently co-occur; however, the reasons for this are unclear. We review the current literature on genetic risk for EDs and SUDs, as well as preliminary findings exploring whether these classes of disorders have overlapping genetic risk. Overall, genetic factors contribute to individual differences in liability to multiple EDs and SUDs. Although initial family studies concluded that no shared familial (which includes genetic) risk between EDs and SUDs exists, twin studies suggest a moderate proportion of shared variance is attributable to overlapping genetic factors, particularly for those EDs characterized by binge eating and/or inappropriate compensatory behaviors. No adoption or molecular genetic studies have examined shared genetic risk between these classes of disorders. Research investigating binge eating and inappropriate compensatory behaviors using emerging statistical genetic methods, as well as examining gene-environment interplay, will provide important clues into the etiology of comorbid EDs and SUDs. PMID:26663753

  11. A Primer on the Genetics of Comorbid Eating Disorders and Substance Use Disorders.

    PubMed

    Munn-Chernoff, Melissa A; Baker, Jessica H

    2016-03-01

    Eating disorders (EDs) and substance use disorders (SUDs) frequently co-occur; however, the reasons for this are unclear. We review the current literature on genetic risk for EDs and SUDs, as well as preliminary findings exploring whether these classes of disorders have overlapping genetic risk. Overall, genetic factors contribute to individual differences in liability to multiple EDs and SUDs. Although initial family studies concluded that no shared familial (which includes genetic) risk between EDs and SUDs exists, twin studies suggest a moderate proportion of shared variance is attributable to overlapping genetic factors, particularly for those EDs characterized by binge eating and/or inappropriate compensatory behaviours. No adoption or molecular genetic studies have examined shared genetic risk between these classes of disorders. Research investigating binge eating and inappropriate compensatory behaviours using emerging statistical genetic methods, as well as examining gene-environment interplay, will provide important clues into the aetiology of comorbid EDs and SUDs.

  12. Multiple means to the same end: the genetic basis of acquired stress resistance in yeast.

    PubMed

    Berry, David B; Guan, Qiaoning; Hose, James; Haroon, Suraiya; Gebbia, Marinella; Heisler, Lawrence E; Nislow, Corey; Giaever, Guri; Gasch, Audrey P

    2011-11-01

    In nature, stressful environments often occur in combination or close succession, and thus the ability to prepare for impending stress likely provides a significant fitness advantage. Organisms exposed to a mild dose of stress can become tolerant to what would otherwise be a lethal dose of subsequent stress; however, the mechanism of this acquired stress tolerance is poorly understood. To explore this, we exposed the yeast gene-deletion libraries, which interrogate all essential and non-essential genes, to successive stress treatments and identified genes necessary for acquiring subsequent stress resistance. Cells were exposed to one of three different mild stress pretreatments (salt, DTT, or heat shock) and then challenged with a severe dose of hydrogen peroxide (H(2)O(2)). Surprisingly, there was little overlap in the genes required for acquisition of H(2)O(2) tolerance after different mild-stress pretreatments, revealing distinct mechanisms of surviving H(2)O(2) in each case. Integrative network analysis of these results with respect to protein-protein interactions, synthetic-genetic interactions, and functional annotations identified many processes not previously linked to H(2)O(2) tolerance. We tested and present several models that explain the lack of overlap in genes required for H(2)O(2) tolerance after each of the three pretreatments. Together, this work shows that acquired tolerance to the same severe stress occurs by different mechanisms depending on prior cellular experiences, underscoring the context-dependent nature of stress tolerance.

  13. Republished: Non-heritable genetics of human disease: spotlight on post-zygotic genetic variation acquired during lifetime

    PubMed Central

    Forsberg, Lars Anders; Absher, Devin; Dumanski, Jan Piotr

    2013-01-01

    The heritability of most common, multifactorial diseases is rather modest and known genetic effects account for a small part of it. The remaining portion of disease aetiology has been conventionally ascribed to environmental effects, with an unknown part being stochastic. This review focuses on recent studies highlighting stochastic events of potentially great importance in human disease—the accumulation of post-zygotic structural aberrations with age in phenotypically normal humans. These findings are in agreement with a substantial mutational load predicted to occur during lifetime within the human soma. A major consequence of these results is that the genetic profile of a single tissue collected at one time point should be used with caution as a faithful portrait of other tissues from the same subject or the same tissue throughout life. Thus, the design of studies in human genetics interrogating a single sample per subject or applying lymphoblastoid cell lines may come into question. Sporadic disorders are common in medicine. We wish to stress the non-heritable genetic variation as a potentially important factor behind the development of sporadic diseases. Moreover, associations between post-zygotic mutations, clonal cell expansions and their relation to cancer predisposition are central in this context. Post-zygotic mutations are amenable to robust examination and are likely to explain a sizable part of non-heritable disease causality, which has routinely been thought of as synonymous with environmental factors. In view of the widespread accumulation of genetic aberrations with age and strong predictions of disease risk from such analyses, studies of post-zygotic mutations may be a fruitful approach for delineation of variants that are causative for common human disorders. PMID:23781115

  14. Non-heritable genetics of human disease: spotlight on post-zygotic genetic variation acquired during lifetime

    PubMed Central

    Forsberg, Lars Anders; Absher, Devin; Dumanski, Jan Piotr

    2013-01-01

    The heritability of most common, multifactorial diseases is rather modest and known genetic effects account for a small part of it. The remaining portion of disease aetiology has been conventionally ascribed to environmental effects, with an unknown part being stochastic. This review focuses on recent studies highlighting stochastic events of potentially great importance in human disease—the accumulation of post-zygotic structural aberrations with age in phenotypically normal humans. These findings are in agreement with a substantial mutational load predicted to occur during lifetime within the human soma. A major consequence of these results is that the genetic profile of a single tissue collected at one time point should be used with caution as a faithful portrait of other tissues from the same subject or the same tissue throughout life. Thus, the design of studies in human genetics interrogating a single sample per subject or applying lymphoblastoid cell lines may come into question. Sporadic disorders are common in medicine. We wish to stress the non-heritable genetic variation as a potentially important factor behind the development of sporadic diseases. Moreover, associations between post-zygotic mutations, clonal cell expansions and their relation to cancer predisposition are central in this context. Post-zygotic mutations are amenable to robust examination and are likely to explain a sizable part of non-heritable disease causality, which has routinely been thought of as synonymous with environmental factors. In view of the widespread accumulation of genetic aberrations with age and strong predictions of disease risk from such analyses, studies of post-zygotic mutations may be a fruitful approach for delineation of variants that are causative for common human disorders. PMID:23172682

  15. Acquired auditory neuropathy spectrum disorder after an attack of chikungunya: case study.

    PubMed

    Prabhu, Prashanth

    2016-01-01

    Auditory neuropathy spectrum disorder (ANSD) is a retrocochlear disorder in which the cochlear functioning is normal but the transmission in the auditory neural pathway is affected. The present study reports of a 14-year-old teenager with acquired ANSD after an attack of chikungunya. He reported symptoms of difficulty in understanding speech, tinnitus and vertigo when exposed to loud sounds. The audiological characteristics suggested auditory neuropathy spectrum disorder with raising audiogram configuration. The results of tinnitus evaluation showed low-pitched tinnitus and it was persistent causing significant handicap to him based on self report tinnitus handicap questionnaire results. The results of depression, anxiety and stress scale also suggested symptoms of mild depression and anxiety. Chikungunya virus is suspected to be neurotropic in nature which can damage auditory nerve cells and may have caused ANSD. The result also shows presence of tullio's phenomenon and absence of cervical vestibular evoked myogenic potentials suggesting damage to the vestibular neuronal system. The possible pathophysiology of chikungunya virus causing ANSD and vestibular symptoms needs to be explored further in future studies.

  16. Heritable and acquired disorders of phosphate metabolism: Etiologies involving FGF23 and current therapeutics.

    PubMed

    Clinkenbeard, Erica L; White, Kenneth E

    2017-01-31

    Phosphate is critical for many cellular processes and structural functions, including as a key molecule for nucleic acid synthesis and energy metabolism, as well as hydroxyapatite formation in bone. Therefore it is critical to maintain tight regulation of systemic phosphate levels. Based upon its broad biological importance, disruption of normal phosphate homeostasis has detrimental effects on skeletal integrity and overall health. Investigating heritable diseases of altered phosphate metabolism has led to key discoveries underlying the regulation and systemic actions of the phosphaturic hormone Fibroblast growth factor-23 (FGF23). Both molecular and clinical studies have revealed novel targets for the development and optimization of therapies for disorders of phosphate handling. This review will focus upon the bridge between genetic discoveries involving disorders of altered FGF23 bioactivity, as well as describe how these findings have translated into pharmacologic application.

  17. Progeria: a rare genetic premature ageing disorder.

    PubMed

    Sinha, Jitendra Kumar; Ghosh, Shampa; Raghunath, Manchala

    2014-05-01

    Progeria is characterized by clinical features that mimic premature ageing. Although the mutation responsible for this syndrome has been deciphered, the mechanism of its action remains elusive. Progeria research has gained momentum particularly in the last two decades because of the possibility of revealing evidences about the ageing process in normal and other pathophysiological conditions. Various experimental models, both in vivo and in vitro, have been developed in an effort to understand the cellular and molecular basis of a number of clinically heterogeneous rare genetic disorders that come under the umbrella of progeroid syndromes (PSs). As per the latest clinical trial reports, Lonafarnib, a farnesyltranferase inhibitor, is a potent 'drug of hope' for Hutchinson-Gilford progeria syndrome (HGPS) and has been successful in facilitating weight gain and improving cardiovascular and skeletal pathologies in progeroid children. This can be considered as the dawn of a new era in progeria research and thus, an apt time to review the research developments in this area highlighting the molecular aspects, experimental models, promising drugs in trial and their implications to gain a better understanding of PSs.

  18. The genetic basis of panic and phobic anxiety disorders.

    PubMed

    Smoller, Jordan W; Gardner-Schuster, Erica; Covino, Jennifer

    2008-05-15

    Panic disorder and phobic anxiety disorders are common disorders that are often chronic and disabling. Genetic epidemiologic studies have documented that these disorders are familial and moderately heritable. Linkage studies have implicated several chromosomal regions that may harbor susceptibility genes; however, candidate gene association studies have not established a role for any specific loci to date. Increasing evidence from family and genetic studies suggests that genes underlying these disorders overlap and transcend diagnostic boundaries. Heritable forms of anxious temperament, anxiety-related personality traits and neuroimaging assays of fear circuitry may represent intermediate phenotypes that predispose to panic and phobic disorders. The identification of specific susceptibility variants will likely require much larger sample sizes and the integration of insights from genetic analyses of animal models and intermediate phenotypes.

  19. Acquired dyslexia in a transparent orthography: an analysis of acquired disorders of reading in the Slovak language.

    PubMed

    Hricová, Marianna; Weekes, Brendan Stuart

    2012-01-01

    The first reports of phonological, surface and deep dyslexia come from orthographies containing quasi-regular mappings between orthography and phonology including English and French. Slovakian is a language with a relatively transparent orthography and hence a mostly regular script. The aim of this study was to investigate impaired oral reading in Slovakian. A novel diagnostic procedure was devised to determine whether disorders of Slovakian reading resemble characteristics in other languages. Slovakian speaking aphasics showed symptoms similar to phonological dyslexia and deep dyslexia in English and French, but there was no evidence of surface dyslexia. The findings are discussed in terms of the orthographic depth hypothesis.

  20. Acquired Dyslexia in a Transparent Orthography: An Analysis of Acquired Disorders of Reading in the Slovak Language

    PubMed Central

    Hricová, Marianna; Weekes, Brendan Stuart

    2012-01-01

    The first reports of phonological, surface and deep dyslexia come from orthographies containing quasi-regular mappings between orthography and phonology including English and French. Slovakian is a language with a relatively transparent orthography and hence a mostly regular script. The aim of this study was to investigate impaired oral reading in Slovakian. A novel diagnostic procedure was devised to determine whether disorders of Slovakian reading resemble characteristics in other languages. Slovakian speaking aphasics showed symptoms similar to phonological dyslexia and deep dyslexia in English and French, but there was no evidence of surface dyslexia. The findings are discussed in terms of the orthographic depth hypothesis. PMID:22713384

  1. Genetics of Anxiety and Trauma-Related Disorders

    PubMed Central

    Norrholm, Seth D.; Ressler, Kerry J.

    2009-01-01

    Anxiety disorders are the most common psychiatric illnesses in the U.S. with approximately 30% of the population experiencing anxiety-related symptoms in their lifetime (Kessler et al., 2005). Notably, a variety of studies have demonstrated that 30−40% of the variance contributing to these disorders is heritable. In the present review, we discuss the latest findings regarding the genetic and environmental influences on the development and symptomatology of anxiety disorders. Specific emphasis is placed on posttraumatic stress disorder (PTSD) due to its uniqueness as an anxiety disorder; its diagnosis is dependent on a precipitating traumatic event and its development appears to be mediated by both genetic and environmental contributions. The co-morbidity of anxiety disorders and the potential reclassification of anxiety disorders as part of DSM-V are reviewed given the potential impact on the interpretation and design of genetic investigations. Lastly, several keys to future genetic studies are highlighted. Thorough analyses of the gene by environment (GxE) interactions that govern one's vulnerability to anxiety disorder(s), the effectiveness of individual treatment strategies, and the severity of symptoms may lead to more effective prophylactic (e.g., social support) and treatment strategies. PMID:19540311

  2. Chromosomal and Multifactorial Genetic Disorders with Oral Manifestations

    PubMed Central

    Patil, Shankargouda; Rao, Roopa S; Majumdar, Barnali

    2014-01-01

    The chromosomal disorders are individually rare, but collectively they are common whereas the multifactorial disorders are the most common form of genetic disorders. The chromosomal anomalies typically arise from alterations in the DNA containing chromosomal regions and can be reliably detected by karyotype analysis, whereas the multifactorial disorders demonstrate multi-gene as well as environmental interactions. Both the chromosomal and multifactorial disorders may manifest signs and symptoms such as a combination of birth defects, physical disabilities, challenging behavior and certain craniofacial defects as well, the knowledge of which can aid in a better patient management in everyday practice of dentistry. PMID:25395808

  3. Genetic Influences on Learning Disabilities and Speech and Language Disorders.

    ERIC Educational Resources Information Center

    Pennington, Bruce F.

    1983-01-01

    Comprehensively reviews known examples of genetically influenced learning disabilities and speech and language disorders, including familial dyslexia, stuttering, and other speech and language disorders, as well as sex-chromosome anomalies, treated PKU, and minor auto-somal anomalies. (Author/RH)

  4. Cross-Disorder Genetic Analysis of Tic Disorders, Obsessive-Compulsive, and Hoarding Symptoms.

    PubMed

    Zilhão, Nuno R; Smit, Dirk J; Boomsma, Dorret I; Cath, Danielle C

    2016-01-01

    Hoarding, obsessive-compulsive disorder (OCD), and Tourette's disorder (TD) are psychiatric disorders that share symptom overlap, which might partly be the result of shared genetic variation. Population-based twin studies have found significant genetic correlations between hoarding and OCD symptoms, with genetic correlations varying between 0.1 and 0.45. For tic disorders, studies examining these correlations are lacking. Other lines of research, including clinical samples and GWAS or CNV data to explore genetic relationships between tic disorders and OCD, have only found very modest if any shared genetic variation. Our aim was to extend current knowledge on the genetic structure underlying hoarding, OC symptoms (OCS), and lifetime tic symptoms and, in a trivariate analysis, assess the degree of common and unique genetic factors contributing to the etiology of these disorders. Data have been gathered from participants in the Netherlands Twin Register comprising a total of 5293 individuals from a sample of adult monozygotic (n = 2460) and dizygotic (n = 2833) twin pairs (mean age 33.61 years). The data on Hoarding, OCS, and tic symptoms were simultaneously analyzed in Mplus. A liability threshold model was fitted to the twin data, analyzing heritability of phenotypes and of their comorbidity. Following the criteria for a probable clinical diagnosis in all phenotypes, 6.8% of participants had a diagnosis of probable hoarding disorder (HD), 6.3% of OCS, and 12.8% of any probable lifetime tic disorder. Genetic factors explained 50.4, 70.1, and 61.1% of the phenotypic covariance between hoarding-OCS, hoarding-tics, and OCS-tics, respectively. Substantial genetic correlations were observed between hoarding and OCS (0.41), hoarding and tics (0.35), and between OCS and tics (0.37). These results support the contribution of genetic factors in the development of these disorders and their comorbidity. Furthermore, tics were mostly influenced by specific

  5. Ethical and Social Implications of Genetic Testing for Communication Disorders

    ERIC Educational Resources Information Center

    Arnos, Kathleen S.

    2008-01-01

    Advances in genetics and genomics have quickly led to clinical applications to human health which have far-reaching consequences at the individual and societal levels. These new technologies have allowed a better understanding of the genetic factors involved in a wide range of disorders. During the past decade, incredible progress has been made in…

  6. The etiology and molecular genetics of human pigmentation disorders

    PubMed Central

    Baxter, Laura L.; Pavan, William J.

    2012-01-01

    Pigmentation, defined as the placement of pigment in skin, hair, and eyes for coloration, is distinctive because the location, amount, and type of pigmentation provides a visual manifestation of genetic heterogeneity in pathways regulating the pigment-producing cells, melanocytes. The scope of this genetic heterogeneity in humans ranges from normal to pathological pigmentation phenotypes. Clinically normal human pigmentation encompasses a variety of skin and hair color as well as with punctate pigmentation such as melanocytic nevi (moles) or ephelides (freckles), while clinically abnormal human pigmentation exhibits markedly reduced or increased pigment levels, known as hypopigmentation and hyperpigmentation, respectively. Elucidation of the molecular genetics underlying pigmentation has revealed genes important for melanocyte development and function. Furthermore, many pigmentation disorders show additional defects in cells other than melanocytes, and identification of the genetic insults in these disorders has revealed pleiotropic genes, where a single gene is required for various functions, often in different cell types. Thus unravelling the genetics of easily visualized pigmentation disorders has identified molecular similarities between melanocytes and less visible cell types/tissues, revealing a common cellular origin and/or common genetic regulatory pathways. Herein we discuss notable human pigmentation disorders and their associated genetic alterations, focusing on the fact that the developmental genetics of pigmentation abnormalities is instructive for understanding normal pathways governing development and function of melanocytes. PMID:23799582

  7. Genetics Home Reference: ALG1-congenital disorder of glycosylation

    MedlinePlus

    ... are more mildly affected and survive into adulthood. Related Information What does it mean if a disorder seems to run in my family? What is the prognosis of a genetic condition? Genetic and Rare Diseases Information Center Frequency ALG1 -CDG appears to be ...

  8. Genetic susceptibility for bipolar disorder and response to antidepressants in major depressive disorder.

    PubMed

    Tansey, Katherine E; Guipponi, Michel; Domenici, Enrico; Lewis, Glyn; Malafosse, Alain; O'Donovan, Michael; Wendland, Jens R; Lewis, Cathryn M; McGuffin, Peter; Uher, Rudolf

    2014-01-01

    The high heterogeneity of response to antidepressant treatment in major depressive disorder (MDD) makes individual treatment outcomes currently unpredictable. It has been suggested that resistance to antidepressant treatment might be due to undiagnosed bipolar disorder or bipolar spectrum features. Here, we investigate the relationship between genetic susceptibility for bipolar disorder and response to treatment with antidepressants in MDD. Polygenic scores indexing risk for bipolar disorder were derived from the Psychiatric Genomics Consortium Bipolar Disorder whole genome association study. Linear regressions tested the effect of polygenic risk scores for bipolar disorder on proportional reduction in depression severity in two large samples of individuals with MDD, treated with antidepressants, NEWMEDS (n=1,791) and STAR*D (n=1,107). There was no significant association between polygenic scores for bipolar disorder and response to treatment with antidepressants. Our data indicate that molecular measure of genetic susceptibility to bipolar disorder does not aid in understanding non-response to antidepressants.

  9. Disorder-induced genetic divergence: A Monte Carlo study

    NASA Astrophysics Data System (ADS)

    Schulz, Michael; Pȩkalski, Andrzej

    2002-10-01

    We present a Monte Carlo simulation of a system composed of several populations, each living in a possibly different habitat. We show the influence of landscape disorder on the genetic pool of finite populations. We demonstrate that a strongly disordered environment generates an increase of the genetic distance between the populations on identical island. The distance becomes permanent for infinitely long times. On the contrary, landscapes with weak disorder offer only a temporarily allelic divergence which vanishes in the long time limit. Similarities between these phenomena and the well-known first-order phase transitions in the thermodynamics are analyzed.

  10. Genetic Forms of Epilepsies and other Paroxysmal Disorders

    PubMed Central

    Olson, Heather E.; Poduri, Annapurna; Pearl, Phillip L.

    2016-01-01

    Genetic mechanisms explain the pathophysiology of many forms of epilepsy and other paroxysmal disorders such as alternating hemiplegia of childhood, familial hemiplegic migraine, and paroxysmal dyskinesias. Epilepsy is a key feature of well-defined genetic syndromes including Tuberous Sclerosis Complex, Rett syndrome, Angelman syndrome, and others. There is an increasing number of singe gene causes or susceptibility factors associated with several epilepsy syndromes, including the early onset epileptic encephalopathies, benign neonatal/infantile seizures, progressive myoclonus epilepsies, genetic generalized and benign focal epilepsies, epileptic aphasias, and familial focal epilepsies. Molecular mechanisms are diverse, and a single gene can be associated with a broad range of phenotypes. Additional features, such as dysmorphisms, head size, movement disorders, and family history may provide clues to a genetic diagnosis. Genetic testing can impact medical care and counseling. We discuss genetic mechanisms of epilepsy and other paroxysmal disorders, tools and indications for genetic testing, known genotype-phenotype associations, the importance of genetic counseling, and a look towards the future of epilepsy genetics. PMID:25192505

  11. Nosology and Classification of Genetic Skeletal Disorders: 2010 Revision

    PubMed Central

    Warman, Matthew L; Cormier-Daire, Valerie; Hall, Christine; Krakow, Deborah; Lachman, Ralph; LeMerrer, Martine; Mortier, Geert; Mundlos, Stefan; Nishimura, Gen; Rimoin, David L; Robertson, Stephen; Savarirayan, Ravi; Sillence, David; Spranger, Juergen; Unger, Sheila; Zabel, Bernhard; Superti-Furga, Andrea

    2011-01-01

    Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to “private” found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene. The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology. © 2011 Wiley-Liss, Inc. PMID:21438135

  12. Genes, brains, and behavior: imaging genetics for neuropsychiatric disorders.

    PubMed

    Arslan, Ayla

    2015-01-01

    The majority of neuropsychiatric disorders show a strong degree of heritability, yet little is known about molecular factors involved in the pathophysiology of diseases like schizophrenia. After a brief historical introduction into the current understanding of neuropsychiatric disorders, the aim of this study is to discuss imaging genetics as a strategy to explore the pathophysiology of neuropsychiatric disorders. The candidate gene approach of imaging genetics is used for validation/replication studies of genes, whereas the hypothesis-free, noncandidate gene approach appears to be a tool for gene discovery. Besides, integration of environmental factors into neuroimaging begins to converge on neuroimaging studies of genetic variation. In the light of data from other avenues such as animal experimentation, these developments show a model of interdisciplinary research, which may lead to identifying markers for neuropsychiatric disorders.

  13. Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders.

    PubMed

    2016-05-01

    Prenatal genetic diagnostic testing is intended to determine, with as much certainty as possible, whether a specific genetic disorder or condition is present in the fetus. In contrast, prenatal genetic screening is designed to assess whether a patient is at increased risk of having a fetus affected by a genetic disorder. Originally, prenatal genetic testing focused primarily on Down syndrome (trisomy 21), but now it is able to detect a broad range of genetic disorders. Although it is necessary to perform amniocentesis or chorionic villus sampling (CVS) to definitively diagnose most genetic disorders, in some circumstances, fetal imaging with ultrasonography, echocardiography, or magnetic resonance imaging may be diagnostic of a particular structural fetal abnormality that is suggestive of an underlying genetic condition.The objective of prenatal genetic testing is to detect health problems that could affect the woman, fetus, or newborn and provide the patient and her obstetrician-gynecologist or other obstetric care provider with enough information to allow a fully informed decision about pregnancy management. Prenatal genetic testing cannot identify all abnormalities or problems in a fetus, and any testing should be focused on the individual patient's risks, reproductive goals, and preferences. It is important that patients understand the benefits and limitations of all prenatal screening and diagnostic testing, including the conditions for which tests are available and the conditions that will not be detected by testing. It also is important that patients realize that there is a broad range of clinical presentations, or phenotypes, for many genetic disorders and that results of genetic testing cannot predict all outcomes. Prenatal genetic testing has many benefits, including reassuring patients when results are normal, identifying disorders for which prenatal treatment may provide benefit, optimizing neonatal outcomes by ensuring the appropriate location for

  14. Genetics Home Reference: congenital mirror movement disorder

    MedlinePlus

    ... Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Congenital mirror movement disorder is a condition in which intentional movements of one side of the body are mirrored by involuntary movements ...

  15. Evolving Roles for Physicians and Genetic Counselors in Managing Complex Genetic Disorders.

    PubMed

    Shelton, Celeste A; Whitcomb, David C

    2015-11-12

    Proponents of personalized medicine predict that genetic information will provide pivotal perspectives for the prevention and management of complex disorders. Personalized medicine differs from traditional Western medicine, in that it focuses on more complex disorders that require mechanistic disease modeling and outcome simulation by integrating genomic risk, environmental stressors, and biomarkers as indicators of disease state. This information could be useful to guide targeted therapy and prevent pathologic outcomes. However, gaps exist in the process of linking the pieces together; currently, genetic data are seldom used to assist physicians in clinical decision making. With rapid growth in genetic data and the requirements for new paradigms for complex disorders comes the need to train professionals to understand and manage the impact of genetic information on patients within these clinical settings. Here we describe the challenges, controversies, and opportunities for genetics and genetic counselors in managing complex disorders and discuss the rationale for modifications in genetic counselor training and function. We conclude that a major paradigm shift is underway and a compelling functional, ethical, and financial argument can be made for employing properly trained genetic counselors to be strategically positioned within the health-care industries that are responsible for managing complex disorders.

  16. The genetic basis of mood and anxiety disorders - changing paradigms.

    PubMed

    Binder, Elisabeth B

    2012-10-01

    Family, twin and epidemiologic studies all point to an important genetic contribution to the risk to develop mood and anxiety disorders. While some progress has been made in identifying relevant pathomechanisms for these disorders, candidate based strategies have often yielded controversial findings. Hopes were thus high when genome-wide genetic association studies became available and affordable and allowed a hypothesis-free approach to study genetic risk factors for these disorders. In an unprecendented scientific collaborative effort, large international consortia formed to allow the analysis of these genome-wide association datasets across thousands of cases and controls ([1] and see also http://www.broadinstitute.org/mpg/ricopili/). Now that large meta-analyses of genome-wide association studies (GWAS) have been published for bipolar disorder and major depression it has become clear that main effects of common variants are difficult to identify in these disorders, suggesting that additional approaches maybe needed to understand the genetic basis of these disorders [2,3].

  17. Disentangling the heterogeneity of autism spectrum disorder through genetic findings

    PubMed Central

    Jeste, Shafali S.; Geschwind, Daniel H.

    2014-01-01

    Autism spectrum disorder (ASD) represents a heterogeneous group of disorders, which presents a substantial challenge to diagnosis and treatment. Over the past decade, considerable progress has been made in the identification of genetic risk factors for ASD that define specific mechanisms and pathways underlying the associated behavioural deficits. In this Review, we discuss how some of the latest advances in the genetics of ASD have facilitated parsing of the phenotypic heterogeneity of this disorder. We argue that only through such advances will we begin to define endophenotypes that can benefit from targeted, hypothesis-driven treatments. We review the latest technologies used to identify and characterize the genetics underlying ASD and then consider three themes—single-gene disorders, the gender bias in ASD, and the genetics of neurological comorbidities—that highlight ways in which we can use genetics to define the many phenotypes within the autism spectrum. We also present current clinical guidelines for genetic testing in ASD and their implications for prognosis and treatment. PMID:24468882

  18. Genetics of ischaemic stroke; single gene disorders.

    PubMed

    Flossmann, Enrico

    2006-08-01

    Examples of single gene disorders have been described for all major subtypes of ischaemic stroke: accelerated atherosclerosis and subsequent thrombo-embolism (e.g. homocysteinuria), weakening of connective tissue resulting in arterial dissections (e.g. Ehler-Danlos type IV), disorders of cerebral small vessels (e.g. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy and the collagen COL4A1 mutation), disorders increasing the thrombogenic potential of the heart through affecting the myocardium or the heart valves or through disturbance of the heart rhythm (e.g. hypertrophic cardiomyopathy), mitochondrial cytopathies increasing cerebral tissue susceptibility to insults (e.g. mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), and finally disorders of coagulation that can either directly cause stroke or act synergistically with the aforementioned abnormalities (e.g. sickle cell disease). Most of these disorders are rare but they are important to consider particularly in young patients with stroke, those with a family history or those who have other characteristics of a particular syndrome.

  19. Recent developments in certain X-linked genetic eye disorders.

    PubMed

    Shastry, B S

    1993-09-08

    Over the past few years, genetic diseases of the ocular system have become very active and fast-growing research areas in the vision field. The rapid development of the recombinant DNA techniques together with somatic cell genetics, during the last two decades has fueled this progress. As a result, many genetic disease genes have been localized in the human chromosome and several of them have been isolated and characterized. These and other studies have profoundly enriched our basic understanding of genetic eye disorders. Although gene replacement therapy, prenatal diagnosis and carrier detection have not been extensively tried for genetic eye diseases, such attempts will now be feasible. Molecular analyses made it clear that there are many challenging problems that need attention. This report highlights some of these initial developments, particularly on the X-linked major genetic eye diseases. In order to help the beginners and general audience, a brief description of the clinical pathology and the molecular probes used to locate the genetic defects of certain disorders are presented. Disorders are arranged according to their linkage from telomere to telomere on the chromosome to give a coherent structure. It is hoped that this information is useful and of general interest for the beginners, established investigators and ophthalmologists.

  20. Guidelines for genetic testing of inherited cardiac disorders.

    PubMed

    Ingles, Jodie; Zodgekar, Poonam R; Yeates, Laura; Macciocca, Ivan; Semsarian, Christopher; Fatkin, Diane

    2011-11-01

    Inherited gene variants have been implicated increasingly in cardiac disorders but the clinical impact of these discoveries has been variable. For some disorders, such as familial hypertrophic cardiomyopathy, long QT syndrome, and familial hypercholesterolaemia, genetic testing has a high yield and has become an integral part of family management. For other disorders, including dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and atrial fibrillation, relatively less is known about the genes involved and genetic testing has a lower yield. Recent advances in sequencing and array-based technologies promise to change the landscape of our understanding of the genetic basis of human disease and will dramatically increase the rate of detection of genomic variants. Since every individual is expected to harbour thousands of variants, many of which may be novel, interpretation of the functional significance of any single variant is critical, and should be undertaken by experienced personnel. Genotype results can have a wide range of medical and psychosocial implications for affected and unaffected individuals and hence, genetic testing should be performed in a specialised cardiac genetic clinic or clinical genetics service where appropriate family management and genetic counselling can be offered.

  1. Kartagener syndrome: a rare genetic disorder.

    PubMed

    Shakya, K

    2009-01-01

    Kartagener Syndrome is a rare autosomal recessive disorder consisting of triad of sinusitis, bronchiectasis and situs inversus with dextrocardia. It is the subset of disorder called primary ciliary dyskinesia in which the cilia have abnormal structure and/or function resulting in multisystem diseases of various severity. Clinical manifestations include lifelong, chronic upper and lower respiratory tract diseases secondary to ineffective mucociliary clearance. Early diagnosis and management of chest infections can prevent irreversible damage to lungs and prevent potential lifelong complications. This case report is on a patient who presented with long standing history of sinusitis, bronchiectasis and on examination situs inversus with dextrocardia.

  2. Nomenclature of genetic movement disorders: Recommendations of the international Parkinson and movement disorder society task force.

    PubMed

    Marras, Connie; Lang, Anthony; van de Warrenburg, Bart P; Sue, Carolyn M; Tabrizi, Sarah J; Bertram, Lars; Mercimek-Mahmutoglu, Saadet; Ebrahimi-Fakhari, Darius; Warner, Thomas T; Durr, Alexandra; Assmann, Birgit; Lohmann, Katja; Kostic, Vladimir; Klein, Christine

    2016-04-01

    The system of assigning locus symbols to specify chromosomal regions that are associated with a familial disorder has a number of problems when used as a reference list of genetically determined disorders,including (I) erroneously assigned loci, (II) duplicated loci, (III) missing symbols or loci, (IV) unconfirmed loci and genes, (V) a combination of causative genes and risk factor genes in the same list, and (VI) discordance between phenotype and list assignment. In this article, we report on the recommendations of the International Parkinson and Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders and present a system for naming genetically determined movement disorders that addresses these problems. We demonstrate how the system would be applied to currently known genetically determined parkinsonism, dystonia, dominantly inherited ataxia, spastic paraparesis, chorea, paroxysmal movement disorders, neurodegeneration with brain iron accumulation, and primary familial brain calcifications. This system provides a resource for clinicians and researchers that, unlike the previous system, can be considered an accurate and criterion-based list of confirmed genetically determined movement disorders at the time it was last updated.

  3. Post-transplant lymphoproliferative disorders: implications for acquired immunodeficiency syndrome-associated malignancies.

    PubMed

    Swinnen, L J

    2001-01-01

    Post-transplant lymphoproliferative disorders (PTLDs) comprise a histologic spectrum, ranging from hyperplastic-appearing lesions to frank non-Hodgkin's lymphoma or multiple myeloma histology. Multiple clones may coexist, each representing a discrete lymphomagenic event, a situation that is unique to immunodeficiency states. The incidence varies from 1% in renal recipients to 5% in heart recipients, but can be markedly increased by the use of anti-T-cell therapies or by T-cell depletion in bone marrow transplantation. PTLD continues to arise, even many years after transplantation, and late T-cell lymphomas have recently been recognized. Pretransplant Epstein-Barr virus (EBV) seronegativity increases risk to as high as 30%-50%. PTLD has a highly variable clinical picture; certain patterns are, however, seen. Reversibility of PTLD with reduction in immunosuppressives has long been recognized. Predicting reversibility has been difficult. The presence or absence of bcl-6 mutations has recently been identified as being of predictive value. Surgical resection can be curative. Cytotoxics, although problematic, can also be curative. Long-term remission has been achieved with anti CD21 and CD24 antibodies; efficacy has been reported for interferon alfa and for rituximab. In vitro expanded EBV-specific T cells have been effective as treatment and as prophylaxis in the setting of bone marrow transplantation. EBV viral load measured in blood appears to associate with the emergence of PTLD and may facilitate prophylactic studies. PTLD is a model of immunodeficiency-related EBV lymphomagenesis. Pathogenetic, therapeutic, and prophylactic insights gained from the study of PTLD are likely to be applicable to the acquired immunodeficiency syndrome setting.

  4. Acquired prosopagnosia as a face-specific disorder: ruling out the general visual similarity account.

    PubMed

    Busigny, Thomas; Graf, Markus; Mayer, Eugène; Rossion, Bruno

    2010-06-01

    Prosopagnosia is classically defined as a disorder of visual recognition specific to faces, following brain damage. However, according to a long-standing alternative view, these patients would rather be generally impaired in recognizing objects belonging to visually homogenous categories, including faces. We tested this alternative hypothesis stringently with a well-documented brain-damaged prosopagnosic patient (PS) in three delayed forced-choice recognition experiments in which visual similarity between a target and its distractor was manipulated parametrically: novel 3D geometric shapes, morphed pictures of common objects, and morphed photographs of a highly homogenous familiar category (cars). In all experiments, PS showed normal performance and speed, and there was no evidence of a steeper increase of error rates and RTs with increasing levels of visual similarity, compared to controls. These data rule out an account of acquired prosopagnosia in terms of a more general impairment in recognizing objects from visually homogenous categories. An additional experiment with morphed faces confirmed that PS was specifically impaired at individual face recognition. However, in stark contrast to the alternative view of prosopagnosia, PS was relatively more impaired at the easiest levels of discrimination, i.e. when individual faces differ clearly in global shape rather than when faces were highly similar and had to be discriminated based on fine-grained details. Overall, these observations as well as a review of previous evidence, lead us to conclude that this alternative view of prosopagnosia does not hold. Rather, it seems that brain damage in adulthood may lead to selective recognition impairment for faces, perhaps the only category of visual stimuli for which holistic/configural perception is not only potentially at play, but is strictly necessary to individualize members of the category efficiently.

  5. Imaging genetics studies on monoaminergic genes in major depressive disorder.

    PubMed

    Won, Eunsoo; Ham, Byung-Joo

    2016-01-04

    Although depression is the leading cause of disability worldwide, current understanding of the neurobiology of depression has failed to be translated into clinical practice. Major depressive disorder (MDD) pathogenesis is considered to be significantly influenced by multiple risk genes, however genetic effects are not simply expressed at a behavioral level. Therefore the concept of endophenotype has been applied in psychiatric genetics. Imaging genetics applies anatomical or functional imaging technologies as phenotypic assays to evaluate genetic variation and their impact on behavior. This paper attempts to provide a comprehensive review of available imaging genetics studies, including reports on genetic variants that have most frequently been linked to MDD, such as the monoaminergic genes (serotonin transporter gene, monoamine oxidase A gene, tryptophan hydroxylase-2 gene, serotonin receptor 1A gene and catechol-O-methyl transferase gene), with regard to key structures involved in emotion processing, such as the hippocampus, amygdala, anterior cingulate cortex and orbitofrontal cortex.

  6. Common Genetic and Environmental Influences on Major Depressive Disorder and Conduct Disorder

    ERIC Educational Resources Information Center

    Subbarao, Anjali; Rhee, Soo Hyun; Young, Susan E.; Ehringer, Marissa A.; Corley, Robin P.; Hewitt, John K.

    2008-01-01

    The evidence for common genetic and environmental influences on conduct disorder (CD) and major depressive disorder (MDD) in adolescents was examined. A sample of 570 monozygotic twin pairs, 592 dizygotic twin pairs, and 426 non-twin siblings, aged 12-18 years, was recruited from the Colorado Twin Registry. For the past year data, there was a…

  7. [Autism and attention deficit hyperactivity disorder: convergences and divergences. Genetics].

    PubMed

    Artigas-Pallarés, Josep

    2013-09-06

    According to the DSM-5, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are different conditions that earlier versions of the DSM stated could not be diagnosed together in the same individual. Yet, over the last few decades the debate on the limits between the two disorders has continued, even though ADHD and ASD are undoubtedly clinically and cognitively different phenotypes, as demonstrated by the simple fact that they have been defined in clearly different ways. Thus, from a perspective anchored in a purely phenomenological view, there would be no grounds whatsoever on which to question the independence between the two disorders. Since, at the present time, the discussion on the convergence between ADHD and ASD cannot be considered to have been solved, this study aims to take the data available from genetics as the basis on which to review the nosological position of the two disorders. The main studies that have addressed this issue are reviewed. The data collected agree on a genetic overlap between ADHD and ASD, which is influenced by common molecular mechanisms that affect the two disorders at the same time. The conclusions that can be drawn from the data collected suggest a new conceptual model not only for ADHD and ASD, but also for complex mental disorders in general. This line of research will transform the way of understanding the treatment of mental disorders and will almost certainly open up new perspectives in this area.

  8. Translational genetics for diagnosis of human disorders of sex development.

    PubMed

    Baxter, Ruth M; Vilain, Eric

    2013-01-01

    Disorders of sex development (DSDs) are congenital conditions with discrepancies between the chromosomal, gonadal, and phenotypic sex of the individual. Such disorders have historically been difficult to diagnose and cause great stress to patients and their families. Genetic analysis of human samples has been instrumental in elucidating the molecules and pathways involved in the development of the bipotential gonad into a functioning testis or ovary. However, many DSD patients still do not receive a genetic diagnosis. New genetic and genomic technologies are expanding our knowledge of the underlying mechanism of DSDs and opening new avenues for clinical diagnosis. We review the genetic technologies that have elucidated the genes that are well established in sex determination in humans, discuss findings from more recent genomic technologies, and propose a new paradigm for clinical diagnosis of DSDs.

  9. Translational Genetics for Diagnosis of Human Disorders of Sex Development

    PubMed Central

    Baxter, Ruth M.; Vilain, Eric

    2015-01-01

    Disorders of sex development (DSDs) are congenital conditions with discrepancies between the chromosomal, gonadal, and phenotypic sex of the individual. Such disorders have historically been difficult to diagnose and cause great stress to patients and their families. Genetic analysis of human samples has been instrumental in elucidating the molecules and pathways involved in the development of the bipotential gonad into a functioning testis or ovary. However, many DSD patients still do not receive a genetic diagnosis. New genetic and genomic technologies are expanding our knowledge of the underlying mechanism of DSDs and opening new avenues for clinical diagnosis. We review the genetic technologies that have elucidated the genes that are well established in sex determination in humans, discuss findings from more recent genomic technologies, and propose a new paradigm for clinical diagnosis of DSDs. PMID:23875799

  10. Antibiotic Resistance, Virulence, and Genetic Background of Community-Acquired Uropathogenic Escherichia coli from Algeria.

    PubMed

    Yahiaoui, Merzouk; Robin, Frédéric; Bakour, Rabah; Hamidi, Moufida; Bonnet, Richard; Messai, Yamina

    2015-10-01

    The aim of the study was to investigate antibiotic resistance mechanisms, virulence traits, and genetic background of 150 nonrepetitive community-acquired uropathogenic Escherichia coli (CA-UPEC) from Algeria. A rate of 46.7% of isolates was multidrug resistant. bla genes detected were blaTEM (96.8% of amoxicillin-resistant isolates), blaCTX-M-15 (4%), overexpressed blaAmpC (4%), blaSHV-2a, blaTEM-4, blaTEM-31, and blaTEM-35 (0.7%). All tetracycline-resistant isolates (51.3%) had tetA and/or tetB genes. Sulfonamides and trimethoprim resistance genes were sul2 (60.8%), sul1 (45.9%), sul3 (6.7%), dfrA14 (25.4%), dfrA1 (18.2%), dfrA12 (16.3%), and dfrA25 (5.4%). High-level fluoroquinolone resistance (22.7%) was mediated by mutations in gyrA (S83L-D87N) and parC (S80I-E84G/V or S80I) genes. qnrB5, qnrS1, and aac(6')-Ib-cr were rare (5.3%). Class 1 and/or class 2 integrons were detected (40.7%). Isolates belonged to phylogroups B2+D (50%), A+B1 (36%), and F+C+Clade I (13%). Most of D (72.2%) and 38.6% of B2 isolates were multidrug resistant; they belong to 14 different sequence types, including international successful ST131, ST73, and ST69, reported for the first time in the community in Algeria and new ST4494 and ST4529 described in this study. Besides multidrug resistance, B2 and D isolates possessed virulence factors of colonization, invasion, and long-term persistence. The study highlighted multidrug-resistant CA-UPEC with high virulence traits and an epidemic genetic background.

  11. Genetics and Function of Neocortical GABAergic Interneurons in Neurodevelopmental Disorders

    PubMed Central

    Rossignol, E.

    2011-01-01

    A dysfunction of cortical and limbic GABAergic circuits has been postulated to contribute to multiple neurodevelopmental disorders in humans, including schizophrenia, autism, and epilepsy. In the current paper, I summarize the characteristics that underlie the great diversity of cortical GABAergic interneurons and explore how the multiple roles of these cells in developing and mature circuits might contribute to the aforementioned disorders. Furthermore, I review the tightly controlled genetic cascades that determine the fate of cortical interneurons and summarize how the dysfunction of genes important for the generation, specification, maturation, and function of cortical interneurons might contribute to these disorders. PMID:21876820

  12. [Genetic factors in obsessive-compulsive disorder: summary of genetic studies].

    PubMed

    Kenézloi, Eszter; Nemoda, Zsófia

    2010-01-01

    Obsessive-compulsive disorder (OCD) affects children and adults. As in most psychiatric disorders, genetic and environmental factors play an important role in the development of OCD. The symptom onset occurs at early age (before 18 years) in 80% of the cases; this early onset OCD has different clinical features compared to the adult form. Family studies suggest that childhood onset OCD is more heritable. In addition, there is male preponderance and a higher rate of comorbid tic and attention deficit hyperactivity disorder in the early onset OCD. These data imply that the early onset OCD might have different etiological background. In this review article we will shortly describe OCD symptoms, possible endophenotypes and neurobiological theories. After an overview of the applied genetic methods, we will summarize the genetic results of the OCD literature, especially candidate gene association studies. Finally, we will outline the possible future trends in psychiatric genetics.

  13. Toward a Deeper Understanding of the Genetics of Bipolar Disorder

    PubMed Central

    Kerner, Berit

    2015-01-01

    Bipolar disorder is a common, complex psychiatric disorder characterized by mania and depression. The disease aggregates in families, but despite much effort, it has been difficult to delineate the basic genetic model or identify specific genetic risk factors. Not only single gene Mendelian transmission and common variant hypotheses but also multivariate threshold models and oligogenic quasi-Mendelian modes of inheritance have dominated the discussion at times. Almost complete sequence information of the human genome and falling sequencing costs now offer the opportunity to test these models in families in which the disorder is transmitted over several generations. Exome-wide sequencing studies have revealed an astonishing number of rare and potentially damaging mutations in brain-expressed genes that could have contributed to the disease manifestation. However, the statistical analysis of these data has been challenging, because genetic risk factors displayed a high degree of dissimilarity across families. This scenario is not unique to bipolar disorder, but similar results have also been found in schizophrenia, a potentially related psychiatric disorder. Recently, our group has published data which supported an oligogenic genetic model of transmission in a family with bipolar disorder. In this family, three affected siblings shared rare, damaging mutations in multiple genes, which were linked to stress response pathways. These pathways are also the target for drugs frequently used to treat bipolar disorder. This article discusses these findings in the context of previously proclaimed disease models and suggests future research directions, including biological confirmation and phenotype stratification as an approach to disease heterogeneity. PMID:26283973

  14. Cross-Disorder Genetic Analysis of Tic Disorders, Obsessive–Compulsive, and Hoarding Symptoms

    PubMed Central

    Zilhão, Nuno R.; Smit, Dirk J.; Boomsma, Dorret I.; Cath, Danielle C.

    2016-01-01

    Hoarding, obsessive–compulsive disorder (OCD), and Tourette’s disorder (TD) are psychiatric disorders that share symptom overlap, which might partly be the result of shared genetic variation. Population-based twin studies have found significant genetic correlations between hoarding and OCD symptoms, with genetic correlations varying between 0.1 and 0.45. For tic disorders, studies examining these correlations are lacking. Other lines of research, including clinical samples and GWAS or CNV data to explore genetic relationships between tic disorders and OCD, have only found very modest if any shared genetic variation. Our aim was to extend current knowledge on the genetic structure underlying hoarding, OC symptoms (OCS), and lifetime tic symptoms and, in a trivariate analysis, assess the degree of common and unique genetic factors contributing to the etiology of these disorders. Data have been gathered from participants in the Netherlands Twin Register comprising a total of 5293 individuals from a sample of adult monozygotic (n = 2460) and dizygotic (n = 2833) twin pairs (mean age 33.61 years). The data on Hoarding, OCS, and tic symptoms were simultaneously analyzed in Mplus. A liability threshold model was fitted to the twin data, analyzing heritability of phenotypes and of their comorbidity. Following the criteria for a probable clinical diagnosis in all phenotypes, 6.8% of participants had a diagnosis of probable hoarding disorder (HD), 6.3% of OCS, and 12.8% of any probable lifetime tic disorder. Genetic factors explained 50.4, 70.1, and 61.1% of the phenotypic covariance between hoarding-OCS, hoarding-tics, and OCS-tics, respectively. Substantial genetic correlations were observed between hoarding and OCS (0.41), hoarding and tics (0.35), and between OCS and tics (0.37). These results support the contribution of genetic factors in the development of these disorders and their comorbidity. Furthermore, tics were mostly influenced by specific

  15. Genetics of aging, progeria and lamin disorders.

    PubMed

    Ghosh, Shrestha; Zhou, Zhongjun

    2014-06-01

    Premature aging disorders, like Werner syndrome, Bloom's syndrome, and Hutchinson-Gilford Progeria Syndrome (HGPS), have been the subjects of immense interest as they recapitulate many of the phenotypes observed in physiological aging. They, therefore, not only provide model systems to study normal aging processes but also give valuable insights into the intricate mechanisms underlying senescence. Recent works on HGPS have revealed alterations in a spectrum of cellular and molecular pathways involved in the maintenance of genomic integrity, thus suggesting a profound impact of the nuclear lamina in nuclear organization, chromatin dynamics, regulation of gene expression and epigenetics.

  16. Genetics Underlying an Individualized Approach to Adult Spinal Disorders

    PubMed Central

    Walker, Corey T.; Bonney, Phillip A.; Martirosyan, Nikolay L.; Theodore, Nicholas

    2016-01-01

    Adult spinal disorders are a significant cause of morbidity across the world and carry significant health and economic burdens. Genetic predispositions are increasingly considered for these conditions and are becoming understood. Advances in molecular technologies since the mid-1990s have made possible genetic characterizations of these diseases in many populations, and recent findings have provided insight into the underlying pathophysiologic mechanisms. These studies have made clear the genetic heterogeneity producing clinical phenotypes and suggest that individualized treatments are possible in the future. We review the genetics and heritability of cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament and perform a systematic review of the genetics of adult lumbar degenerative scoliotic deformity, highlighting recent discoveries and the potential for personalized future therapeutics for these patients. PMID:27921035

  17. Clinical Genetic Aspects of ASD Spectrum Disorders

    PubMed Central

    Schaefer, G. Bradley

    2016-01-01

    Early presumptions opined that autism spectrum disorder (ASD) was related to the rearing of these children by emotionally-distant mothers. Advances in the 1960s and 1970s clearly demonstrated the biologic basis of autism with a high heritability. Recent advances have demonstrated that specific etiologic factors in autism spectrum disorders can be identified in 30%–40% of cases. Based on early reports newer, emerging genomic technologies are likely to increase this diagnostic yield to over 50%. To date these investigations have focused on etiologic factors that are largely mono-factorial. The currently undiagnosed causes of ASDs will likely be found to have causes that are more complex. Epigenetic, multiple interacting loci, and four dimensional causes (with timing as a variable) are likely to be associated with the currently unidentifiable cases. Today, the “Why” is more important than ever. Understanding the causes of ASDs help inform families of important issues such as recurrence risk, prognosis, natural history, and predicting associated co-morbid medical conditions. In the current era of emerging efforts in “personalized medicine”, identifying an etiology will be critical in identifying endo-phenotypic groups and individual variations that will allow for tailored treatment for persons with ASD. PMID:26840296

  18. Social and Psychological Aspects of Genetic Disorders: A Selected Bibliography.

    ERIC Educational Resources Information Center

    National Center for Education in Maternal and Child Health, Washington, DC.

    The scope of this bibliography encompasses the social and psychological aspects of genetic disorders. The bibliography lists selected English-language articles and books from the professional literature along with audiovisual materials produced by both voluntary organizations and professional filmmakers. The entries are organized by the following…

  19. Visual and Verbal Learning in a Genetic Metabolic Disorder

    ERIC Educational Resources Information Center

    Spilkin, Amy M.; Ballantyne, Angela O.; Trauner, Doris A.

    2009-01-01

    Visual and verbal learning in a genetic metabolic disorder (cystinosis) were examined in the following three studies. The goal of Study I was to provide a normative database and establish the reliability and validity of a new test of visual learning and memory (Visual Learning and Memory Test; VLMT) that was modeled after a widely used test of…

  20. Behaviour Problems in Children with Genetic Disorders Causing Intellectual Disability

    ERIC Educational Resources Information Center

    Einfeld, Stewart L.

    2005-01-01

    This paper reviews several genetic syndromes that are associated with intellectual disability. The specific focus is on the behavioural patterns associated with the syndrome. Included in this review are the patterns of disruptive behaviour disorders associated with Fragile X, Prader-Willi, and Williams syndromes. Understanding and recognition of…

  1. Genetic Advances in the Study of Speech and Language Disorders

    PubMed Central

    Newbury, D.F.; Monaco, A.P.

    2010-01-01

    Summary Developmental speech and language disorders cover a wide range of childhood conditions with overlapping but heterogeneous phenotypes and underlying etiologies. This characteristic heterogeneity hinders accurate diagnosis, can complicate treatment strategies, and causes difficulties in the identification of causal factors. Nonetheless, over the last decade, genetic variants have been identified that may predispose certain individuals to different aspects of speech and language difficulties. In this review, we summarize advances in the genetic investigation of stuttering, speech-sound disorder (SSD), specific language impairment (SLI), and developmental verbal dyspraxia (DVD). We discuss how the identification and study of specific genes and pathways, including FOXP2, CNTNAP2, ATP2C2, CMIP, and lysosomal enzymes, may advance our understanding of the etiology of speech and language disorders and enable us to better understand the relationships between the different forms of impairment across the spectrum. PMID:20955937

  2. Crouzon’s Syndrome: A Rare Genetic Disorder

    PubMed Central

    Bhatia, Hindpal; Sharma, Naresh

    2016-01-01

    Crouzon’s syndrome, also known as brachial arch syndrome, is an autosomal dominant disorder with complete penetrance and variable expressivity. Described by a French neurosurgeon in 1912, it is a rare genetic disorder. Crouzon’s syndrome is caused by mutation in the fibroblast growth factor receptor 2 (FGFR2) gene. Normally, the sutures in the human skull fuse after the complete growth of the brain, but if any of these sutures close early, then it may interfere with the growth of the brain. The disease is characterized by craniosynostosis, with associated dentofacial anomalies. This report describes the different clinical features in a 10-year-old male patient, with particular reference to characteristic findings of this syndrome. How to cite this article Kaushik A, Bhatia H, Sharma N. Crouzon’s Syndrome: A Rare Genetic Disorder. Int J Clin Pediatr Dent 2016;9(4):384-387. PMID:28127173

  3. Molecular genetics of RecQ helicase disorders.

    PubMed

    Hanada, K; Hickson, I D

    2007-09-01

    The RecQ helicases belong to the Superfamily II group of DNA helicases, and are defined by amino acid motifs that show sequence similarity to the catalytic domain of Escherichia coli RecQ. RecQ helicases have crucial roles in the maintenance of genome stability. In humans, there are five RecQ helicases and deficiencies in three of them cause genetic disorders characterised by cancer predisposition, premature aging and/or developmental abnormalities. RecQ helicase-deficient cells exhibit aberrant genetic recombination and/or DNA replication, which result in chromosomal instability and a decreased potential for proliferation. Here, we review the current knowledge of the molecular genetics of RecQ helicases, focusing on the human RecQ helicase disorders and mouse models of these conditions.

  4. Genetics of developmental psychiatric disorders: pathways to discovery

    PubMed Central

    Joober, Ridha; Sengupta, Sarojini; Boksa, Patricia

    2005-01-01

    Genetics has captured the imagination of the public, the interest of the media and a large place in the sciences. Since the discovery of the structure of DNA by Watson and Crick, the double helix has epitomized the main dogma of genetics: everything from the tiniest details of the human body to the most complex of behaviours is encoded in the genes. This belief has been strengthened by the tremendous success that has been achieved in cloning more than 1000 genes that cause simple Mendelian disorders. However, for complex disorders, particularly psychiatric conditions, the search for genes has been frustrating and has not yielded definitive results, although claims of gene discoveries are made regularly. In this article, we discuss the possible causes for these difficulties, along with some directions that may help in reducing these problems. We also consider the implications of psychiatric genetic research for individual and public health. PMID:16151540

  5. Imaging genetics in obsessive-compulsive disorder: linking genetic variations to alterations in neuroimaging.

    PubMed

    Grünblatt, Edna; Hauser, Tobias U; Walitza, Susanne

    2014-10-01

    Obsessive-compulsive disorder (OCD) occurs in ∼1-3% of the general population, and its often rather early onset causes major disabilities in the everyday lives of patients. Although the heritability of OCD is between 35 and 65%, many linkage, association, and genome-wide association studies have failed to identify single genes that exhibit high effect sizes. Several neuroimaging studies have revealed structural and functional alterations mainly in cortico-striato-thalamic loops. However, there is also marked heterogeneity across studies. These inconsistencies in genetic and neuroimaging studies may be due to the heterogeneous and complex phenotypes of OCD. Under the consideration that genetic variants may also influence neuroimaging in OCD, researchers have started to combine both domains in the field of imaging genetics. Here, we conducted a systematic search of PubMed and Google Scholar literature for articles that address genetic imaging in OCD and related disorders (published through March 2014). We selected 8 publications that describe the combination of imaging genetics with OCD, and extended it with 43 publications of comorbid psychiatric disorders. The most promising findings of this systematic review point to the involvement of variants in genes involved in the serotonergic (5-HTTLPR, HTR2A), dopaminergic (COMT, DAT), and glutamatergic (SLC1A1, SAPAP) systems. However, the field of imaging genetics must be further explored, best through investigations that combine multimodal imaging techniques with genetic profiling, particularly profiling techniques that employ polygenetic approaches, with much larger sample sizes than have been used up to now.

  6. The Evolving Diagnostic and Genetic Landscapes of Autism Spectrum Disorder.

    PubMed

    Ziats, Mark N; Rennert, Owen M

    2016-01-01

    The autism spectrum disorders (ASD) are a heterogeneous set of neurodevelopmental syndromes defined by impairments in verbal and non-verbal communication, restricted social interaction, and the presence of stereotyped patterns of behavior. The prevalence of ASD is rising, and the diagnostic criteria and clinical perspectives on the disorder continue to evolve in parallel. Although the majority of individuals with ASD will not have an identifiable genetic cause, almost 25% of cases have identifiable causative DNA variants. The rapidly improving ability to identify genetic mutations because of advances in next generation sequencing, coupled with previous epidemiological studies demonstrating high heritability of ASD, have led to many recent attempts to identify causative genetic mutations underlying the ASD phenotype. However, although hundreds of mutations have been identified to date, they are either rare variants affecting only a handful of ASD patients, or are common variants in the general population conferring only a small risk for ASD. Furthermore, the genes implicated thus far are heterogeneous in their structure and function, hampering attempts to understand shared molecular mechanisms among all ASD patients; an understanding that is crucial for the development of targeted diagnostics and therapies. However, new work is beginning to suggest that the heterogeneous set of genes implicated in ASD may ultimately converge on a few common pathways. In this review, we discuss the parallel evolution of our diagnostic and genetic understanding of autism spectrum disorders, and highlight recent attempts to infer common biology underlying this complicated syndrome.

  7. The Evolving Diagnostic and Genetic Landscapes of Autism Spectrum Disorder

    PubMed Central

    Ziats, Mark N.; Rennert, Owen M.

    2016-01-01

    The autism spectrum disorders (ASD) are a heterogeneous set of neurodevelopmental syndromes defined by impairments in verbal and non-verbal communication, restricted social interaction, and the presence of stereotyped patterns of behavior. The prevalence of ASD is rising, and the diagnostic criteria and clinical perspectives on the disorder continue to evolve in parallel. Although the majority of individuals with ASD will not have an identifiable genetic cause, almost 25% of cases have identifiable causative DNA variants. The rapidly improving ability to identify genetic mutations because of advances in next generation sequencing, coupled with previous epidemiological studies demonstrating high heritability of ASD, have led to many recent attempts to identify causative genetic mutations underlying the ASD phenotype. However, although hundreds of mutations have been identified to date, they are either rare variants affecting only a handful of ASD patients, or are common variants in the general population conferring only a small risk for ASD. Furthermore, the genes implicated thus far are heterogeneous in their structure and function, hampering attempts to understand shared molecular mechanisms among all ASD patients; an understanding that is crucial for the development of targeted diagnostics and therapies. However, new work is beginning to suggest that the heterogeneous set of genes implicated in ASD may ultimately converge on a few common pathways. In this review, we discuss the parallel evolution of our diagnostic and genetic understanding of autism spectrum disorders, and highlight recent attempts to infer common biology underlying this complicated syndrome. PMID:27200076

  8. Ethical and social implications of genetic testing for communication disorders

    PubMed Central

    Arnos, Kathleen S.

    2013-01-01

    Advances in genetics and genomics have quickly led to clinical applications to human health which have far-reaching consequences at the individual and societal levels. These new technologies have allowed a better understanding of the genetic factors involved in a wide range of disorders. During the past decade, incredible progress has been made in the identification of genes involved in the normal process of hearing. The resulting clinical applications have presented consumers with new information and choices. Many of the same gene identification techniques are increasingly being applied to the investigation of complex disorders of speech and language. In parallel with gene identification, studies of the legal, ethical and psychosocial impacts of the clinical application of these advances and their influence on specific behaviors of individuals with communication disorders are paramount, but often lag behind. These studies will help to ensure that new technologies are introduced into clinical practice in a responsible manner. Learning outcomes As a result of this activity, the participant will be able to (1) explain the differences between Mendelian and complex forms of inheritance and why these differences complicate the ethical impact of genetic testing, (2) explain how publicly funded genome research through the Human Genome Project, the International HapMap Project and others have examined the ethical, legal and social implications of genome research, (3) list some of the ethical complexities of prenatal, newborn and predictive testing for various genetic disorders and (4) discuss the importance of evidence-based practice to the development of public policy for the introduction and clinical use of genetic tests. PMID:18452941

  9. Brain structure–function associations in multi-generational families genetically enriched for bipolar disorder

    PubMed Central

    Schür, Remmelt; Sjouwerman, Rachel; Service, Susan K.; Araya, Carmen; Araya, Xinia; Bejarano, Julio; Knowles, Emma; Gomez-Makhinson, Juliana; Lopez, Maria C.; Aldana, Ileana; Teshiba, Terri M.; Abaryan, Zvart; Al-Sharif, Noor B.; Navarro, Linda; Tishler, Todd A.; Altshuler, Lori; Bartzokis, George; Escobar, Javier I.; Glahn, David C.; Thompson, Paul M.; Lopez-Jaramillo, Carlos; Macaya, Gabriel; Molina, Julio; Reus, Victor I.; Sabatti, Chiara; Cantor, Rita M.; Freimer, Nelson B.; Bearden, Carrie E.

    2015-01-01

    Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain–behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain–behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18–87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain–behaviour associations and test whether brain–behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain–behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non

  10. Brain structure-function associations in multi-generational families genetically enriched for bipolar disorder.

    PubMed

    Fears, Scott C; Schür, Remmelt; Sjouwerman, Rachel; Service, Susan K; Araya, Carmen; Araya, Xinia; Bejarano, Julio; Knowles, Emma; Gomez-Makhinson, Juliana; Lopez, Maria C; Aldana, Ileana; Teshiba, Terri M; Abaryan, Zvart; Al-Sharif, Noor B; Navarro, Linda; Tishler, Todd A; Altshuler, Lori; Bartzokis, George; Escobar, Javier I; Glahn, David C; Thompson, Paul M; Lopez-Jaramillo, Carlos; Macaya, Gabriel; Molina, Julio; Reus, Victor I; Sabatti, Chiara; Cantor, Rita M; Freimer, Nelson B; Bearden, Carrie E

    2015-07-01

    Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain-behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain-behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18-87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain-behaviour associations and test whether brain-behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain-behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non-bipolar disorder family

  11. The epidemiology and genetics of binge eating disorder (BED).

    PubMed

    Davis, Caroline

    2015-12-01

    This narrative review provides an overview of the epidemiology of binge eating disorder (BED), highlighting the medical history of this disorder and its entry as an independent condition in the Feeding and Eating Disorders section of the recently published Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Estimates of prevalence are provided, as well as recognition that the female to male ratio is lower in BED than in other eating disorders. Evidence is also provided of the most common comorbidities of BED, including mood and anxiety disorders and a range of addiction disorders. In addition, discussion of the viewpoint that BED itself may be an addiction - at least in severe cases - is presented. Although the genetic study of BED is still in its infancy, current research is reviewed with a focus on certain neurotransmitter genes that regulate brain reward mechanisms. To date, a focal point of this research has been on the dopamine and the μ-opioid receptor genes. Preliminary evidence suggests that a predisposing risk factor for BED may be a heightened sensitivity to reward, which could manifest as a strong dopamine signal in the brain's striatal region. Caution is encouraged, however, in the interpretation of current findings, since samples are relatively small in much of the research. To date, no genome-wide association studies have focused exclusively on BED.

  12. Genetic disorders with both hearing loss and cardiovascular abnormalities.

    PubMed

    Belmont, John W; Craigen, William; Martinez, Hugo; Jefferies, John Lynn

    2011-01-01

    There has been a growing appreciation for conditions that affect hearing and which are accompanied by significant cardiovascular disorders. In this chapter we consider several broad classes of conditions including deafness due to abnormal structural development of the inner ear, those with physiological abnormalities in the inner ear sensory apparatus, and conditions with progressive loss of function of sensory cells or middle ear functions. Because of shared developmental controls, inner ear malformations are often associated with congenital heart defects and can be part of complex syndromes that affect other organs and neurodevelopmental outcome. Physiological disorders of the hair cells can lead to hearing loss and can be associated with cardiac arrhythmias, especially long QT syndrome. In addition, cellular energy defects such as mitochondrial disorders can affect maintenance of hair cells and are often associated with cardiomyopathy. Lysosomal storage diseases and other disorders affecting connective tissue can lead to chronic middle ear disease, with conductive hearing loss and also cause cardiac valve disease and/or cardiomyopathy. The genetic basis for these conditions is heterogeneous and includes chromosomal/genomic disorders, de novo dominant mutations, and familial dominant, autosomal-recessive, and mitochondrial (matrilineal) inheritance. Taken together, there are more than 100 individual genes implicated in genetic hearing impairment that are also associated with congenital and/or progressive cardiac abnormalities. These genes encode transcription factors, chromatin remodeling factors, components of signal transduction pathways, ion channels, mitochondrial proteins and assembly factors, extracellular matrix proteins, and enzymes involved in lysosomal functions.

  13. Genetic association between NRG1 and schizophrenia, major depressive disorder, bipolar disorder in Han Chinese population.

    PubMed

    Wen, Zujia; Chen, Jianhua; Khan, Raja Amjad Waheed; Song, Zhijian; Wang, Meng; Li, Zhiqiang; Shen, Jiawei; Li, Wenjin; Shi, Yongyong

    2016-04-01

    Schizophrenia, major depressive disorder, and bipolar disorder are three major psychiatric disorders affecting around 0.66%, 3.3%, and 1.5% of the Han Chinese population respectively. Several genetic linkage analyses and genome wide association studies identified NRG1 as a susceptibility gene of schizophrenia, which was validated by its role in neurodevelopment, glutamate, and other neurotransmitter receptor expression regulation. To further investigate whether NRG1 is a shared risk gene for major depressive disorder, bipolar disorder as well as schizophrenia, we performed an association study among 1,248 schizophrenia cases, 1,056 major depression cases, 1,344 bipolar disorder cases, and 1,248 controls. Totally 15 tag SNPs were genotyped and analyzed, and no population stratification was found in our sample set. Among the sites, rs4236710 (corrected Pgenotye  = 0.015) and rs4512342 (Pallele  = 0.03, Pgenotye  = 0.045 after correction) were associated with schizophrenia, and rs2919375 (corrected Pgenotye  = 0.004) was associated with major depressive disorder. The haplotype rs4512342-rs6982890 showed association with schizophrenia (P = 0.03 for haplotype "TC" after correction), and haplotype rs4531002-rs11989919 proved to be a shared risk factor for both major depressive disorder ("CC": corrected P = 0.009) and bipolar disorder ("CT": corrected P = 0.003). Our results confirmed that NRG1 was a shared common susceptibility gene for major mental disorders in Han Chinese population.

  14. A Searchable Database of Genetic Evidence for Psychiatric Disorders

    PubMed Central

    Konneker, Thomas; Barnes, Todd; Furberg, Helena; Losh, Molly; Bulik, Cynthia M.; Sullivan, Patrick F.

    2008-01-01

    This paper describes a new bioinformatic tool for use in psychiatric research, “SLEP” (Sullivan Lab Evidence Project). SLEP is a searchable archive of findings from psychiatric genetics that is freely available on the web for non-commercial use (http://slep.unc.edu). Via a simple interface, users can retrieve findings from genomewide linkage, genomewide association, and microarray studies for ADHD, autism, bipolar disorder, eating disorders, major depression, nicotine dependence, and schizophrenia. Findings can be save to disk or viewed via a genome browser. PMID:18548508

  15. Genetic risk score analysis indicates migraine with and without comorbid depression are genetically different disorders.

    PubMed

    Ligthart, Lannie; Hottenga, Jouke-Jan; Lewis, Cathryn M; Farmer, Anne E; Craig, Ian W; Breen, Gerome; Willemsen, Gonneke; Vink, Jacqueline M; Middeldorp, Christel M; Byrne, Enda M; Heath, Andrew C; Madden, Pamela A F; Pergadia, Michele L; Montgomery, Grant W; Martin, Nicholas G; Penninx, Brenda W J H; McGuffin, Peter; Boomsma, Dorret I; Nyholt, Dale R

    2014-02-01

    Migraine and major depressive disorder (MDD) are comorbid, moderately heritable and to some extent influenced by the same genes. In a previous paper, we suggested the possibility of causality (one trait causing the other) underlying this comorbidity. We present a new application of polygenic (genetic risk) score analysis to investigate the mechanisms underlying the genetic overlap of migraine and MDD. Genetic risk scores were constructed based on data from two discovery samples in which genome-wide association analyses (GWA) were performed for migraine and MDD, respectively. The Australian Twin Migraine GWA study (N = 6,350) included 2,825 migraine cases and 3,525 controls, 805 of whom met the diagnostic criteria for MDD. The RADIANT GWA study (N = 3,230) included 1,636 MDD cases and 1,594 controls. Genetic risk scores for migraine and for MDD were used to predict pure and comorbid forms of migraine and MDD in an independent Dutch target sample (NTR-NESDA, N = 2,966), which included 1,476 MDD cases and 1,058 migraine cases (723 of these individuals had both disorders concurrently). The observed patterns of prediction suggest that the 'pure' forms of migraine and MDD are genetically distinct disorders. The subgroup of individuals with comorbid MDD and migraine were genetically most similar to MDD patients. These results indicate that in at least a subset of migraine patients with MDD, migraine may be a symptom or consequence of MDD.

  16. Network dysfunction of emotional and cognitive processes in those at genetic risk of bipolar disorder.

    PubMed

    Breakspear, Michael; Roberts, Gloria; Green, Melissa J; Nguyen, Vinh T; Frankland, Andrew; Levy, Florence; Lenroot, Rhoshel; Mitchell, Philip B

    2015-11-01

    The emotional and cognitive vulnerabilities that precede the development of bipolar disorder are poorly understood. The inferior frontal gyrus-a key cortical hub for the integration of cognitive and emotional processes-exhibits both structural and functional changes in bipolar disorder, and is also functionally impaired in unaffected first-degree relatives, showing diminished engagement during inhibition of threat-related emotional stimuli. We hypothesized that this functional impairment of the inferior frontal gyrus in those at genetic risk of bipolar disorder reflects the dysfunction of broader network dynamics underlying the coordination of emotion perception and cognitive control. To test this, we studied effective connectivity in functional magnetic resonance imaging data acquired from 41 first-degree relatives of patients with bipolar disorder, 45 matched healthy controls and 55 participants with established bipolar disorder. Dynamic causal modelling was used to model the neuronal interaction between key regions associated with fear perception (the anterior cingulate), inhibition (the left dorsolateral prefrontal cortex) and the region upon which these influences converge, namely the inferior frontal gyrus. Network models that embodied non-linear, hierarchical relationships were the most strongly supported by data from our healthy control and bipolar participants. We observed a marked difference in the hierarchical influence of the anterior cingulate on the effective connectivity from the dorsolateral prefrontal cortex to the inferior frontal gyrus that is unique to the at-risk cohort. Non-specific, non-hierarchical mechanisms appear to compensate for this network disturbance. We thus establish a specific network disturbance suggesting dysfunction in the processes that support hierarchical relationships between emotion and cognitive control in those at high genetic risk for bipolar disorder.

  17. Disorder-specific genetic factors in obsessive-compulsive disorder: A comprehensive meta-analysis.

    PubMed

    Taylor, Steven

    2016-04-01

    Much remains to be learned about the etiology of obsessive-compulsive disorder (OCD). Twin studies suggest that it arises from both disorder-specific and non-specific genetic factors. To understand the etiology of OCD per se, it is necessary to identify disorder-specific factors. Previous research shows that OCD is associated with serotonin-related polymorphisms (5-HTTLPR coded as triallelic and HTR2A rs6311/rs6313) and, in males, a polymorphism involved in catecholamine modulation; COMT (rs4680). The present study is the first comprehensive meta-analysis to investigate whether these polymorphisms are specific to OCD. A meta-analysis was conducted for genetic association studies of OCD or any other psychiatric disorder, published in any language, in any country. A total of 551 studies were examined, of which 290 were included, consisting of 47,358 cases and 68,942 controls from case control studies, and 2,443 trios from family based studies. The main meta-analysis was limited to those disorders in which there were at least five datasets (studies or sub-studies) per disorder. Results confirmed that OCD is associated with polymorphisms of 5-HTTLPR, HTR2A, and, in males only, COMT. These polymorphisms were not associated with almost all other forms of psychopathology, including unipolar mood disorders, bipolar disorder, panic disorder, schizophrenia, and alcohol dependence. OCD, compared to most other disorders, had a significantly stronger association with particular alleles of each of the polymorphisms. Results did not differ across ancestral groups (Asian vs. Caucasian), designs (case control vs. family based), or diagnostic systems. Results suggest that the polymorphisms investigated in this study are relatively specific to OCD.

  18. The genetics of schizophrenia and bipolar disorder: dissecting psychosis.

    PubMed

    Craddock, N; O'Donovan, M C; Owen, M J

    2005-03-01

    Much work has been done to identify susceptibility genes in schizophrenia and bipolar disorder. Several well established linkages have emerged in schizophrenia. Strongly supported regions are 6p24-22, 1q21-22, and 13q32-34, while other promising regions include 8p21-22, 6q16-25, 22q11-12, 5q21-q33, 10p15-p11, and 1q42. Genomic regions of interest in bipolar disorder include 6q16-q22, 12q23-q24, and regions of 9p22-p21, 10q21-q22, 14q24-q32, 13q32-q34, 22q11-q22, and chromosome 18. Recently, specific genes or loci have been implicated in both disorders and, crucially, replicated. Current evidence supports NRG1, DTNBP1, DISC1, DAOA(G72), DAO, and RGS4 as schizophrenia susceptibility loci. For bipolar disorder the strongest evidence supports DAOA(G72) and BDNF. Increasing evidence suggests an overlap in genetic susceptibility across the traditional classification systems that dichotomised psychotic disorders into schizophrenia or bipolar disorder, most notably with association findings at DAOA(G72), DISC1, and NRG1. Future identification of psychosis susceptibility genes will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry.

  19. Genetic approaches to understanding post-traumatic stress disorder

    PubMed Central

    Almli, Lynn M.; Fani, Negar; Smith, Alicia K.; Ressler, Kerry J.

    2015-01-01

    Post-traumatic stress disorder (PTSD) is increasingly recognized as both a disorder of enormous mental health and societal burden, but also as an anxiety disorder that may be particularly understandable from a scientific perspective. Specifically, PTSD can be conceptualized as a disorder of fear and stress dysregulation, and the neural circuitry underlying these pathways in both animals and humans are becoming increasingly well understood. Furthermore, PTSD is the only disorder in psychiatry in which the initiating factor, the trauma exposure, can be identified. Thus, the pathophysiology of the fear and stress response underlying PTSD can be examined and potentially interrupted. Twin studies have shown that the development of PTSD following a trauma is heritable, and that genetic risk factors may account for up to 30–40% of this heritability. A current goal is to understand the gene pathways that are associated with PTSD, and how those genes act on the fear/stress circuitry to mediate risk vs. resilience for PTSD. This review will examine gene pathways that have recently been analysed, primarily through candidate gene studies (including neuroimaging studies of candidate genes), in addition to genome-wide associations and the epigenetic regulation of PTSD. Future and on-going studies are utilizing larger and collaborative cohorts to identify novel gene candidates through genome-wide association and other powerful genomic approaches. Identification of PTSD biological pathways strengthens the hope of progress in the mechanistic understanding of a model psychiatric disorder and allows for the development of targeted treatments and interventions. PMID:24103155

  20. Parkinsonism, movement disorders and genetics in frontotemporal dementia.

    PubMed

    Baizabal-Carvallo, José Fidel; Jankovic, Joseph

    2016-03-01

    Frontotemporal dementia (FTD) refers to a group of clinically and genetically heterogeneous neurodegenerative disorders that are a common cause of adult-onset behavioural and cognitive impairment. FTD often presents in combination with various hyperkinetic or hypokinetic movement disorders, and evidence suggests that various genetic mutations underlie these different presentations. Here, we review the known syndromatic-genetic correlations in FTD. Although no direct genotype-phenotype correlations have been identified, mutations in multiple genes have been associated with various presentations. Mutations in the genes that encode microtubule-associated protein tau (MAPT) and progranulin (PGRN) can manifest as symmetrical parkinsonism, including the phenotypes of Richardson syndrome and corticobasal syndrome (CBS). Expansions in the C9orf72 gene are most frequently associated with familial FTD, typically combined with motor neuron disease, but other manifestations, such as symmetrical parkinsonism, CBS and multiple system atrophy-like presentations, have been described in patients with these mutations. Less common gene mutations, such as those in TARDBP, CHMP2B, VCP, FUS and TREM2, can also present as atypical parkinsonism. The most common hyperkinetic movement disorders in FTD are motor and vocal stereotypies, which have been observed in up to 78% of patients with autopsy-proven FTD. Other hyperkinetic movements, such as chorea, orofacial dyskinesias, myoclonus and dystonia, are also observed in some patients with FTD.

  1. Genetic Disorders of the Skeleton: A Developmental Approach

    PubMed Central

    Kornak, Uwe; Mundlos, Stefan

    2003-01-01

    Although disorders of the skeleton are individually rare, they are of clinical relevance because of their overall frequency. Many attempts have been made in the past to identify disease groups in order to facilitate diagnosis and to draw conclusions about possible underlying pathomechanisms. Traditionally, skeletal disorders have been subdivided into dysostoses, defined as malformations of individual bones or groups of bones, and osteochondrodysplasias, defined as developmental disorders of chondro-osseous tissue. In light of the recent advances in molecular genetics, however, many phenotypically similar skeletal diseases comprising the classical categories turned out not to be based on defects in common genes or physiological pathways. In this article, we present a classification based on a combination of molecular pathology and embryology, taking into account the importance of development for the understanding of bone diseases. PMID:12900795

  2. Keratinization Disorders and Genetic Aspects in Palmar and Plantar Keratodermas.

    PubMed

    Stypczyńska, Ewa; Placek, Waldemar; Zegarska, Barbara; Czajkowski, Rafał

    2016-06-01

    Palmoplantar keratoderma (PPK) is a heterogeneous group of hereditary and acquired disorders characterized by abnormal thickening of the palms and soles. There are three clinical patterns: diffuse, focal, and punctuate. Palmoplantar keratodermas can be divided into the following functional subgroups: disturbed gene functions in structural proteins (keratins), cornified envelope (loricrin, transglutaminase), cohesion (plakophilin, desmoplakin, desmoglein 1), cell-to-cell communication (connexins) and transmembrane signal transduction (cathepsin C). Unna-Thost disease is the most common variety of hereditary PPK. Mutations in keratin 1 have been reported in Unna-Thost disease. We report 12 cases in which Unna-Thost disease was diagnosed. Genealogical study demonstrated that the genodermatosis was a familial disease inherited as an autosomal dominant disorder. Dermatological examination revealed yellowish hyperkeratosis on the palms and soles. Oral mucosa, teeth, and nails remained unchanged. Histopathological examination of the biopsy sample taken from the soles of the patients showed orthokeratotic keratosis, hypergranulosis, and acanthosis without epidermolysis.

  3. Genetic and Immunologic Aspects of Sleep and Sleep Disorders

    PubMed Central

    2013-01-01

    The study of genetics is providing new and exciting insights into the pathogenesis, diagnosis, and treatment of disease. Both normal sleep and several types of sleep disturbances have been found to have significant genetic influences, as have traits of normal sleep, such as those evident in EEG patterns and the circadian sleep-wake cycle. The circadian sleep-wake cycle is based on a complex feedback loop of genetic transcription over a 24-h cycle. Restless legs syndrome (RLS) and periodic limb movements in sleep (PLMS) have familial aggregation, and several genes have a strong association with them. Recent genome-wide association studies have identified single nucleotide polymorphisms linked to RLS/PLMS, although none has a definite functional correlation. Narcolepsy/cataplexy are associated with HLA DQB1*0602 and a T-cell receptor α locus, although functional correlations have not been evident. Obstructive sleep apnea is a complex disorder involving multiple traits, such as anatomy of the oropharynx, ventilatory control, and traits associated with obesity. Although there is clear evidence of familial aggregation in the obstructive sleep apnea syndrome, no specific gene or locus has been identified for it. Angiotensin-converting enzyme has been proposed as a risk variant, but evidence is weak. Fatal familial insomnia and advanced sleep phase syndrome are sleep disorders with a definite genetic basis. PMID:23648914

  4. Additive genetic contribution to symptom dimensions in major depressive disorder.

    PubMed

    Pearson, Rahel; Palmer, Rohan H C; Brick, Leslie A; McGeary, John E; Knopik, Valerie S; Beevers, Christopher G

    2016-05-01

    Major depressive disorder (MDD) is a phenotypically heterogeneous disorder with a complex genetic architecture. In this study, genomic-relatedness-matrix restricted maximum-likelihood analysis (GREML) was used to investigate the extent to which variance in depression symptoms/symptom dimensions can be explained by variation in common single nucleotide polymorphisms (SNPs) in a sample of individuals with MDD (N = 1,558) who participated in the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. A principal components analysis of items from the Hamilton Rating Scale for Depression (HRSD) obtained prior to treatment revealed 4 depression symptom components: (a) appetite, (b) core depression symptoms (e.g., depressed mood, anhedonia), (c) insomnia, and (d) anxiety. These symptom dimensions were associated with SNP-based heritability (hSNP2) estimates of 30%, 14%, 30%, and 5%, respectively. Results indicated that the genetic contribution of common SNPs to depression symptom dimensions were not uniform. Appetite and insomnia symptoms in MDD had a relatively strong genetic contribution whereas the genetic contribution was relatively small for core depression and anxiety symptoms. While in need of replication, these results suggest that future gene discovery efforts may strongly benefit from parsing depression into its constituent parts. (PsycINFO Database Record

  5. Toward a genetically-informed model of borderline personality disorder.

    PubMed

    Livesley, John

    2008-02-01

    This article describes a conceptual framework for describing borderline personality disorder (BPD) based on empirical studies of the phenotypic structure and genetic architecture of personality. The proposed phenotype has 2 components: (1) a description of core self and interpersonal pathology-the defining features of personality disorder-as these features are expressed in the disorder; and (2) a set of traits based on the anxious-dependent or emotional dysregulation factor of the four-factor model of PD. Four kinds of traits are described: emotional (anxiousness, emotional reactivity, emotional intensity, and pessimistic-anhedonia), interpersonal (submissiveness, insecure attachment, social apprehensiveness, and need for approval), cognitive (cognitive dysregulation), and self-harm (behaviors and ideas). Formulation of the phenotype was guided by the conceptualization of personality as a system of interrelated sub-systems. The psychopathology associated with BPD involves most components of the system. The trait structure of the disorder is assumed to reflect the genetic architecture of personality and individual traits are assumed to be based on adaptive mechanisms. It is suggested that borderline traits are organized around the trait of anxiousness and that an important feature of BPD is dysregulation of the threat management system leading to pervasive fearfulness and unstable emotions. The interpersonal traits are assumed to be heritable characteristics that evolved to deal with interpersonal threats that arose as a result of social living. The potential for unstable and conflicted interpersonal relationships that is inherent to the disorder is assumed to result from the interplay between the adaptive structure of personality and psychosocial adversity. The etiology of the disorder is discussed in terms of biological and environmental factors associated with each component of the phenotype.

  6. Understanding the covariation among childhood externalizing symptoms: genetic and environmental influences on conduct disorder, attention deficit hyperactivity disorder, and oppositional defiant disorder symptoms.

    PubMed

    Dick, Danielle M; Viken, Richard J; Kaprio, Jaakko; Pulkkinen, Lea; Rose, Richard J

    2005-04-01

    Conduct disorder (CD), attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD) are common childhood externalizing disorders that frequently co-occur. However, the causes of their comorbidity are not well understood. To address that question, we analyzed data from >600 Finnish twin pairs, who completed standardized interviews at age 14. Behavior genetic methods were used to examine how genetic/environmental factors contribute to each disorder's symptoms and to their covariation. We found significant genetic effects on each disorder with only modest evidence of shared environmental influences. Our data suggest the comorbidity among CD, ADHD, and ODD is primarily explained by shared genetic influences; however, each disorder was also under unique genetic influence, supporting the distinction of each disorder.

  7. Skeleton Genetics: a comprehensive database for genes and mutations related to genetic skeletal disorders

    PubMed Central

    Chen, Chong; Jiang, Yi; Xu, Chenyang; Liu, Xinting; Hu, Lin; Xiang, Yanbao; Chen, Qingshuang; Chen, Denghui; Li, Huanzheng; Xu, Xueqin; Tang, Shaohua

    2016-01-01

    Genetic skeletal disorders (GSD) involving the skeletal system arises through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their clinical heterogeneity and genetic variety. Over the past decades, tremendous effort platforms have been made to explore the complex heterogeneity, and massive new genes and mutations have been identified in different GSD, but the information supplied by literature is still limited and it is hard to meet the further needs of scientists and clinicians. In this study, combined with Nosology and Classification of genetic skeletal disorders, we developed the first comprehensive and annotated genetic skeletal disorders database, named ‘SkeletonGenetics’, which contains information about all GSD-related knowledge including 8225 mutations in 357 genes, with detailed information associated with 481 clinical diseases (2260 clinical phenotype) classified in 42 groups defined by molecular, biochemical and/or radiographic criteria from 1698 publications. Further annotations were performed to each entry including Gene Ontology, pathways analysis, protein–protein interaction, mutation annotations, disease–disease clustering and gene–disease networking. Furthermore, using concise search methods, intuitive graphical displays, convenient browsing functions and constantly updatable features, ‘SkeletonGenetics’ could serve as a central and integrative database for unveiling the genetic and pathways pre-dispositions of GSD. Database URL: http://101.200.211.232/skeletongenetics/ PMID:27580923

  8. Acquired epileptiform aphasia: a dimensional view of Landau-Kleffner syndrome and the relation to regressive autistic spectrum disorders.

    PubMed

    Stefanatos, Gerry A; Kinsbourne, Marcel; Wasserstein, Jeanette

    2002-09-01

    Acquired epileptiform aphasia (AEA) is characterized by deterioration in language in childhood associated with seizures or epileptiform electroencephalographic abnormalities. Despite an extensive literature, discrepancies and contradictions surround its definition and nosological boundaries. This paper reviews current conceptions of AEA and highlights variations in the aphasic disturbance, age of onset, epileptiform EEG abnormalities, temporal course, and long-term outcome. We suggest that AEA, rather than being a discrete entity, is comprised of multiple variants that have in common the features of language regression and epileptiform changes on EEG. Viewed this way, we argue that AEA can be conceptualized on a spectrum with other epileptiform neurocognitive disorders that may share pathophysiological features. The implications of this viewpoint are discussed, with emphasis on parallels between the AEA variants and regressive autistic spectrum disorders.

  9. Famous people and genetic disorders: from monarchs to geniuses--a portrait of their genetic illnesses.

    PubMed

    Ho, Nicola C; Park, Susan S; Maragh, Kevin D; Gutter, Emily M

    2003-04-15

    Famous people with genetic disorders have always been a subject of interest because such news feeds the curiosity the public has for celebrities. It gives further insight into their lives and provides a medical basis for any unexplained or idiosyncratic feature or behavior they exhibit. It draws admiration from society of those who excel in their specialized fields despite the impositions of their genetic illnesses and also elicits sympathy even in the most casual observer. Such news certainly catapults a rare genetic disorder into the realm of public awareness. We hereby present six famous figures: King George III, Toulouse-Lautrec, Queen Victoria, Nicolo Paganini, Abraham Lincoln, and Vincent van Gogh, all of whom made a huge indelible mark in either the history of politics or that of the arts.

  10. Acquiring a Pet Dog Significantly Reduces Stress of Primary Carers for Children with Autism Spectrum Disorder: A Prospective Case Control Study

    ERIC Educational Resources Information Center

    Wright, H. F.; Hall, S.; Hames, A.; Hardiman, J.; Mills, R.; Mills, D. S.

    2015-01-01

    This study describes the impact of pet dogs on stress of primary carers of children with Autism Spectrum Disorder (ASD). Stress levels of 38 primary carers acquiring a dog and 24 controls not acquiring a dog were sampled at: Pre-intervention (17 weeks before acquiring a dog), post-intervention (3-10 weeks after acquisition) and follow-up…

  11. Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders.

    PubMed

    Soejima, Hidenobu; Higashimoto, Ken

    2013-07-01

    Genomic imprinting is an epigenetic phenomenon that leads to parent-specific differential expression of a subset of genes. Most imprinted genes form clusters, or imprinting domains, and are regulated by imprinting control regions. As imprinted genes have an important role in growth and development, aberrant expression of imprinted genes due to genetic or epigenetic abnormalities is involved in the pathogenesis of human disorders, or imprinting disorders. Beckwith-Wiedemann syndrome (BWS) is a representative imprinting disorder characterized by macrosomia, macroglossia and abdominal wall defects, and exhibits a predisposition to tumorigenesis. The relevant imprinted chromosomal region in BWS is 11p15.5, which consists of two imprinting domains, IGF2/H19 and CDKN1C/KCNQ1OT1. BWS has five known causative epigenetic and genetic alterations: loss of methylation (LOM) at KvDMR1, gain of methylation (GOM) at H19DMR, paternal uniparental disomy, CDKN1C mutations and chromosomal rearrangements. Opposite methylation defects, GOM and LOM, at H19DMR are known to cause clinically opposite disorders: BWS and Silver-Russell syndrome, respectively. Interestingly, a recent study discovered that loss of function or gain of function of CDKN1C also causes clinically opposite disorders, BWS and IMAGe (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genital anomalies) syndrome, respectively. Furthermore, several clinical studies have suggested a relationship between assisted reproductive technology (ART) and the risk of imprinting disorders, along with the existence of trans-acting factors that regulate multiple imprinted differentially methylated regions. In this review, we describe the latest knowledge surrounding the imprinting mechanism of 11p15.5, in addition to epigenetic and genetic etiologies of BWS, associated childhood tumors, the effects of ART and multilocus hypomethylation disorders.

  12. Sexual Orientation and Gender as Factors in Socioculturally Acquired Vulnerability to Body Dissatisfaction and Eating Disorders.

    ERIC Educational Resources Information Center

    Siever, Michael D.

    1994-01-01

    Investigated hypothesis that gay men and heterosexual women are dissatisfied with their bodies and vulnerable to eating disorders because of shared emphasis on physical attractiveness and thinness based on desire to please men. Findings from 53 lesbian, 59 gay, 62 heterosexual female, and 63 heterosexual male college students generally confirmed…

  13. The anatomical foundations of acquired reading disorders: a neuropsychological verification of the dual-route model of reading.

    PubMed

    Ripamonti, E; Aggujaro, S; Molteni, F; Zonca, G; Frustaci, M; Luzzatti, C

    2014-07-01

    In this study we investigated the neural correlates of acquired reading disorders through an anatomo-correlative procedure of the lesions of 59 focal brain damaged patients suffering from acquired surface, phonological, deep, undifferentiated dyslexia and pure alexia. Two reading tasks, one of words and nonwords and one of words with unpredictable stress position, were used for this study. We found that surface dyslexia was predominantly associated with left temporal lesions, while in phonological dyslexia the lesions overlapped in the left insula and the left inferior frontal gyrus (pars opercularis) and that pure alexia was associated with lesions in the left fusiform gyrus. A number of areas and white matter tracts, which seemed to involve processing along both the lexical and the sublexical routes, were identified for undifferentiated dyslexia. Two cases of deep dyslexia with relatively dissimilar anatomical correlates were studied, one compatible with Coltheart's right-hemisphere hypothesis (1980) whereas the other could be interpreted in the context of Morton and Patterson's (1980), multiply-damaged left-hemisphere hypothesis. In brief, the results of this study are only partially consistent with the current state of the art, and propose new and stimulating challenges; indeed, based on these results we suggest that different types of acquired dyslexia may ensue after different cortical damage, but white matter disconnection may play a crucial role in some cases.

  14. Management of developmental speech and language disorders. Part 2: acquired conditions.

    PubMed

    O'Hare, Anne

    2016-03-01

    Many children who present with these acquired impairments of communication have a clear preceding event such as an acquired brain injury from a road traffic accident. Children often respond differently in this situation to adult presentations. They may have a period of mutism when the prognosis might look poor and yet they subsequently make rapid progress and recover speech. They have greater potential for neural plasticity and language recovery, although they often have persisting difficulties in oral and written language. Alternatively, there may be a presentation with a paroxysmal event such as a seizure or a period of depressed consciousness, and the unusual behaviour that may accompany dysphasia and dysarthria may be misinterpreted in the child, whereas for the adult with the more common 'stroke-like' presentation, it would be immediately considered. Rarely the aphasia/dysphasia may itself be the paroxysmal event where actually recognising that the child's disrupted communication is the basis of any observed behaviours can be the greater challenge.

  15. B-cell Lymphoproliferative Disorders Associated with Primary and Acquired Immunodeficiency.

    PubMed

    Low, Lawrence K; Song, Joo Y

    2016-03-01

    The diagnosis of lymphoproliferative disorders associated with immunodeficiency can be challenging because many of these conditions have overlapping clinical and pathologic features and share similarities with their counterparts in the immunocompetent setting. There are subtle but important differences between these conditions that are important to recognize for prognostic and therapeutic purposes. This article provides a clinicopathologic update on how understanding of these B-cell lymphoproliferations in immunodeficiency has evolved over the past decade.

  16. Percept-genetic signs of repression in histrionic personality disorder.

    PubMed

    Rubino, I A; Saya, A; Pezzarossa, B

    1992-04-01

    Several types of perceptual distortions of two anxiety-arousing visual stimuli are coded as repression in the Defense Mechanism Test, a tachistoscopic, percept-genetic technique. Given the well-established correspondence between hysteria and repression, the study included a clinical validation of these variants of repression against the diagnosis of histrionic personality disorder. 41 subjects with evidence of this disorder on the Millon Clinical Multiaxial Inventory-II were compared with 41 nonhistrionic controls. Significantly more histrionics were coded for the type of repression in which the threatening figure is transformed into a harmless object (code 1:42), while animal- and statue-repressions, when combined (codes 1:1 and 1:2), were significantly more characteristic of the nonhistrionic group. As an unpredicted finding, significantly more histrionic subjects employed defensive strategies, currently coded as reaction formations (code 4:). Histrionic subjects without concomitant compulsive features were coded more frequently for introaggression (code 6:) compared both with nonhistrionic controls and with histrionic-compulsive subjects. The findings are discussed within the context of the available percept-genetic literature. It is suggested that the Defense Mechanism Test may be further employed to objectify and investigate the defense mechanisms of the DSM-III-R disorders.

  17. Overview of genetics and obsessive-compulsive disorder.

    PubMed

    Nicolini, Humberto; Arnold, Paul; Nestadt, Gerald; Lanzagorta, Nuria; Kennedy, James L

    2009-11-30

    This paper reviews the current state of research into the genetics of obsessive-compulsive disorder (OCD). Heredity has a major role in OCD etiology. This evidence comes from several methodological approaches such as family, twin, and segregation analysis studies. A major single gene effect as well as a polygenic hypothesis has been suggested based on segregation studies. In addition, candidate gene association and linkage analyses have shown not only one gene, but a few interesting genes and areas of the genome that may be relevant in OCD. In this search for genes, new definitions of the OCD phenotype have emerged, and some of them may be considered intermediate phenotypes between the gene effect and OCD-DSM-IV diagnosis. The phenotypic and genetic heterogeneity of OCD magnifies the challenge of locating susceptibility genes; at the same time, the identification of vulnerability genes will elucidate the identification of subtypes or dimensions of the disorder. Therefore research strategies that take advantage of clinical subtyping and that redefine the OCD phenotype in the context of genetic studies may potentially contribute to the nosology of OCD and ultimately pathophysiology. There is a lack of understanding about how genes and environment interact in OCD. However, there are some reports that will be discussed, which have attempted to evaluate how the environment contributes to OCD.

  18. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.

    PubMed

    Lee, S Hong; Ripke, Stephan; Neale, Benjamin M; Faraone, Stephen V; Purcell, Shaun M; Perlis, Roy H; Mowry, Bryan J; Thapar, Anita; Goddard, Michael E; Witte, John S; Absher, Devin; Agartz, Ingrid; Akil, Huda; Amin, Farooq; Andreassen, Ole A; Anjorin, Adebayo; Anney, Richard; Anttila, Verneri; Arking, Dan E; Asherson, Philip; Azevedo, Maria H; Backlund, Lena; Badner, Judith A; Bailey, Anthony J; Banaschewski, Tobias; Barchas, Jack D; Barnes, Michael R; Barrett, Thomas B; Bass, Nicholas; Battaglia, Agatino; Bauer, Michael; Bayés, Mònica; Bellivier, Frank; Bergen, Sarah E; Berrettini, Wade; Betancur, Catalina; Bettecken, Thomas; Biederman, Joseph; Binder, Elisabeth B; Black, Donald W; Blackwood, Douglas H R; Bloss, Cinnamon S; Boehnke, Michael; Boomsma, Dorret I; Breen, Gerome; Breuer, René; Bruggeman, Richard; Cormican, Paul; Buccola, Nancy G; Buitelaar, Jan K; Bunney, William E; Buxbaum, Joseph D; Byerley, William F; Byrne, Enda M; Caesar, Sian; Cahn, Wiepke; Cantor, Rita M; Casas, Miguel; Chakravarti, Aravinda; Chambert, Kimberly; Choudhury, Khalid; Cichon, Sven; Cloninger, C Robert; Collier, David A; Cook, Edwin H; Coon, Hilary; Cormand, Bru; Corvin, Aiden; Coryell, William H; Craig, David W; Craig, Ian W; Crosbie, Jennifer; Cuccaro, Michael L; Curtis, David; Czamara, Darina; Datta, Susmita; Dawson, Geraldine; Day, Richard; De Geus, Eco J; Degenhardt, Franziska; Djurovic, Srdjan; Donohoe, Gary J; Doyle, Alysa E; Duan, Jubao; Dudbridge, Frank; Duketis, Eftichia; Ebstein, Richard P; Edenberg, Howard J; Elia, Josephine; Ennis, Sean; Etain, Bruno; Fanous, Ayman; Farmer, Anne E; Ferrier, I Nicol; Flickinger, Matthew; Fombonne, Eric; Foroud, Tatiana; Frank, Josef; Franke, Barbara; Fraser, Christine; Freedman, Robert; Freimer, Nelson B; Freitag, Christine M; Friedl, Marion; Frisén, Louise; Gallagher, Louise; Gejman, Pablo V; Georgieva, Lyudmila; Gershon, Elliot S; Geschwind, Daniel H; Giegling, Ina; Gill, Michael; Gordon, Scott D; Gordon-Smith, Katherine; Green, Elaine K; Greenwood, Tiffany A; Grice, Dorothy E; Gross, Magdalena; Grozeva, Detelina; Guan, Weihua; Gurling, Hugh; De Haan, Lieuwe; Haines, Jonathan L; Hakonarson, Hakon; Hallmayer, Joachim; Hamilton, Steven P; Hamshere, Marian L; Hansen, Thomas F; Hartmann, Annette M; Hautzinger, Martin; Heath, Andrew C; Henders, Anjali K; Herms, Stefan; Hickie, Ian B; Hipolito, Maria; Hoefels, Susanne; Holmans, Peter A; Holsboer, Florian; Hoogendijk, Witte J; Hottenga, Jouke-Jan; Hultman, Christina M; Hus, Vanessa; Ingason, Andrés; Ising, Marcus; Jamain, Stéphane; Jones, Edward G; Jones, Ian; Jones, Lisa; Tzeng, Jung-Ying; Kähler, Anna K; Kahn, René S; Kandaswamy, Radhika; Keller, Matthew C; Kennedy, James L; Kenny, Elaine; Kent, Lindsey; Kim, Yunjung; Kirov, George K; Klauck, Sabine M; Klei, Lambertus; Knowles, James A; Kohli, Martin A; Koller, Daniel L; Konte, Bettina; Korszun, Ania; Krabbendam, Lydia; Krasucki, Robert; Kuntsi, Jonna; Kwan, Phoenix; Landén, Mikael; Långström, Niklas; Lathrop, Mark; Lawrence, Jacob; Lawson, William B; Leboyer, Marion; Ledbetter, David H; Lee, Phil H; Lencz, Todd; Lesch, Klaus-Peter; Levinson, Douglas F; Lewis, Cathryn M; Li, Jun; Lichtenstein, Paul; Lieberman, Jeffrey A; Lin, Dan-Yu; Linszen, Don H; Liu, Chunyu; Lohoff, Falk W; Loo, Sandra K; Lord, Catherine; Lowe, Jennifer K; Lucae, Susanne; MacIntyre, Donald J; Madden, Pamela A F; Maestrini, Elena; Magnusson, Patrik K E; Mahon, Pamela B; Maier, Wolfgang; Malhotra, Anil K; Mane, Shrikant M; Martin, Christa L; Martin, Nicholas G; Mattheisen, Manuel; Matthews, Keith; Mattingsdal, Morten; McCarroll, Steven A; McGhee, Kevin A; McGough, James J; McGrath, Patrick J; McGuffin, Peter; McInnis, Melvin G; McIntosh, Andrew; McKinney, Rebecca; McLean, Alan W; McMahon, Francis J; McMahon, William M; McQuillin, Andrew; Medeiros, Helena; Medland, Sarah E; Meier, Sandra; Melle, Ingrid; Meng, Fan; Meyer, Jobst; Middeldorp, Christel M; Middleton, Lefkos; Milanova, Vihra; Miranda, Ana; Monaco, Anthony P; Montgomery, Grant W; Moran, Jennifer L; Moreno-De-Luca, Daniel; Morken, Gunnar; Morris, Derek W; Morrow, Eric M; Moskvina, Valentina; Muglia, Pierandrea; Mühleisen, Thomas W; Muir, Walter J; Müller-Myhsok, Bertram; Murtha, Michael; Myers, Richard M; Myin-Germeys, Inez; Neale, Michael C; Nelson, Stan F; Nievergelt, Caroline M; Nikolov, Ivan; Nimgaonkar, Vishwajit; Nolen, Willem A; Nöthen, Markus M; Nurnberger, John I; Nwulia, Evaristus A; Nyholt, Dale R; O'Dushlaine, Colm; Oades, Robert D; Olincy, Ann; Oliveira, Guiomar; Olsen, Line; Ophoff, Roel A; Osby, Urban; Owen, Michael J; Palotie, Aarno; Parr, Jeremy R; Paterson, Andrew D; Pato, Carlos N; Pato, Michele T; Penninx, Brenda W; Pergadia, Michele L; Pericak-Vance, Margaret A; Pickard, Benjamin S; Pimm, Jonathan; Piven, Joseph; Posthuma, Danielle; Potash, James B; Poustka, Fritz; Propping, Peter; Puri, Vinay; Quested, Digby J; Quinn, Emma M; Ramos-Quiroga, Josep Antoni; Rasmussen, Henrik B; Raychaudhuri, Soumya; Rehnström, Karola; Reif, Andreas; Ribasés, Marta; Rice, John P; Rietschel, Marcella; Roeder, Kathryn; Roeyers, Herbert; Rossin, Lizzy; Rothenberger, Aribert; Rouleau, Guy; Ruderfer, Douglas; Rujescu, Dan; Sanders, Alan R; Sanders, Stephan J; Santangelo, Susan L; Sergeant, Joseph A; Schachar, Russell; Schalling, Martin; Schatzberg, Alan F; Scheftner, William A; Schellenberg, Gerard D; Scherer, Stephen W; Schork, Nicholas J; Schulze, Thomas G; Schumacher, Johannes; Schwarz, Markus; Scolnick, Edward; Scott, Laura J; Shi, Jianxin; Shilling, Paul D; Shyn, Stanley I; Silverman, Jeremy M; Slager, Susan L; Smalley, Susan L; Smit, Johannes H; Smith, Erin N; Sonuga-Barke, Edmund J S; St Clair, David; State, Matthew; Steffens, Michael; Steinhausen, Hans-Christoph; Strauss, John S; Strohmaier, Jana; Stroup, T Scott; Sutcliffe, James S; Szatmari, Peter; Szelinger, Szabocls; Thirumalai, Srinivasa; Thompson, Robert C; Todorov, Alexandre A; Tozzi, Federica; Treutlein, Jens; Uhr, Manfred; van den Oord, Edwin J C G; Van Grootheest, Gerard; Van Os, Jim; Vicente, Astrid M; Vieland, Veronica J; Vincent, John B; Visscher, Peter M; Walsh, Christopher A; Wassink, Thomas H; Watson, Stanley J; Weissman, Myrna M; Werge, Thomas; Wienker, Thomas F; Wijsman, Ellen M; Willemsen, Gonneke; Williams, Nigel; Willsey, A Jeremy; Witt, Stephanie H; Xu, Wei; Young, Allan H; Yu, Timothy W; Zammit, Stanley; Zandi, Peter P; Zhang, Peng; Zitman, Frans G; Zöllner, Sebastian; Devlin, Bernie; Kelsoe, John R; Sklar, Pamela; Daly, Mark J; O'Donovan, Michael C; Craddock, Nicholas; Sullivan, Patrick F; Smoller, Jordan W; Kendler, Kenneth S; Wray, Naomi R

    2013-09-01

    Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.

  19. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

    PubMed Central

    2013-01-01

    Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17–29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn’s disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders. PMID:23933821

  20. Ethical and legal issues arising from complex genetic disorders. DOE final report

    SciTech Connect

    Andrews, Lori

    2002-10-09

    The project analyzed the challenges raised by complex genetic disorders in genetic counselling, for clinical practice, for public health, for quality assurance, and for protection against discrimination. The research found that, in some settings, solutions created in the context of single gene disorders are more difficult to apply to complex disorders. In other settings, the single gene solutions actually backfired and created additional problems when applied to complex genetic disorders. The literature of five common, complex genetic disorders--Alzheimer's, asthma, coronary heart disease, diabetes, and psychiatric illnesses--was evaluated in depth.

  1. Neurocognitive-genetic and neuroimaging-genetic research paradigms in schizophrenia and bipolar disorder.

    PubMed

    Kurnianingsih, Yoanna Arlina; Kuswanto, Carissa Nadia; McIntyre, Roger S; Qiu, Anqi; Ho, Beng Choon; Sim, Kang

    2011-11-01

    Studies examining intermediate phenotypes such as neurocognitive and neuroanatomical measures along with susceptibility genes are important for improving our understanding of the neural basis of schizophrenia (SZ) and bipolar disorder (BD). In this paper, we review extant studies involving neurocognitive-genetic and neuroimaging-genetic perspectives and particularly related to catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin-1 (NRG1) genes in SZ and BD. In terms of neurocognitive-genetic investigations, COMT and BDNF are the two most studied candidate genes especially in patients with SZ. Whereas BDNF Met carriers perform worse on verbal working memory, problem solving and visuo-spatial abilities, COMT Met carriers perform better in working memory, attention, executive functioning with evidence of genotype by diagnosis interactions including high-risk individuals. In terms of genetic-structural MRI studies, patients with SZ are found to have reductions in the frontal, temporal, parietal cortices, and limbic regions, which are associated with BDNF, COMT, and NRGI genes. Genetic-functional MRI studies in psychotic disorders are sparse, especially with regard to BD. These neurocognitive and neuroimaging findings are associated with genes which are implicated in functional pathways related to neuronal signaling, inter-neuronal communication and neuroplasticity.

  2. The genetics of schizophrenia and bipolar disorder: dissecting psychosis

    PubMed Central

    Craddock, N; O'Donovan, M; Owen, M

    2005-01-01

    Much work has been done to identify susceptibility genes in schizophrenia and bipolar disorder. Several well established linkages have emerged in schizophrenia. Strongly supported regions are 6p24–22, 1q21–22, and 13q32–34, while other promising regions include 8p21–22, 6q16–25, 22q11–12, 5q21–q33, 10p15–p11, and 1q42. Genomic regions of interest in bipolar disorder include 6q16–q22, 12q23–q24, and regions of 9p22–p21, 10q21–q22, 14q24–q32, 13q32–q34, 22q11–q22, and chromosome 18. Recently, specific genes or loci have been implicated in both disorders and, crucially, replicated. Current evidence supports NRG1, DTNBP1, DISC1, DAOA(G72), DAO, and RGS4 as schizophrenia susceptibility loci. For bipolar disorder the strongest evidence supports DAOA(G72) and BDNF. Increasing evidence suggests an overlap in genetic susceptibility across the traditional classification systems that dichotomised psychotic disorders into schizophrenia or bipolar disorder, most notably with association findings at DAOA(G72), DISC1, and NRG1. Future identification of psychosis susceptibility genes will have a major impact on our understanding of disease pathophysiology and will lead to changes in classification and the clinical practice of psychiatry. PMID:15744031

  3. Genetics of long-term treatment outcome in bipolar disorder.

    PubMed

    Fabbri, Chiara; Serretti, Alessandro

    2016-02-04

    Bipolar disorder (BD) shows one of the strongest genetic predispositions among psychiatric disorders and the identification of reliable genetic predictors of treatment response could significantly improve the prognosis of the disease. The present study investigated genetic predictors of long-term treatment-outcome in 723 patients with BD type I from the STEP-BD (Systematic Treatment Enhancement Program for Bipolar Disorder) genome-wide dataset. BD I patients with >6months of follow-up and without any treatment restriction (reflecting a natural setting scenario) were included. Phenotypes were the total and depressive episode rates and the occurrence of one or more (hypo)manic/mixed episodes during follow-up. Quality control of genome-wide data was performed according to standard criteria and linear/logistic regression models were used as appropriate under an additive hypothesis. Top genes were further analyzed through a pathway analysis. Genes previously involved in the susceptibility to BD (DFNB31, SORCS2, NRXN1, CNTNAP2, GRIN2A, GRM4, GRIN2B), antidepressant action (DEPTOR, CHRNA7, NRXN1), and mood stabilizer or antipsychotic action (NTRK2, CHRNA7, NRXN1) may affect long-term treatment outcome of BD. Promising findings without previous strong evidence were TRAF3IP2-AS1, NFYC, RNLS, KCNJ2, RASGRF1, NTF3 genes. Pathway analysis supported particularly the involvement of molecules mediating the positive regulation of MAPK cascade and learning/memory processes. Further studies focused on the outlined genes may be helpful to provide validated markers of BD treatment outcome.

  4. Obsessive-compulsive disorder: an integrative genetic and neurobiological perspective.

    PubMed

    Pauls, David L; Abramovitch, Amitai; Rauch, Scott L; Geller, Daniel A

    2014-06-01

    Obsessive-compulsive disorder (OCD) is characterized by repetitive thoughts and behaviours that are experienced as unwanted. Family and twin studies have demonstrated that OCD is a multifactorial familial condition that involves both polygenic and environmental risk factors. Neuroimaging studies have implicated the cortico-striato-thalamo-cortical circuit in the pathophysiology of the disorder, which is supported by the observation of specific neuropsychological impairments in patients with OCD, mainly in executive functions. Genetic studies indicate that genes affecting the serotonergic, dopaminergic and glutamatergic systems, and the interaction between them, play a crucial part in the functioning of this circuit. Environmental factors such as adverse perinatal events, psychological trauma and neurological trauma may modify the expression of risk genes and, hence, trigger the manifestation of obsessive-compulsive behaviours.

  5. Developmental dilatation of Virchow-Robin spaces: a genetic disorder?

    PubMed

    Bruna, Anne-Laure; Martins, Ilda; Husson, Beatrice; Landrieu, Pierre

    2009-10-01

    In childhood, widening of Virchow-Robin spaces is rarely secondary to specific progressive disorders, but more often appears in poorly characterized developmental conditions. From data collected in a neuropediatric department, we examined whether clinical data associated with "constitutional widening of Virchow-Robin spaces" allowed delineation of recognizable entities. Signs in 10 patients, mostly boys, suggested nonspecific cerebral dysfunctions, e.g., developmental delay, nonspecific epilepsy, headaches, or benign macrocephaly. Spaces were sometimes round, subsequently mimicking microcystic malacic lesions. In two patients, abnormal magnetic resonance imaging signals were evident in white matter contiguous to widened perivascular spaces, suggesting a broader disorder of fluid exchanges. Four cases occurred in two sibships. In two families, other patients exhibited early developmental difficulties. Long-term clinical and magnetic resonance imaging surveillance will clarify which cases of primary Virchow-Robin space dilatation imply a benign prognosis. Performance of magnetic resonance imaging on any relative exhibiting minor neuropsychologic handicaps would permit estimations of real genetic incidence.

  6. Genetic connections between neurological disorders and cholesterol metabolism

    PubMed Central

    Björkhem, Ingemar; Leoni, Valerio; Meaney, Steve

    2010-01-01

    Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Over the last decade, evidence has accumulated that disturbances in cholesterol metabolism are associated with the development of various neurological conditions. In addition to genetically defined defects in cholesterol synthesis, which will be covered in another review in this Thematic Series, defects in cholesterol metabolism (cerebrotendinous xanthomatosis) and intracellular transport (Niemann Pick Syndrome) lead to neurological disease. A subform of hereditary spastic paresis (type SPG5) and Huntington's disease are neurological diseases with mutations in genes that are of importance for cholesterol metabolism. Neurodegeneration is generally associated with disturbances in cholesterol metabolism, and presence of the E4 isoform of the cholesterol transporter apolipoprotein E as well as hypercholesterolemia are important risk factors for development of Alzheimer's disease. In the present review, we discuss the links between genetic disturbances in cholesterol metabolism and the above neurological disorders. PMID:20466796

  7. Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan

    PubMed Central

    2014-01-01

    Glycosaminoglycans (GAGs) are constructed through the stepwise addition of respective monosaccharides by various glycosyltransferases and maturated by epimerases and sulfotransferases. The structural diversity of GAG polysaccharides, including their sulfation patterns and sequential arrangements, is essential for a wide range of biological activities such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Studies using knockout mice of enzymes responsible for the biosynthesis of the GAG side chains of proteoglycans have revealed their physiological functions. Furthermore, mutations in the human genes encoding glycosyltransferases, sulfotransferases, and related enzymes responsible for the biosynthesis of GAGs cause a number of genetic disorders including chondrodysplasia, spondyloepiphyseal dysplasia, and Ehlers-Danlos syndromes. This review focused on the increasing number of glycobiological studies on knockout mice and genetic diseases caused by disturbances in the biosynthetic enzymes for GAGs. PMID:25126564

  8. Down syndrome--genetic and nutritional aspects of accompanying disorders.

    PubMed

    Mazurek, Dominika; Wyka, Joanna

    2015-01-01

    Down syndrome (DS) is one of the more commonly occurring genetic disorders, where mental retardation is combined with nutritional diseases. It is caused by having a third copy of chromosome 21, and there exist 3 forms; Simple Trisomy 21, Translocation Trisomy and Mosaic Trisomy. Symptoms include intellectual disability/mental retardation, early onset of Alzheimer's disease and the appearance of various phenotypic features such as narrow slanted eyes, flat nose and short stature. In addition, there are other health problems throughout the body, consisting in part of cardiac defects and thyroid function abnormalities along with nutritional disorders (ie. overweight, obesity, hypercholesterolemia and deficiencies of vitamins and minerals). Those suffering DS have widespread body frame abnormalities and impaired brain development and function; the latter leading to impaired intellectual development. Many studies indicate excessive or deficient nutrient uptakes associated with making inappropriate foodstuff choices, food intolerance, (eg. celiac disease) or malabsorption. DS persons with overweight or obesity are linked with a slow metabolic rate, abnormal blood leptin concentrations and exhibit low levels of physical activity. Vitamin B group deficiencies and abnormal blood homocysteine levels decrease the rate of intellectual development in DS cases. Zinc deficiencies result in short stature, thyroid function disorders and an increased appetite caused by excessive supplementation. Scientific advances in the research and diagnosis of DS, as well as preventing any associated conditions, have significantly increased life expectancies of those with this genetic disorder. Early dietary interventions by parents or guardians of DS children afford an opportunity for decreasing the risk or delaying some of the DS associated conditions from appearing, thus beneficially impacting on their quality of life.

  9. Neuromuscular disorders: genes, genetic counseling and therapeutic trials

    PubMed Central

    Zatz, Mayana; Passos-Bueno, Maria Rita; Vainzof, Mariz

    2016-01-01

    Abstract Neuromuscular disorders (NMD) are a heterogeneous group of genetic conditions, with autosomal dominant, recessive, or X-linked inheritance. They are characterized by progressive muscle degeneration and weakness. Here, we are presenting our major contributions to the field during the past 30 years. We have mapped and identified several novel genes responsible for NMD. Genotype-phenotype correlations studies enhanced our comprehension on the effect of gene mutations on related proteins and their impact on clinical findings. The search for modifier factors allowed the identification of a novel "protective"; variant which may have important implication on therapeutic developments. Molecular diagnosis was introduced in the 1980s and new technologies have been incorporated since then. Next generation sequencing greatly improved our capacity to identify disease-causing mutations with important benefits for research and prevention through genetic counseling of patients' families. Stem cells researches, from and for patients, have been used as tools to study human genetic diseases mechanisms and for therapies development. The clinical effect of preclinical trials in mice and canine models for muscular dystrophies are under investigation. Finally, the integration of our researches and genetic services with our post-graduation program resulted in a significant output of new geneticists, spreading out this expertise to our large country. PMID:27575431

  10. Genetic basis for natural and acquired resistance to the diarylquinoline R207910 in mycobacteria.

    PubMed

    Petrella, Stephanie; Cambau, Emmanuelle; Chauffour, Aurelie; Andries, Koen; Jarlier, Vincent; Sougakoff, Wladimir

    2006-08-01

    The atpE gene encoding the subunit c of the ATP synthase of Mycobacterium tuberculosis, the target of the new diarylquinoline drug R207910, has been sequenced from in vitro mutants resistant to the drug. The previously reported mutation A63P and a new mutation, I66M, were found. The genetic diversity of atpE in 13 mycobacterial species was also investigated, revealing that the region involved in resistance to R207910 is conserved, except in Mycobacterium xenopi in which the highly conserved residue Ala63 is replaced by Met, a modification that may be associated with the natural resistance of M. xenopi to R207910.

  11. Genetic Basis for Natural and Acquired Resistance to the Diarylquinoline R207910 in Mycobacteria

    PubMed Central

    Petrella, Stephanie; Cambau, Emmanuelle; Chauffour, Aurelie; Andries, Koen; Jarlier, Vincent; Sougakoff, Wladimir

    2006-01-01

    The atpE gene encoding the subunit c of the ATP synthase of Mycobacterium tuberculosis, the target of the new diarylquinoline drug R207910, has been sequenced from in vitro mutants resistant to the drug. The previously reported mutation A63P and a new mutation, I66M, were found. The genetic diversity of atpE in 13 mycobacterial species was also investigated, revealing that the region involved in resistance to R207910 is conserved, except in Mycobacterium xenopi in which the highly conserved residue Ala63 is replaced by Met, a modification that may be associated with the natural resistance of M. xenopi to R207910. PMID:16870785

  12. Genetic Predisposition To Acquire a Polybasic Cleavage Site for Highly Pathogenic Avian Influenza Virus Hemagglutinin.

    PubMed

    Nao, Naganori; Yamagishi, Junya; Miyamoto, Hiroko; Igarashi, Manabu; Manzoor, Rashid; Ohnuma, Aiko; Tsuda, Yoshimi; Furuyama, Wakako; Shigeno, Asako; Kajihara, Masahiro; Kishida, Noriko; Yoshida, Reiko; Takada, Ayato

    2017-02-14

    Highly pathogenic avian influenza viruses with H5 and H7 hemagglutinin (HA) subtypes evolve from low-pathogenic precursors through the acquisition of multiple basic amino acid residues at the HA cleavage site. Although this mechanism has been observed to occur naturally only in these HA subtypes, little is known about the genetic basis for the acquisition of the polybasic HA cleavage site. Here we show that consecutive adenine residues and a stem-loop structure, which are frequently found in the viral RNA region encoding amino acids around the cleavage site of low-pathogenic H5 and H7 viruses isolated from waterfowl reservoirs, are important for nucleotide insertions into this RNA region. A reporter assay to detect nontemplated nucleotide insertions and deep-sequencing analysis of viral RNAs revealed that an increased number of adenine residues and enlarged stem-loop structure in the RNA region accelerated the multiple adenine and/or guanine insertions required to create codons for basic amino acids. Interestingly, nucleotide insertions associated with the HA cleavage site motif were not observed principally in the viral RNA of other subtypes tested (H1, H2, H3, and H4). Our findings suggest that the RNA editing-like activity is the key mechanism for nucleotide insertions, providing a clue as to why the acquisition of the polybasic HA cleavage site is restricted to the particular HA subtypes.IMPORTANCE Influenza A viruses are divided into subtypes based on the antigenicity of the viral surface glycoproteins hemagglutinin (HA) and neuraminidase. Of the 16 HA subtypes (H1 to -16) maintained in waterfowl reservoirs of influenza A viruses, H5 and H7 viruses often become highly pathogenic through the acquisition of multiple basic amino acid residues at the HA cleavage site. Although this mechanism has been known since the 1980s, the genetic basis for nucleotide insertions has remained unclear. This study shows the potential role of the viral RNA secondary structure for

  13. Modeling AEC-New approaches to study rare genetic disorders.

    PubMed

    Koch, Peter J; Dinella, Jason; Fete, Mary; Siegfried, Elaine C; Koster, Maranke I

    2014-10-01

    Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is a rare monogenetic disorder that is characterized by severe abnormalities in ectoderm-derived tissues, such as skin and its appendages. A major cause of morbidity among affected infants is severe and chronic skin erosions. Currently, supportive care is the only available treatment option for AEC patients. Mutations in TP63, a gene that encodes key regulators of epidermal development, are the genetic cause of AEC. However, it is currently not clear how mutations in TP63 lead to the various defects seen in the patients' skin. In this review, we will discuss current knowledge of the AEC disease mechanism obtained by studying patient tissue and genetically engineered mouse models designed to mimic aspects of the disorder. We will then focus on new approaches to model AEC, including the use of patient cells and stem cell technology to replicate the disease in a human tissue culture model. The latter approach will advance our understanding of the disease and will allow for the development of new in vitro systems to identify drugs for the treatment of skin erosions in AEC patients. Further, the use of stem cell technology, in particular induced pluripotent stem cells (iPSC), will enable researchers to develop new therapeutic approaches to treat the disease using the patient's own cells (autologous keratinocyte transplantation) after correction of the disease-causing mutations.

  14. [Genetic findings in Attention-Deficit and Hyperactivity Disorder (ADHD)].

    PubMed

    Schimmelmann, Benno Graf; Friedel, Susann; Christiansen, Hanna; Dempfle, Astrid; Hinney, Anke; Hebebrand, Johannes

    2006-11-01

    Attention-Deficit and Hyperactivity Disorder (ADHD) is a common child and adolescent psychiatric disorder with a prevalence rate of 3-7%. Formal genetic studies provided an estimated heritability of 0.6-0.8 and an approximately five-fold elevated risk for ADHD in first-degree relatives. Currently, four genome scans have led to the identification of chromosomal regions potentially relevant in ADHD; especially the evidence for linkage to chromosome 5p13 is convincing. Meta-analyses of a large number of candidate gene studies suggest association with gene variants of the dopaminergic receptors DRD4 and DRD5, the serotonergic receptor HTR1B, and the synaptosomal receptor protein (SNAP-25). Hyperactivity has been investigated particularly in animal models, focusing on knockout- and quantitative trait loci (QTL) designs, with promising results for the dopaminergic system. It is likely that several gene polymorphisms with moderate to small effect sizes contribute to the phenotype ADHD; different combinations of such predisposing variants presumably underlie ADHD in different individuals. Therefore, large samples for molecular genetic studies are mandatory to detect these polymorphisms. Accordingly, several of today's findings have to be regarded as preliminary. The understanding of ADHD's neurobiology may be advanced by new technologies, such as SNP-based genome scans performed with gene chips comprising 10,000-1,000,000 SNPs, as well as using more sophisticated animal model designs.

  15. Disorders of sexual differentiation: I. Genetics and pathology

    PubMed Central

    El-Sherbiny, Mohamed

    2013-01-01

    Objectives To provide a summary of the recent major advances in the field of molecular genetics and understanding of psychosexual development, as these developments have resulted in changes in terminology and classification of disorders of sexual differentiation (DSD)/intersex; and to provide a quick and simplified review of the basic information. Methods Recent publications (over the last 10 years) were identified by a PubMed search, as were relevant previous studies, using the keywords; ‘sex chromosomes’, ‘psychosexual development’, ‘classifications’, ‘disorders of sexual differentiation’, ‘Chicago consensus’, ‘gonadal malignancy’, ‘intersex’ and ‘ambiguous genitalia’. Results The newly proposed terminology and classification has eliminated some confusion for both patient and family, as well as among health professionals. The new advances have facilitated the categorisation of gonadal malignancy in patients with DSD into high-, intermediate- and low-risk groups. Conclusions The major changes in terminology and classification of DSD should be considered as the first steps on a long road of research effort. The current available data remain far from sufficient. More molecular genetics studies will allow a better understanding of the causes of each condition of DSD. PMID:26579240

  16. Molecular genetics and animal models in autistic disorder.

    PubMed

    Andres, Christian

    2002-01-01

    Autistic disorder is a behavioural syndrome beginning before the age of 3 years and lasting over the whole lifetime. It is characterised by impaired communication, impaired social interactions, and repetitive interests and behaviour. The prevalence is about 7/10,000 taking a restrictive definition and more than 1/500 with a broader definition, including all the pervasive developmental disorders. The importance of genetic factors has been highlighted by epidemiological studies showing that autistic disorder is one of the most genetic neuropsychiatric diseases. The relative risk of first relatives is about 100-fold higher than the risk in the normal population and the concordance in monozygotic twin is about 60%. Different strategies have been applied on the track of susceptibility genes. The systematic search of linked loci led to contradictory results, in part due to the heterogeneity of the clinical definitions, to the differences in the DNA markers, and to the different methods of analysis used. An oversimplification of the inferred model is probably also cause of our disappointment. More work is necessary to give a clearer picture. One region emerges more frequently: the long arm of chromosome 7. Several candidate genes have been studied and some gave indications of association: the Reelin gene and the Wnt2 gene. Cytogenetical abnormalities are frequent at 15q11-13, the region of the Angelman and Prader-Willi syndrome. Imprinting plays an important role in this region, no candidate gene has been identified in autism. Biochemical abnormalities have been found in the serotonin system. Association and linkage studies gave no consistent results with some serotonin receptors and in the transporter, although it seems interesting to go further in the biochemical characterisation of the serotonin transporter activity, particularly in platelets, easily accessible. Two monogenic diseases have been associated with autistic disorder: tuberous sclerosis and fragile X. A

  17. Genetic linkage study of bipolar disorder and the serotonin transporter

    SciTech Connect

    Kelsoe, J.R.; Morison, M.; Mroczkowski-Parker, Z.; Bergesch, P.; Rapaport, M.H.; Mirow, A.L.

    1996-04-09

    The serotonin transporter (HTT) is an important candidate gene for the genetic transmission of bipolar disorder. It is the site of action of many antidepressants, and plays a key role in the regulation of serotonin neurotransmission. Many studies of affectively ill patients have found abnormalities in serotonin metabolism, and dysregulation of the transporter itself. The human serotonin transporter has been recently cloned and mapped to chromosome 17. We have identified a PstI RFLP at the HTT locus, and here report our examination of this polymorphism for possible linkage to bipolar disorder. Eighteen families were examined from three populations: the Old Order Amish, Iceland, and the general North American population. In addition to HTT, three other microsatellite markers were examined, which span an interval known to contain HTT. Linkage analyses were conducted under both dominant and recessive models, as well as both narrow (bipolar only) and broad (bipolar + recurrent unipolar) diagnostic models. Linkage could be excluded to HTT under all models examined. Linkage to the interval spanned by the microsatellites was similarly excluded under the dominant models. In two individual families, maximum lod scores of 1.02 and 0.84 were obtained at D17S798 and HTT, respectively. However, these data overall do not support the presence of a susceptibility locus for bipolar disorder near the serotonin transporter. 20 refs., 2 tabs.

  18. Endosomal system genetics and autism spectrum disorders: A literature review.

    PubMed

    Patak, Jameson; Zhang-James, Yanli; Faraone, Stephen V

    2016-06-01

    Autism spectrum disorders (ASDs) are a group of debilitating neurodevelopmental disorders thought to have genetic etiology, due to their high heritability. The endosomal system has become increasingly implicated in ASD pathophysiology. In an attempt to summarize the association between endosomal system genes and ASDs we performed a systematic review of the literature. We searched PubMed for relevant articles. Simons Foundation Autism Research Initiative (SFARI) gene database was used to exclude articles regarding genes with less than minimal evidence for association with ASDs. Our search retained 55 articles reviewed in two categories: genes that regulate and genes that are regulated by the endosomal system. Our review shows that the endosomal system is a novel pathway implicated in ASDs as well as other neuropsychiatric disorders. It plays a central role in aspects of cellular physiology on which neurons and glial cells are particularly reliant, due to their unique metabolic and functional demands. The system shows potential for biomarkers and pharmacological intervention and thus more research into this pathway is warranted.

  19. The genetic bases of speech sound disorders: evidence from spoken and written language.

    PubMed

    Lewis, Barbara A; Shriberg, Lawrence D; Freebairn, Lisa A; Hansen, Amy J; Stein, Catherine M; Taylor, H Gerry; Iyengar, Sudha K

    2006-12-01

    The purpose of this article is to review recent findings suggesting a genetic susceptibility for speech sound disorders (SSD), the most prevalent communication disorder in early childhood. The importance of genetic studies of SSD and the hypothetical underpinnings of these genetic findings are reviewed, as well as genetic associations of SSD with other language and reading disabilities. The authors propose that many genes contribute to SSD. They further hypothesize that some genes contribute to SSD disorders alone, whereas other genes influence both SSD and other written and spoken language disorders. The authors postulate that underlying common cognitive traits, or endophenotypes, are responsible for shared genetic influences of spoken and written language. They review findings from their genetic linkage study and from the literature to illustrate recent developments in this area. Finally, they discuss challenges for identifying genetic influence on SSD and propose a conceptual framework for study of the genetic basis of SSD.

  20. Orthodontic Treatment, Genetic Factors and Risk of Temporomandibular Disorder

    PubMed Central

    Slade, Gary D.; Diatchenko, Luda; Ohrbach, Richard; Maixner, William

    2008-01-01

    Traditionally, four groups of factors have been identified in the etiology of temporomandibular disorder (TMD): anatomical variation in the masticatory system; psychosocial characteristics; pain in other body regions; and demographics. Orthodontic treatment has been variously cited both as a protective and harmful factor in TMD etiology. Recently, a search has begun for a genetic influence on TMD etiology. Genetic markers can be of additional value in identifying gene-environment interactions, that is, isolating population sub-groups, defined by genotype in which environmental influences play a relatively greater or lesser etiological role. This paper reviews concepts and study design requirements for epidemiological investigations into TMD etiology. Findings are presented from a prospective cohort study of 186 females that illustrate an example of gene-environment interaction in TMD onset. Among people with a variant of the gene encoding catechol-O-methyl-transferase, an enzyme associated with pain responsiveness, risk of developing TMD was significantly greater for subjects who reported a history of orthodontic treatment compared with subjects who did not (P=0.04). While further studies are needed to investigate TMD etiology, this genetic variant potentially could help to identify patients whose risk of developing TMD is heightened following orthodontic treatment, hence serving as a risk marker useful in planning orthodontic care. PMID:18663384

  1. Emerging adenoviral vectors for stable correction of genetic disorders.

    PubMed

    Jager, Lorenz; Ehrhardt, Anja

    2007-08-01

    Recent drawbacks in treating patients with severe combined immunodeficiency disorders with retroviral vectors underline the importance of generating novel tools for stable transduction of mammalian cells. Substantial progress has been made over the recent years which may offer important steps towards stable and more importantly safer correction of genetic diseases. This article discusses recent advances for stable transduction of target cells based on adenoviral gene transfer. There is accumulating evidence that recombinant adenoviral vectors (AdVs) based on various human serotypes with a broad cellular tropism and adenoviruses (Ads) from different species will play an important role in future gene therapy applications. In combination with recombinant AdVs for somatic integration these gene transfer vectors offer high transduction efficiencies with potentially safer integration patterns. Other approaches for persistent transgene expression include excision of stable episomes from the adenoviral vector genome, but also long-term persistence of the complete adenoviral vector genome as an episomal DNA molecule was demonstrated and exemplified by the treatment of various genetic diseases in small and large animal models. This review displays advantages but also limitations of these Ad based vector systems. This is the perfect time to pursue such approaches because alternative strategies for stable transduction of mammalian cells undergoing many cell divisions are urgently needed. Looking into the future, we believe that a combination of different components from different viral vectors in concert with non-viral vector systems will be successful in designing significantly optimized transfer vehicles for a broad range of different genetic diseases.

  2. Genetic Predisposition To Acquire a Polybasic Cleavage Site for Highly Pathogenic Avian Influenza Virus Hemagglutinin

    PubMed Central

    Nao, Naganori; Yamagishi, Junya; Miyamoto, Hiroko; Igarashi, Manabu; Manzoor, Rashid; Ohnuma, Aiko; Tsuda, Yoshimi; Furuyama, Wakako; Shigeno, Asako; Kajihara, Masahiro; Kishida, Noriko; Yoshida, Reiko

    2017-01-01

    ABSTRACT Highly pathogenic avian influenza viruses with H5 and H7 hemagglutinin (HA) subtypes evolve from low-pathogenic precursors through the acquisition of multiple basic amino acid residues at the HA cleavage site. Although this mechanism has been observed to occur naturally only in these HA subtypes, little is known about the genetic basis for the acquisition of the polybasic HA cleavage site. Here we show that consecutive adenine residues and a stem-loop structure, which are frequently found in the viral RNA region encoding amino acids around the cleavage site of low-pathogenic H5 and H7 viruses isolated from waterfowl reservoirs, are important for nucleotide insertions into this RNA region. A reporter assay to detect nontemplated nucleotide insertions and deep-sequencing analysis of viral RNAs revealed that an increased number of adenine residues and enlarged stem-loop structure in the RNA region accelerated the multiple adenine and/or guanine insertions required to create codons for basic amino acids. Interestingly, nucleotide insertions associated with the HA cleavage site motif were not observed principally in the viral RNA of other subtypes tested (H1, H2, H3, and H4). Our findings suggest that the RNA editing-like activity is the key mechanism for nucleotide insertions, providing a clue as to why the acquisition of the polybasic HA cleavage site is restricted to the particular HA subtypes. PMID:28196963

  3. Genetics of Attention Deficit Hyperactivity Disorder: A Current Review and Future Prospects

    ERIC Educational Resources Information Center

    Levy, Florence; Hay, David A.; Bennett, Kellie S.

    2006-01-01

    While there have been significant advances in both the behaviour genetics and molecular genetics of Attention Deficit Hyperactivity Disorder (ADHD), researchers are now beginning to develop hypotheses about relationships between phenotypes and genetic mechanisms. Twin studies are able to model genetic, shared environmental and non-shared…

  4. Inherited, congenital and acquired disorders by hemostasis (vascular, platelet & plasmatic phases) with repercussions in the therapeutic oral sphere

    PubMed Central

    Arrieta-Blanco, Juan J.; Martínez-López, Federico; Oñate-Cabrerizo, Daniel; Cabrerizo-Merino, Maria C.

    2014-01-01

    The hemostasis alterations, either congenital or hereditary origin, and acquired, are circumstances that hinder oral care to patients who suffer them and also generates in the professional who has to attend, high stress. Bleeding control once established and dental treatment planning, both in the aspect of preparation, as the realization of the odonto-stomatological therapeutic, has suffered updates that do need to remember certain aspects of the care of these patients. But we must not forget that the hematologist or internist who controls the patient’s medical condition, is a cornerstone for the planning and implementation of treatment plans. We must also remember that, in certain circumstances, treatment should be performed in a hospital setting. In this review, we aim to provide the odonto-stomatologist guidance on how to address the problem and provide simple and updated guidelines to apply in the treatment of these people. Key words:Hemostasis disorder, oral care protocols, haemorrhagic and thrombotic disorders, haemophilia, von willebrand disease, desmopressin, purple, thrombocytopenia, thrombocytopathies. PMID:24121923

  5. Response to lithium in bipolar disorder: clinical and genetic findings.

    PubMed

    Rybakowski, Janusz K

    2014-06-18

    The use of lithium is a cornerstone for preventing recurrences in bipolar disorder (BD). The response of patients with bipolar disorder to lithium has different levels of magnitude. About one-third of lithium-treated patients are excellent lithium responders (ELR), showing total prevention of the episodes. A number of clinical characteristics were delineated in patients with favorable response to lithium as regards to clinical course, family history of mood disorders, and psychiatric comorbidity. We have also demonstrated that temperamental features of hypomania (a hyperthymic temperament) and a lack of cognitive disorganization predict the best results of lithium prophylaxis. A degree of prevention against manic and depressive episodes has been regarded as an endophenotype for pharmacogenetic studies. The majority of data have been gathered from so-called "candidate" gene studies. The candidates were selected on the basis of neurobiology of bipolar disorder and mechanisms of lithium action including, among others, neurotransmission, intracellular signaling, neuroprotection or circadian rhythms. We demonstrated that response to lithium has been connected with the genotype of BDNF gene and serum BDNF levels and have shown that ELR have normal cognitive functions and serum BDNF levels, even after long-term duration of the illness. A number of genome-wide association studies (GWAS) of BD have been also performed in recent years, some of which also focused on lithium response. The Consortium on Lithium Genetics (ConLiGen) has established the large sample for performing the genome-wide association study (GWAS) of lithium response in BD, and the first results have already been published.

  6. GeneAnalytics Pathway Analysis and Genetic Overlap among Autism Spectrum Disorder, Bipolar Disorder and Schizophrenia

    PubMed Central

    Khanzada, Naveen S.; Butler, Merlin G.; Manzardo, Ann M.

    2017-01-01

    Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway analysis and genetic profiling to characterize common susceptibility genes obtained from published lists for ASD (792 genes), BPD (290 genes) and SCH (560 genes). Rank scores were derived from the number and nature of overlapping genes, gene-disease association, tissue specificity and gene functions subdivided into categories (e.g., diseases, tissues or functional pathways). Twenty-three genes were common to all three disorders and mapped to nine biological Superpathways including Circadian entrainment (10 genes, score = 37.0), Amphetamine addiction (five genes, score = 24.2), and Sudden infant death syndrome (six genes, score = 24.1). Brain tissues included the medulla oblongata (11 genes, score = 2.1), thalamus (10 genes, score = 2.0) and hypothalamus (nine genes, score = 2.0) with six common genes (BDNF, DRD2, CHRNA7, HTR2A, SLC6A3, and TPH2). Overlapping genes impacted dopamine and serotonin homeostasis and signal transduction pathways, impacting mood, behavior and physical activity level. Converging effects on pathways governing circadian rhythms support a core etiological relationship between neuropsychiatric illnesses and sleep disruption with hypoxia and central brain stem dysfunction. PMID:28264500

  7. Brush and spray: a high-throughput systemic acquired resistance assay suitable for large-scale genetic screening.

    PubMed

    Jing, Beibei; Xu, Shaohua; Xu, Mo; Li, Yan; Li, Shuxin; Ding, Jinmei; Zhang, Yuelin

    2011-11-01

    Systemic acquired resistance (SAR) is a defense mechanism induced in the distal parts of plants after primary infection. It confers long-lasting protection against a broad spectrum of microbial pathogens. Lack of high-throughput assays has hampered the forward genetic analysis of SAR. Here, we report the development of an easy and efficient assay for SAR and its application in a forward genetic screen for SAR-deficient mutants in Arabidopsis (Arabidopsis thaliana). Using the new assay for SAR, we identified six flavin-dependent monooxygenase1, four AGD2-like defense response protein1, three salicylic acid induction-deficient2, one phytoalexin deficient4, and one avrPphB-susceptible3 alleles as well as a gain-of-function mutant of CALMODULIN-BINDING TRANSCRIPTION ACTIVATOR3 designated camta3-3D. Like transgenic plants overexpressing CAMTA3, camta3-3D mutant plants exhibit compromised SAR and enhanced susceptibility to virulent pathogens, suggesting that CAMTA3 is a critical regulator of both basal resistance and SAR.

  8. The genetic relationship between handedness and neurodevelopmental disorders.

    PubMed

    Brandler, William M; Paracchini, Silvia

    2014-02-01

    Handedness and brain asymmetry have been linked to neurodevelopmental disorders such as dyslexia and schizophrenia. The genetic nature of this correlation is not understood. Recent discoveries have shown handedness is determined in part by the biological pathways that establish left/right (LR) body asymmetry during development. Cilia play a key role in this process, and candidate genes for dyslexia have also been recently shown to be involved in cilia formation. Defective cilia result not only in LR body asymmetry phenotypes but also brain midline phenotypes such as an absent corpus callosum. These findings suggest that the mechanisms for establishing LR asymmetry in the body are reused for brain midline development, which in turn influences traits such as handedness and reading ability.

  9. Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders

    PubMed Central

    Francis, S.M.; Sagar, A.; Levin-Decanini, T.; Liu, W.; Carter, C.S.; Jacob, S.

    2015-01-01

    Oxytocin (OT) and arginine vasopressin (AVP) are two small, related neuropeptide hormones found in many mammalian species, including humans. Dysregulation of these neuropeptides have been associated with changes in behavior, especially social interactions. We review how the OT and AVP systems have been investigated in Autism Spectrum Disorder (ASD), Prader–Willi Syndrome (PWS), Williams Syndrome (WS) and Fragile X syndrome (FXS). All of these neurodevelopmental disorders (NDD) are marked by social deficits. While PWS, WS and FXS have identified genetic mutations, ASD stems from multiple genes with complex interactions. Animal models of NDD are invaluable for studying the role and relatedness of OT and AVP in the developing brain. We present data from a FXS mouse model affecting the fragile X mental retardation 1 (Fmr1) gene, resulting in decreased OT and AVP staining cells in some brain regions. Reviewing the research about OT and AVP in these NDD suggests that altered OT pathways may be downstream from different etiological factors and perturbations in development. This has implications for ongoing studies of the therapeutic application of OT in NDD. PMID:24462936

  10. Reverse Pathway Genetic Approach Identifies Epistasis in Autism Spectrum Disorders

    PubMed Central

    Traglia, Michela; Tsang, Kathryn; Bearden, Carrie E.; Rauen, Katherine A.

    2017-01-01

    Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs) in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies), we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02). We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10−16), with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway. PMID:28076348

  11. Tooth dentin defects reflect genetic disorders affecting bone mineralization

    PubMed Central

    Vital, S. Opsahl; Gaucher, C.; Bardet, C.; Rowe, P.S.; George, A.; Linglart, A.; Chaussain, C.

    2012-01-01

    Several genetic disorders affecting bone mineralization may manifest during dentin mineralization. Dentin and bone are similar in several aspects, especially pertaining to the composition of the extracellular matrix (ECM) which is secreted by well-differentiated odontoblasts and osteoblasts, respectively. However, unlike bone, dentin is not remodelled and is not involved in the regulation of calcium and phosphate metabolism. In contrast to bone, teeth are accessible tissues with the shedding of deciduous teeth and the extractions of premolars and third molars for orthodontic treatment. The feasibility of obtaining dentin makes this a good model to study biomineralization in physiological and pathological conditions. In this review, we focus on two genetic diseases that disrupt both bone and dentin mineralization. Hypophosphatemic rickets is related to abnormal secretory proteins involved in the ECM organization of both bone and dentin, as well as in the calcium and phosphate metabolism. Osteogenesis imperfecta affects proteins involved in the local organization of the ECM. In addition, dentin examination permits evaluation of the effects of the systemic treatment prescribed to hypophosphatemic patients during growth. In conclusion, dentin constitutes a valuable tool for better understanding of the pathological processes affecting biomineralization. PMID:22296718

  12. The epidemiology of eating disorders: genetic, environmental, and societal factors

    PubMed Central

    Mitchison, Deborah; Hay, Phillipa J

    2014-01-01

    Background The aim of this review was to summarize the literature to date regarding the sociodemographic, environmental, and genetic correlates of eating disorders (EDs) in adults. Method A keyword search was entered into Scopus (SciVerse, Elsevier) to identify relevant articles published in English up until June 2013. Articles were assessed against a range of a priori inclusion and exclusion criteria. Results A total of 149 full-text articles were found to be eligible for the review and included 86 articles with data on sociodemographic correlates, 57 on environmental correlates, and 13 on genetic correlates. Female sex, younger age, sexual and physical abuse, participation in esthetic or weight-oriented sports, and heritability were found to be most consistently associated with higher ED prevalence and incidence. Conversely, ethnicity, socioeconomic status, education, and urbanicity did not appear to have strong associations with ED epidemiology. Conclusion More community-based research, with an equal representation of males, needs to be conducted to confirm the current findings and provide evidence for emerging factors that may be related to EDs. PMID:24728136

  13. Molecular genetics of obsessive-compulsive disorder: a comprehensive meta-analysis of genetic association studies.

    PubMed

    Taylor, S

    2013-07-01

    Twin studies indicate that obsessive-compulsive disorder (OCD) is strongly influenced by additive genetic factors. Yet, molecular genetic association studies have yielded inconsistent results, possibly because of differences across studies in statistical power. Meta-analysis can yield greater power. This study reports the first comprehensive meta-analysis of the relationship between OCD and all previously examined polymorphisms for which there was sufficient information in the source studies to compute odds ratios (ORs). A total of 230 polymorphisms from 113 genetic association studies were identified. A full meta-analysis was conducted for 20 polymorphisms that were examined in 5 or more data sets, and a secondary meta-analysis (limited to the computation of mean effect sizes) was conducted for 210 polymorphisms that were examined in fewer than 5 data sets. In the main meta-analysis, OCD was associated with serotonin-related polymorphisms (5-HTTLPR and HTR2A) and, in males only, with polymorphisms involved in catecholamine modulation (COMT and MAOA). Nonsignificant trends were identified for two dopamine-related polymorphisms (DAT1 and DRD3) and a glutamate-related polymorphism (rs3087879). The secondary meta-analysis identified another 18 polymorphisms with significant ORs that merit further investigation. This study demonstrates that OCD is associated with multiple genes, with most having a modest association with OCD. This suggests a polygenic model of OCD, consistent with twin studies, in which multiple genes make small, incremental contributions to the risk of developing the disorder. Future studies, with sufficient power to detect small effects, are needed to investigate the genetic basis of OCD subtypes, such as early vs late onset OCD.

  14. Shared Genetic Influences on Negative Emotionality and Major Depression/Conduct Disorder Comorbidity

    ERIC Educational Resources Information Center

    Tackett, Jennifer L.; Waldman, Irwin D.; Van Hulle, Carol A.; Lahey, Benjamin B.

    2011-01-01

    Objective: To investigate whether genetic contributions to major depressive disorder and conduct disorder comorbidity are shared with genetic influences on negative emotionality. Method: Primary caregivers of 2,022 same- and opposite-sex twin pairs 6 to 18 years of age comprised a population-based sample. Participants were randomly selected across…

  15. Predictors of Outcome following Acquired Brain Injury in Children

    ERIC Educational Resources Information Center

    Johnson, Abigail R.; DeMatt, Ellen; Salorio, Cynthia F.

    2009-01-01

    Acquired brain injury (ABI) in children and adolescents can result from multiple causes, including trauma, central nervous system infections, noninfectious disorders (epilepsy, hypoxia/ischemia, genetic/metabolic disorders), tumors, and vascular abnormalities. Prediction of outcomes is important, to target interventions, allocate resources,…

  16. The Genetics of Child Psychiatric Disorders: Focus on autism and Tourette syndrome

    PubMed Central

    State, Matthew W.

    2012-01-01

    Investigations into the genetics of child psychiatric disorders have begun to shed light on molecular and cellular mechanisms of psychopathology. The first strains of success are the result of an increasingly sophisticated appreciation of the allelic architecture of common neuropsychiatric disorders; the consolidation of large patient cohorts; the emergence of genomic tools enabling comprehensive studies of rare as well as common genetic variation; and advances in developmental neuroscience that are fueling the rapid translation of genetic findings. These issues, as well as the opportunities and challenges that now confront gene discovery efforts in genetically complex conditions, are addressed with regard to two paradigmatic childhood disorders: autism and Tourette syndrome. PMID:20955933

  17. Cross-species behavioural genetics: A starting point for unravelling the neurobiology of human psychiatric disorders.

    PubMed

    de Mooij-van Malsen, Annetrude J G; Vinkers, Christiaan H; Peterse, Danielle P; Olivier, Berend; Kas, Martien J H

    2011-08-01

    Identifying the genetic and neurobiological mechanisms underlying certain behavioural traits is an important strategy to understand the aetiology of various psychiatric disorders and to find potential new treatment possibilities. It has proven a great challenge to develop paradigms that allow translational research for behavioural phenotypes that are relevant for disorders across the psychiatric spectrum. Recently, there has been increasing attention for studies that implement rodent behavioural paradigms in the home cage to assess the association between genetic backgrounds and behavioural traits. The application of interspecies genetics to unravel these traits has revealed novel insights in the genetic mechanisms that are encoding phenotypes relevant to biological processes underlying psychiatric disorders. By means of two examples, namely the stress-induced hyperthermia paradigm and the home cage environment, this review aims to show that by using individual genetic variations with phenotypes obtained from mice and across categories of neuropsychiatric disorders, novel insights in the neurobiological trajectory of psychiatric disorders can be obtained.

  18. Comparison of a therapeutic-only versus prophylactic platelet transfusion policy for people with congenital or acquired bone marrow failure disorders

    PubMed Central

    Ashraf, Asma; Hadjinicolaou, Andreas V; Doree, Carolyn; Hopewell, Sally; Trivella, Marialena; Estcourt, Lise J

    2016-01-01

    This is the protocol for a review and there is no abstract. The objectives are as follows: To compare a therapeutic-only versus prophylactic platelet transfusion policy for people with myelodysplasia, inherited or acquired aplastic anaemia, and other congenital bone marrow failure disorders. PMID:27660553

  19. Additional Evidence Is Needed to Recommend Acquiring a Dog to Families of Children with Autism Spectrum Disorder: A Response to Wright and Colleagues

    ERIC Educational Resources Information Center

    Crossman, Molly K.; Kazdin, Alan E.

    2016-01-01

    Caregivers of children with autism spectrum disorder are vulnerable to overstated benefits of interventions, and such overstatements are common with interventions involving animals. This response to Wright, Hall, Hames, Hardmin, Mills, the Paws Team, and Mills' (2015) article, "Acquiring a Pet Dog Significantly Reduces Stress of Primary…

  20. Recent advances in approach to treatment of genetic disorders: clinicians perspective.

    PubMed

    Gupta, Neerja; Kabra, Madhulika

    2007-05-01

    There is no cure for most of the genetic disorders. The only option in most situations is prevention by counseling and prenatal diagnosis. However, over a decade, with the completion of the human genome project and other advances there is better understanding of pathogenesis, improvement in diagnostic strategies and various treatment avenues are opening up for these disorders. The aim of this article is to make the pediatricians aware of the approaches to treatment of common genetic disorders and recent available therapeutic interventions.

  1. Children's Understanding of the Transmission of Genetic Disorders and Contagious Illnesses

    ERIC Educational Resources Information Center

    Raman, Lakshmi; Gelman, Susan A.

    2005-01-01

    The authors conducted 4 studies suggesting that children attribute different modes of transmission to genetic disorders and contagious illnesses. Study 1 presented preschoolers through 5th graders and adults with "switched-at-birth" scenarios for various disorders. Study 2 presented preschoolers with the same disorders but used contagion links in…

  2. Tourette's Disorder: Genetic Update, Neurological Correlates, and Evidence-Based Interventions

    ERIC Educational Resources Information Center

    Phelps, LeAdelle

    2008-01-01

    This article provides an update of the search for genetic markers related to Tourette's Disorder. The probable neurophysiology of the disorder is reviewed. Frequently prescribed medications are related to the probable biological bases of the disorder. Behavioral interventions and assessment tools are examined. It is concluded that evidence based…

  3. Genetics Home Reference: nonsyndromic congenital nail disorder 10

    MedlinePlus

    ... congenital nail disorder 10 nonsyndromic congenital nail disorder 10 Enable Javascript to view the expand/collapse boxes. ... All Close All Description Nonsyndromic congenital nail disorder 10 is a condition that affects the fingernails and ...

  4. Genetic Markers in Biological Fluids for Aging-Related Major Neurocognitive Disorder

    PubMed Central

    Castro-Chavira, S.A.; Fernández, T.; Nicolini, H.; Diaz-Cintra, S.; Prado-Alcalá, R.A.

    2015-01-01

    Aging-related major neurocognitive disorder (NCD), formerly named dementia, comprises of the different acquired diseases whose primary deficit is impairment in cognitive functions such as complex attention, executive function, learning and memory, language, perceptual/motor skills, and social cognition, and that are related to specific brain regions and/or networks. According to its etiology, the most common subtypes of major NCDs are due to Alzheimer’s disease (AD), vascular disease (VaD), Lewy body disease (LBD), and frontotemporal lobar degeneration (FTLD). These pathologies are frequently present in mixed forms, i.e., AD plus VaD or AD plus LBD, thus diagnosed as due to multiple etiologies. In this paper, the definitions, criteria, pathologies, subtypes and genetic markers for the most common age-related major NCD subtypes are summarized. The current diagnostic criteria consider cognitive decline leading to major NCD or dementia as a progressive degenerative process with an underlying neuropathology that begins before the manifestation of symptoms. Biomarkers associated with this asymptomatic phase are being developed as accurate risk factor and biomarker assessments are fundamental to provide timely treatment since no treatments to prevent or cure NCD yet exist. Biological fluid assessment represents a safer, cheaper and less invasive method compared to contrast imaging studies to predict NCD appearance. Genetic factors particularly have a key role not only in predicting development of the disease but also the age of onset as well as the presentation of comorbidities that may contribute to the disease pathology and trigger synergistic mechanisms which may, in turn, accelerate the neurodegenerative process and its resultant behavioral and functional disorders. PMID:25731625

  5. [Neurofibromatosis--an inborn genetic disorder with susceptibility to neoplasia].

    PubMed

    Karwacki, Marek W; Woźniak, Wojciech

    2006-01-01

    Among different subtypes of neurofibromatosis (Nf), type 1 (Nf-1) predominates in frequency (approximately 97% of Nfs' patients) with an incidence of approximately 1 in 3500 live births. Nf-2, comprises 2% of the Nf population and is a very rare disease (1:40,000). Both are autosomal dominant disorders with 100% penetration, variable expression and 50% rate of new (de novo) mutations. The protein products of both, NF1 andNF2 genes are best known and the genes serve as tumour suppressors. Mutations result in a predisposition to develop a variety of tumours of the central and peripheral nervous systems, as well as other malignancies. Nf-2 is a multisystem genetic disorder associated with bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas, gliomas, and juvenile cataracts with a paucity of cutaneous features, which are seen more consistently in Nf-1. In contrast to Nf-1, Nf-2 is associated with significant morbidity and decreased life span and a higher incidence of CNS tumours. However, morbidity and mortality rates in Nf-1 are not negligible. The cardinal features of Nf-1 are cafe-au-lait spots, axillary and inguinal freckling, cutaneous neurofibromas, and iris hamartomas (Lisch nodules). Optic gliomas and both malignant and benign peripheral nerve sheet tumours are the most common malignancies arising in Nf-1 patients. Among neurological symptoms epilepsy, intellectual disability and learning difficulty are also observed. Bone dysplasia results in scoliosis. There is no known medical treatment beneficial to both groups of patients. The mainstay of care for Nf patients is anticipatory guidance, and early detection and symptomatic treatment of disease complications.

  6. Clinical Exome Sequencing for Genetic Identification of Rare Mendelian Disorders

    PubMed Central

    Lee, Hane; Deignan, Joshua L.; Dorrani, Naghmeh; Strom, Samuel P.; Kantarci, Sibel; Quintero-Rivera, Fabiola; Das, Kingshuk; Toy, Traci; Harry, Bret; Yourshaw, Michael; Fox, Michelle; Fogel, Brent L.; Martinez-Agosto, Julian A.; Wong, Derek A.; Chang, Vivian Y.; Shieh, Perry B.; Palmer, Christina G. S.; Dipple, Katrina M.; Grody, Wayne W.; Vilain, Eric; Nelson, Stanley F.

    2014-01-01

    Importance Clinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders. Objective To report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types. Design, Setting, and Participants Clinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available. Main outcomes and Measures Clinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES. Results Of the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants. Conclusions and Relevance In this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the

  7. Neuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders.

    PubMed

    Lotan, Amit; Fenckova, Michaela; Bralten, Janita; Alttoa, Aet; Dixson, Luanna; Williams, Robert W; van der Voet, Monique

    2014-01-01

    Major neuropsychiatric disorders are highly heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. In the current article we systematically test the degree of genetic commonality across six major neuropsychiatric disorders-attention deficit hyperactivity disorder (ADHD), anxiety disorders (Anx), autistic spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). We curated a well-vetted list of genes based on large-scale human genetic studies based on the NHGRI catalog of published genome-wide association studies (GWAS). A total of 180 genes were accepted into the analysis on the basis of low but liberal GWAS p-values (<10(-5)). 22% of genes overlapped two or more disorders. The most widely shared subset of genes-common to five of six disorders-included ANK3, AS3MT, CACNA1C, CACNB2, CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Using a suite of neuroinformatic resources, we showed that many of the shared genes are implicated in the postsynaptic density (PSD), expressed in immune tissues and co-expressed in developing human brain. Using a translational cross-species approach, we detected two distinct genetic components that were both shared by each of the six disorders; the 1st component is involved in CNS development, neural projections and synaptic transmission, while the 2nd is implicated in various cytoplasmic organelles and cellular processes. Combined, these genetic components account for 20-30% of the genetic load. The remaining risk is conferred by distinct, disorder-specific variants. Our systematic comparative analysis of shared and unique genetic factors highlights key gene sets and molecular processes that may ultimately translate into improved diagnosis and treatment of these debilitating disorders.

  8. Expanding the Genetic and Phenotypic Spectrum of Popliteal Pterygium Disorders

    PubMed Central

    Leslie, Elizabeth J.; O'Sullivan, James; Cunningham, Michael L.; Singh, Ankur; Goudy, Steven L.; Ababneh, Faroug; Alsubaie, Lamia; Ch'ng, Gaik-Siew; van der Laar, Ingrid M.B.H.; Hoogeboom, A. Jeannette M.; Dunnwald, Martine; Kapoor, Seema; Jiramongkolchai, Pawina; Standley, Jennifer; Manak, J. Robert; Murray, Jeffrey C.; Dixon, Michael J.

    2015-01-01

    The popliteal pterygia syndromes are a distinct subset of the hundreds of Mendelian orofacial clefting syndromes. Popliteal pterygia syndromes have considerable variability in severity and in the associated phenotypic features but are all characterized by cutaneous webbing across one or more major joints, cleft lip and/or palate, syndactyly, and genital malformations. Heterozygous mutations in IRF6 cause popliteal pterygium syndrome (PPS) while homozygous mutations in RIPK4 or CHUK (IKKA) cause the more severe Bartsocas-Papas syndrome (BPS) and Cocoon syndrome, respectively. In this study we report mutations in six pedigrees with children affected with PPS or BPS. Using a combination of Sanger and exome sequencing, we report the first case of an autosomal recessive popliteal pterygium syndrome caused by homozygous mutation of IRF6 and the first case of uniparental disomy of chromosome 21 leading to a recessive disorder. We also demonstrate that mutations in RIPK4 can cause features with a range of severity along the PPS-BPS spectrum and that mutations in IKKA can cause a range of features along the BPS-Cocoon spectrum. Our findings have clinical implications for genetic counseling of families with pterygia syndromes and further implicate IRF6, RIPK4, and CHUK (IKKA) in potentially interconnected pathways governing epidermal and craniofacial development. PMID:25691407

  9. Role of Genetics in the Etiology of Autistic Spectrum Disorder: Towards a Hierarchical Diagnostic Strategy

    PubMed Central

    Robert, Cyrille; Pasquier, Laurent; Cohen, David; Fradin, Mélanie; Canitano, Roberto; Damaj, Léna; Odent, Sylvie; Tordjman, Sylvie

    2017-01-01

    Progress in epidemiological, molecular and clinical genetics with the development of new techniques has improved knowledge on genetic syndromes associated with autism spectrum disorder (ASD). The objective of this article is to show the diversity of genetic disorders associated with ASD (based on an extensive review of single-gene disorders, copy number variants, and other chromosomal disorders), and consequently to propose a hierarchical diagnostic strategy with a stepwise evaluation, helping general practitioners/pediatricians and child psychiatrists to collaborate with geneticists and neuropediatricians, in order to search for genetic disorders associated with ASD. The first step is a clinical investigation involving: (i) a child psychiatric and psychological evaluation confirming autism diagnosis from different observational sources and assessing autism severity; (ii) a neuropediatric evaluation examining neurological symptoms and developmental milestones; and (iii) a genetic evaluation searching for dysmorphic features and malformations. The second step involves laboratory and if necessary neuroimaging and EEG studies oriented by clinical results based on clinical genetic and neuropediatric examinations. The identification of genetic disorders associated with ASD has practical implications for diagnostic strategies, early detection or prevention of co-morbidity, specific treatment and follow up, and genetic counseling. PMID:28287497

  10. Interpreting genetics in the context of eating disorders: evidence of disease, not diversity.

    PubMed

    Easter, Michele

    2014-07-01

    How is genetic involvement interpreted for disorders whose medicalisation is contested? Framing psychiatric and behavioural disorders in terms of genetics is expected to make them seem more medical. Yet a genetic aetiology can also be used to frame behaviour as acceptable human variation, rather than a medical problem (for example, sexual orientation). I analyse responses to the idea that there is a genetic component in anorexia and bulimia nervosa (AN or BN) via semi-structured interviews with a sample of 50 women diagnosed with an eating disorder (25 had recovered). All but three volunteered that genetics would medicalise AN or BN by (i) making eating disorders seem more like 'real diseases'; implying that these disorders need (ii) professional treatment or (iii) a biologically based treatment. The results also indicate there are several counter-logics by which genetic framing could support non-medical definitions of AN or BN. I argue that genetic framing reduces perceived individual responsibility, which can support definitions of behaviour as either a reflection of disease (which entails intervention) or a reflection of normal human diversity (which does not). In the context of public scepticism as to the 'reality' of AN or BN, genetic involvement was taken as evidence of disease in ongoing negotiations about the medical and moral status of people with eating disorders.

  11. Human Genetic Disorders Caused by Mutations in Genes Encoding Biosynthetic Enzymes for Sulfated Glycosaminoglycans*

    PubMed Central

    Mizumoto, Shuji; Ikegawa, Shiro; Sugahara, Kazuyuki

    2013-01-01

    A number of genetic disorders are caused by mutations in the genes encoding glycosyltransferases and sulfotransferases, enzymes responsible for the synthesis of sulfated glycosaminoglycan (GAG) side chains of proteoglycans, including chondroitin sulfate, dermatan sulfate, and heparan sulfate. The phenotypes of these genetic disorders reflect disturbances in crucial biological functions of GAGs in human. Recent studies have revealed that mutations in genes encoding chondroitin sulfate and dermatan sulfate biosynthetic enzymes cause various disorders of connective tissues. This minireview focuses on growing glycobiological studies of recently described genetic diseases caused by disturbances in biosynthetic enzymes for sulfated GAGs. PMID:23457301

  12. Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

    PubMed Central

    2012-01-01

    This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies. PMID:22958744

  13. Genetics of Autism Spectrum Disorder: Current Status and Possible Clinical Applications

    PubMed Central

    2015-01-01

    Autism spectrum disorder (ASD) is one of the most complex behavioral disorders with a strong genetic influence. The objectives of this article are to review the current status of genetic research in ASD, and to provide information regarding the potential candidate genes, mutations, and genetic loci possibly related to pathogenesis in ASD. Investigations on monogenic causes of ASD, candidate genes among common variants, rare de novo mutations, and copy number variations are reviewed. The current possible clinical applications of the genetic knowledge and their future possibilities are highlighted. PMID:26713075

  14. Genetics Home Reference: 46,XX testicular disorder of sex development

    MedlinePlus

    ... of sex development 46,XX testicular disorder of sex development Enable Javascript to view the expand/collapse ... Close All Description 46,XX testicular disorder of sex development is a condition in which individuals with ...

  15. Interpreting genetics in the context of eating disorders: Evidence of disease, not diversity

    PubMed Central

    Easter, Michele

    2013-01-01

    How is genetic involvement interpreted for disorders whose medicalisation is contested? Framing psychiatric and behavioral disorders in terms of genetics is expected to make them seem “more medical.” Yet, genetic etiology can also be used to frame behavior as acceptable human variation, rather than a medical problem (e.g., sexual orientation). I analyze responses to the idea of a genetic component in anorexia and bulimia nervosa (AN/BN) via semi-structured interviews with a sample of 50 women diagnosed with an eating disorder (25 recovered). All but three volunteered that genetics would medicalise AN/BN, by (1) making eating disorders seem more like “real” diseases; (2) implying a need for professional treatment; or (3) for biologically-based treatment. Results also indicate several “counter-logics,” by which genetic framing could support non-medical definitions of AN/BN. I argue that genetic framing reduces perceived individual responsibility, which can support definitions of behavior as either a reflection of disease (which entails intervention) or a reflection of normal human diversity (which does not). In the context of public skepticism as to the “reality” of AN/BN, genetic involvement was taken as evidence of disease in ongoing negotiations about the medical and moral status of people with eating disorders. PMID:24286479

  16. Disorders of sex development: a genetic study of patients in a multidisciplinary clinic

    PubMed Central

    Laino, Luigi; Majore, Silvia; Preziosi, Nicoletta; Grammatico, Barbara; De Bernardo, Carmelilia; Scommegna, Salvatore; Rapone, Anna Maria; Marrocco, Giacinto; Bottillo, Irene; Grammatico, Paola

    2014-01-01

    Sex development is a process under genetic control directing both the bi-potential gonads to become either a testis or an ovary, and the consequent differentiation of internal ducts and external genitalia. This complex series of events can be altered by a large number of genetic and non-genetic factors. Disorders of sex development (DSD) are all the medical conditions characterized by an atypical chromosomal, gonadal, or phenotypical sex. Incomplete knowledge of the genetic mechanisms involved in sex development results in a low probability of determining the molecular definition of the genetic defect in many of the patients. In this study, we describe the clinical, cytogenetic, and molecular study of 88 cases with DSD, including 29 patients with 46,XY and disorders in androgen synthesis or action, 18 with 46,XX and disorders in androgen excess, 17 with 46,XY and disorders of gonadal (testicular) development, 11 classified as 46,XX other, eight with 46,XX and disorders of gonadal (ovarian) development, and five with sex chromosome anomalies. In total, we found a genetic variant in 56 out of 88 of them, leading to the clinical classification of every patient, and we outline the different steps required for a coherent genetic testing approach. In conclusion, our results highlight the fact that each category of DSD is related to a large number of different DNA alterations, thus requiring multiple genetic studies to achieve a precise etiological diagnosis for each patient. PMID:25248670

  17. Neuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders

    PubMed Central

    Lotan, Amit; Fenckova, Michaela; Bralten, Janita; Alttoa, Aet; Dixson, Luanna; Williams, Robert W.; van der Voet, Monique

    2014-01-01

    Major neuropsychiatric disorders are highly heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. In the current article we systematically test the degree of genetic commonality across six major neuropsychiatric disorders—attention deficit hyperactivity disorder (ADHD), anxiety disorders (Anx), autistic spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). We curated a well-vetted list of genes based on large-scale human genetic studies based on the NHGRI catalog of published genome-wide association studies (GWAS). A total of 180 genes were accepted into the analysis on the basis of low but liberal GWAS p-values (<10−5). 22% of genes overlapped two or more disorders. The most widely shared subset of genes—common to five of six disorders–included ANK3, AS3MT, CACNA1C, CACNB2, CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Using a suite of neuroinformatic resources, we showed that many of the shared genes are implicated in the postsynaptic density (PSD), expressed in immune tissues and co-expressed in developing human brain. Using a translational cross-species approach, we detected two distinct genetic components that were both shared by each of the six disorders; the 1st component is involved in CNS development, neural projections and synaptic transmission, while the 2nd is implicated in various cytoplasmic organelles and cellular processes. Combined, these genetic components account for 20–30% of the genetic load. The remaining risk is conferred by distinct, disorder-specific variants. Our systematic comparative analysis of shared and unique genetic factors highlights key gene sets and molecular processes that may ultimately translate into improved diagnosis and treatment of these debilitating disorders. PMID:25414627

  18. Genetic and epigenetic insights into fetal alcohol spectrum disorders

    PubMed Central

    2010-01-01

    The magnitude of the detrimental effects following in utero alcohol exposure, including fetal alcohol syndrome and other fetal alcohol spectrum disorders (FASD), is globally underestimated. The effects include irreversible cognitive and behavioral disabilities as a result of abnormal brain development, pre- and postnatal growth retardation and facial dysmorphism. Parental alcohol exposure and its effect on offspring has been recognized for centuries, but only recently have we begun to gain molecular insight into the mechanisms involved in alcohol teratogenesis. Genetic attributes (susceptibility and protective alleles) of the mother and the fetus contribute to the risk of developing FASD and specific additional environmental conditions, including malnutrition, have an important role. The severity of FASD depends on the level of alcohol exposure, the developmental stage at which exposure occurs and the nature of the exposure (chronic or acute), and although the most vulnerable period is during the first trimester, damage can occur throughout gestation. Preconception alcohol exposure can also have a detrimental effect on the offspring. Several developmental pathways are affected in FASD, including nervous system development, growth and remodeling of tissues, as well as metabolic pathways that regulate glucocorticoid signaling and balanced levels of retinol, insulin and nitric oxide. A body of knowledge has accumulated to support the role of environmentally induced epigenetic remodeling during gametogenesis and after conception as a key mechanism for the teratogenic effects of FASD that persist into adulthood. Transgenerational effects are likely to contribute to the global burden of alcohol-related disease. FASD results in lifelong disability and preventative programs should include both maternal alcohol abstention and preconception alcohol avoidance. PMID:20423530

  19. Prenatal diagnosis and genetic analysis of fetal akinesia deformation sequence and multiple pterygium syndrome associated with neuromuscular junction disorders: a review.

    PubMed

    Chen, Chih-Ping

    2012-03-01

    Fetal akinesia deformation sequence is a clinically and genetically heterogeneous disorder characterized by a variable combination of arthrogryposis, fetal akinesia, intrauterine growth restriction, developmental abnormalities such as cystic hygroma, pulmonary hypoplasia, cleft palate, cryptorchidism, cardiac defects and intestinal malrotation, and occasional pterygia of the limbs. Multiple pterygium syndrome is a clinically and genetically heterogeneous disorder characterized by pterygia of the neck, elbows and/or knees, arthrogryposis, and other phenotypic features such as short stature, genital abnormalities, craniofacial abnormalities, clubfoot, kyphoscoliosis, and cardiac abnormalities. Fetal akinesia deformation sequence may phenotypically overlap with the lethal type of multiple pterygium syndrome. This article provides a comprehensive review of prenatal diagnosis and genetic analysis of fetal akinesia deformation sequence and multiple pterygium syndrome associated with neuromuscular junction disorders. Prenatal diagnosis of fetal akinesia along with cystic hygroma, increased nuchal translucency, nuchal edema, hydrops fetalis, arthrogryposis, pterygia, and other structural abnormalities should include a differential diagnosis of neuromuscular junction disorders. Genetic analysis of mutations in the neuromuscular junction genes such as CHRNA1, CHRND, CHRNG, CNTN1, DOK7, RAPSN, and SYNE1 may unveil the pathogenetic cause of fetal akinesia deformation sequence and multiple pterygium syndrome, and the information acquired is helpful for genetic counseling and clinical management.

  20. Additional Evidence is Needed to Recommend Acquiring a Dog to Families of Children with Autism Spectrum Disorder: A Response to Wright and Colleagues.

    PubMed

    Crossman, Molly K; Kazdin, Alan E

    2016-01-01

    Caregivers of children with autism spectrum disorder are vulnerable to overstated benefits of interventions, and such overstatements are common with interventions involving animals. This response to Wright, Hall, Hames, Hardmin, Mills, the Paws Team, and Mills' (2015) article, "Acquiring a Pet Dog Significantly Reduces Stress of Primary Careers for Children with Autism Spectrum Disorder: A Prospective Case Control Study," details why that study's conclusions are premature. Specific limitations of the study are detailed, including overstatements of the supportive literature, problems with the design, and mismatch between the findings and conclusions. The purpose is not to challenge the benefits of pet ownership, but to point out that those benefits have not yet been established.

  1. Acquiring a Pet Dog Significantly Reduces Stress of Primary Carers for Children with Autism Spectrum Disorder: A Prospective Case Control Study.

    PubMed

    Wright, H F; Hall, S; Hames, A; Hardiman, J; Mills, R; Mills, D S

    2015-08-01

    This study describes the impact of pet dogs on stress of primary carers of children with Autism Spectrum Disorder (ASD). Stress levels of 38 primary carers acquiring a dog and 24 controls not acquiring a dog were sampled at: Pre-intervention (17 weeks before acquiring a dog), post-intervention (3-10 weeks after acquisition) and follow-up (25-40 weeks after acquisition), using the Parenting Stress Index. Analysis revealed significant improvements in the intervention compared to the control group for Total Stress, Parental Distress and Difficult Child. A significant number of parents in the intervention group moved from clinically high to normal levels of Parental Distress. The results highlight the potential of pet dogs to reduce stress in primary carers of children with an ASD.

  2. Influence of genetic variability at the surfactant proteins A and D in community-acquired pneumonia: a prospective, observational, genetic study

    PubMed Central

    2011-01-01

    Introduction Genetic variability of the pulmonary surfactant proteins A and D may affect clearance of microorganisms and the extent of the inflammatory response. The genes of these collectins (SFTPA1, SFTPA2 and SFTPD) are located in a cluster at 10q21-24. The objective of this study was to evaluate the existence of linkage disequilibrium (LD) among these genes, and the association of variability at these genes with susceptibility and outcome of community-acquired pneumonia (CAP). We also studied the effect of genetic variability on SP-D serum levels. Methods Seven non-synonymous polymorphisms of SFTPA1, SFTPA2 and SFTPD were analyzed. For susceptibility, 682 CAP patients and 769 controls were studied in a case-control study. Severity and outcome were evaluated in a prospective study. Haplotypes were inferred and LD was characterized. SP-D serum levels were measured in healthy controls. Results The SFTPD aa11-C allele was significantly associated with lower SP-D serum levels, in a dose-dependent manner. We observed the existence of LD among the studied genes. Haplotypes SFTPA1 6A2 (P = 0.0009, odds ration (OR) = 0.78), SFTPA2 1A0 (P = 0.002, OR = 0.79), SFTPA1-SFTPA2 6A2-1A0 (P = 0.0005, OR = 0.77), and SFTPD-SFTPA1-SFTPA2 C-6A2-1A0 (P = 0.00001, OR = 0.62) were underrepresented in patients, whereas haplotypes SFTPA2 1A10 (P = 0.00007, OR = 6.58) and SFTPA1-SFTPA2 6A3-1A (P = 0.0007, OR = 3.92) were overrepresented. Similar results were observed in CAP due to pneumococcus, though no significant differences were now observed after Bonferroni corrections. 1A10 and 6A-1A were associated with higher 28-day and 90-day mortality, and with multi-organ dysfunction syndrome (MODS) and acute respiratory distress syndrome (ARDS) respectively. SFTPD aa11-C allele was associated with development of MODS and ARDS. Conclusions Our study indicates that missense single nucleotide polymorphisms and haplotypes of SFTPA1, SFTPA2 and SFTPD are associated with susceptibility to CAP, and

  3. Community engagement and education: addressing the needs of South Asian families with genetic disorders.

    PubMed

    Khan, Nasaim; Kerr, Gifford; Kingston, Helen

    2016-10-01

    Consanguineous marriage is common among the South Asian heritage community in the UK. While conferring social and cultural benefits, consanguinity is associated with an increased risk of autosomal recessive disorders and an increase in childhood death and disability. We have previously developed a genetic service to address the needs of this community. We report the extension of this service to include community-based initiatives aimed at promoting understanding of genetic issues related to consanguinity and improving access to genetic services. Our approach was to develop integrated clinical, educational and community engagement initiatives that would be sustainable on a long-term basis. The service provided for South Asian families by a specialist genetic counsellor was extended, and a series of genetics education and awareness sessions were provided for a diverse range of frontline healthcare workers. Two community genetic outreach worker posts were established to facilitate the engagement of the local South Asian population with genetics. The education and awareness sessions helped address the lack of genetic knowledge among primary health care professionals and community workers. Engagement initiatives by the genetic outreach worker raised awareness of genetic issues in the South Asian community and families affected by autosomal recessive disorders. All three elements of the extended service generated positive feedback. A three-stranded approach to addressing the needs of consanguineous families affected by autosomal recessive disorders as recommended by the World Health Organisation is suggested to be an acceptable, effective and sustainable approach to delivery of service in the UK.

  4. Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders.

    PubMed

    de Sousa, Rafael T; Loch, Alexandre A; Carvalho, André F; Brunoni, André R; Haddad, Marie Reine; Henter, Ioline D; Zarate, Carlos A; Machado-Vieira, Rodrigo

    2017-03-01

    Both bipolar disorder (BD) and major depressive disorder (MDD) have high morbidity and share a genetic background. Treatment options for these mood disorders are currently suboptimal for many patients; however, specific genetic variables may be involved in both pathophysiology and response to treatment. Agents such as the glutamatergic modulator ketamine are effective in treatment-resistant mood disorders, underscoring the potential importance of the glutamatergic system as a target for improved therapeutics. Here we review genetic studies linking the glutamatergic system to the pathophysiology and therapeutics of mood disorders. We screened 763 original genetic studies of BD or MDD that investigated genes encoding targets of the pathway/mediators related to the so-called tripartite glutamate synapse, including pre- and post-synaptic neurons and glial cells; 60 papers were included in this review. The findings suggest the involvement of glutamate-related genes in risk for mood disorders, treatment response, and phenotypic characteristics, although there was no consistent evidence for a specific gene. Target genes of high interest included GRIA3 and GRIK2 (which likely play a role in emergent suicidal ideation after antidepressant treatment), GRIK4 (which may influence treatment response), and GRM7 (which potentially affects risk for mood disorders). There was stronger evidence that glutamate-related genes influence risk for BD compared with MDD. Taken together, the studies show a preliminary relationship between glutamate-related genes and risk for mood disorders, suicide, and treatment response, particularly with regard to targets on metabotropic and ionotropic receptors.

  5. Large-scale discovery of novel genetic causes of developmental disorders.

    PubMed

    2015-03-12

    Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.

  6. Studying Interactions, Reactions, and Perceptions: Can Genetic Disorders Serve as Behavioral Proxies?

    ERIC Educational Resources Information Center

    Hodapp, Robert M.

    2004-01-01

    Different genetic disorders predispose individuals to display specific, etiology-related profiles, personalities, and maladaptive behaviors. Using groups with genetic etiologies as stand-ins or proxies for a specific behavior or set of behaviors, one can then examine how others in the child's environment react and whether such reactions are…

  7. InterRett, a Model for International Data Collection in a Rare Genetic Disorder

    ERIC Educational Resources Information Center

    Louise, Sandra; Fyfe, Sue; Bebbington, Ami; Bahi-Buisson, Nadia; Anderson, Alison; Pineda, Merce; Percy, Alan; Zeev, Bruria Ben; Wu, Xi Ru; Bao, Xinhua; MacLeod, Patrick; Armstrong, Judith; Leonard, Helen

    2009-01-01

    Rett syndrome (RTT) is a rare genetic disorder within the autistic spectrum. This study compared socio-demographic, clinical and genetic characteristics of the international database, InterRett, and the population-based Australian Rett syndrome database (ARSD). It also explored the strengths and limitations of InterRett in comparison with other…

  8. Autism Spectrum Disorders in Genetic Syndromes: Implications for Diagnosis, Intervention and Understanding the Wider Autism Spectrum Disorder Population

    ERIC Educational Resources Information Center

    Moss, J.; Howlin, P.

    2009-01-01

    Background: An emerging literature on behavioural phenotypes has highlighted apparent associations between autism spectrum disorders (ASDs) or ASD-related phenomenology and a number of different genetically determined syndromes. Method: A systematic review of the current literature regarding the association with ASD and ASD characteristics was…

  9. [Acquired coagulant factor inhibitors].

    PubMed

    Nogami, Keiji

    2015-02-01

    Acquired coagulation factor inhibitors are an autoimmune disease causing bleeding symptoms due to decreases in the corresponding factor (s) which result from the appearance of autoantibodies against coagulation factors (inhibitor). This disease is quite different from congenital coagulation factor deficiencies based on genetic abnormalities. In recent years, cases with this disease have been increasing, and most have anti-factor VIII autoantibodies. The breakdown of the immune control mechanism is speculated to cause this disease since it is common in the elderly, but the pathology and pathogenesis are presently unclear. We herein describe the pathology and pathogenesis of factor VIII and factor V inhibitors. Characterization of these inhibitors leads to further analysis of the coagulation process and the activation mechanisms of clotting factors. In the future, with the development of new clotting examination method (s), we anticipate that further novel findings will be obtained in this field through inhibitor analysis. In addition, detailed elucidation of the coagulation inhibitory mechanism possibly leading to hemostatic treatment strategies for acquired coagulation factor disorders will be developed.

  10. The Fourth International Symposium on Genetic Disorders of the Ras/MAPK Pathway

    PubMed Central

    Stevenson, David A.; Schill, Lisa; Schoyer, Lisa; Andresen, Brage S.; Bakker, Annette; Bayrak-Toydemir, Pinar; Burkitt-Wright, Emma; Chatfield, Kathryn; Elefteriou, Florent; Elgersma, Ype; Fisher, Michael J.; Franz, David; Gelb, Bruce D.; Goriely, Anne; Gripp, Karen W.; Hardan, Antonio Y.; Keppler-Noreuil, Kim M.; Kerr, Bronwyn; Korf, Bruce; Leoni, Chiara; McCormick, Frank; Plotkin, Scott R.; Rauen, Katherine A.; Reilly, Karlyne; Roberts, Amy; Sandler, Abby; Siegel, Dawn; Walsh, Karin; Widemann, Brigitte C.

    2016-01-01

    The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation–arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field. PMID:27155140

  11. Assessment and Treatment in Autism Spectrum Disorders: A Focus on Genetics and Psychiatry

    PubMed Central

    Butler, Merlin G.; Youngs, Erin L.; Roberts, Jennifer L.; Hellings, Jessica A.

    2012-01-01

    Autism spectrum disorders (ASDs) are neurobehavioral disorders characterized by abnormalities in three behavioral domains including social interaction, impaired communication, and repetitive stereotypic behaviors. ASD affects approximately 1% of children and is on the rise with significant genetic mechanisms underlying these disorders. We review the current understanding of the role of genetic and metabolic factors contributing to ASD with the use of new genetic technology. Fifty percent is diagnosed with chromosomal abnormalities, small DNA deletions/duplications, single-gene conditions, or metabolic disturbances. Genetic evaluation is discussed along with psychiatric treatment and approaches for selection of medication to treat associated challenging behaviors or comorbidities seen in ASD. We emphasize the importance of prioritizing treatment based on target symptom clusters and in what order for individuals with ASD, as the treatment may vary from patient to patient. PMID:22934170

  12. Practice Bulletin No. 162 Summary: Prenatal Diagnostic Testing for Genetic Disorders.

    PubMed

    2016-05-01

    Prenatal genetic diagnostic testing is intended to determine, with as much certainty as possible, whether a specific genetic disorder or condition is present in the fetus. In contrast, prenatal genetic screening is designed to assess whether a patient is at increased risk of having a fetus affected by a genetic disorder. Originally, prenatal genetic testing focused primarily on Down syndrome (trisomy 21), but now it is able to detect a broad range of genetic disorders. Although it is necessary to perform amniocentesis or chorionic villus sampling (CVS) to definitively diagnose most genetic disorders, in some circumstances, fetal imaging with ultrasonography, echocardiography, or magnetic resonance imaging may be diagnostic of a particular structural fetal abnormality that is suggestive of an underlying genetic condition.The objective of prenatal genetic testing is to detect health problems that could affect the woman, fetus, or newborn and provide the patient and her obstetrician-gynecologist or other obstetric care provider with enough information to allow a fully informed decision about pregnancy management. Prenatal genetic testing cannot identify all abnormalities or problems in a fetus, and any testing should be focused on the individual patient's risks, reproductive goals, and preferences. It is important that patients understand the benefits and limitations of all prenatal screening and diagnostic testing, including the conditions for which tests are available and the conditions that will not be detected by testing. It also is important that patients realize that there is a broad range of clinical presentations, or phenotypes, for many genetic disorders and that results of genetic testing cannot predict all outcomes. Prenatal genetic testing has many benefits, including reassuring patients when results are normal, identifying disorders for which prenatal treatment may provide benefit, optimizing neonatal outcomes by ensuring the appropriate location for

  13. The Genetic Basis of Thought Disorder and Language and Communication Disturbances in Schizophrenia

    PubMed Central

    Levy, Deborah L.; Coleman, Michael J.; Sung, Heejong; Ji, Fei; Matthysse, Steven; Mendell, Nancy R.; Titone, Debra

    2009-01-01

    Thought disorder as well as language and communication disturbances are associated with schizophrenia and are over-represented in clinically unaffected relatives of schizophrenics. All three kinds of dysfunction involve some element of deviant verbalizations, most notably, semantic anomalies. Of particular importance, thought disorder characterized primarily by deviant verbalizations has a higher recurrence in relatives of schizophrenic patients than schizophrenia itself. These findings suggest that deviant verbalizations may be more penetrant expressions of schizophrenia susceptibility genes than schizophrenia. This paper reviews the evidence documenting the presence of thought, language and communication disorders in schizophrenic patients and in their first-degree relatives. This familial aggregation potentially implicates genetic factors in the etiology of thought disorder, language anomalies, and communication disturbances in schizophrenia families. We also present two examples of ways in which thought, language and communication disorders can enrich genetic studies, including those involving schizophrenia. PMID:20161689

  14. Genetics Home Reference: FOXP2-related speech and language disorder

    MedlinePlus

    ... disorder Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description FOXP2 - ... provides instructions for making a protein called forkhead box P2, which appears to be essential for the ...

  15. Genetics Home Reference: ALG6-congenital disorder of glycosylation

    MedlinePlus

    ... also known as congenital disorder of glycosylation type Ic) is an inherited condition that affects many parts ... Condition ALG6-CDG carbohydrate-deficient glycoprotein syndrome type Ic carbohydrate-deficient glycoprotein syndrome type V CDG syndrome ...

  16. The molecular genetics of Marfan syndrome and related disorders

    PubMed Central

    Robinson, P N; Arteaga‐Solis, E; Baldock, C; Collod‐Béroud, G; Booms, P; De Paepe, A; Dietz, H C; Guo, G; Handford, P A; Judge, D P; Kielty, C M; Loeys, B; Milewicz, D M; Ney, A; Ramirez, F; Reinhardt, D P; Tiedemann, K; Whiteman, P; Godfrey, M

    2006-01-01

    Marfan syndrome (MFS), a relatively common autosomal dominant hereditary disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the gene for fibrillin‐1 (FBN1). The leading cause of premature death in untreated individuals with MFS is acute aortic dissection, which often follows a period of progressive dilatation of the ascending aorta. Recent research on the molecular physiology of fibrillin and the pathophysiology of MFS and related disorders has changed our understanding of this disorder by demonstrating changes in growth factor signalling and in matrix‐cell interactions. The purpose of this review is to provide a comprehensive overview of recent advances in the molecular biology of fibrillin and fibrillin‐rich microfibrils. Mutations in FBN1 and other genes found in MFS and related disorders will be discussed, and novel concepts concerning the complex and multiple mechanisms of the pathogenesis of MFS will be explained. PMID:16571647

  17. Molecular approaches in the prenatal diagnosis and therapy of genetic disorders.

    PubMed

    Myrianthopoulos, N C

    1987-01-01

    During the last decade a new class of DNA markers, the restriction fragment length polymorphisms (RFLPs), has been developed by molecular genetic techniques. Genetic linkage studies using RFLPs have resulted in a large number of chromosome assignments of genes, making possible prenatal diagnosis and presymptomatic testing in many genetic disorders. Even so, of the estimated 100,000 genes that comprise the human genome fewer than 2,000, or 2%, have been mapped. Studies of the molecular basis of some of these mutant genes have brought to light a remarkable multiplicity and diversity of mutations that produce relatively few clinical phenotypes. Many genetic disorders including the thalassemias, familial hypercholesterolemia, Tay-Sachs disease, cystic fibrosis, and congenital adrenal hyperplasia, have been shown to be genetically heterogeneous. It is necessary, therefore, to know the precise mutation in order to make accurate diagnosis and restore proper enzyme or gene function.

  18. Familial resemblance of borderline personality disorder features: genetic or cultural transmission?

    PubMed

    Distel, Marijn A; Rebollo-Mesa, Irene; Willemsen, Gonneke; Derom, Catherine A; Trull, Timothy J; Martin, Nicholas G; Boomsma, Dorret I

    2009-01-01

    Borderline personality disorder is a severe personality disorder for which genetic research has been limited to family studies and classical twin studies. These studies indicate that genetic effects explain 35 to 45% of the variance in borderline personality disorder and borderline personality features. However, effects of non-additive (dominance) genetic factors, non-random mating and cultural transmission have generally not been explored. In the present study an extended twin-family design was applied to self-report data of twins (N = 5,017) and their siblings (N = 1,266), parents (N = 3,064) and spouses (N = 939) from 4,015 families, to estimate the effects of additive and non-additive genetic and environmental factors, cultural transmission and non-random mating on individual differences in borderline personality features. Results showed that resemblance among biological relatives could completely be attributed to genetic effects. Variation in borderline personality features was explained by additive genetic (21%; 95% CI 17-26%) and dominant genetic (24%; 95% CI 17-31%) factors. Environmental influences (55%; 95% CI 51-60%) explained the remaining variance. Significant resemblance between spouses was observed, which was best explained by phenotypic assortative mating, but it had only a small effect on the genetic variance (1% of the total variance). There was no effect of cultural transmission from parents to offspring.

  19. Promoting Adaptive Behavior in Persons with Acquired Brain Injury, Extensive Motor and Communication Disabilities, and Consciousness Disorders

    ERIC Educational Resources Information Center

    Lancioni, Giulio E.; Singh, Nirbhay N.; O'Reilly, Mark F.; Sigafoos, Jeff; Belardinelli, Marta Olivetti; Buonocunto, Francesca; Sacco, Valentina; Navarro, Jorge; Lanzilotti, Crocifissa; De Tommaso, Marina; Megna, Marisa; Badagliacca, Francesco

    2012-01-01

    These two studies extended the evidence on the use of technology-based intervention packages to promote adaptive behavior in persons with acquired brain injury and multiple disabilities. Study I involved five participants in a minimally conscious state who were provided with intervention packages based on specific arrangements of optic, tilt, or…

  20. Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette Syndrome and Obsessive-Compulsive Disorder

    PubMed Central

    Yu, Dongmei; Mathews, Carol A.; Scharf, Jeremiah M.; Neale, Benjamin M.; Davis, Lea K.; Gamazon, Eric R.; Derks, Eske M.; Evans, Patrick; Edlund, Christopher K.; Crane, Jacquelyn; Fagerness, Jesen A.; Osiecki, Lisa; Gallagher, Patience; Gerber, Gloria; Haddad, Stephen; Illmann, Cornelia; McGrath, Lauren M.; Mayerfeld, Catherine; Arepalli, Sampath; Barlassina, Cristina; Barr, Cathy L.; Bellodi, Laura; Benarroch, Fortu; Berrió, Gabriel Bedoya; Bienvenu, O. Joseph; Black, Donald; Bloch, Michael H.; Brentani, Helena; Bruun, Ruth D.; Budman, Cathy L.; Camarena, Beatriz; Campbell, Desmond D.; Cappi, Carolina; Cardona Silgado, Julio C.; Cavallini, Maria C.; Chavira, Denise A.; Chouinard, Sylvain; Cook, Edwin H.; Cookson, M. R.; Coric, Vladimir; Cullen, Bernadette; Cusi, Daniele; Delorme, Richard; Denys, Damiaan; Dion, Yves; Eapen, Valsama; Egberts, Karin; Falkai, Peter; Fernandez, Thomas; Fournier, Eduardo; Garrido, Helena; Geller, Daniel; Gilbert, Donald; Girard, Simon L.; Grabe, Hans J.; Grados, Marco A.; Greenberg, Benjamin D.; Gross-Tsur, Varda; Grünblatt, Edna; Hardy, John; Heiman, Gary A.; Hemmings, Sian M.J.; Herrera, Luis D.; Hezel, Dianne M.; Hoekstra, Pieter J.; Jankovic, Joseph; Kennedy, James L.; King, Robert A.; Konkashbaev, Anuar I.; Kremeyer, Barbara; Kurlan, Roger; Lanzagorta, Nuria; Leboyer, Marion; Leckman, James F.; Lennertz, Leonhard; Liu, Chunyu; Lochner, Christine; Lowe, Thomas L.; Lupoli, Sara; Macciardi, Fabio; Maier, Wolfgang; Manunta, Paolo; Marconi, Maurizio; McCracken, James T.; Mesa Restrepo, Sandra C.; Moessner, Rainald; Moorjani, Priya; Morgan, Jubel; Muller, Heike; Murphy, Dennis L.; Naarden, Allan L.; Ochoa, William Cornejo; Ophoff, Roel A.; Pakstis, Andrew J.; Pato, Michele T.; Pato, Carlos N.; Piacentini, John; Pittenger, Christopher; Pollak, Yehuda; Rauch, Scott L.; Renner, Tobias; Reus, Victor I.; Richter, Margaret A.; Riddle, Mark A.; Robertson, Mary M.; Romero, Roxana; Rosário, Maria C.; Rosenberg, David; Ruhrmann, Stephan; Sabatti, Chiara; Salvi, Erika; Sampaio, Aline S.; Samuels, Jack; Sandor, Paul; Service, Susan K.; Sheppard, Brooke; Singer, Harvey S.; Smit, Jan H.; Stein, Dan J.; Strengman, Eric; Tischfield, Jay A.; Turiel, Maurizio; Valencia Duarte, Ana V.; Vallada, Homero; Veenstra-VanderWeele, Jeremy; Walitza, Susanne; Walkup, John; Wang, Ying; Weale, Mike; Weiss, Robert; Wendland, Jens R.; Westenberg, Herman G.M.; Yao, Yin; Hounie, Ana G.; Miguel, Euripedes C.; Nicolini, Humberto; Wagner, Michael; Ruiz-Linares, Andres; Cath, Danielle C.; McMahon, William; Posthuma, Danielle; Oostra, Ben A.; Nestadt, Gerald; Rouleau, Guy A.; Purcell, Shaun; Jenike, Michael A.; Heutink, Peter; Hanna, Gregory L.; Conti, David V.; Arnold, Paul D.; Freimer, Nelson; Stewart, S. Evelyn; Knowles, James A.; Cox, Nancy J.; Pauls, David L.

    2014-01-01

    Obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS) are highly heritable neurodevelopmental disorders that are thought to share genetic risk factors. However, the identification of definitive susceptibility genes for these etiologically complex disorders remains elusive. Here, we report a combined genome-wide association study (GWAS) of TS and OCD in 2723 cases (1310 with OCD, 834 with TS, 579 with OCD plus TS/chronic tics (CT)), 5667 ancestry-matched controls, and 290 OCD parent-child trios. Although no individual single nucleotide polymorphisms (SNPs) achieved genome-wide significance, the GWAS signals were enriched for SNPs strongly associated with variations in brain gene expression levels, i.e. expression quantitative loci (eQTLs), suggesting the presence of true functional variants that contribute to risk of these disorders. Polygenic score analyses identified a significant polygenic component for OCD (p=2×10−4), predicting 3.2% of the phenotypic variance in an independent data set. In contrast, TS had a smaller, non-significant polygenic component, predicting only 0.6% of the phenotypic variance (p=0.06). No significant polygenic signal was detected across the two disorders, although the sample is likely underpowered to detect a modest shared signal. Furthermore, the OCD polygenic signal was significantly attenuated when cases with both OCD and TS/CT were included in the analysis (p=0.01). Previous work has shown that TS and OCD have some degree of shared genetic variation. However, the data from this study suggest that there are also distinct components to the genetic architectures of TS and OCD. Furthermore, OCD with co-occurring TS/CT may have different underlying genetic susceptibility compared to OCD alone. PMID:25158072

  1. Borderline personality traits and adult attention-deficit hyperactivity disorder symptoms: a genetic analysis of comorbidity.

    PubMed

    Distel, Marijn A; Carlier, Angela; Middeldorp, Christel M; Derom, Catherine A; Lubke, Gitta H; Boomsma, Dorret I

    2011-12-01

    Previous research has established the comorbidity of adult Attention-Deficit Hyperactivity Disorder (ADHD) with different personality disorders including Borderline Personality Disorder (BPD). The association between adult ADHD and BPD has primarily been investigated at the phenotypic level and not yet at the genetic level. The present study investigates the genetic and environmental contributions to the association between borderline personality traits (BPT) and ADHD symptoms in a sample of 7,233 twins and siblings (aged 18-90 years) registered with the Netherlands Twin Register and the East Flanders Prospective Twin Survey (EFPTS) . Participants completed the Conners' Adult ADHD Rating Scales (CAARS-S:SV) and the Personality Assessment Inventory-Borderline Features Scale (PAI-BOR). A bivariate genetic analysis was performed to determine the extent to which genetic and environmental factors influence variation in BPT and ADHD symptoms and the covariance between them. The heritability of BPT and ADHD symptoms was estimated at 45 and 36%, respectively. The remaining variance in BPT and ADHD symptoms was explained by unique environmental influences. The phenotypic correlation between BPT and ADHD symptoms was estimated at r = 0.59, and could be explained for 49% by genetic factors and 51% by environmental factors. The genetic and environmental correlations between BPT and ADHD symptoms were 0.72 and 0.51, respectively. The shared etiology between BPT and ADHD symptoms is thus a likely cause for the comorbidity of the two disorders.

  2. Genetics and Epigenetics of Circadian Rhythms and Their Potential Roles in Neuropsychiatric Disorders

    PubMed Central

    Liu, Chunyu; Chung, Michael

    2015-01-01

    Circadian rhythms alterations have been implicated in multiple neuropsychiatric disorders, particularly sleep-wake disorders, addiction, and anxiety and mood disorders. Circadian rhythms are known to be maintained by a set of classic clock genes that form complex mutual and self regulatory loops. While many other genes showing rhythmic expression have been identified through genome-wide studies, their roles in the circadian regulation remain largely unknown. In attempts to directly connect circadian rhythms and neuropsychiatric disorders, genetic studies have identified genes with mutations associated with several rare forms of sleep disorders or sleep-related traits. Other than that, genetic studies of circadian genes in psychiatric disorders have yielded limited success. As important mediator of environmental factors and regulators of circadian rhythms, the epigenetic system may hold the key to the etiology or pathology of psychiatric disorders, their subtypes or endophenotypes. Epigenomic regulations of the circadian system and its related changes have not been thoroughly explored in the context of neuropsychiatric disorders. We argue for systematic investigation of the circadian system, particularly epigenetic regulation, and its involvement in neuropsychiatric disorders, to improve our understanding of human behavior and disease etiology. PMID:25652815

  3. Emerging Genetic Counselor Roles within the Biotechnology and Pharmaceutical Industries: as Industry Interest Grows in Rare Genetic Disorders, How are Genetic Counselors Joining the Discussion?

    PubMed

    Field, Tessa; Brewster, Stephanie Jo; Towne, Meghan; Campion, MaryAnn W

    2016-08-01

    Traditionally, the biotechnology and pharmaceutical industry (BPI) has focused drug development at the mass-market level targeting common medical issues. However, a recent trend is the development of therapies for orphan or rare disorders, including many genetic disorders. Developing treatments for genetic disorders requires an understanding of the needs of the community and translating genomic information to clinical and non-clinical audiences. The core skills of genetic counselors (GCs) include a deep knowledge of genetics and ability to communicate complex information to a broad audience, making GCs a choice fit for this shift in drug development. To date there is limited data defining the roles GCs hold within this industry. This exploratory study aimed to define the roles and motivation of GCs working in BPI, assess job satisfaction, and identify translatable skills and current gaps in GC training programs. The authors surveyed 26 GCs working in BPI in the United States; 79 % work for companies focused on rare disorders. GC positions in BPI are growing, with 57 % of respondents being the first GC in their role. GCs in BPI continue to utilize core genetic counseling competencies, though 72 % felt their training did not fully prepare them for BPI. These data suggest opportunities for exposure to BPI in GC training to better prepare future generations of GCs for these career opportunities. GC satisfaction was high in BPI, notably in areas traditionally reported as less satisfying on the National Society for Genetic Counselors Professional Status Survey: salary and advancement opportunities. BPI's growing interest in rare disorders represents a career opportunity for GCs, addressing both historic areas of dissatisfaction for GCs and BPI's genomic communication needs.

  4. Antibacterial resistance, genes encoding toxins and genetic background among Staphylococcus aureus isolated from community-acquired skin and soft tissue infections in France: a national prospective survey.

    PubMed

    Lamy, B; Laurent, F; Gallon, O; Doucet-Populaire, F; Etienne, J; Decousser, J-W

    2012-06-01

    The epidemiology of staphylococcal community-acquired skin and soft tissues infections (CA-SSTIs) has changed dramatically. We described prospectively the characteristics of the Staphylococcus aureus isolated from 71 non-teaching French hospitals and implicated in CA-SSTIs: antimicrobial susceptibility (mecA polymerase chain reaction [PCR], disk diffusion method), virulence factor gene (sea, tst, pvl) prevalence and genetic background (agr allele). During November 2006, 235 strains were collected (wound infection: 51%, abscess: 21%, whitlow: 8%, diabetic foot: 7%, furunculosis: 3%). sea, tst and pvl were identified in 22.1, 13.2 and 8.9% strains, respectively. agr allele 1 was the most frequently encountered genetic background, whatever the methicillin susceptibility. Among the 34 methicillin-resistant S. aureus (MRSA, 14.5% of all S. aureus), only one strain (2.9%) harboured pvl (belonging to the European ST80 clone), four (11.8%) tst (belonging to two endemic French clones) and 18 (52.9%) sea gene (mainly the Lyon clone). According to their in vitro activity, pristinamycin or trimethoprim/sulfamethoxazole could be considered as first-choice antibiotics. To date, the international pvl-positive MRSA clones have not spread in France. MRSA strains isolated from putative CA-SSTIs exhibited a genetic and phenotypic background of hospital-acquired (HA) clones. National survey should be continued, in order to monitor the emergence of virulent clones.

  5. Imaging-Genetics in Autism Spectrum Disorder: Advances, Translational Impact, and Future Directions

    PubMed Central

    Ameis, Stephanie H.; Szatmari, Peter

    2012-01-01

    Autism Spectrum Disorder (ASD) refers to a group of heterogeneous neurodevelopmental disorders that are unified by impairments in reciprocal social communication and a pattern of inflexible behaviors. Recent genetic advances have resolved some of the complexity of the genetic architecture underlying ASD by identifying several genetic variants that contribute to the disorder. Different etiological pathways associated with ASD may converge through effects on common molecular mechanisms, such as synaptogenesis, neuronal motility, and axonal guidance. Recently, with more sophisticated techniques, neuroimaging, and neuropathological studies have provided some consistency of evidence that altered structure, activity, and connectivity within complex neural networks is present in ASD, compared to typically developing children. The imaging-genetics approach promises to help bridge the gap between genetic variation, resultant biological effects on the brain, and production of complex neuropsychiatric symptoms. Here, we review recent findings from the developing field of imaging-genetics applied to ASD. Studies to date have indicated that relevant risk genes are associated with alterations in circuits that mediate socio-emotional, visuo-spatial, and language processing. Longitudinal studies ideally focused on early development, in conjunction with investigation for gene–gene, and gene–environment interactions may move the promise of imaging-genetics in ASD closer to the clinical domain. PMID:22615702

  6. Neuroimaging and genetic risk for Alzheimer's disease and addiction-related degenerative brain disorders.

    PubMed

    Roussotte, Florence F; Daianu, Madelaine; Jahanshad, Neda; Leonardo, Cassandra D; Thompson, Paul M

    2014-06-01

    Neuroimaging offers a powerful means to assess the trajectory of brain degeneration in a variety of disorders, including Alzheimer's disease (AD). Here we describe how multi-modal imaging can be used to study the changing brain during the different stages of AD. We integrate findings from a range of studies using magnetic resonance imaging (MRI), positron emission tomography (PET), functional MRI (fMRI) and diffusion weighted imaging (DWI). Neuroimaging reveals how risk genes for degenerative disorders affect the brain, including several recently discovered genetic variants that may disrupt brain connectivity. We review some recent neuroimaging studies of genetic polymorphisms associated with increased risk for late-onset Alzheimer's disease (LOAD). Some genetic variants that increase risk for drug addiction may overlap with those associated with degenerative brain disorders. These common associations offer new insight into mechanisms underlying neurodegeneration and addictive behaviors, and may offer new leads for treating them before severe and irreversible neurological symptoms appear.

  7. Environmental, Physiological, and Cultural Injuries and Genetic Disorders

    Technology Transfer Automated Retrieval System (TEKTRAN)

    There are some disorders of citrus that are not currently known to be caused by a pathogenic agent, but appears to be inherited, physiologically based, or caused by environmental conditions. Environmental injuries include heat injury and sunburn; wind injury; smog; flooding; hail damage; lightning; ...

  8. Birth defects and genetic disorders among Arab Americans--Michigan, 1992-2003.

    PubMed

    Yanni, Emad A; Copeland, Glenn; Olney, Richard S

    2010-06-01

    Birth defects and genetic disorders are leading causes of infant morbidity and mortality in many countries. Population-based data on birth defects among Arab-American children have not been documented previously. Michigan has the second largest Arab-American community in the United States after California. Using data from the Michigan Birth Defects Registry (MBDR), which includes information on parents' country of birth and ancestry, birth prevalences were estimated in offspring of Michigan women of Arab ancestry for 21 major categories of birth defects and 12 congenital endocrine, metabolic, and hereditary disorders. Compared with other non-Hispanic white children in Michigan, Arab-American children had similar or lower birth prevalences of the selected types of structural birth defects, with higher rates of certain hereditary blood disorders and three categories of metabolic disorders. These estimates are important for planning preconception and antenatal health care, genetic counseling, and clinical care for Arab Americans.

  9. Genetic Counseling in Autism and Pervasive Developmental Disorders.

    ERIC Educational Resources Information Center

    Simonoff, Emily

    1998-01-01

    Provides a protocol for counseling families with an autistic member concerning the risk of having an autistic child. Reports data regarding empirical recurrence risks and identifies the key elements that influence recurrence risks for individual couples. Counseling expertise in both diagnosis and treatment of autism and in the genetics of complex…

  10. Progress in the genetics of polygenic brain disorders: significant new challenges for neurobiology.

    PubMed

    McCarroll, Steven A; Hyman, Steven E

    2013-10-30

    Advances in genome analysis, accompanied by the assembly of large patient cohorts, are making possible successful genetic analyses of polygenic brain disorders. If the resulting molecular clues, previously hidden in the genomes of affected individuals, are to yield useful information about pathogenesis and inform the discovery of new treatments, neurobiology will have to rise to many difficult challenges. Here we review the underlying logic of the genetic investigations, describe in more detail progress in schizophrenia and autism, and outline the challenges for neurobiology that lie ahead. We argue that technologies at the disposal of neuroscience are adequately advanced to begin to study the biology of common and devastating polygenic disorders.

  11. Is PFAPA syndrome really a sporadic disorder or is it genetic?

    PubMed

    Akelma, Ahmet Zulfikar; Cizmeci, Mehmet Nevzat; Kanburoglu, Mehmet Kenan; Mete, Emin; Bozkaya, Davut; Tufan, Naile; Catal, Ferhat

    2013-08-01

    Periodic fever syndromes are a group of disorders sharing similar symptoms, characterized primarily by regularly recurring fevers. PFAPA syndrome, one of the members of this group of disorders, is a clinical entity of unknown etiology which is frequently seen in the early childhood. Currently, the pathogenesis and the genetic basis of most of the disorders in the periodic fever spectrum are known, other than that of PFAPA syndrome. Although, classically PFAPA syndrome is known as a sporadic disease, we propose that it is not sporadic. We think that PFAPA syndrome may be an inherited disease and this hypothesis is supported by the clinical mimicry of PFAPA syndrome with other periodic fever syndromes with well-known genetic transmissions, frequent occurrence of the condition in members of the same family and emergence of common genetic mutations in the periodic fever syndrome spectrum. Moreover, our clinical observation that most of the patients diagnosed with PFAPA syndrome were of the same families strongly suggest a probable genetic transmission of this disorder. We have decided to discuss this hypothesis to contribute to the literature and assist our colleagues who are dealing with this commonly overlooked and often misdiagnosed disorder.

  12. Hardikar syndrome: long term outcome of a rare genetic disorder.

    PubMed

    Nydegger, Andreas; Van Dyck, Maria; Fisher, Robert A; Jaeken, Jaak; Hardikar, Winita

    2008-10-01

    Hardikar syndrome is a rare disorder of unknown etiology. Features of the syndrome are manifold with a predominance of liver and renal involvement. The syndrome is clearly distinct from other previously described syndromes such as Alagille syndrome, congenital hepatic fibrosis, Caroli disease, and Kabuki make-up syndrome. To date, only four cases of Hardikar syndrome have been published worldwide. We report here on the long term outcome of these patients.

  13. The Genetic and Phenotypic Basis of Infertility in Men with Pediatric Urologic Disorders

    PubMed Central

    Hsieh, Michael H.; Hollander, Adam; Lamb, Dolores J.; Turek, Paul J.

    2010-01-01

    Of infertile couples, approximately one-third feature male factor issues. A subset of male factor infertility is attributable to congenital or acquired pediatric urologic conditions, and patients with these disorders are often challenging to treat. Prior to the development of in vitro fertilization (IVF) in the 1970s and intracytoplasmic sperm injection (ICSI) in 1992 [1], many forms of infertility due to pediatric urologic conditions were untreatable. These technologies have enabled many previously infertile men to father children, but the effectiveness of these techniques in men with pediatric urologic disorders has never been systematically examined. In this review we provide a contemporary survey of the fertility status of men with pediatric urologic disorders in light of advances in assisted reproductive technology (ART). We examine currently available treatments as well as developing technologies and discoveries that may apply to pediatric urologic disorders. PMID:20451977

  14. The genetics of skeletal muscle disorders in horses.

    PubMed

    Mickelson, James R; Valberg, Stephanie J

    2015-01-01

    Horses are remarkable athletes and a fascinating species in which to study the genetic bases of athletic performance, skeletal muscle biology, and neuromuscular disease. Genetic selection in horses has resulted in many breeds that possess anatomical, physiological, and metabolic variations linked to speed, power, and endurance that are beginning to be defined at the molecular level. Along with the concentration of positive traits, equine breeding programs have also inadvertently concentrated heritable muscle diseases for which mutations impacting electrical conduction, muscle contraction, and energy metabolism within and across breeds have been characterized. The study of heritable muscle diseases in horses has provided exciting insights into the normal structure and function of muscle and important diagnostic tools for veterinarians. Results empower breeders and breed associations to make difficult decisions about how to use this information to improve the overall health and well-being of horses.

  15. The genetics of ocular disorders: insights from the zebrafish.

    PubMed

    Morris, Ann C

    2011-09-01

    Proper formation of the vertebrate eye requires a precisely coordinated sequence of morphogenetic events that integrate the developmental contributions of the skin ectoderm, neuroectoderm, and head mesenchyme. Disruptions in this process result in ocular malformations or retinal degeneration and can cause significant visual impairment. The zebrafish is an excellent vertebrate model for the study of eye development and disease due to the transparency of the embryo, its ex utero development, and its amenability to forward genetic screens. This review will present an overview of the genetic methodologies utilized in the zebrafish, a description of several zebrafish models of congenital ocular diseases, and a discussion of the utility of the zebrafish for assessing the pathogenicity of candidate disease alleles.

  16. Strabismus genetics across a spectrum of eye misalignment disorders

    PubMed Central

    Ye, XC; Pegado, V; Patel, MS; Wasserman, WW

    2014-01-01

    Eye misalignment, called strabismus, is amongst the most common phenotypes observed, occurring in up to 5% of individuals in a studied population. While misalignment is frequently observed in rare complex syndromes, the majority of strabismus cases are non-syndromic. Over the past decade, genes and pathways associated with syndromic forms of strabismus have emerged, but the genes contributing to non-syndromic strabismus remain elusive. Genetic testing for strabismus risk may allow for earlier diagnosis and treatment, as well as decreased frequency of surgery. We review human and model organism literature describing non-syndromic strabismus, including family, twin, linkage, and gene expression studies. Recent advances in the genetics of Duane retraction syndrome are considered, as relatives of those impacted show elevated familial rates of non-syndromic strabismus. As whole genome sequencing efforts are advancing for the discovery of the elusive strabismus genes, this overview is intended to support the interpretation of the new findings. PMID:24579652

  17. Imaging of genetic and degenerative disorders primarily causing Parkinsonism.

    PubMed

    Brooks, David J

    2016-01-01

    In this chapter the structural and functional imaging changes associated with both genetic causes of Parkinson's disease and the sporadic condition are reviewed. The role of imaging for supporting diagnosis and detecting subclinical disease is discussed and the potential use and drawbacks of using imaging biomarkers for monitoring disease progression are debated. Additionally, the use of imaging for differentiating atypical parkinsonian syndromes from Parkinson's disease is presented.

  18. Genetic Counselling for Psychiatric Disorders: Accounts of Psychiatric Health Professionals in the United Kingdom.

    PubMed

    Jenkins, Sian; Arribas-Ayllon, Michael

    2016-12-01

    Genetic counselling is not routinely offered for psychiatric disorders in the United Kingdom through NHS regional clinical genetics departments. However, recent genomic advances, confirming a genetic contribution to mental illness, are anticipated to increase demand for psychiatric genetic counselling. This is the first study of its kind to employ qualitative methods of research to explore accounts of psychiatric health professionals regarding the prospects for genetic counselling services within clinical psychiatry in the UK. Data were collected from 32 questionnaire participants, and 9 subsequent interviewees. Data analysis revealed that although participants had not encountered patients explicitly demanding psychiatric genetic counselling, psychiatric health professionals believe that such a service would be useful and desirable. Genomic advances may have significant implications for genetic counselling in clinical psychiatry even if these discoveries do not lead to genetic testing. Psychiatric health professionals describe clinical genetics as a skilled profession capable of combining complex risk communication with much needed psychosocial support. However, participants noted barriers to the implementation of psychiatric genetic counselling services including, but not limited to, the complexities of uncertainty in psychiatric diagnoses, patient engagement and ethical concerns regarding limited capacity.

  19. A review of cognitive neuropsychiatry in the taxonomy of eating disorders: state, trait, or genetic?

    PubMed

    Kanakam, Natalie; Treasure, Janet

    2013-01-01

    A greater understanding of neuropsychological traits in eating disorders may help to construct a more biologically based taxonomy. The aim of this paper is to review the current evidence base of neuropsychological traits in people with eating disorders. Evidence of difficulties in set shifting, weak central coherence, emotional processing difficulties, and altered reward sensitivity is presented for people both in the acute and recovered phase of the illness. These traits are also seen in first degree relatives. At present there is limited research linking these neuropsychological traits with genetic and neuroanatomical measures. In addition to improving the taxonomy of eating disorders, neuropsychological traits may be of value in producing targeted treatments.

  20. RDoC and Translational Perspectives on the Genetics of Trauma-Related Psychiatric Disorders

    PubMed Central

    Montalvo-Ortiz, Janitza L.; Gelernter, Joel; Hudziak, James; Kaufman, Joan

    2016-01-01

    Individuals with a history of child abuse are at high risk for depression, anxiety disorders, aggressive behavior, and substance use problems. The goal of this paper is to review studies of the genetics of these stress-related psychiatric disorders. An informative subset of studies that examined candidate gene by environment (GxE) predictors of these psychiatric problems in individuals maltreated as children is reviewed, together with extant genome wide association studies (GWAS). Emerging findings on epigenetic changes associated with adverse early experiences are also reviewed. Meta-analytic support and replicated findings are evident for several genetic risk factors; however, extant research suggests the effects are pleiotropic. Genetic factors are not associated with distinct psychiatric disorders, but rather diverse clinical phenotypes. Research also suggests adverse early life experiences are associated with changes in gene expression of multiple known candidate genes, genes involved in DNA transcription and translation, and genes necessary for brain circuitry development, with changes in gene expression reported in key brain structures implicated in the pathophysiology of psychiatric and substance use disorders. The finding of pleiotropy highlights the value of using the Research Domain Criteria (RDoC) framework in future studies of the genetics of stress-related psychiatric disorders, and not trying simply to link genes to multifaceted clinical syndromes, but to more limited phenotypes that map onto distinct neural circuits. Emerging work in the field of epigenetics also suggests that translational studies that integrate numerous unbiased genome-wide approaches will help to further unravel the genetics of stress-related psychiatric disorders. PMID:26592203

  1. Acquired Genetic Mechanisms of a Multiresistant Bacterium Isolated from a Treatment Plant Receiving Wastewater from Antibiotic Production

    PubMed Central

    Johnning, Anna; Moore, Edward R. B.; Svensson-Stadler, Liselott; Shouche, Yogesh S.; Larsson, D. G. Joakim

    2013-01-01

    The external environment, particularly wastewater treatment plants (WWTPs), where environmental bacteria meet human commensals and pathogens in large numbers, has been highlighted as a potential breeding ground for antibiotic resistance. We have isolated the extensively drug-resistant Ochrobactrum intermedium CCUG 57381 from an Indian WWTP receiving industrial wastewater from pharmaceutical production contaminated with high levels of quinolones. Antibiotic susceptibility testing against 47 antibiotics showed that the strain was 4 to >500 times more resistant to sulfonamides, quinolones, tetracyclines, macrolides, and the aminoglycoside streptomycin than the type strain O. intermedium LMG 3301T. Whole-genome sequencing identified mutations in the Indian strain causing amino acid substitutions in the target enzymes of quinolones. We also characterized three acquired regions containing resistance genes to sulfonamides (sul1), tetracyclines [tet(G) and tetR], and chloramphenicol/florfenicol (floR). Furthermore, the Indian strain harbored acquired mechanisms for horizontal gene transfer, including a type I mating pair-forming system (MPFI), a MOBP relaxase, and insertion sequence transposons. Our results highlight that WWTPs serving antibiotic manufacturing may provide nearly ideal conditions for the recruitment of resistance genes into human commensal and pathogenic bacteria. PMID:24038701

  2. Acquired genetic mechanisms of a multiresistant bacterium isolated from a treatment plant receiving wastewater from antibiotic production.

    PubMed

    Johnning, Anna; Moore, Edward R B; Svensson-Stadler, Liselott; Shouche, Yogesh S; Larsson, D G Joakim; Kristiansson, Erik

    2013-12-01

    The external environment, particularly wastewater treatment plants (WWTPs), where environmental bacteria meet human commensals and pathogens in large numbers, has been highlighted as a potential breeding ground for antibiotic resistance. We have isolated the extensively drug-resistant Ochrobactrum intermedium CCUG 57381 from an Indian WWTP receiving industrial wastewater from pharmaceutical production contaminated with high levels of quinolones. Antibiotic susceptibility testing against 47 antibiotics showed that the strain was 4 to >500 times more resistant to sulfonamides, quinolones, tetracyclines, macrolides, and the aminoglycoside streptomycin than the type strain O. intermedium LMG 3301T. Whole-genome sequencing identified mutations in the Indian strain causing amino acid substitutions in the target enzymes of quinolones. We also characterized three acquired regions containing resistance genes to sulfonamides (sul1), tetracyclines [tet(G) and tetR], and chloramphenicol/florfenicol (floR). Furthermore, the Indian strain harbored acquired mechanisms for horizontal gene transfer, including a type I mating pair-forming system (MPFI), a MOBP relaxase, and insertion sequence transposons. Our results highlight that WWTPs serving antibiotic manufacturing may provide nearly ideal conditions for the recruitment of resistance genes into human commensal and pathogenic bacteria.

  3. Non-human Primate Models for Brain Disorders - Towards Genetic Manipulations via Innovative Technology.

    PubMed

    Qiu, Zilong; Li, Xiao

    2017-04-01

    Modeling brain disorders has always been one of the key tasks in neurobiological studies. A wide range of organisms including worms, fruit flies, zebrafish, and rodents have been used for modeling brain disorders. However, whether complicated neurological and psychiatric symptoms can be faithfully mimicked in animals is still debatable. In this review, we discuss key findings using non-human primates to address the neural mechanisms underlying stress and anxiety behaviors, as well as technical advances for establishing genetically-engineered non-human primate models of autism spectrum disorders and other disorders. Considering the close evolutionary connections and similarity of brain structures between non-human primates and humans, together with the rapid progress in genome-editing technology, non-human primates will be indispensable for pathophysiological studies and exploring potential therapeutic methods for treating brain disorders.

  4. Alstrom syndrome: A rare genetic disorder and its anaesthetic significance

    PubMed Central

    Tiwari, Akhilesh; Awasthi, Disha; Tayal, Swapnil; Ganguly, S

    2010-01-01

    Alstrom syndrome is a rare autosomal recessive disorder that was first described in 1959, by Carl Henry Alstrom, characterised by multiorgan system involvement ranging from ocular, aural, endocrinal, hepatorenal, gastrointestinal, respiratory and cardiac to the musculoskeletal system, among many others. It exposes the patient to various risks ranging from pulmonary aspiration and increased cardiac morbidity to separational anxiety, and may necessitate postoperative elective ventilation. We hereby present the successful management of one such diagnosed case in a 12-year-old boy, who presented to us for incision and drainage of an abscess present over the nape of his neck, along with foreign body removal from his right ear. PMID:20661355

  5. Parent and peer influences on emerging adult substance use disorder: A genetically informed study

    PubMed Central

    Bountress, Kaitlin; Chassin, Laurie; Lemery-Chalfant, Kathryn

    2017-01-01

    The present study utilizes longitudinal data from a high-risk community sample to examine the unique effects of genetic risk, parental knowledge about the daily activities of adolescents, and peer substance use on emerging adult substance use disorders (SUDs). These effects are examined over and above a polygenic risk score. In addition, this polygenic risk score is used to examine gene–environment correlation and interaction. The results show that during older adolescence, higher adolescent genetic risk for SUDs predicts less parental knowledge, but this relation is nonsignificant in younger adolescence. Parental knowledge (using mother report) mediates the effects of parental alcohol use disorder (AUD) and adolescent genetic risk on risk for SUD, and peer substance use mediates the effect of parent AUD on offspring SUD. Finally, there are significant gene–environment interactions such that, for those at the highest levels of genetic risk, less parental knowledge and more peer substance use confers greater risk for SUDs. However, for those at medium and low genetic risk, these effects are attenuated. These findings suggest that the evocative effects of adolescent genetic risk on parenting increase with age across adolescence. They also suggest that some of the most important environmental risk factors for SUDs exert effects that vary across level of genetic propensity. PMID:26753847

  6. Morph-specific genetic and environmental variation in innate and acquired immune response in a color polymorphic raptor.

    PubMed

    Gangoso, Laura; Roulin, Alexandre; Ducrest, Anne-Lyse; Grande, Juan Manuel; Figuerola, Jordi

    2015-08-01

    Genetic color polymorphism is widespread in nature. There is an increasing interest in understanding the adaptive value of heritable color variation and trade-off resolution by differently colored individuals. Melanin-based pigmentation is often associated with variation in many different life history traits. These associations have recently been suggested to be the outcome of pleiotropic effects of the melanocortin system. Although pharmacological research supports that MC1R, a gene with a major role in vertebrate pigmentation, has important immunomodulatory effects, evidence regarding pleiotropy at MC1R in natural populations is still under debate. We experimentally assessed whether MC1R-based pigmentation covaries with both inflammatory and humoral immune responses in the color polymorphic Eleonora's falcon. By means of a cross-fostering experiment, we disentangled potential genetic effects from environmental effects on the covariation between coloration and immunity. Variation in both immune responses was primarily due to genetic factors via the nestlings' MC1R-related color genotype/phenotype, although environmental effects via the color morph of the foster father also had an influence. Overall, dark nestlings had lower immune responses than pale ones. The effect of the color morph of the foster father was also high, but in the opposite direction, and nestlings raised by dark eumelanic foster fathers had higher immune responses than those raised by pale foster fathers. Although we cannot completely discard alternative explanations, our results suggest that MC1R might influence immunity in this species. Morph-specific variation in immunity as well as pathogen pressure may therefore contribute to the long-term maintenance of genetic color polymorphism in natural populations.

  7. Screening for genetic disorders: therapeutic abortion and IVF.

    PubMed

    Michael, M; Buckle, S

    1990-03-01

    This paper examines a proposal to make use of IVF techniques to provide an alternative to therapeutic abortion of fetuses with genetic abnormalities. We begin by describing the proposed procedure, and then show that, considered in itself, it is morally on a par with therapeutic abortion. However, once the wider practical implications are brought into view, the proposed new procedure loses its initial appeal. The pros and cons are not sufficiently clear-cut entirely to rule out the IVF procedure, so the paper concludes by indicating some further complications which may follow, should the procedure come to be adopted.

  8. Genetics of bipolar disorder: focus on BDNF Val66Met polymorphism.

    PubMed

    Fan, Jinbo; Sklar, Pamela

    2008-01-01

    Bipolar disorder is a chronic severe mood disorder that has been consistently demonstrated to have a strong inherited component. Traditional approaches to gene discovery have produced conflicting results regarding the association between genes and bipolar disorder. Numerous genes have been proposed as associated with bipolar disorder. This paper will focus on one of these, brain-derived neurotrophic factor (BDNF). BDNF is an interesting candidate gene for bipolar disorder because of its important role in the neurodevelopment of the CNS. Previous genetic work has identified a potential association between a Val66Met polymorphism in the BDNF gene and bipolar disorder. Meta-analysis based on all original published association studies between the Val66Met polymorphism and bipolar disorder up to May 2007 shows modest but statistically significant evidence for the association between the Val66Met polymorphism and bipolar disorder (random-effects pooled odds ratio [OR] = 1.13, 95% Confidence Interval [CI] = 1.04-1.23, Z = 2.85, P = 0.004) from 14 studies consisting of 4248 cases, 7080 control subjects and 858 nuclear families. Further large-scale studies are warranted to elucidate the relevant BDNF gene variation(s) that act as risk factors for bipolar disorder susceptibility.

  9. Inherited Platelet Function Disorders: Algorithms for Phenotypic and Genetic Investigation.

    PubMed

    Gresele, Paolo; Bury, Loredana; Falcinelli, Emanuela

    2016-04-01

    Inherited platelet function disorders (IPFDs) manifest with mucocutaneous bleeding and are frequently difficult to diagnose due to their heterogeneity, the complexity of the platelet activation pathways and a lack of standardization of the platelet function laboratory assays and of their use for this purpose. A rational diagnostic approach to IPFDs should follow an algorithm where clinical examination and a stepwise laboratory evaluation play a crucial role. A streamlined panel of laboratory tests, with consecutive steps of increasing level of complexity, allows the phenotypic characterization of most IPFDs. A first-line diagnosis of a significant fraction of the IPFD may be made also at nonspecialized centers by using relatively simple tests, including platelet count, peripheral blood smear, light transmission aggregometry, measurement of platelet granule content and release, and the expression of glycoproteins by flow cytometry. Some of the most complex, second- and third-step tests may be performed only in highly specialized laboratories. Genotyping, including the widespread application of next-generation sequencing, has enabled discovery in the last few years of several novel genes associated with platelet disorders and this method may eventually become a first-line diagnostic approach; however, a preliminary clinical and laboratory phenotypic characterization nowadays still remains crucial for diagnosis of IPFDs.

  10. Spermatogonial Stem Cells: Implications for Genetic Disorders and Prevention

    PubMed Central

    Yamada, Makiko; De Chiara, Letizia

    2016-01-01

    Spermatogonial stem cells (SSCs) propagate mammalian spermatogenesis throughout male reproductive life by continuously self-renewing and differentiating, ultimately, into sperm. SSCs can be cultured for long periods and restore spermatogenesis upon transplantation back into the native microenvironment in vivo. Conventionally, SSC research has been focused mainly on male infertility and, to a lesser extent, on cell reprogramming. With the advent of genome-wide sequencing technology, however, human studies have uncovered a wide range of pathogenic alleles that arise in the male germ line. A subset of de novo point mutations was shown to originate in SSCs and cause congenital disorders in children. This review describes both monogenic diseases (eg, Apert syndrome) and complex disorders that are either known or suspected to be driven by mutations in SSCs. We propose that SSC culture is a suitable model for studying the origin and mechanisms of these diseases. Lastly, we discuss strategies for future clinical implementation of SSC-based technology, from detecting mutation burden by sperm screening to gene correction in vitro. PMID:27596369

  11. Personality Mediation of Genetic Effects on Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Martel, Michelle M.; Nikolas, Molly; Jernigan, Katherine; Friderici, Karen; Nigg, Joel T.

    2010-01-01

    Personality traits may be viable candidates for mediators of the relationship between genetic risk and ADHD. Participants were 578 children (331 boys; 320 children with ADHD) between the ages of six and 18. Parents and teachers completed a comprehensive, multi-stage diagnostic procedure to assess ADHD and comorbid disorders. Mother completed the…

  12. Delineation of Behavioral Phenotypes in Genetic Syndromes: Characteristics of Autism Spectrum Disorder, Affect and Hyperactivity

    ERIC Educational Resources Information Center

    Oliver, Chris; Berg, Katy; Moss, Jo; Arron, Kate; Burbidge, Cheryl

    2011-01-01

    We investigated autism spectrum disorder (ASD) symptomatology, hyperactivity and affect in seven genetic syndromes; Angelman (AS; n = 104), Cri du Chat (CdCS; 58), Cornelia de Lange (CdLS; 101), Fragile X (FXS; 191), Prader-Willi (PWS; 189), Smith-Magenis (SMS; 42) and Lowe (LS; 56) syndromes (age range 4-51). ASD symptomatology was heightened in…

  13. Autism and 15q11-q13 Disorders: Behavioral, Genetic, and Pathophysiological Issues

    ERIC Educational Resources Information Center

    Dykens, Elisabeth M.; Sutcliffe, James S.; Levitt, Pat

    2004-01-01

    New insights into biological factors that underlie autism may be gained by comparing autism to other neurodevelopmental disorders that have autistic features and relatively well-delineated genetic etiologies or neurobiological findings. This review moves beyond global diagnoses of autism and instead uses an endophenotypic approach to compare…

  14. Identification of Genetic Loci Underlying the Phenotypic Constructs of Autism Spectrum Disorders

    ERIC Educational Resources Information Center

    Liu, Xiao-Qing; Georgiades, Stelios; Duku, Eric; Thompson, Ann; Devlin, Bernie; Cook, Edwin H.; Wijsman, Ellen M.; Paterson, Andrew D.; Szatmari, Peter

    2011-01-01

    Objective: To investigate the underlying phenotypic constructs in autism spectrum disorders (ASD) and to identify genetic loci that are linked to these empirically derived factors. Method: Exploratory factor analysis was applied to two datasets with 28 selected Autism Diagnostic Interview-Revised (ADI-R) algorithm items. The first dataset was from…

  15. Featural versus Configural Face Processing in a Rare Genetic Disorder: Williams Syndrome

    ERIC Educational Resources Information Center

    Isaac, L.; Lincoln, A.

    2011-01-01

    Background: Williams syndrome (WMS) is a rare genetic disorder with an estimated prevalence of 1 in 20,000 live births. Among other characteristics, WMS has a distinctive cognitive profile with spared face processing and language skills that contrasts with impairment in the cognitive domains of spatial cognition, problem solving and planning. It…

  16. Multi-system Component Phenotypes of Bipolar Disorder for Genetic Investigations of Extended Pedigrees

    PubMed Central

    Fears, Scott C.; Service, Susan K.; Kremeyer, Barbara; Araya, Carmen; Araya, Xinia; Bejarano, Julio; Ramirez, Margarita; Castrillón, Gabriel; Gomez-Franco, Juliana; Lopez, Maria C.; Montoya, Gabriel; Montoya, Patricia; Aldana, Ileana; Teshiba, Terri M.; Abaryan, Zvart; Al-Sharif, Noor B.; Ericson, Marissa; Jalbrzikowski, Maria; Luykx, Jurjen J.; Navarro, Linda; Tishler, Todd A.; Altshuler, Lori; Bartzokis, George; Escobar, Javier; Glahn, David C.; Ospina-Duque, Jorge; Risch, Neil; Ruiz-Linares, Andrés; Thompson, Paul M.; Cantor, Rita M.; Lopez-Jaramillo, Carlos; Macaya, Gabriel; Molina, Julio; Reus, Victor I.; Sabatti, Chiara; Freimer, Nelson B.; Bearden, Carrie E.

    2014-01-01

    IMPORTANCE Genetic factors contribute to risk for bipolar disorder (BP), yet its pathogenesis remains poorly understood. A focus on measuring multi-system quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that impact on BP as well as its component phenotypes. OBJECTIVE To identify quantitative neurocognitive, temperament-related, and neuroanatomic phenotypes that appear heritable and associated with severe bipolar disorder (BP-I), and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk. DESIGN Multi-generational pedigree study in two closely related, genetically isolated populations: the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (ANT). PARTICIPANTS 738 individuals, all from CVCR and ANT pedigrees, of whom 181 are affected with BP-I. MAIN OUTCOME MEASURE Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) phenotypes. RESULTS Seventy-five percent (126) of the phenotypes investigated were significantly heritable, and 31% (53) were associated with BP-I. About 1/4 of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions, and volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture. CONCLUSIONS AND

  17. New technologies provide insights into genetic basis of psychiatric disorders and explain their co-morbidity.

    PubMed

    Rudan, Igor

    2010-06-01

    The completion of Human Genome Project and the "HapMap" project was followed by translational activities from companies within the private sector. This led to the introduction of genome-wide scans based on hundreds of thousands of single nucleotide polymorphysms (SNP). These scans were based on common genetic variants in human populations. This new and powerful technology was then applied to the existing DNA-based datasets with information on psychiatric disorders. As a result, an unprecedented amount of novel scientific insights related to the underlying biology and genetics of psychiatric disorders was obtained. The dominant design of these studies, so called "genome-wide association studies" (GWAS), used statistical methods which minimized the risk of false positive reports and provided much greater power to detect genotype-phenotype associations. All findings were entirely data-driven rather than hypothesis-driven, which often made it difficult for researchers to understand or interpret the findings. Interestingly, this work in genetics is indicating how non-specific some genes are for psychiatric disorders, having associations in common for schizophrenia, bipolar disorder and autism. This suggests that the earlier stages of psychiatric disorders may be multi-valent and that early detection, coupled with a clearer understanding of the environmental factors, may allow prevention. At the present time, the rich "harvest" from GWAS still has very limited power to predict the variation in psychiatric disease status at individual level, typically explaining less than 5% of the total risk variance. The most recent studies of common genetic variation implicated the role of major histocompatibility complex in schizophrenia and other disorders. They also provided molecular evidence for a substantial polygenic component to the risk of psychiatric diseases, involving thousands of common alleles of very small effect. The studies of structural genetic variation, such as copy

  18. Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development.

    PubMed

    Arboleda, V A; Lee, H; Sánchez, F J; Délot, E C; Sandberg, D E; Grody, W W; Nelson, S F; Vilain, E

    2013-01-01

    Disorders of sex development (DSD) are rare disorders in which there is discordance between chromosomal, gonadal, and phenotypic sex. Only a minority of patients clinically diagnosed with DSD obtains a molecular diagnosis, leaving a large gap in our understanding of the prevalence, management, and outcomes in affected patients. We created a novel DSD-genetic diagnostic tool, in which sex development genes are captured using RNA probes and undergo massively parallel sequencing. In the pilot group of 14 patients, we determined sex chromosome dosage, copy number variation, and gene mutations. In the patients with a known genetic diagnosis (obtained either on a clinical or research basis), this test identified the molecular cause in 100% (7/7) of patients. In patients in whom no molecular diagnosis had been made, this tool identified a genetic diagnosis in two of seven patients. Targeted sequencing of genes representing a specific spectrum of disorders can result in a higher rate of genetic diagnoses than current diagnostic approaches. Our DSD diagnostic tool provides for first time, in a single blood test, a comprehensive genetic diagnosis in patients presenting with a wide range of urogenital anomalies.

  19. Primary dystonias and genetic disorders with dystonia as clinical feature of the disease.

    PubMed

    Moghimi, Narges; Jabbari, Bahman; Szekely, Anna M

    2014-01-01

    Dystonia is probably the most common form of movement disorder encountered in the clinical practice. It is characterized by sustained muscle contractions, usually producing twisting and repetitive movements or abnormal postures or positions. Dystonias can be classified in several ways, including primarily by the clinical phenomenology or by the underlining etiology, in particular to understand if the presentation is genetically determined. By advances of genetics, including contemporary genomic technologies, there is a growing understanding of the molecular underpinnings of genetically determined dystonias. The intricacy of information requires a user friendly, novel database that may efficiently serve clinicians to inform of advances of the field and to diagnose and manage these often complex cases. Here we present an up to date, comprehensive review - in tabulated formats - of genetically determined primary dystonias and complex Mendelian disorders with dystonia as central feature. The detailed search up to December 24, 2012, identified 24 hereditary primary dystonias (DYT1 to DYT 25) that are mostly monogenic disorders, and a larger group (>70) of genetic syndromes in which dystonia is one of the characteristic clinical features. We organized the findings not only by individual information (name of the conditions, pattern of inheritance, chromosome and gene abnormality, clinical features, relevant ancillary tests and key references), but also provide symptom-oriented organization of the clinical entities for efficient inquiries.

  20. Autism Spectrum and Obsessive–Compulsive Disorders: OC Behaviors, Phenotypes and Genetics

    PubMed Central

    Jacob, Suma; Landeros-Weisenberger, Angeli; Leckman, James F.

    2014-01-01

    Autism spectrum disorders (ASDs) are a phenotypically and etiologically heterogeneous set of disorders that include obsessive–compulsive behaviors (OCB) that partially overlap with symptoms associated with obsessive–compulsive disorder (OCD). The OCB seen in ASD vary depending on the individual’s mental and chronological age as well as the etiology of their ASD. Although progress has been made in the measurement of the OCB associated with ASD, more work is needed including the potential identification of heritable endophenotypes. Likewise, important progress toward the understanding of genetic influences in ASD has been made by greater refinement of relevant phenotypes using a broad range of study designs, including twin and family-genetic studies, parametric and nonparametric linkage analyses, as well as candidate gene studies and the study of rare genetic variants. These genetic analyses could lead to the refinement of the OCB phenotypes as larger samples are studied and specific associations are replicated. Like ASD, OCB are likely to prove to be multidimensional and polygenic. Some of the vulnerability genes may prove to be generalist genes influencing the phenotypic expression of both ASD and OCD while others will be specific to subcomponents of the ASD phenotype. In order to discover molecular and genetic mechanisms, collaborative approaches need to generate shared samples, resources, novel genomic technologies, as well as more refined phenotypes and innovative statistical approaches. There is a growing need to identify the range of molecular pathways involved in OCB related to ASD in order to develop novel treatment interventions. PMID:20029829

  1. Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders

    PubMed Central

    Heyes, Samuel; Pratt, Wendy S.; Rees, Elliott; Dahimene, Shehrazade; Ferron, Laurent; Owen, Michael J.; Dolphin, Annette C.

    2015-01-01

    This review summarises genetic studies in which calcium channel genes have been connected to the spectrum of neuropsychiatric syndromes, from bipolar disorder and schizophrenia to autism spectrum disorders and intellectual impairment. Among many other genes, striking numbers of the calcium channel gene superfamily have been implicated in the aetiology of these diseases by various DNA analysis techniques. We will discuss how these relate to the known monogenic disorders associated with point mutations in calcium channels. We will then examine the functional evidence for a causative link between these mutations or single nucleotide polymorphisms and the disease processes. A major challenge for the future will be to translate the expanding psychiatric genetic findings into altered physiological function, involvement in the wider pathology of the diseases, and what potential that provides for personalised and stratified treatment options for patients. PMID:26386135

  2. Predictive Medicine: Recombinant DNA Technology and Adult-Onset Genetic Disorders

    PubMed Central

    Hayden, Michael

    1988-01-01

    Genetic factors are of great importance in common adult-onset disorders such as atherosclerosis, cancer, and neuro-degenerative diseases. Advances in DNA technology now allow identification of persons at high-risk of developing some of these diseases. This advance is leading to predictive medicine. In some genetic disorders, such as those leading to atherosclerosis and cancer, identification of high-risk individuals allows intervention which alters the natural history of the disorder. In other diseases, for which there is no treatment, such as Huntington's disease, the application of this technology provides information that relieves uncertainty and may affect quality of life, but does not alter the course of the illness. General implementation of predictive testing programs awaits the results of pilot projects, which will demonstrate the needs, appropriate levels of support, and guidelines for delivery of such testing. PMID:21253100

  3. Perspective on the Genetics and Diagnosis of Congenital Hyperinsulinism Disorders

    PubMed Central

    2016-01-01

    Context: Congenital hyperinsulinism (HI) is the most common cause of hypoglycemia in children. The risk of permanent brain injury in infants with HI continues to be as high as 25–50% due to delays in diagnosis and inadequate treatment. Congenital HI has been described since the birth of the JCEM under various terms, including “idiopathic hypoglycemia of infancy,” “leucine-sensitive hypoglycemia,” or “nesidioblastosis.” Evidence Acquisition: In the past 20 years, it has become apparent that HI is caused by genetic defects in the pathways that regulate pancreatic β-cell insulin secretion. Evidence Synthesis: There are now 11 genes associated with monogenic forms of HI (ABCC8, KCNJ11, GLUD1, GCK, HADH1, UCP2, MCT1, HNF4A, HNF1A, HK1, PGM1), as well as several syndromic genetic forms of HI (eg, Beckwith-Wiedemann, Kabuki, and Turner syndromes). HI is also the cause of hypoglycemia in transitional neonatal hypoglycemia and in persistent hypoglycemia in various groups of high-risk neonates (such as birth asphyxia, small for gestational age birthweight, infant of diabetic mother). Management of HI is one of the most difficult problems faced by pediatric endocrinologists and frequently requires difficult choices, such as near-total pancreatectomy and/or highly intensive care with continuous tube feedings. For 50 years, diazoxide, a KATP channel agonist, has been the primary drug for infants with HI; however, it is ineffective in most cases with mutations of ABCC8 or KCNJ11, which constitute the majority of infants with monogenic HI. Conclusions: Genetic mutation testing has become standard of care for infants with HI and has proven to be useful not only in projecting prognosis and family counseling, but also in diagnosing infants with surgically curable focal HI lesions. 18F-fluoro-L-dihydroxyphenylalanine (18F-DOPA) PET scans have been found to be highly accurate for localizing such focal lesions preoperatively. New drugs under investigation provide hope

  4. Merging data from genetic and epigenetic approaches to better understand autistic spectrum disorder

    PubMed Central

    Grayson, Dennis R; Guidotti, Alessandro

    2016-01-01

    Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is characterized by a wide range of cognitive and behavioral abnormalities. Genetic research has identified large numbers of genes that contribute to ASD phenotypes. There is compelling evidence that environmental factors contribute to ASD through influences that differentially impact the brain through epigenetic mechanisms. Both genetic mutations and epigenetic influences alter gene expression in different cell types of the brain. Mutations impact the expression of large numbers of genes and also have downstream consequences depending on specific pathways associated with the mutation. Environmental factors impact the expression of sets of genes by altering methylation/hydroxymethylation patterns, local histone modification patterns and chromatin remodeling. Herein, we discuss recent developments in the research of ASD with a focus on epigenetic pathways as a complement to current genetic screening. PMID:26551091

  5. Carrier testing for Ashkenazi Jewish disorders in the prenatal setting: navigating the genetic maze.

    PubMed

    Ferreira, Jose Carlos P; Schreiber-Agus, Nicole; Carter, Suzanne M; Klugman, Susan; Gregg, Anthony R; Gross, Susan J

    2014-09-01

    Exciting developments in the fields of genetics and genomics have facilitated the identification of the etiological basis of many Mendelian disorders. Several of the methods used in gene discovery have focused initially on homogeneous populations, including the Ashkenazi Jewish population. The founder effect is well recognized in this community, in which historical events and cultural behaviors have resulted in a limited number of mutations underlying genetic disorders with substantial health impact. New technologies have made it possible to rapidly expand the test panels, changing testing paradigms, and thereby creating challenges for the physician in deciphering the appropriate approach to genetic screening in this population. The goal of this review is to help primary obstetric health care providers navigate through this quickly moving field so as to better counsel and support their patients of Ashkenazi Jewish heritage.

  6. Attitudes Toward Pre-implantation Genetic Diagnosis (PGD) for Genetic Disorders Among Potential Users in Malaysia.

    PubMed

    Olesen, Angelina Patrick; Nor, Siti Nurani Mohd; Amin, Latifah

    2016-02-01

    While pre-implantation genetic diagnosis (PGD) is available and legal in Malaysia, there is an ongoing controversy debate about its use. There are few studies available on individuals' attitudes toward PGD, particularly among those who have a genetic disease, or whose children have a genetic disease. To the best of our knowledge, this is, in fact, the first study of its kind in Malaysia. We conducted in-depth interviews, using semi-structured questionnaires, with seven selected potential PGD users regarding their knowledge, attitudes and decisions relating to the use PGD. The criteria for selecting potential PGD users were that they or their children had a genetic disease, and they desired to have another child who would be free of genetic disease. All participants had heard of PGD and five of them were considering its use. The participants' attitudes toward PGD were based on several different considerations that were influenced by various factors. These included: the benefit-risk balance of PGD, personal experiences of having a genetic disease, religious beliefs, personal values and cost. The study's findings suggest that the selected Malaysian participants, as potential PGD users, were supportive but cautious regarding the use of PGD for medical purposes, particularly in relation to others whose experiences were similar. More broadly, the paper highlights the link between the participants' personal experiences and their beliefs regarding the appropriateness, for others, of individual decision-making on PGD, which has not been revealed by previous studies.

  7. Definitions of Normal Liver Fat and the Association of Insulin Sensitivity with Acquired and Genetic NAFLD—A Systematic Review

    PubMed Central

    Petäjä, Elina M.; Yki-Järvinen, Hannele

    2016-01-01

    Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of disease ranging from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) and fibrosis. “Obese/Metabolic NAFLD” is closely associated with obesity and insulin resistance and therefore predisposes to type 2 diabetes and cardiovascular disease. NAFLD can also be caused by common genetic variants, the patatin-like phospholipase domain-containing 3 (PNPLA3) or the transmembrane 6 superfamily member 2 (TM6SF2). Since NAFL, irrespective of its cause, can progress to NASH and liver fibrosis, its definition is of interest. We reviewed the literature to identify data on definition of normal liver fat using liver histology and different imaging tools, and analyzed whether NAFLD caused by the gene variants is associated with insulin resistance. Histologically, normal liver fat content in liver biopsies is most commonly defined as macroscopic steatosis in less than 5% of hepatocytes. In the population-based Dallas Heart Study, the upper 95th percentile of liver fat measured by proton magnetic spectroscopy (1H-MRS) in healthy subjects was 5.6%, which corresponds to approximately 15% histological liver fat. When measured by magnetic resonance imaging (MRI)-based techniques such as the proton density fat fraction (PDFF), 5% macroscopic steatosis corresponds to a PDFF of 6% to 6.4%. In contrast to “Obese/metabolic NAFLD”, NAFLD caused by genetic variants is not associated with insulin resistance. This implies that NAFLD is heterogeneous and that “Obese/Metabolic NAFLD” but not NAFLD due to the PNPLA3 or TM6SF2 genetic variants predisposes to type 2 diabetes and cardiovascular disease. PMID:27128911

  8. Association between Hypoalbuminaemia and Mortality in Patients with Community-Acquired Bacteraemia Is Primarily Related to Acute Disorders

    PubMed Central

    Magnussen, Bjarne; Oren Gradel, Kim; Gorm Jensen, Thøger; Kolmos, Hans Jørn; Pedersen, Court; Just Vinholt, Pernille; Touborg Lassen, Annmarie

    2016-01-01

    We sought to investigate whether hypoalbuminaemia was mainly caused by acute or chronic factors in patients with community-acquired bacteraemia. In this population-based study, we considered 1844 adult cases of community-acquired bacteraemia that occurred in Funen, Denmark between 2000 and 2008. We used a stepwise prognostic predisposition-insult-response-organ dysfunction (PIRO) logistic regression model by initially including age and comorbidity, then added bacterial species, and finally sepsis severity. The models were furthermore analysed using receiver operating characteristic (ROC) curves. Outcomes comprised mortality incidence on days 0–30 and 31–365 after the bacteraemia episode. Each step was performed with and without baseline albumin level measured on the date of bacteraemia. In 422 patients, their latest albumin measurement taken 8–30 days before the date of bacteraemia was also used in the analysis together with the baseline albumin level. For each decrease of 1g/L in plasma albumin level, the odds ratios (95% confidence intervals) of mortality in the period of 0–30 days after bacteraemia were 0.86 (0.84–0.88) in both predisposition (P) and predisposition-insult (PI) models and 0.87 (0.85–0.89) in the full PIRO-model. The AUC values were 0.78 and 0.66 for mortality in the period of 0–30 days in the model comprising only predisposition factors with and without albumin levels added as a factor, respectively. The AUC values in the full PIRO-model were 0.81 and 0.73 with and without consideration of albumin levels, respectively. A higher proportion of patients died within 30 days if there was a decrease in the albumin level between days 8 and 30 before bacteraemia and the actual bacteraemia date. A single plasma albumin measurement on the bacteraemia date was a better prognostic predictor of short-term mortality than the sepsis severity score. PMID:27611431

  9. Social Engagement with Parents in 11-Month-Old Siblings at High and Low Genetic Risk for Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Campbell, Susan B.; Leezenbaum, Nina B.; Mahoney, Amanda S.; Day, Taylor N.; Schmidt, Emily N.

    2015-01-01

    Infant siblings of children with an autism spectrum disorder are at heightened genetic risk to develop autism spectrum disorder. We observed high risk (n?=?35) and low risk (n?=?27) infants at 11?months during free play with a parent. Children were assessed for autism spectrum disorder in toddlerhood. High-risk infants with a later diagnosis…

  10. Structural, Genetic, and Functional Signatures of Disordered Neuro-Immunological Development in Autism Spectrum Disorder

    PubMed Central

    Saxena, Vishal; Ramdas, Shweta; Ochoa, Courtney Rothrock; Wallace, David; Bhide, Pradeep; Kohane, Isaac

    2012-01-01

    Background Numerous linkage studies have been performed in pedigrees of Autism Spectrum Disorders, and these studies point to diverse loci and etiologies of autism in different pedigrees. The underlying pattern may be identified by an integrative approach, especially since ASD is a complex disorder manifested through many loci. Method Autism spectrum disorder (ASD) was studied through two different and independent genome-scale measurement modalities. We analyzed the results of copy number variation in autism and triangulated these with linkage studies. Results Consistently across both genome-scale measurements, the same two molecular themes emerged: immune/chemokine pathways and developmental pathways. Conclusion Linkage studies in aggregate do indeed share a thematic consistency, one which structural analyses recapitulate with high significance. These results also show for the first time that genomic profiling of pathways using a recombination distance metric can capture pathways that are consistent with those obtained from copy number variations (CNV). PMID:23239965

  11. Attention Deficit Hyperactivity Disorder with Reading Disabilities: Preliminary Genetic Findings on the Involvement of the ADRA2A Gene

    ERIC Educational Resources Information Center

    Stevenson, J.; Langley, K.; Pay, H.; Payton, A.; Worthington, J.; Ollier, W.; Thapar, A.

    2005-01-01

    Background: Attention deficit/hyperactivity disorder (ADHD) and reading disability (RD) tend to co-occur and quantitative genetic studies have shown this to arise primarily through shared genetic influences. However, molecular genetic studies have shown different genes to be associated with each of these conditions. Neurobiological studies have…

  12. The genetics of disorders of sex development in humans.

    PubMed

    Ohnesorg, Thomas; Vilain, Eric; Sinclair, Andrew H

    2014-01-01

    One of the defining events during human embryonic development with the most far-reaching effects for the individual is whether the embryo develops as male or female. The crucial step in this process is the differentiation of the bipotential embryonic gonads into either testes or ovaries. If the embryo inherits X and Y sex chromosomes, the Y-linked SRY (sex determining region in Y) gene initiates a network of genes that results in a functional testis and ultimately a male phenotype. By contrast, in an embryo with 2 X chromosomes, the undifferentiated gonad develops as an ovary resulting in a female phenotype. Perturbation of any of the genes in either the testicular or ovarian developmental pathway can result in individuals with disorders of sex development. In this review, we provide a summary of known components of testicular or ovarian pathways and their antagonistic actions and give a brief overview of new technologies currently used to identify the missing pieces of the sex development network.

  13. Widespread Macromolecular Interaction Perturbations in Human Genetic Disorders

    PubMed Central

    Sahni, Nidhi; Yi, Song; Taipale, Mikko; Fuxman Bass, Juan I.; Coulombe-Huntington, Jasmin; Yang, Fan; Peng, Jian; Weile, Jochen; Karras, Georgios I.; Wang, Yang; Kovács, István A.; Kamburov, Atanas; Krykbaeva, Irina; Lam, Mandy H.; Tucker, George; Khurana, Vikram; Sharma, Amitabh; Liu, Yang-Yu; Yachie, Nozomu; Zhong, Quan; Shen, Yun; Palagi, Alexandre; San-Miguel, Adriana; Fan, Changyu; Balcha, Dawit; Dricot, Amelie; Jordan, Daniel M.; Walsh, Jennifer M.; Shah, Akash A.; Yang, Xinping; Stoyanova, Ani; Leighton, Alex; Calderwood, Michael A.; Jacob, Yves; Cusick, Michael E.; Salehi-Ashtiani, Kourosh; Whitesell, Luke J.; Sunyaev, Shamil; Berger, Bonnie; Barabási, Albert-László; Charloteaux, Benoit; Hill, David E.; Hao, Tong; Roth, Frederick P.; Xia, Yu; Walhout, Albertha J.M.; Lindquist, Susan; Vidal, Marc

    2015-01-01

    SUMMARY How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to “edgetic” alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread. PMID:25910212

  14. Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate

    PubMed Central

    Georgi, Benjamin; Craig, David; Kember, Rachel L.; Liu, Wencheng; Lindquist, Ingrid; Nasser, Sara; Brown, Christopher; Egeland, Janice A.; Paul, Steven M.; Bućan, Maja

    2014-01-01

    Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP-array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders. PMID:24625924

  15. Genetic and Disorder-Specific Aspects of Resting State EEG Abnormalities in Schizophrenia

    PubMed Central

    Venables, Noah C.; Bernat, Edward M.; Sponheim, Scott R.

    2009-01-01

    We evaluated whether abnormal frequency composition of the resting state electroencephalogram (EEG) in schizophrenia was associated with genetic liability for the disorder by studying first-degree biological relatives of schizophrenia patients. The study included a data-driven method for defining EEG frequency components and determined the specificity of resting state EEG frequency abnormalities by assessing schizophrenia patients, bipolar disorder patients, and relatives of both patient groups. Schizophrenia patients and their relatives, but not bipolar patients or their relatives, exhibited increased high-frequency activity (beta) providing evidence for disturbances in resting state brain activity being specific to genetic liability for schizophrenia. Schizophrenia patients exhibited augmented low-frequency EEG activity (delta, theta), while bipolar disorder patients and the 2 groups of relatives generally failed to manifest similar low-frequency EEG abnormalities. The Val158Met polymorphism for the catechol-O-methyl transferase (COMT) gene was most strongly associated with delta and theta activity in schizophrenia patients. Met homozygote schizophrenia patients exhibited augmented activity for the 2 low-frequency bands compared with control subjects. Excessive high-frequency EEG activity over frontal brain regions may serve as an endophenotype that reflects cortical expression of genetic vulnerability for schizophrenia. Low-frequency resting state EEG anomalies in schizophrenia may relate to disorder-specific pathophysiology in schizophrenia and the influence of the COMT gene on tonic dopamanergic function. PMID:18381357

  16. [Diagnostics of the genetic causes of autism spectrum disorders - a clinical geneticist's view].

    PubMed

    Szczaluba, Krzysztof

    2014-01-01

    Explanation of the genetic basis of autism spectrum disorders has, for many decades, been a part of interest of researchers and clinicians. In recent years, thanks to modern molecular and cytogenetic techniques, a significant progress has been achieved in the diagnosis of genetic causes of autism. This applies particularly, but not exclusively, to those cases of autism that are accompanied by other clinical signs (i. e. complex phenotypes). The important clinical markers belong to different categories, and include congenital defects/anomalies, dysmorphism and macro-/microcephaly, to name the few. Thus, the choice of the diagnostic strategy depends on the clinical and pedigree information and, under Polish circumstances, the availability of specific diagnostic techniques and the amount of reimbursement under the National Health Service. Overall, the identification of the genetic causes of autism spectrum disorders is possible in about 10-30% of patients. In this paper the practical aspects of the use of different diagnostic techniques are briefly described. Some clinical examples and current recommendations for the diagnosis of patients with autism spectrum disorders are also presented. The point of view of a specialist in clinical genetics, increasingly involved, as part of the multidisciplinary care team, in the diagnostics of an autistic child has been demonstrated.

  17. Human Urine-Derived Renal Progenitors for Personalized Modeling of Genetic Kidney Disorders.

    PubMed

    Lazzeri, Elena; Ronconi, Elisa; Angelotti, Maria Lucia; Peired, Anna; Mazzinghi, Benedetta; Becherucci, Francesca; Conti, Sara; Sansavini, Giulia; Sisti, Alessandro; Ravaglia, Fiammetta; Lombardi, Duccio; Provenzano, Aldesia; Manonelles, Anna; Cruzado, Josep M; Giglio, Sabrina; Roperto, Rosa Maria; Materassi, Marco; Lasagni, Laura; Romagnani, Paola

    2015-08-01

    The critical role of genetic and epigenetic factors in the pathogenesis of kidney disorders is gradually becoming clear, and the need for disease models that recapitulate human kidney disorders in a personalized manner is paramount. In this study, we describe a method to select and amplify renal progenitor cultures from the urine of patients with kidney disorders. Urine-derived human renal progenitors exhibited phenotype and functional properties identical to those purified from kidney tissue, including the capacity to differentiate into tubular cells and podocytes, as demonstrated by confocal microscopy, Western blot analysis of podocyte-specific proteins, and scanning electron microscopy. Lineage tracing studies performed with conditional transgenic mice, in which podocytes are irreversibly tagged upon tamoxifen treatment (NPHS2.iCreER;mT/mG), that were subjected to doxorubicin nephropathy demonstrated that renal progenitors are the only urinary cell population that can be amplified in long-term culture. To validate the use of these cells for personalized modeling of kidney disorders, renal progenitors were obtained from (1) the urine of children with nephrotic syndrome and carrying potentially pathogenic mutations in genes encoding for podocyte proteins and (2) the urine of children without genetic alterations, as validated by next-generation sequencing. Renal progenitors obtained from patients carrying pathogenic mutations generated podocytes that exhibited an abnormal cytoskeleton structure and functional abnormalities compared with those obtained from patients with proteinuria but without genetic mutations. The results of this study demonstrate that urine-derived patient-specific renal progenitor cultures may be an innovative research tool for modeling of genetic kidney disorders.

  18. Exploiting the unique regenerative capacity of the liver to underpin cell and gene therapy strategies for genetic and acquired liver disease.

    PubMed

    Logan, Grant J; de Alencastro, Gustavo; Alexander, Ian E; Yeoh, George C

    2014-11-01

    The number of genetic or acquired diseases of the liver treatable by organ transplantation is ever-increasing as transplantation techniques improve placing additional demands on an already limited organ supply. While cell and gene therapies are distinctly different modalities, they offer a synergistic alternative to organ transplant due to distinct architectural and physiological properties of the liver. The hepatic blood supply and fenestrated endothelial system affords relatively facile accessibility for cell and/or gene delivery. More importantly, however, the remarkable capacity of hepatocytes to proliferate and repopulate the liver creates opportunities for new treatments based on emerging technologies. This review will summarise current understanding of liver regeneration, describe clinical and experimental cell and gene therapeutic modalities and discuss critical challenges to translate these new technologies to wider clinical utility. This article is part of a Directed Issue entitled: "Regenerative Medicine: the challenge of translation".

  19. Familial clustering of Taenia solium cysticercosis in the rural pigs of Mexico: hints of genetic determinants in innate and acquired resistance to infection.

    PubMed

    Sciutto, E; Martínez, J J; Huerta, M; Avila, R; Fragoso, G; Villalobos, N; de Aluja, A; Larralde, C

    2003-10-20

    In two rural villages of the state of Puebla, Mexico, where Taenia solium pig cysticercosis is highly endemic, 120 pairs of young out-bred piglets were used to assay what proved to be an effective synthetic peptide vaccine against naturally acquired cysticercosis. Because the piglets used were all sired by one of three distinct studs in many different out-bred sows, the prevalence and intensity of infection, as well as degree of protection conferred by the vaccine, could be related to each of the three stud families (A-C). The highest prevalence was found in the C family (25%), whilst the prevalence of B and A families were 21.6 and 4.4%, respectively. Familial clustering of cases was even more conspicuous in vaccinated pigs than in not-vaccinated ones: seven of the nine cysticercosis cases that occurred in the vaccinated group belonged to the C family (7/26) and two to the B family (2/23), whilst the vaccine rendered the A family totally resistant (0/71). Parasite numbers were also higher in the C family in both nai;ve and vaccinated pigs. Familial clustering of cases and of large parasite numbers in naive and vaccinated pigs hint to the relevance of their genetic background in their innate and acquired resistance to cysticercosis.

  20. Imaging Phenotypes of Major Depressive Disorder: Genetic Correlates

    PubMed Central

    Savitz, Jonathan B; Drevets, Wayne C

    2009-01-01

    Imaging techniques are a potentially powerful method of identifying phenotypes that are associated with, or are indicative of a vulnerability to developing major depressive disorder (MDD). Here we identify seven promising MDD-associated traits identified by magnetic resonance imaging (MRI) or positron emission tomography (PET). We evaluate whether these traits are state-independent, heritable endophenotypes, or state-dependent phenotypes that may be useful markers of treatment efficacy. In MDD, increased activity of the amygdala in response to negative stimuli appears to be a mood-congruent phenomenon, and is likely moderated by the serotonin transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR). Hippocampal volume loss is characteristic of elderly or chronically-ill samples and may be impacted by the val66met brain-derived neurotrophic factor (BDNF) gene variant and the 5-HTTLPR SLC6A4 polymorphism. White matter pathology is salient in elderly MDD cohorts but is associated with cerebrovascular disease, and is unlikely to be a useful marker of a latent MDD diathesis. Increased blood flow or metabolism of the subgenual anterior cingulate cortex (sgACC), together with gray matter volume loss in this region, is a well-replicated finding in MDD. An attenuation of the usual pattern of fronto-limbic connectivity, particularly a decreased temporal correlation in amygdala-anterior cingulate cortex (ACC) activity, is another MDD-associated trait. Concerning neuroreceptor PET imaging, decreased 5-HT1A binding potential in the raphe, medial temporal lobe, and medial prefrontal cortex (mPFC) has been strongly associated with MDD, and may be impacted by a functional single nucleotide polymorphism in the promoter region of the 5-HT1A gene (HTR1A: –1019C/G; rs6295). Potentially indicative of inter-study variation in MDD etiology or mood state, both increased and decreased binding potential of the serotonin transporter has been reported. Challenges facing the field include

  1. Molecular, Phenotypic Aspects and Therapeutic Horizons of Rare Genetic Bone Disorders

    PubMed Central

    Dhawan, Naveen; Vohra, Shivani; Tu, Khin; Abdelmagid, Samir M.

    2014-01-01

    A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities. PMID:25530967

  2. Molecular, phenotypic aspects and therapeutic horizons of rare genetic bone disorders.

    PubMed

    Faruqi, Taha; Dhawan, Naveen; Bahl, Jaya; Gupta, Vineet; Vohra, Shivani; Tu, Khin; Abdelmagid, Samir M

    2014-01-01

    A rare disease afflicts less than 200,000 individuals, according to the National Organization for Rare Diseases (NORD) of the United States. Over 6,000 rare disorders affect approximately 1 in 10 Americans. Rare genetic bone disorders remain the major causes of disability in US patients. These rare bone disorders also represent a therapeutic challenge for clinicians, due to lack of understanding of underlying mechanisms. This systematic review explored current literature on therapeutic directions for the following rare genetic bone disorders: fibrous dysplasia, Gorham-Stout syndrome, fibrodysplasia ossificans progressiva, melorheostosis, multiple hereditary exostosis, osteogenesis imperfecta, craniometaphyseal dysplasia, achondroplasia, and hypophosphatasia. The disease mechanisms of Gorham-Stout disease, melorheostosis, and multiple hereditary exostosis are not fully elucidated. Inhibitors of the ACVR1/ALK2 pathway may serve as possible therapeutic intervention for FOP. The use of bisphosphonates and IL-6 inhibitors has been explored to be useful in the treatment of fibrous dysplasia, but more research is warranted. Cell therapy, bisphosphonate polytherapy, and human growth hormone may avert the pathology in osteogenesis imperfecta, but further studies are needed. There are still no current effective treatments for these bone disorders; however, significant promising advances in therapeutic modalities were developed that will limit patient suffering and treat their skeletal disabilities.

  3. Combat-acquired traumatic brain injury, posttraumatic stress disorder, and their relative associations with postdeployment binge drinking

    PubMed Central

    Adams, Rachel Sayko; Larson, Mary Jo; Corrigan, John D.; Ritter, Grant A.; Horgan, Constance M.; Bray, Robert M.; Williams, Thomas V.

    2014-01-01

    Objective To examine whether experiencing a traumatic brain injury (TBI) on a recent combat deployment was associated with postdeployment binge drinking, independent of posttraumatic stress disorder (PTSD). Methods Using the 2008 Department of Defense Survey of Health Related Behaviors among Active Duty Military Personnel, an anonymous survey completed by 28,546 personnel, the study sample included 6,824 personnel who had a combat deployment in the past year. Path analysis was used to examine whether PTSD accounted for the total association between TBI and binge drinking. Main Measures The dependent variable, binge drinking days, was an ordinal measure capturing the number of times personnel drank 5+ drinks on one occasion (4+ for women) in the past month. TBI-level captured the severity of TBI after a combat injury event exposure: TBI-AC (altered consciousness only), TBI-LOC≤20 (loss of consciousness up to 20 minutes), and TBI-LOC>20 (loss of consciousness greater than 20 minutes). APTSD positive screen relied on the standard diagnostic cutoff of 50+ on the PCL-C. Results The final path model found that while the direct effect of TBI (0.097) on binge drinking was smaller than that of PTSD (0.156), both were significant. Almost 70% of the total effect of TBI on binge drinking was from the direct effect; only 30% represented the indirect effect through PTSD. Conclusion Further research is needed to replicate these findings and to understand the underlying mechanisms that explain the relationship between TBI and increased postdeployment drinking. PMID:25310293

  4. Integrating Genetic, Neuropsychological and Neuroimaging Data to Model Early-Onset Obsessive Compulsive Disorder Severity.

    PubMed

    Mas, Sergi; Gassó, Patricia; Morer, Astrid; Calvo, Anna; Bargalló, Nuria; Lafuente, Amalia; Lázaro, Luisa

    2016-01-01

    We propose an integrative approach that combines structural magnetic resonance imaging data (MRI), diffusion tensor imaging data (DTI), neuropsychological data, and genetic data to predict early-onset obsessive compulsive disorder (OCD) severity. From a cohort of 87 patients, 56 with complete information were used in the present analysis. First, we performed a multivariate genetic association analysis of OCD severity with 266 genetic polymorphisms. This association analysis was used to select and prioritize the SNPs that would be included in the model. Second, we split the sample into a training set (N = 38) and a validation set (N = 18). Third, entropy-based measures of information gain were used for feature selection with the training subset. Fourth, the selected features were fed into two supervised methods of class prediction based on machine learning, using the leave-one-out procedure with the training set. Finally, the resulting model was validated with the validation set. Nine variables were used for the creation of the OCD severity predictor, including six genetic polymorphisms and three variables from the neuropsychological data. The developed model classified child and adolescent patients with OCD by disease severity with an accuracy of 0.90 in the testing set and 0.70 in the validation sample. Above its clinical applicability, the combination of particular neuropsychological, neuroimaging, and genetic characteristics could enhance our understanding of the neurobiological basis of the disorder.

  5. Integrating Genetic, Neuropsychological and Neuroimaging Data to Model Early-Onset Obsessive Compulsive Disorder Severity

    PubMed Central

    Mas, Sergi; Gassó, Patricia; Morer, Astrid; Calvo, Anna; Bargalló, Nuria; Lafuente, Amalia; Lázaro, Luisa

    2016-01-01

    We propose an integrative approach that combines structural magnetic resonance imaging data (MRI), diffusion tensor imaging data (DTI), neuropsychological data, and genetic data to predict early-onset obsessive compulsive disorder (OCD) severity. From a cohort of 87 patients, 56 with complete information were used in the present analysis. First, we performed a multivariate genetic association analysis of OCD severity with 266 genetic polymorphisms. This association analysis was used to select and prioritize the SNPs that would be included in the model. Second, we split the sample into a training set (N = 38) and a validation set (N = 18). Third, entropy-based measures of information gain were used for feature selection with the training subset. Fourth, the selected features were fed into two supervised methods of class prediction based on machine learning, using the leave-one-out procedure with the training set. Finally, the resulting model was validated with the validation set. Nine variables were used for the creation of the OCD severity predictor, including six genetic polymorphisms and three variables from the neuropsychological data. The developed model classified child and adolescent patients with OCD by disease severity with an accuracy of 0.90 in the testing set and 0.70 in the validation sample. Above its clinical applicability, the combination of particular neuropsychological, neuroimaging, and genetic characteristics could enhance our understanding of the neurobiological basis of the disorder. PMID:27093171

  6. The Genetic and Environmental Sources of Resemblance Between Normative Personality and Personality Disorder Traits.

    PubMed

    Kendler, K S; Aggen, S H; Gillespie, Nathan; Neale, M C; Knudsen, G P; Krueger, R F; Czajkowski, Nikolai; Ystrom, Eivind; Reichborn-Kjennerud, T

    2016-06-20

    Recent work has suggested a high level of congruence between normative personality, most typically represented by the "big five" factors, and abnormal personality traits. In 2,293 Norwegian adult twins ascertained from a population-based registry, the authors evaluated the degree of sharing of genetic and environmental influences on normative personality, assessed by the Big Five Inventory (BFI), and personality disorder traits (PDTs), assessed by the Personality Inventory for DSM-5-Norwegian Brief Form (PID-5-NBF). For four of the five BFI dimensions, the strongest genetic correlation was observed with the expected PID-5-NBF dimension (e.g., neuroticism with negative affectivity [+], conscientiousness with disinhibition [-]). However, neuroticism, conscientiousness, and agreeableness had substantial genetic correlations with other PID-5-NBF dimensions (e.g., neuroticism with compulsivity [+], agreeableness with detachment [-]). Openness had no substantial genetic correlations with any PID-5-NBF dimension. The proportion of genetic risk factors shared in aggregate between the BFI traits and the PID-5-NBF dimensions was quite high for conscientiousness and neuroticism, relatively robust for extraversion and agreeableness, but quite low for openness. Of the six PID-5-NBF dimensions, three (negative affectivity, detachment, and disinhibition) shared, in aggregate, most of their genetic risk factors with normative personality traits. Genetic factors underlying psychoticism, antagonism, and compulsivity were shared to a lesser extent, suggesting that they are influenced by etiological factors not well indexed by the BFI.

  7. A Comprehensive Review of Progressive Familial Intrahepatic Cholestasis (PFIC): Genetic Disorders of Hepatocanalicular Transporters

    PubMed Central

    Amer, Syed; Hajira, Amtul

    2014-01-01

    Progressive familial intrahepatic cholestasis or PFIC is a general term used to describe a group of genetic disorders involving the hepatocanalicular transporters. These diseases are characterized by persistent cholestasis, pruritus and jaundice. Type I PFIC is characterized by defect in the gene that codes for aminophospholipid translocase protein and maintains canalicular membrane stability. Types 2 and 3 are caused by defect in genes that code for bile acid transporter and a phospholipid translocase, respectively. This review summarizes the genetics, clinical features, diagnosis and treatment of the three types of PFIC. PMID:27785268

  8. A Comprehensive Review of Progressive Familial Intrahepatic Cholestasis (PFIC): Genetic Disorders of Hepatocanalicular Transporters.

    PubMed

    Amer, Syed; Hajira, Amtul

    2014-04-01

    Progressive familial intrahepatic cholestasis or PFIC is a general term used to describe a group of genetic disorders involving the hepatocanalicular transporters. These diseases are characterized by persistent cholestasis, pruritus and jaundice. Type I PFIC is characterized by defect in the gene that codes for aminophospholipid translocase protein and maintains canalicular membrane stability. Types 2 and 3 are caused by defect in genes that code for bile acid transporter and a phospholipid translocase, respectively. This review summarizes the genetics, clinical features, diagnosis and treatment of the three types of PFIC.

  9. [Investigation of the genetic background of bipolar disorder and schizophrenia (introduction)].

    PubMed

    Gábor, Gaszner

    2007-06-01

    The hereditability of bipolar disorder (Bpd) and schizophrenia (Sch) is a well known fact, twin studies are applied to estimate the contribution of the genetic background. Gene linkage studies provided from suicidal brain samples are used to identify mutation of susceptibility genes involved in the etiology. Numerous genes are playing role in the altered signal transduction pathways. Based on the combined effects and functional interactions between the enzymes expressed by these key genes, it could be possible to estimate the genetic risk. Through targeting the intracellular enzymes we can affect the pathogenesis and modify neuronal plasticity of Bpd and Sch, thus developing new psychoactive drugs.

  10. Genetic variations of human neuropsin gene and psychiatric disorders: polymorphism screening and possible association with bipolar disorder and cognitive functions.

    PubMed

    Izumi, Aiko; Iijima, Yoshimi; Noguchi, Hiroko; Numakawa, Tadahiro; Okada, Takeya; Hori, Hiroaki; Kato, Tadafumi; Tatsumi, Masahiko; Kosuga, Asako; Kamijima, Kunitoshi; Asada, Takashi; Arima, Kunimasa; Saitoh, Osamu; Shiosaka, Sadao; Kunugi, Hiroshi

    2008-12-01

    Human neuropsin (NP) (hNP) has been implicated in the progressive change of cognitive abilities during primate evolution. The hNP gene maps to chromosome 19q13, a region reportedly linked to schizophrenia and bipolar disorder. Therefore, hNP is a functional and positional candidate gene for association with schizophrenia, mood disorders, and cognitive ability. Polymorphism screening was performed for the entire hNP gene. The core promoter region was determined and whether or not transcriptional activity alters in an allele-dependent manner was examined by using the dual-luciferase system. Allelic and genotypic distributions of five single-nucleotide polymorphisms (SNPs) were compared between patients with schizophrenia (n=439), major depression (n=409), bipolar disorder (n=207), and controls (n=727). A possible association of the hNP genotype with memory index (assessed with Wechsler Memory Scale, revised, WMS-R) and intelligence quotient (IQ assessed with Wechsler Adult Intelligence Scale, revised; WAIS-R) was examined in healthy controls (n=166). A total of 28 SNPs, including nine novel SNPs, were identified. No significant effects on transcriptional activity were observed for SNPs in the promoter region. A significant allelic association was found between several SNPs and bipolar disorder (for SNP23 at the 3' regulatory region; odds ratio 1.48, 95% confidential interval 1.16-1.88, P=0.0015). However, such an association was not detected for schizophrenia or depression. Significant differences were observed between SNP23 and attention/concentration sub-scale score of WMS-R (P=0.016) and verbal IQ (P<0.001). Genetic variation of the hNP gene may contribute to molecular mechanisms of bipolar disorder and some aspects of memory and intelligence.

  11. Large animal models of rare genetic disorders: sheep as phenotypically relevant models of human genetic disease.

    PubMed

    Pinnapureddy, Ashish R; Stayner, Cherie; McEwan, John; Baddeley, Olivia; Forman, John; Eccles, Michael R

    2015-09-02

    Animals that accurately model human disease are invaluable in medical research, allowing a critical understanding of disease mechanisms, and the opportunity to evaluate the effect of therapeutic compounds in pre-clinical studies. Many types of animal models are used world-wide, with the most common being small laboratory animals, such as mice. However, rodents often do not faithfully replicate human disease, despite their predominant use in research. This discordancy is due in part to physiological differences, such as body size and longevity. In contrast, large animal models, including sheep, provide an alternative to mice for biomedical research due to their greater physiological parallels with humans. Completion of the full genome sequences of many species, and the advent of Next Generation Sequencing (NGS) technologies, means it is now feasible to screen large populations of domesticated animals for genetic variants that resemble human genetic diseases, and generate models that more accurately model rare human pathologies. In this review, we discuss the notion of using sheep as large animal models, and their advantages in modelling human genetic disease. We exemplify several existing naturally occurring ovine variants in genes that are orthologous to human disease genes, such as the Cln6 sheep model for Batten disease. These, and other sheep models, have contributed significantly to our understanding of the relevant human disease process, in addition to providing opportunities to trial new therapies in animals with similar body and organ size to humans. Therefore sheep are a significant species with respect to the modelling of rare genetic human disease, which we summarize in this review.

  12. Genetic disorders and the ethical status of germ-line gene therapy.

    PubMed

    Berger, E M; Gert, B M

    1991-12-01

    Recombinant DNA technology will soon allow physicians an opportunity to carry out both somatic cell- and germ-line gene therapy. While somatic cell gene therapy raises no new ethical problems, gene therapy of gametes, fertilized eggs or early embryos does raise several novel concerns. The first issue discussed here relates to making a distinction between negative and positive eugenics; the second issue deals with the evolutionary consequences of lost genetic diversity. In distinguishing between positive and negative eugenics, the concept of malady is applied as a definitional criterion for identifying genetic disorders that could qualify for germ-line therapy. Because gene replacement techniques are currently unavailable for humans, and because even if they were possible the number of people involved would be quite small, the loss of diversity concern seems moot. Finally, we discuss the issue of iatrogenic disorders associated with gene therapy and discuss several 'real world considerations.'

  13. The genetics of mammalian circadian order and disorder: implications for physiology and disease.

    PubMed

    Takahashi, Joseph S; Hong, Hee-Kyung; Ko, Caroline H; McDearmon, Erin L

    2008-10-01

    Circadian cycles affect a variety of physiological processes, and disruptions of normal circadian biology therefore have the potential to influence a range of disease-related pathways. The genetic basis of circadian rhythms is well studied in model organisms and, more recently, studies of the genetic basis of circadian disorders has confirmed the conservation of key players in circadian biology from invertebrates to humans. In addition, important advances have been made in understanding how these molecules influence physiological functions in tissues throughout the body. Together, these studies set the scene for applying our knowledge of circadian biology to the understanding and treatment of a range of human diseases, including cancer and metabolic and behavioural disorders.

  14. Addressing the Genetics of Human Mental Health Disorders in Model Organisms.

    PubMed

    McCammon, Jasmine M; Sive, Hazel

    2015-01-01

    Mental health disorders are notoriously difficult to diagnose and treat for a variety of reasons, including genetic heterogeneity, comorbidities, and qualitative diagnostic criteria. Discovery of the molecular pathology underlying these disorders is crucial to the development of quantitative biomarkers and novel therapeutics. In this review, we discuss contributions to the mental health field of different cellular and whole-animal approaches in characterizing psychiatric genetics and molecular pathology. These approaches include mammalian cell and neuronal culture, cerebral organoids, induced pluripotent stem cells, and the whole-animal models of nematodes, flies, mollusks, frogs, mice, and zebrafish, on the last of which we place extra emphasis. Integrative use of these cellular and animal systems in a complementary and informative fashion maximizes the potential contributions to the mental health field as a whole.

  15. Relationship of genetically transmitted alpha EEG traits to anxiety disorders and alcoholism

    SciTech Connect

    Enoch, M.A.; Rohrbaugh, W.; Harris, C.R.

    1995-10-09

    We tested the hypothesis that a heritable EEG trait, the low voltage alpha (LV), is associated with psychiatric disorders. Modest to moderate evidence for genetic linkage of both panic disorder and the low voltage alpha trait to the same region of chromosome 20q has recently been reported, raising the issue of whether there is a phenotypic correlation between these traits. A total of 124 subjects including 50 unrelated index subjects and 74 relatives were studied. Alpha EEG power was measured and EEG phenotypes were impressionistically classified. Subjects were psychiatrically interviewed using the SADS-L and blind-rated by RDC criteria. Alcoholics were four times more likely to be LV (including so-called borderline low voltage alpha) than were nonalcoholic, nonanxious subjects. Alcoholics with anxiety disorder are 10 times more likely to be LV. However, alcoholics without anxiety disorder were similar to nonalcoholics in alpha power. An anxiety disorder (panic disorder, phobia, or generalized anxiety) was found in 14/17 LV subjects as compared to 34/101 of the rest of the sample (P < 0.01). Support for these observations was found in the unrelated index subjects in whom no traits would be shared by familial clustering. Lower alpha power in anxiety disorders was not state-dependent, as indicated by the Spielberger Anxiety Scale. Familial covariance of alpha power was 0.25 (P < 0.01). These findings indicate there may be a shared factor underlying the transmissible low voltage alpha EEG variant and vulnerability to anxiety disorders with associated alcoholism. This factor is apparently not rare, because LV was found in approximately 10% of unrelated index subjects and 5% of subjects free of alcoholism and anxiety disorders. 43 refs., 1 fig., 3 tabs.

  16. Genetic and environmental determinants of violence risk in psychotic disorders: a multivariate quantitative genetic study of 1.8 million Swedish twins and siblings

    PubMed Central

    Sariaslan, A; Larsson, H; Fazel, S

    2016-01-01

    Patients diagnosed with psychotic disorders (for example, schizophrenia and bipolar disorder) have elevated risks of committing violent acts, particularly if they are comorbid with substance misuse. Despite recent insights from quantitative and molecular genetic studies demonstrating considerable pleiotropy in the genetic architecture of these phenotypes, there is currently a lack of large-scale studies that have specifically examined the aetiological links between psychotic disorders and violence. Using a sample of all Swedish individuals born between 1958 and 1989 (n=3 332 101), we identified a total of 923 259 twin-sibling pairs. Patients were identified using the National Patient Register using validated algorithms based on International Classification of Diseases (ICD) 8–10. Univariate quantitative genetic models revealed that all phenotypes (schizophrenia, bipolar disorder, substance misuse, and violent crime) were highly heritable (h2=53–71%). Multivariate models further revealed that schizophrenia was a stronger predictor of violence (r=0.32; 95% confidence interval: 0.30–0.33) than bipolar disorder (r=0.23; 0.21–0.25), and large proportions (51–67%) of these phenotypic correlations were explained by genetic factors shared between each disorder, substance misuse, and violence. Importantly, we found that genetic influences that were unrelated to substance misuse explained approximately a fifth (21% 20–22%) of the correlation with violent criminality in bipolar disorder but none of the same correlation in schizophrenia (Pbipolar disorder<0.001; Pschizophrenia=0.55). These findings highlight the problems of not disentangling common and unique sources of covariance across genetically similar phenotypes as the latter sources may include aetiologically important clues. Clinically, these findings underline the importance of assessing risk of different phenotypes together and integrating interventions for psychiatric disorders, substance misuse, and

  17. A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder

    PubMed Central

    Ashbrook, David G.; Williams, Robert W.; Lu, Lu; Hager, Reinmar

    2015-01-01

    Bipolar disorder (BD) is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS) have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium's bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis. We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1, and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG, and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG, and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG, and TNR influence intercellular signaling in the striatum. PMID:26190982

  18. Waardenburg syndrome: A rare genetic disorder, a report of two cases

    PubMed Central

    Kumar, Sudesh; Rao, Kiran

    2012-01-01

    Waardenburg syndrome (WS) is a rare genetic disorder. Patients have heterochromia or eyes with iris of different color, increased inter-canthal distance, distopia canthorum, pigmentation anomalies, and varying degree of deafness. It usually follows autosomal dominant pattern. In this report, two cases have been discussed but no familial history of WS has been found. Counseling of the patient is necessary and cases of irreversible deafness have been treated. PMID:23162308

  19. Waardenburg syndrome: A rare genetic disorder, a report of two cases.

    PubMed

    Kumar, Sudesh; Rao, Kiran

    2012-05-01

    Waardenburg syndrome (WS) is a rare genetic disorder. Patients have heterochromia or eyes with iris of different color, increased inter-canthal distance, distopia canthorum, pigmentation anomalies, and varying degree of deafness. It usually follows autosomal dominant pattern. In this report, two cases have been discussed but no familial history of WS has been found. Counseling of the patient is necessary and cases of irreversible deafness have been treated.

  20. Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture

    PubMed Central

    Davis, Lea K.; Yu, Dongmei; Keenan, Clare L.; Gamazon, Eric R.; Konkashbaev, Anuar I.; Derks, Eske M.; Neale, Benjamin M.; Yang, Jian; Lee, S. Hong; Evans, Patrick; Barr, Cathy L.; Bellodi, Laura; Benarroch, Fortu; Berrio, Gabriel Bedoya; Bienvenu, Oscar J.; Bloch, Michael H.; Blom, Rianne M.; Bruun, Ruth D.; Budman, Cathy L.; Camarena, Beatriz; Campbell, Desmond; Cappi, Carolina; Cardona Silgado, Julio C.; Cath, Danielle C.; Cavallini, Maria C.; Chavira, Denise A.; Chouinard, Sylvain; Conti, David V.; Cook, Edwin H.; Coric, Vladimir; Cullen, Bernadette A.; Deforce, Dieter; Delorme, Richard; Dion, Yves; Edlund, Christopher K.; Egberts, Karin; Falkai, Peter; Fernandez, Thomas V.; Gallagher, Patience J.; Garrido, Helena; Geller, Daniel; Girard, Simon L.; Grabe, Hans J.; Grados, Marco A.; Greenberg, Benjamin D.; Gross-Tsur, Varda; Haddad, Stephen; Heiman, Gary A.; Hemmings, Sian M. J.; Hounie, Ana G.; Illmann, Cornelia; Jankovic, Joseph; Jenike, Michael A.; Kennedy, James L.; King, Robert A.; Kremeyer, Barbara; Kurlan, Roger; Lanzagorta, Nuria; Leboyer, Marion; Leckman, James F.; Lennertz, Leonhard; Liu, Chunyu; Lochner, Christine; Lowe, Thomas L.; Macciardi, Fabio; McCracken, James T.; McGrath, Lauren M.; Mesa Restrepo, Sandra C.; Moessner, Rainald; Morgan, Jubel; Muller, Heike; Murphy, Dennis L.; Naarden, Allan L.; Ochoa, William Cornejo; Ophoff, Roel A.; Osiecki, Lisa; Pakstis, Andrew J.; Pato, Michele T.; Pato, Carlos N.; Piacentini, John; Pittenger, Christopher; Pollak, Yehuda; Rauch, Scott L.; Renner, Tobias J.; Reus, Victor I.; Richter, Margaret A.; Riddle, Mark A.; Robertson, Mary M.; Romero, Roxana; Rosàrio, Maria C.; Rosenberg, David; Rouleau, Guy A.; Ruhrmann, Stephan; Ruiz-Linares, Andres; Sampaio, Aline S.; Samuels, Jack; Sandor, Paul; Sheppard, Brooke; Singer, Harvey S.; Smit, Jan H.; Stein, Dan J.; Strengman, E.; Tischfield, Jay A.; Valencia Duarte, Ana V.; Vallada, Homero; Van Nieuwerburgh, Filip; Veenstra-VanderWeele, Jeremy; Walitza, Susanne; Wang, Ying; Wendland, Jens R.; Westenberg, Herman G. M.; Shugart, Yin Yao; Miguel, Euripedes C.; McMahon, William; Wagner, Michael; Nicolini, Humberto; Posthuma, Danielle; Hanna, Gregory L.; Heutink, Peter; Denys, Damiaan; Arnold, Paul D.; Oostra, Ben A.; Nestadt, Gerald; Freimer, Nelson B.; Pauls, David L.; Wray, Naomi R.

    2013-01-01

    The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures. PMID:24204291

  1. Attitudes towards bipolar disorder and predictive genetic testing among patients and providers.

    PubMed Central

    Smith, L B; Sapers, B; Reus, V I; Freimer, N B

    1996-01-01

    Attitudes about bipolar disorder (manic depressive disorder) and genetic testing were investigated. Three groups of subjects were surveyed including members of a manic depressive support group, medical students, and psychiatry residents. The questionnaire was intended to elicit impressions and attitudes about bipolar disorder (BP) from mental health consumers and health care providers with varying levels of personal and professional familiarity with the disorder. Attitudes towards prenatal testing and pregnancy termination were also assessed. The intention hypothetically to terminate a pregnancy was influenced by the likelihood of developing BP a well as the projected course and severity of illness. Nearly half of the total sample would terminate pregnancy if the fetus were definitely to develop an unspecified form of bipolar disorder. Presumed severity of illness was also found to be a modifying factor in the decision, with a low percentage of subjects electing to terminate for a mild course of bipolar disorder and a majority opting for termination in the case of an extremely severe presentation. Support group members were the least likely to terminate a hypothetical pregnancy in the case of a positive prenatal test and were the most likely to desire childhood testing in the absence of preventive or treatment options. The possible implications of these findings, as well as avenues of future research, are discussed. PMID:8818938

  2. Comparing targeted exome and whole exome approaches for genetic diagnosis of neuromuscular disorders

    PubMed Central

    Gorokhova, Svetlana; Cerino, Mathieu; Mathieu, Yves; Courrier, Sébastien; Desvignes, Jean-Pierre; Salgado, David; Béroud, Christophe; Krahn, Martin; Bartoli, Marc

    2015-01-01

    Massively parallel sequencing is rapidly becoming a widely used method in genetic diagnostics. However, there is still no clear consensus as to which approach can most efficiently identify the pathogenic mutations carried by a given patient, while avoiding false negative and false positive results. We developed a targeted exome approach (MyoPanel2) in order to optimize genetic diagnosis of neuromuscular disorders. Using this approach, we were able to analyse 306 genes known to be mutated in myopathies as well as in related disorders, obtaining 98.8% target sequence coverage at 20 ×. Moreover, MyoPanel2 was able to detect 99.7% of 11,467 known mutations responsible for neuromuscular disorders. We have then used several quality control parameters to compare performance of the targeted exome approach with that of whole exome sequencing. The results of this pilot study of 140 DNA samples suggest that targeted exome sequencing approach is an efficient genetic diagnostic test for most neuromuscular diseases. PMID:27054082

  3. Molecular and Genetic Characterization of Depression: Overlap with other Psychiatric Disorders and Aging.

    PubMed

    Ding, Ying; Chang, Lun-Ching; Wang, Xingbin; Guilloux, Jean-Philippe; Parrish, Jenna; Oh, Hyunjung; French, Beverly J; Lewis, David A; Tseng, George C; Sibille, Etienne

    2015-05-01

    Genome-wide expression and genotyping technologies have uncovered the genetic bases of complex diseases at unprecedented rates; However despite its heavy burden and high prevalence, the molecular characterization of major depressive disorder (MDD) has lagged behind. Transcriptome studies report multiple brain disturbances but are limited by small sample sizes. Genome-wide association studies (GWAS) report weak results but suggest overlapping genetic risk with other neuropsychiatric disorders. We performed systematic molecular characterization of altered brain function in MDD, using meta-analysis of differential expression in eight gene array studies in three corticolimbic brain regions in 101 subjects. The identified "metaA-MDD" genes suggest altered neurotrophic support, brain plasticity and neuronal signaling in MDD. Notably, metaA-MDD genes display low connectivity and hubness in coexpression networks, and uniform genomic distribution, consistent with diffuse polygenic mechanisms. We next integrated these findings with results from over 1800 published GWAS and show that genetic variations nearby metaA-MDD genes predict greater risk for neuropsychiatric disorders and notably for age-related phenotypes, but not for other medical illnesses, including those frequently co-morbid with depression, or body characteristics. Collectively, the intersection of unbiased investigations of gene function (transcriptome) and structure (GWAS) provides novel leads to investigate molecular mechanisms of MDD and suggest common biological pathways between depression, other neuropsychiatric diseases, and brain aging.

  4. Acquired color vision deficiency.

    PubMed

    Simunovic, Matthew P

    2016-01-01

    Acquired color vision deficiency occurs as the result of ocular, neurologic, or systemic disease. A wide array of conditions may affect color vision, ranging from diseases of the ocular media through to pathology of the visual cortex. Traditionally, acquired color vision deficiency is considered a separate entity from congenital color vision deficiency, although emerging clinical and molecular genetic data would suggest a degree of overlap. We review the pathophysiology of acquired color vision deficiency, the data on its prevalence, theories for the preponderance of acquired S-mechanism (or tritan) deficiency, and discuss tests of color vision. We also briefly review the types of color vision deficiencies encountered in ocular disease, with an emphasis placed on larger or more detailed clinical investigations.

  5. Online Mendelian Inheritance in Man (OMIM), a knowledgebase of human genes and genetic disorders.

    PubMed

    Hamosh, Ada; Scott, Alan F; Amberger, Joanna S; Bocchini, Carol A; McKusick, Victor A

    2005-01-01

    Online Mendelian Inheritance in Man (OMIM) is a comprehensive, authoritative and timely knowledgebase of human genes and genetic disorders compiled to support human genetics research and education and the practice of clinical genetics. Started by Dr Victor A. McKusick as the definitive reference Mendelian Inheritance in Man, OMIM (http://www.ncbi.nlm.nih.gov/omim/) is now distributed electronically by the National Center for Biotechnology Information, where it is integrated with the Entrez suite of databases. Derived from the biomedical literature, OMIM is written and edited at Johns Hopkins University with input from scientists and physicians around the world. Each OMIM entry has a full-text summary of a genetically determined phenotype and/or gene and has numerous links to other genetic databases such as DNA and protein sequence, PubMed references, general and locus-specific mutation databases, HUGO nomenclature, MapViewer, GeneTests, patient support groups and many others. OMIM is an easy and straightforward portal to the burgeoning information in human genetics.

  6. Genetic polymorphisms: impact on the risk of fetal alcohol spectrum disorders.

    PubMed

    Warren, Kenneth R; Li, Ting-Kai

    2005-04-01

    Clinical reports on monozygotic and dizygotic twins provided the initial evidence for the involvement of genetic factors in risk vulnerability for fetal alcohol spectrum disorders (FASD) including fetal alcohol syndrome (FAS). Research with selectively bred and inbred rodents, genetic crosses of these lines and strains, and embryo culture studies have further clarified the role of both maternal and fetal genetics in the development of FASD. Research to identify specific polymorphisms contributing to FASD is still at an early stage. To date, polymorphisms of only one of the genes for the alcohol dehydrogenase enzyme family, the ADH1B, have been demonstrated to contribute to FASD vulnerability. In comparison with ADH1B*1, both maternal and fetal ADH1B*2 have been shown to reduce risk for FAS in a mixed ancestry South African population. ADH1B*3 appears to afford protection for FASD outcomes in African-American populations. Other candidate genes should be examined with respect to FASD risk, including those for the enzymes of serotonin metabolism, in particular the serotonin transporter. By its very nature, alcohol teratogenesis is the expression of the interaction of genes with environment. The study of genetic factors in FASD falls within the new field of ecogenetics. Understanding of the array of genetic factors in FASD will be enhanced by future genetic investigations, including case-control, family association, and linkage studies.

  7. Accuracy of preimplantation genetic diagnosis (PGD) of single gene and chromosomal disorders

    SciTech Connect

    Verlinsky, Y.; Strom, C.; Rechitsky, S.

    1994-09-01

    We have developed a polar body inferred approach for preconception diagnosis of single gene and chromosomal disorders. Preconception PCR or FISH analysis was performed in a total of 310 first polar bodies for the following genetic conditions: cystic fibrosis, hemophilia A, alpha-1-antitrypsin deficiency, Tay Sachs disease, retinitis pigmentosa and common chromosomal trisomies. An important advantage of this approach is the avoidance of sperm (DNA) contamination, which is the major problem of PGD. We are currently applying FISH analysis of biopsied blastomeres, in combination with PCR or separately, and have demonstrated a significant improvement of the accuracy of PGD of X-linked disorders at this stage. Our data have also demonstrated feasibility of the application of FISH technique for PGD of chromosomal disorders. It was possible to detect chromosomal non-disjunctions and chromatid malsegregations in the first meiotic division, as well as to evaluate chromosomal mutations originating from the second meiotic nondisjunction.

  8. The variation game: Cracking complex genetic disorders with NGS and omics data.

    PubMed

    Cui, Hongzhu; Dhroso, Andi; Johnson, Nathan; Korkin, Dmitry

    2015-06-01

    Tremendous advances in Next Generation Sequencing (NGS) and high-throughput omics methods have brought us one step closer towards mechanistic understanding of the complex disease at the molecular level. In this review, we discuss four basic regulatory mechanisms implicated in complex genetic diseases, such as cancer, neurological disorders, heart disease, diabetes, and many others. The mechanisms, including genetic variations, copy-number variations, posttranscriptional variations, and epigenetic variations, can be detected using a variety of NGS methods. We propose that malfunctions detected in these mechanisms are not necessarily independent, since these malfunctions are often found associated with the same disease and targeting the same gene, group of genes, or functional pathway. As an example, we discuss possible rewiring effects of the cancer-associated genetic, structural, and posttranscriptional variations on the protein-protein interaction (PPI) network centered around P53 protein. The review highlights multi-layered complexity of common genetic disorders and suggests that integration of NGS and omics data is a critical step in developing new computational methods capable of deciphering this complexity.

  9. Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: obsessive-compulsive disorder as an example of overlapping clinical and genetic heterogeneity.

    PubMed

    Murphy, Dennis L; Moya, Pablo R; Fox, Meredith A; Rubenstein, Liza M; Wendland, Jens R; Timpano, Kiara R

    2013-01-01

    Individuals with obsessive-compulsive disorder (OCD) have also been shown to have comorbid lifetime diagnoses of major depressive disorder (MDD; rates greater than 70%), bipolar disorder (rates greater than 10%) and other anxiety disorders (e.g. panic disorder, post-traumatic stress disorder (PTSD)). In addition, overlap exists in some common genetic variants (e.g. the serotonin transporter gene (SLC6A4), the brain-derived neurotrophic factor (BDNF) gene), and rare variants in genes/chromosomal abnormalities (e.g. the 22q11 microdeletion syndrome) found across the affective/anxiety disorder spectrums. OCD has been proposed as a possible independent entity for DSM-5, but by others thought best retained as an anxiety disorder subtype (its current designation in DSM-IV), and yet by others considered best in the affective disorder spectrum. This review focuses on OCD, a well-studied but still puzzling heterogeneous disorder, regarding alterations in serotonergic, dopaminergic and glutamatergic neurotransmission in addition to other systems involved, and how related genes may be involved in the comorbidity of anxiety and affective disorders. OCD resembles disorders such as depression, in which gene × gene interactions, gene × environment interactions and stress elements coalesce to yield OC symptoms and, in some individuals, full-blown OCD with multiple comorbid disorders.

  10. Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: obsessive–compulsive disorder as an example of overlapping clinical and genetic heterogeneity

    PubMed Central

    Murphy, Dennis L.; Moya, Pablo R.; Fox, Meredith A.; Rubenstein, Liza M.; Wendland, Jens R.; Timpano, Kiara R.

    2013-01-01

    Individuals with obsessive–compulsive disorder (OCD) have also been shown to have comorbid lifetime diagnoses of major depressive disorder (MDD; rates greater than 70%), bipolar disorder (rates greater than 10%) and other anxiety disorders (e.g. panic disorder, post-traumatic stress disorder (PTSD)). In addition, overlap exists in some common genetic variants (e.g. the serotonin transporter gene (SLC6A4), the brain-derived neurotrophic factor (BDNF) gene), and rare variants in genes/chromosomal abnormalities (e.g. the 22q11 microdeletion syndrome) found across the affective/anxiety disorder spectrums. OCD has been proposed as a possible independent entity for DSM-5, but by others thought best retained as an anxiety disorder subtype (its current designation in DSM-IV), and yet by others considered best in the affective disorder spectrum. This review focuses on OCD, a well-studied but still puzzling heterogeneous disorder, regarding alterations in serotonergic, dopaminergic and glutamatergic neurotransmission in addition to other systems involved, and how related genes may be involved in the comorbidity of anxiety and affective disorders. OCD resembles disorders such as depression, in which gene × gene interactions, gene × environment interactions and stress elements coalesce to yield OC symptoms and, in some individuals, full-blown OCD with multiple comorbid disorders. PMID:23440468

  11. Genetic effects influencing risk for major depressive disorder in China and Europe.

    PubMed

    Bigdeli, T B; Ripke, S; Peterson, R E; Trzaskowski, M; Bacanu, S-A; Abdellaoui, A; Andlauer, T F M; Beekman, A T F; Berger, K; Blackwood, D H R; Boomsma, D I; Breen, G; Buttenschøn, H N; Byrne, E M; Cichon, S; Clarke, T-K; Couvy-Duchesne, B; Craddock, N; de Geus, E J C; Degenhardt, F; Dunn, E C; Edwards, A C; Fanous, A H; Forstner, A J; Frank, J; Gill, M; Gordon, S D; Grabe, H J; Hamilton, S P; Hardiman, O; Hayward, C; Heath, A C; Henders, A K; Herms, S; Hickie, I B; Hoffmann, P; Homuth, G; Hottenga, J-J; Ising, M; Jansen, R; Kloiber, S; Knowles, J A; Lang, M; Li, Q S; Lucae, S; MacIntyre, D J; Madden, P A F; Martin, N G; McGrath, P J; McGuffin, P; McIntosh, A M; Medland, S E; Mehta, D; Middeldorp, C M; Milaneschi, Y; Montgomery, G W; Mors, O; Müller-Myhsok, B; Nauck, M; Nyholt, D R; Nöthen, M M; Owen, M J; Penninx, B W J H; Pergadia, M L; Perlis, R H; Peyrot, W J; Porteous, D J; Potash, J B; Rice, J P; Rietschel, M; Riley, B P; Rivera, M; Schoevers, R; Schulze, T G; Shi, J; Shyn, S I; Smit, J H; Smoller, J W; Streit, F; Strohmaier, J; Teumer, A; Treutlein, J; Van der Auwera, S; van Grootheest, G; van Hemert, A M; Völzke, H; Webb, B T; Weissman, M M; Wellmann, J; Willemsen, G; Witt, S H; Levinson, D F; Lewis, C M; Wray, N R; Flint, J; Sullivan, P F; Kendler, K S

    2017-03-28

    Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.

  12. Disorders of heavy metals.

    PubMed

    Woimant, France; Trocello, Jean-Marc

    2014-01-01

    Heavy metals and trace elements play an important role in relation to the physiology and pathology of the nervous system. Neurologic diseases related to disorders of metabolism of copper and iron are reviewed. Copper disorders are divided into two classes: ATP7A- or ATP7B-related inherited copper transport disorders (Menkes disease, occipital horn syndrome, ATP7A-related distal motor neuropathy, and Wilson disease) and acquired diseases associated with copper deficiency or copper excess. Iron brain disorders are divided into genetic neurodegeneration with brain iron accumulation (NBIA, neuroferritinopathy, and aceruloplasminemia), genetic systemic iron accumulation with neurologic features (hemochromatosis), and acquired diseases associated with iron excess (superficial siderosis) or iron deficiency (restless leg syndrome). The main features of cadmium, lead, aluminum, mercury, and manganese toxicity are summarized.

  13. Genetic-linkage mapping of complex hereditary disorders to a whole-genome molecular-interaction network.

    PubMed

    Iossifov, Ivan; Zheng, Tian; Baron, Miron; Gilliam, T Conrad; Rzhetsky, Andrey

    2008-07-01

    Common hereditary neurodevelopmental disorders such as autism, bipolar disorder, and schizophrenia are most likely both genetically multifactorial and heterogeneous. Because of these characteristics traditional methods for genetic analysis fail when applied to such diseases. To address the problem we propose a novel probabilistic framework that combines the standard genetic linkage formalism with whole-genome molecular-interaction data to predict pathways or networks of interacting genes that contribute to common heritable disorders. We apply the model to three large genotype-phenotype data sets, identify a small number of significant candidate genes for autism (24), bipolar disorder (21), and schizophrenia (25), and predict a number of gene targets likely to be shared among the disorders.

  14. Simons Variation in Individuals Project (Simons VIP): a genetics-first approach to studying autism spectrum and related neurodevelopmental disorders.

    PubMed

    2012-03-22

    We describe a project aimed at studying a large number of individuals (>200) with specific recurrent genetic variations (deletion or duplication of segment 16p11.2) that increase the risk of developing autism spectrum (ASD) and other developmental disorders. The genetics-first approach augmented by web-based recruitment, multisite collaboration and calibration, and robust data-sharing policies could be adopted by other groups studying neuropsychiatric disorders to accelerate the pace of research.

  15. Genetic relationships between suicide attempts, suicidal ideation and major psychiatric disorders: A genome-wide association and polygenic scoring study

    PubMed Central

    Mullins, Niamh; Perroud, Nader; Uher, Rudolf; Butler, Amy W; Cohen-Woods, Sarah; Rivera, Margarita; Malki, Karim; Euesden, Jack; Power, Robert A; Tansey, Katherine E; Jones, Lisa; Jones, Ian; Craddock, Nick; Owen, Michael J; Korszun, Ania; Gill, Michael; Mors, Ole; Preisig, Martin; Maier, Wolfgang; Rietschel, Marcella; Rice, John P; Müller-Myhsok, Bertram; Binder, Elisabeth B; Lucae, Susanne; Ising, Marcus; Craig, Ian W; Farmer, Anne E; McGuffin, Peter; Breen, Gerome; Lewis, Cathryn M

    2014-01-01

    Epidemiological studies have recognized a genetic diathesis for suicidal behavior, which is independent of other psychiatric disorders. Genome-wide association studies (GWAS) on suicide attempt (SA) and ideation have failed to identify specific genetic variants. Here, we conduct further GWAS and for the first time, use polygenic score analysis in cohorts of patients with mood disorders, to test for common genetic variants for mood disorders and suicide phenotypes. Genome-wide studies for SA were conducted in the RADIANT and GSK-Munich recurrent depression samples and London Bipolar Affective Disorder Case-Control Study (BACCs) then meta-analysis was performed. A GWAS on suicidal ideation during antidepressant treatment had previously been conducted in the Genome Based Therapeutic Drugs for Depression (GENDEP) study. We derived polygenic scores from each sample and tested their ability to predict SA in the mood disorder cohorts or ideation status in the GENDEP study. Polygenic scores for major depressive disorder, bipolar disorder and schizophrenia from the Psychiatric Genomics Consortium were used to investigate pleiotropy between psychiatric disorders and suicide phenotypes. No significant evidence for association was detected at any SNP in GWAS or meta-analysis. Polygenic scores for major depressive disorder significantly predicted suicidal ideation in the GENDEP pharmacogenetics study and also predicted SA in a combined validation dataset. Polygenic scores for SA showed no predictive ability for suicidal ideation. Polygenic score analysis suggests pleiotropy between psychiatric disorders and suicidal ideation whereas the tendency to act on such thoughts may have a partially independent genetic diathesis. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals, Inc. PMID:24964207

  16. Methemoglobinemia - acquired

    MedlinePlus

    ... blood disorder in which the body cannot reuse hemoglobin because it is damaged. Hemoglobin is the oxygen-carrying molecule found in red blood cells. In some cases of methemoglobinemia, the hemoglobin is unable to carry enough oxygen to body ...

  17. Inbreeding levels in Northeast Brazil: Strategies for the prospecting of new genetic disorders

    PubMed Central

    2010-01-01

    A new autosomal recessive genetic condition, the SPOAN syndrome (an acronym for spastic paraplegia, optic atrophy and neuropathy syndrome), was recently discovered in an isolated region of the State of Rio Grande do Norte in Northeast Brazil, in a population that was identified by the IBGE (Brazilian Institute of Geography and Statistics) as belonging to the Brazilian communities with the highest rates of “deficiencies” (Neri, 2003), a term used to describe diseases, malformations, and handicaps in general. This prompted us to conduct a study of consanguinity levels in five of its municipal districts by directly interviewing their inhabitants. Information on 7,639 couples (corresponding to about 40% of the whole population of the studied districts) was obtained. The research disclosed the existence of very high frequencies of consanguineous marriages, which varied from about 9% to 32%, suggesting the presence of a direct association between genetic diseases such as the SPOAN syndrome, genetic drift and inbreeding levels. This fact calls for the introduction of educational programs for the local populations, as well as for further studies aiming to identify and characterize other genetic conditions. Epidemiological strategies developed to collect inbreeding data, with the collaboration of health systems available in the region, might be very successful in the prospecting of genetic disorders. PMID:21637472

  18. Inbreeding levels in Northeast Brazil: Strategies for the prospecting of new genetic disorders.

    PubMed

    Santos, Silvana; Kok, Fernando; Weller, Mathias; de Paiva, Francisco Rennan Lopes; Otto, Paulo A

    2010-04-01

    A new autosomal recessive genetic condition, the SPOAN syndrome (an acronym for spastic paraplegia, optic atrophy and neuropathy syndrome), was recently discovered in an isolated region of the State of Rio Grande do Norte in Northeast Brazil, in a population that was identified by the IBGE (Brazilian Institute of Geography and Statistics) as belonging to the Brazilian communities with the highest rates of "deficiencies" (Neri, 2003), a term used to describe diseases, malformations, and handicaps in general. This prompted us to conduct a study of consanguinity levels in five of its municipal districts by directly interviewing their inhabitants. Information on 7,639 couples (corresponding to about 40% of the whole population of the studied districts) was obtained. The research disclosed the existence of very high frequencies of consanguineous marriages, which varied from about 9% to 32%, suggesting the presence of a direct association between genetic diseases such as the SPOAN syndrome, genetic drift and inbreeding levels. This fact calls for the introduction of educational programs for the local populations, as well as for further studies aiming to identify and characterize other genetic conditions. Epidemiological strategies developed to collect inbreeding data, with the collaboration of health systems available in the region, might be very successful in the prospecting of genetic disorders.

  19. Genome-wide Association Study of Dermatomyositis Reveals Genetic Overlap with other Autoimmune Disorders

    PubMed Central

    Miller, Frederick W.; Cooper, Robert G.; Vencovsky, Jiri; Rider, Lisa G.; Danko, Katalin; Wedderburn, Lucy R.; Lundberg, Ingrid E.; Pachman, Lauren M.; Reed, Ann M.; Ytterberg, Steven R.; Padyukov, Leonid; Selva-O’Callaghan, Albert; Radstake, Timothy; Isenberg, David A.; Chinoy, Hector; Ollier, William E. R.; O’Hanlon, Terrance P.; Peng, Bo; Lee, Annette; Lamb, Janine A.; Chen, Wei; Amos, Christopher I.; Gregersen, Peter K.

    2014-01-01

    Objective To identify new genetic associations with juvenile and adult dermatomyositis (DM). Methods We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1178) and controls (n = 4724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. Results Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5x10−8) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that three SNPs linked with three genes were associated with DM, with a false discovery rate (FDR) < 0.05. These genes were phospholipase C like 1 (PLCL1, rs6738825, FDR=0.00089), B lymphoid tyrosine kinase (BLK, rs2736340, FDR=0.00031), and chemokine (C-C motif) ligand 21 (CCL21, rs951005, FDR=0.0076). None of these genes was previously reported to be associated with DM. Conclusion Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches. PMID:23983088

  20. Disordered models of acquired dyslexia

    NASA Astrophysics Data System (ADS)

    Virasoro, M. A.

    We show that certain specific correlations in the probability of errors observed in dyslexic patients that are normally explained by introducing additional complexity in the model for the reading process are typical of any Neural Network system that has learned to deal with a quasiregular environment. On the other hand we show that in Neural Networks the more regular behavior does not become naturally the default behavior.

  1. Genetic Variation in Melatonin Pathway Enzymes in Children with Autism Spectrum Disorder and Comorbid Sleep Onset Delay

    ERIC Educational Resources Information Center

    Veatch, Olivia J.; Pendergast, Julie S.; Allen, Melissa J.; Leu, Roberta M.; Johnson, Carl Hirschie; Elsea, Sarah H.; Malow, Beth A.

    2015-01-01

    Sleep disruption is common in individuals with autism spectrum disorder (ASD). Genes whose products regulate endogenous melatonin modify sleep patterns and have been implicated in ASD. Genetic factors likely contribute to comorbid expression of sleep disorders in ASD. We studied a clinically unique ASD subgroup, consisting solely of children with…

  2. Current Issues in the Neurology and Genetics of Learning-Related Traits and Disorders: Introduction to the Special Issue.

    ERIC Educational Resources Information Center

    Gilger, Jeffrey W.

    2001-01-01

    This introductory article briefly describes each of the following eight articles in this special issue on the neurology and genetics of learning related disorders. It notes the greater appreciation of learning disability as a set of complex disorders with broad and intricate neurological bases and of the large individual differences in how these…

  3. The Genetics of Obsessive-Compulsive Disorder and Tourette Syndrome: An Epidemiological and Pathway-Based Approach for Gene Discovery

    ERIC Educational Resources Information Center

    Grados, Marco A.

    2010-01-01

    Objective: To provide a contemporary perspective on genetic discovery methods applied to obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). Method: A review of research trends in genetics research in OCD and TS is conducted, with emphasis on novel approaches. Results: Genome-wide association studies (GWAS) are now in progress in OCD…

  4. Genetic Disorders with Dyshidrosis: Ectodermal Dysplasia, Incontinentia Pigmenti, Fabry Disease, and Congenital Insensitivity to Pain with Anhidrosis.

    PubMed

    Wataya-Kaneda, Mari

    2016-01-01

    Sweating is regulated by various neurohormonal mechanisms. A disorder in any part of the sweating regulatory pathways, such as the thermal center, neurotransmitters in the central to peripheral nerve, innervation of periglandular neurotransmission, and sweat secretion in the sweat gland itself, induces dyshidrosis. Therefore, hereditary disorders with dyshidrosis result from a variety of causes. These diseases have characteristic symptoms derived from each pathogenesis besides dyshidrosis. The information in this chapter is useful for the differential diagnosis of representative genetic disorders with dyshidrosis.

  5. Predicting response to lithium in mood disorders: role of genetic polymorphisms.

    PubMed

    Serretti, Alessandro; Artioli, Paola

    2003-01-01

    Lithium is considered to be the first choice mood stabilizer in recurrent mood disorders. Its widespread and large-scale use is the result of its proven efficacy. In spite of this fact, patients have been observed to show a variable response to lithium treatment: in some cases it is completely effective in preventing manic or depressive relapses, while in other cases it appears to show no influence on the disease course. The possible definition of a genetic liability profile for adverse effects and efficacy will be of great help, as lithium therapy needs at least 6 months to be effective in stabilizing mood disorders. During the last few years, a number of groups have reported possible liability genes. Lithium long-term prophylactic efficacy has been associated with serotonin transporter protein, tryptophan hydroxylase and inositol polyphosphate 1-phosphatase variants. A number of other candidate genes and anonymous markers did not yield positive associations. Therefore, even if some positive results have been reported, no unequivocal susceptibility gene for lithium efficacy has been identified. Although the available data may not currently allow a meaningful prediction of lithium response, future research is aimed at the development of individualized treament of mood disorders, including the possibility of 'pharmacological genetic counseling'.

  6. The genetic basis of female reproductive disorders: Etiology and clinical testing ☆

    PubMed Central

    Layman, Lawrence C.

    2013-01-01

    With the advent of improved molecular biology techniques, the genetic basis of an increasing number of reproductive disorders has been elucidated. Mutations in at least 20 genes cause hypogonadotropic hypogonadism including Kallmann syndrome in about 35–40% of patients. The two most commonly involved genes are FGFR1 and CHD7. When combined pituitary hormone deficiency includes hypogonadotropic hypogonadism as a feature, PROP1 mutations are the most common of the six genes involved. For hypergonadotropic hypogonadism, mutations in 14 genes cause gonadal failure in 15% of affected females, most commonly in FMR1. In eugonadal disorders, activating FSHR mutations have been identified for spontaneous ovarian hyperstimulation syndrome; and WNT4 mutations have been described in mullerian aplasia. For other eugonadal disorders, such as endometriosis, polycystic ovary syndrome, and leiomyomata, specific germline gene mutations have not been identified, but some chromosomal regions are associated with the corresponding phenotype. Practical genetic testing is possible to perform in both hypogonadotropic and hypergonadotropic hypogonadism and spontaneous ovarian hyperstimulation syndrome. However, clinical testing for endometriosis, polycystic ovary syndrome, and leiomyomata is not currently practical for the clinician. PMID:23499866

  7. Genetics of borderline personality disorder: systematic review and proposal of an integrative model.

    PubMed

    Amad, Ali; Ramoz, Nicolas; Thomas, Pierre; Jardri, Renaud; Gorwood, Philip

    2014-03-01

    Borderline personality disorder (BPD) is one of the most common mental disorders and is characterized by a pervasive pattern of emotional lability, impulsivity, interpersonal difficulties, identity disturbances, and disturbed cognition. Here, we performed a systematic review of the literature concerning the genetics of BPD, including familial and twin studies, association studies, and gene-environment interaction studies. Moreover, meta-analyses were performed when at least two case-control studies testing the same polymorphism were available. For each gene variant, a pooled odds ratio (OR) was calculated using fixed or random effects models. Familial and twin studies largely support the potential role of a genetic vulnerability at the root of BPD, with an estimated heritability of approximately 40%. Moreover, there is evidence for both gene-environment interactions and correlations. However, association studies for BPD are sparse, making it difficult to draw clear conclusions. According to our meta-analysis, no significant associations were found for the serotonin transporter gene, the tryptophan hydroxylase 1 gene, or the serotonin 1B receptor gene. We hypothesize that such a discrepancy (negative association studies but high heritability of the disorder) could be understandable through a paradigm shift, in which "plasticity" genes (rather than "vulnerability" genes) would be involved. Such a framework postulates a balance between positive and negative events, which interact with plasticity genes in the genesis of BPD.

  8. Modern molecular genetic approaches to complex traits: implications for psychiatric disorders.

    PubMed

    Owen, M J; Craddock, N

    1996-03-01

    The majority of common psychiatric disorders pose problems for geneticists because of their complex and non-Mendelian modes of inheritance. Early attempts to map genes for mental illness have so far largely overlooked this and sought genes of major effect in multiplex families using the lod score method of linkage analysis. However it seems that major genes are likely to be at best rare causes of common mental disorders, and the majority of cases probably reflect the interaction of several and perhaps many genes of comparatively small effect. There are two complementary sets of strategies that allow such genes to be identified. The first is to perform linkage analysis based on allele sharing in pairs of affected relatives. The second is to carry out association studies on samples of unrelated individuals. These methods and their applicability to psychiatric disorders are described. Psychiatric genetics has traditionally focussed on categorical phenotypes, but if valid continuous measures can be developed, powerful quantitative trait loci (QTL) approaches may also become feasible. Another important area is likely to be the study of relevant models in animals such as rodents in which genetic studies have many advantages. Finally we should not overlook the possibility that there are molecular explanations for irregular patterns of transmission such as mitochondrial inheritance, genomic imprinting and dynamic mutations.

  9. Good laboratory practices for biochemical genetic testing and newborn screening for inherited metabolic disorders.

    PubMed

    2012-04-06

    Biochemical genetic testing and newborn screening are essential laboratory services for the screening, detection, diagnosis, and monitoring of inborn errors of metabolism or inherited metabolic disorders. Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations, laboratory testing is categorized on the basis of the level of testing complexity as either waived (i.e., from routine regulatory oversight) or nonwaived testing (which includes tests of moderate and high complexity). Laboratories that perform biochemical genetic testing are required by CLIA regulations to meet the general quality systems requirements for nonwaived testing and the personnel requirements for high-complexity testing. Laboratories that perform public health newborn screening are subject to the same CLIA regulations and applicable state requirements. As the number of inherited metabolic diseases that are included in state-based newborn screening programs continues to increase, ensuring the quality of performance and delivery of testing services remains a continuous challenge not only for public health laboratories and other newborn screening facilities but also for biochemical genetic testing laboratories. To help ensure the quality of laboratory testing, CDC collaborated with the Centers for Medicare & Medicaid Services, the Food and Drug Administration, the Health Resources and Services Administration, and the National Institutes of Health to develop guidelines for laboratories to meet CLIA requirements and apply additional quality assurance measures for these areas of genetic testing. This report provides recommendations for good laboratory practices that were developed based on recommendations from the Clinical Laboratory Improvement Advisory Committee, with additional input from the Secretary's Advisory Committee on Genetics, Health, and Society; the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children; and representatives of newborn

  10. Clinical practice and genetic counseling for cystic fibrosis and CFTR-related disorders

    PubMed Central

    Moskowitz, Samuel M.; Chmiel, James F.; Sternen, Darci L.; Cheng, Edith; Gibson, Ronald L; Marshall, Susan G.; Cutting, Garry R.

    2009-01-01

    Cystic fibrosis transmembrane conductance regulator-related disorders encompass a disease spectrum from focal male reproductive tract involvement in congenital absence of the vas deferens to multiorgan involvement in classic cystic fibrosis. The reproductive, gastrointestinal, and exocrine manifestations of cystic fibrosis transmembrane conductance regulator deficiency are correlated with CFTR genotype, whereas the respiratory manifestations that are the main cause of morbidity and mortality in cystic fibrosis are less predictable. Molecular genetic testing of CFTR has led to new diagnostic strategies and will enable targeting of molecular therapies now in development. Older diagnostic methods that measure sweat chloride and nasal potential difference nonetheless remain important because of their sensitivity and specificity. In addition, the measurement of immunoreactive trypsinogen and the genotyping of CFTR alleles are key to newborn screening programs because of low cost. The multiorgan nature of cystic fibrosis leads to a heavy burden of care, thus therapeutic regimens are tailored to the specific manifestations present in each patient. The variability of cystic fibrosis lung disease and the variable expressivity of mild CFTR alleles complicate genetic counseling for this autosomal recessive disorder. Widespread implementation of newborn screening programs among populations with significant cystic fibrosis mutation carrier frequencies is expected to result in increasing demands on genetic counseling resources. PMID:19092437

  11. Acquired hyperpigmentations*

    PubMed Central

    Cestari, Tania Ferreira; Dantas, Lia Pinheiro; Boza, Juliana Catucci

    2014-01-01

    Cutaneous hyperpigmentations are frequent complaints, motivating around 8.5% of all dermatological consultations in our country. They can be congenital, with different patterns of inheritance, or acquired in consequence of skin problems, systemic diseases or secondary to environmental factors. The vast majority of them are linked to alterations on the pigment melanin, induced by different mechanisms. This review will focus on the major acquired hyperpigmentations associated with increased melanin, reviewing their mechanisms of action and possible preventive measures. Particularly prominent aspects of diagnosis and therapy will be emphasized, with focus on melasma, post-inflammatory hyperpigmentation, periorbital pigmentation, dermatosis papulosa nigra, phytophotodermatoses, flagellate dermatosis, erythema dyschromicum perstans, cervical poikiloderma (Poikiloderma of Civatte), acanthosis nigricans, cutaneous amyloidosis and reticulated confluent dermatitis PMID:24626644

  12. Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders

    PubMed Central

    Coleman, Jonathan R. I.; Roberts, Susanna; Keers, Robert; Breen, Gerome; Bögels, Susan; Creswell, Cathy; Hudson, Jennifer L.; McKinnon, Anna; Nauta, Maaike; Rapee, Ronald M.; Schneider, Silvia; Silverman, Wendy K.; Thastum, Mikael; Waite, Polly; Wergeland, Gro Janne H.; Eley, Thalia C.

    2016-01-01

    Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re‐emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N = 1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre‐ and post‐treatment and during the follow‐up period in the full sample and a subset with fear‐based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P < 0.05) with two SNPs. During the follow‐up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear‐based subset, the effect of rs806365 survived multiple testing corrections (P < 0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc. PMID:27346075

  13. Clinical and genetic factors associated with suicide in mood disorder patients.

    PubMed

    Antypa, Niki; Souery, Daniel; Tomasini, Mario; Albani, Diego; Fusco, Federica; Mendlewicz, Julien; Serretti, Alessandro

    2016-03-01

    Suicidality is a continuum ranging from ideation to attempted and completed suicide, with a complex etiology involving both genetic heritability and environmental factors. The majority of suicide events occur in the context of psychiatric conditions, preeminently major depression and bipolar disorder. The present study investigates clinical factors associated with suicide in a sample of 553 mood disorder patients, recruited within the 'Psy Pluriel' center, Centre Européen de Psychologie Médicale, and the Department of Psychiatry of Erasme Hospital (Brussels). Furthermore, genetic association analyses examining polymorphisms within COMT, BDNF, MAPK1 and CREB1 genes were performed in a subsample of 259 bipolar patients. The presence or absence of a previous suicide attempt and of current suicide risk were assessed. A positive association with suicide attempt was reported for younger patients, females, lower educated, smokers, those with higher scores on depressive symptoms and higher functional disability and those with anxiety comorbidity and familial history of suicidality in first- and second-degree relatives. Anxiety disorder comorbidity was the stronger predictor of current suicide risk. No associations were found with polymorphisms within COMT and BDNF genes, whereas significant associations were found with variations in rs13515 (MAPK1) and rs6740584 (CREB1) polymorphisms. From a clinical perspective, our study proposes several clinical characteristics, such as increased depressive symptomatology, anxiety comorbidity, functional disability and family history of suicidality, as correlates associated with suicide. Genetic risk variants in MAPK1 and CREB1 genes might be involved in a dysregulation of inflammatory and neuroplasticity pathways and are worthy of future investigation.

  14. Genetic variation in the endocannabinoid system and response to Cognitive Behavior Therapy for child anxiety disorders.

    PubMed

    Lester, Kathryn J; Coleman, Jonathan R I; Roberts, Susanna; Keers, Robert; Breen, Gerome; Bögels, Susan; Creswell, Cathy; Hudson, Jennifer L; McKinnon, Anna; Nauta, Maaike; Rapee, Ronald M; Schneider, Silvia; Silverman, Wendy K; Thastum, Mikael; Waite, Polly; Wergeland, Gro Janne H; Eley, Thalia C

    2017-03-01

    Extinction learning is an important mechanism in the successful psychological treatment of anxiety. Individual differences in response and relapse following Cognitive Behavior Therapy may in part be explained by variability in the ease with which fears are extinguished or the vulnerability of these fears to re-emerge. Given the role of the endocannabinoid system in fear extinction, this study investigates whether genetic variation in the endocannabinoid system explains individual differences in response to CBT. Children (N = 1,309) with a primary anxiety disorder diagnosis were recruited. We investigated the relationship between variation in the CNR1, CNR2, and FAAH genes and change in primary anxiety disorder severity between pre- and post-treatment and during the follow-up period in the full sample and a subset with fear-based anxiety disorder diagnoses. Change in symptom severity during active treatment was nominally associated (P < 0.05) with two SNPs. During the follow-up period, five SNPs were nominally associated with a poorer treatment response (rs806365 [CNR1]; rs2501431 [CNR2]; rs2070956 [CNR2]; rs7769940 [CNR1]; rs2209172 [FAAH]) and one with a more favorable response (rs6928813 [CNR1]). Within the fear-based subset, the effect of rs806365 survived multiple testing corrections (P < 0.0016). We found very limited evidence for an association between variants in endocannabinoid system genes and treatment response once multiple testing corrections were applied. Larger, more homogenous cohorts are needed to allow the identification of variants of small but statistically significant effect and to estimate effect sizes for these variants with greater precision in order to determine their potential clinical utility. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

  15. Psychosis genetics: modeling the relationship between schizophrenia, bipolar disorder, and mixed (or "schizoaffective") psychoses.

    PubMed

    Craddock, Nick; O'Donovan, M C; Owen, M J

    2009-05-01

    As a result of improving technologies and greatly increased sample sizes, the last 2 years has seen unprecedented advances in identification of specific genetic risk factors for psychiatric phenotypes. Strong genetic associations have been reported at common polymorphisms within ANK3 and CACNA1C in bipolar disorder and ZNF804A in schizophrenia and a relatively specific association between common variation in GABA(A) receptor genes and cases with features of both bipolar disorder and schizophrenia. Further, the occurrence of rare copy number variants (CNVs) has been shown to be increased in schizophrenia compared with controls. These emerging data provide a powerful resource for exploring the relationship between psychiatric phenotypes and can, and should, be used to inform conceptualization, classification, and diagnosis in psychiatry. It is already clear that, in general, genetic associations are not specific to one of the traditional diagnostic categories. For example, variation at ZNF804A is associated with risk of both bipolar disorder and schizophrenia, and some rare CNVs are associated with risk of autism and epilepsy as well as schizophrenia. These data are not consistent with a simple dichotomous model of functional psychosis and indicate the urgent need for moves toward approaches that (a) better represent the range of phenotypic variation seen in the clinical population and (b) reflect the underlying biological variation that gives rise to the phenotypes. We consider the implications for models of psychosis and the importance of recognizing and studying illness that has prominent affective and psychotic features. We conclude that if psychiatry is to translate the opportunities offered by new research methodologies, we must finally abandon a 19th-century dichotomy and move to a classificatory approach that is worthy of the 21st century.

  16. Clinical and Molecular Features of Laron Syndrome, A Genetic Disorder Protecting from Cancer.

    PubMed

    Janecka, Anna; Kołodziej-Rzepa, Marta; Biesaga, Beata

    2016-01-01

    Laron syndrome (LS) is a rare, genetic disorder inherited in an autosomal recessive manner. The disease is caused by mutations of the growth hormone (GH) gene, leading to GH/insulin-like growth factor type 1 (IGF1) signalling pathway defect. Patients with LS have characteristic biochemical features, such as a high serum level of GH and low IGF1 concentration. Laron syndrome was first described by the Israeli physician Zvi Laron in 1966. Globally, around 350 people are affected by this syndrome and there are two large groups living in separate geographic regions: Israel (69 individuals) and Ecuador (90 individuals). They are all characterized by typical appearance such as dwarfism, facial phenotype, obesity and hypogenitalism. Additionally, they suffer from hypoglycemia, hypercholesterolemia and sleep disorders, but surprisingly have a very low cancer risk. Therefore, studies on LS offer a unique opportunity to better understand carcinogenesis and develop new strategies of cancer treatment.

  17. A genetic model of substrate deprivation therapy for a glycosphingolipid storage disorder

    PubMed Central

    Liu, Yujing; Wada, Ryuichi; Kawai, Hiromichi; Sango, Kazunori; Deng, Chuxia; Tai, Tadashi; McDonald, Michael P.; Araujo, Kristlyn; Crawley, Jacqueline N.; Bierfreund, Uwe; Sandhoff, Konrad; Suzuki, Kinuko; Proia, Richard L.

    1999-01-01

    Inherited defects in the degradation of glycosphingolipids (GSLs) cause a group of severe diseases known as GSL storage disorders. There are currently no effective treatments for the majority of these disorders. We have explored a new treatment paradigm, substrate deprivation therapy, by constructing a genetic model in mice. Sandhoff's disease mice, which abnormally accumulate GSLs, were bred with mice that were blocked in their synthesis of GSLs. The mice with simultaneous defects in GSL synthesis and degradation no longer accumulated GSLs, had improved neurologic function, and had a much longer life span. However, these mice eventually developed a late-onset neurologic disease because of accumulation of another class of substrate, oligosaccharides. The results support the validity of the substrate deprivation therapy and also highlight some limitations. PMID:10021458

  18. Velo-cardio-facial syndrome and psychotic disorders: Implications for psychiatric genetics

    SciTech Connect

    Chow, W.C.; Bassett, A.S.; Weksberg, R.

    1994-06-15

    Psychiatric disorders have been reported in over 10% of patients with velo-cardio-facial syndrome (VCFS) in long-term follow-up. To further explore the behavioral and psychiatric findings associated with VCFS in adulthood, detailed clinical histories of two patients - one with VCFS who developed a psychotic illness, and one with schizophrenia who was found to have dysmorphological features associated with VCFS - are described in the current report. The observed overlap of physical and psychiatric symptoms in these two patients suggests that VCFS and psychotic disorders may share a pathogenetic mechanism. This could be consistent with a contiguous gene model for VCFS and psychosis, suggesting chromosome 22q11 as a possible candidate region for genetic studies of schizophrenia. 26 refs., 2 tabs.

  19. Evidence for a genetic association between alleles of monoamine oxidase A gene and bipolar affective disorder

    SciTech Connect

    Lim, L.C.C.; Sham, P.; Castle, D.

    1995-08-14

    We present evidence of a genetic association between bipolar disorder and alleles at 3 monoamine oxidase A (MAOA) markers, but not with alleles of a monoamine oxidase B (MAOB) polymorphism. The 3 MAOA markers, including one associated with low MAOA activity, show strong allelic association with each other but surprisingly not with MAOB. Our results are significantly only for females, though the number of males in our sample is too small to draw any definite conclusions. Our data is consistent with recent reports of reduced MAOA activity in patients with abnormal behavioral phenotypes. The strength of the association is weak, but significant, which suggests that alleles at the MAOA locus contribute to susceptibility to bipolar disorder rather than being a major determinant. 58 refs., 1 fig., 3 tabs.

  20. Accelerating discovery for complex neurological and behavioral disorders through systems genetics and integrative genomics in the laboratory mouse.

    PubMed

    Bubier, Jason A; Chesler, Elissa J

    2012-04-01

    Recent advances in systems genetics and integrative functional genomics have greatly improved the study of complex neurological and behavioral traits. The methods developed for the integrated characterization of new, high-resolution mouse genetic reference populations and systems genetics enable behavioral geneticists an unprecedented opportunity to address questions of the molecular basis of neurological and psychiatric disorders and their comorbidities. Integrative genomics augment these strategies by enabling rapid informatics-assisted candidate gene prioritization, cross-species translation, and mechanistic comparison across related disorders from a wealth of existing data in mouse and other model organisms. Ultimately, through these complementary approaches, finding the mechanisms and sources of genetic variation underlying complex neurobehavioral disease related traits is becoming tractable. Furthermore, these methods enable categorization of neurobehavioral disorders through their underlying biological basis. Together, these model organism-based approaches can lead to a refinement of diagnostic categories and targeted treatment of neurological and psychiatric disease.

  1. Familial Comorbidity of Bipolar Disorder and Multiple Sclerosis: Genetic Susceptibility, Coexistence or Causal Relationship?

    PubMed Central

    Kosmidis, Mary H.; Bozikas, Vasilis P.; Giannouli, Vaitsa; Karavatos, Athanasios; Fokas, Konstantinos

    2012-01-01

    Our purpose in undertaking the present study was to examine the hypotheses proposed for explaining the frequent comorbidity of bipolar disorder and multiple sclerosis. One hypothesis posits that, when there is comorbidity, MS plays a causal role in psychiatric manifestations. Another suggests that both disorders have a common underlying physiological process that increases the likelihood of their co-occurrence. We examined two adult siblings with comorbidity and their relatives, including three generations of family members with psychiatric morbidity. We found an extensive multigenerational history of bipolar disorder in this family. This history would seem to support the hypothesis of a common underlying brain process (potentially genetically-based) to explain the comorbidity of BD and MS, but cannot clarify whether this comorbidity implies a relationship between the two disorders or merely reflects parallel processes of brain deterioration. We cannot, however, rule out the possibility of a subclinical MS-related process leading to the early manifestation of BD, with MS appearing much later in time, or even a third, undetermined factor, leading to familial comorbidity. Although we have insufficient information to support either hypothesis definitively, we present the familial cases as a springboard for a discussion of dilemmas related to teasing apart MS and BD comorbidity. Further observation of the clinical course of the younger family members, who have not yet shown any neurological signs, over the next few years may elucidate the current picture further. PMID:22713400

  2. Mathematical limits of multilocus models: The genetic transmission of bipolar disorder

    SciTech Connect

    Craddock, N.; Khodel, V.; Van Eerdewegh, P.; Reich, T.

    1995-09-01

    We describe a simple, graphical method for determining plausible modes of inheritance for complex traits and apply this to bipolar disorder. The constraints that allele frequencies and penetrances lie in the interval 0-1 impose limits on recurrence risks, K{sub R}, in relatives of an affected proband for a given population prevalence, K{sub p}. We have investigated these limits for K{sub R} in three classes of relatives (MZ co-twin, sibling, and parent/offspring) for the general single-locus model and for two types of multilocus models: heterogeneity and multiplicative. In our models we have assumed Hardy-Weinberg equilibrium, an all-or-none trait, absence of nongenetic resemblance between relatives, and negligible mutation at the disease loci. Although the true values of K{sub p} and the K{sub R}`s are only approximately known, observed population and family data for bipolar disorder are inconsistent with a single-locus model or with any heterogeneity model. In contrast, multiplicative models involving three or more loci are consistent with observed data and, thus, represent plausible models for the inheritance of bipolar disorder. Studies to determine the genetic basis of most bipolar disorder should use methods capable of detecting interacting oligogenes. 32 refs., 5 figs.

  3. Moving towards causality in attention-deficit hyperactivity disorder: overview of neural and genetic mechanisms

    PubMed Central

    Gallo, Eduardo F; Posner, Jonathan

    2016-01-01

    Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by developmentally inappropriate levels of inattention and hyperactivity or impulsivity. The heterogeneity of its clinical manifestations and the differential responses to treatment and varied prognoses have long suggested myriad underlying causes. Over the past decade, clinical and basic research efforts have uncovered many behavioural and neurobiological alterations associated with ADHD, from genes to higher order neural networks. Here, we review the neurobiology of ADHD by focusing on neural circuits implicated in the disorder and discuss how abnormalities in circuitry relate to symptom presentation and treatment. We summarise the literature on genetic variants that are potentially related to the development of ADHD, and how these, in turn, might affect circuit function and relevant behaviours. Whether these underlying neurobiological factors are causally related to symptom presentation remains unresolved. Therefore, we assess efforts aimed at disentangling issues of causality, and showcase the shifting research landscape towards endophenotype refinement in clinical and preclinical settings. Furthermore, we review approaches being developed to understand the neurobiological underpinnings of this complex disorder including the use of animal models, neuromodulation, and pharmaco-imaging studies. PMID:27183902

  4. Biological underpinnings of trauma and post-traumatic stress disorder: focusing on genetics and epigenetics.

    PubMed

    Ryan, Joanne; Chaudieu, Isabelle; Ancelin, Marie-Laure; Saffery, Richard

    2016-11-01

    Certain individuals are more susceptible to stress and trauma, as well as the physical and mental health consequences following such exposure, including risk for post-traumatic stress disorder (PTSD). This differing vulnerability is likely to be influenced by genetic predisposition and specific characteristics of the stress itself (nature, intensity and duration), as well as epigenetic mechanisms. In this review we provide an overview of research findings in this field. We highlight some of the key genetic risk factors identified for PTSD, and the evidence that epigenetic processes might play a role in the biological response to trauma, as well as being potential biomarkers of PTSD risk. We also discuss important considerations for future research in this area.

  5. Neurobiology of obsessive-compulsive disorder: insights into neural circuitry dysfunction through mouse genetics.

    PubMed

    Ting, Jonathan T; Feng, Guoping

    2011-12-01

    The precise causal factors for obsessive-compulsive disorder (OCD) are not known, although, decades of research have honed in on the cortico-striatal-thalamo-cortical (CSTC) circuitry in the brain as a critical pathway involved in obsessions and the intimately linked compulsive-repetitive behaviors. Recent progress in human and mouse genetics have led to the identification of novel candidate susceptibility genes, which in turn have facilitated a more focused approach to unraveling the nature of circuitry dysfunction in OCD. The ability to perform invasive techniques in genetic animal models of OCD will be crucial for rapid advances in this field, and as such we review the most recent developments and highlight the importance of searching out common circuitry defects underlying compulsive-repetitive behaviors.

  6. The molecular genetics of autism spectrum disorders: genomic mechanisms, neuroimmunopathology, and clinical implications.

    PubMed

    Guerra, Daniel J

    2011-01-01

    Autism spectrum disorders (ASDs) have become increasingly common in recent years. The discovery of single-nucleotide polymorphisms and accompanying copy number variations within the genome has increased our understanding of the architecture of the disease. These genetic and genomic alterations coupled with epigenetic phenomena have pointed to a neuroimmunopathological mechanism for ASD. Model animal studies, developmental biology, and affective neuroscience laid a foundation for dissecting the neural pathways impacted by these disease-generating mechanisms. The goal of current autism research is directed toward a systems biological approach to find the most basic genetic and environmental causes to this severe developmental disease. It is hoped that future genomic and neuroimmunological research will be directed toward finding the road toward prevention, treatment, and cure of ASD.

  7. The Molecular Genetics of Autism Spectrum Disorders: Genomic Mechanisms, Neuroimmunopathology, and Clinical Implications

    PubMed Central

    Guerra, Daniel J.

    2011-01-01

    Autism spectrum disorders (ASDs) have become increasingly common in recent years. The discovery of single-nucleotide polymorphisms and accompanying copy number variations within the genome has increased our understanding of the architecture of the disease. These genetic and genomic alterations coupled with epigenetic phenomena have pointed to a neuroimmunopathological mechanism for ASD. Model animal studies, developmental biology, and affective neuroscience laid a foundation for dissecting the neural pathways impacted by these disease-generating mechanisms. The goal of current autism research is directed toward a systems biological approach to find the most basic genetic and environmental causes to this severe developmental disease. It is hoped that future genomic and neuroimmunological research will be directed toward finding the road toward prevention, treatment, and cure of ASD. PMID:22937247

  8. A qualitative inquiry of the financial concerns of couples opting to use preimplantation genetic diagnosis to prevent the transmission of known genetic disorders.

    PubMed

    Drazba, Kathryn T; Kelley, Michele A; Hershberger, Patricia E

    2014-04-01

    Preimplantation genetic diagnosis (PGD) is an innovative prenatal testing option because the determination of whether a genetic disorder or chromosomal abnormality is evident occurs prior to pregnancy. However, PGD is not covered financially under the majority of private and public health insurance institutions in the United States, leaving couples to decide whether PGD is financially feasible. The aim of this qualitative study was to understand the role of finances in the decision-making process among couples who were actively considering PGD. In-depth, semi-structured interviews were completed with 18 genetic high-risk couples (36 individual partners). Grounded theory guided the analysis, whereby three themes emerged: 1) Cost is salient, 2) Emotions surrounding affordability, and 3) Financial burden and sacrifice. Ultimately, couples determined that the opportunity to avoid passing on a genetic disorder to a future child was paramount to the cost of PGD, but expressed financial concerns and recognized financial access as a major barrier to PGD utilization.

  9. Genetic overlap between type 2 diabetes and major depressive disorder identified by bioinformatics analysis.

    PubMed

    Ji, Hong-Fang; Zhuang, Qi-Shuai; Shen, Liang

    2016-04-05

    Our study investigated the shared genetic etiology underlying type 2 diabetes (T2D) and major depressive disorder (MDD) by analyzing large-scale genome wide association studies statistics. A total of 496 shared SNPs associated with both T2D and MDD were identified at p-value ≤ 1.0E-07. Functional enrichment analysis showed that the enriched pathways pertained to immune responses (Fc gamma R-mediated phagocytosis, T cell and B cell receptors signaling), cell signaling (MAPK, Wnt signaling), lipid metabolism, and cancer associated pathways. The findings will have potential implications for future interventional studies of the two diseases.

  10. Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue.

    PubMed

    Alazami, Anas M; Al-Qattan, Sarah M; Faqeih, Eissa; Alhashem, Amal; Alshammari, Muneera; Alzahrani, Fatema; Al-Dosari, Mohammed S; Patel, Nisha; Alsagheir, Afaf; Binabbas, Bassam; Alzaidan, Hamad; Alsiddiky, Abdulmonem; Alharbi, Nasser; Alfadhel, Majid; Kentab, Amal; Daza, Riza M; Kircher, Martin; Shendure, Jay; Hashem, Mais; Alshahrani, Saif; Rahbeeni, Zuhair; Khalifa, Ola; Shaheen, Ranad; Alkuraya, Fowzan S

    2016-05-01

    Ehlers-Danlos syndrome (EDS) describes a group of clinical entities in which the connective tissue, primarily that of the skin, joint and vessels, is abnormal, although the resulting clinical manifestations can vary widely between the different historical subtypes. Many cases of hereditary disorders of connective tissue that do not seem to fit these historical subtypes exist. The aim of this study is to describe a large series of patients with inherited connective tissue disorders evaluated by our clinical genetics service and for whom a likely causal variant was identified. In addition to clinical phenotyping, patients underwent various genetic tests including molecular karyotyping, candidate gene analysis, autozygome analysis, and whole-exome and whole-genome sequencing as appropriate. We describe a cohort of 69 individuals representing 40 families, all referred because of suspicion of an inherited connective tissue disorder by their primary physician. Molecular lesions included variants in the previously published disease genes B3GALT6, GORAB, ZNF469, B3GAT3, ALDH18A1, FKBP14, PYCR1, CHST14 and SPARC with interesting variations on the published clinical phenotypes. We also describe the first recessive EDS-like condition to be caused by a recessive COL1A1 variant. In addition, exome capture in a familial case identified a homozygous truncating variant in a novel and compelling candidate gene, AEBP1. Finally, we also describe a distinct novel clinical syndrome of cutis laxa and marked facial features and propose ATP6V1E1 and ATP6V0D2 (two subunits of vacuolar ATPase) as likely candidate genes based on whole-genome and whole-exome sequencing of the two families with this new clinical entity. Our study expands the clinical spectrum of hereditary disorders of connective tissue and adds three novel candidate genes including two that are associated with a highly distinct syndrome.

  11. Genetics of Migraine: Insights into the Molecular Basis of Migraine Disorders.

    PubMed

    Sutherland, Heidi G; Griffiths, Lyn R

    2017-04-01

    Migraine is a complex, debilitating neurovascular disorder, typically characterized by recurring, incapacitating attacks of severe headache often accompanied by nausea and neurological disturbances. It has a strong genetic basis demonstrated by rare migraine disorders caused by mutations in single genes (monogenic), as well as familial clustering of common migraine which is associated with polymorphisms in many genes (polygenic). Hemiplegic migraine is a dominantly inherited, severe form of migraine with associated motor weakness. Family studies have found that mutations in three different ion channels genes, CACNA1A, ATP1A2, and SCN1A can be causal. Functional studies of these mutations has shown that they can result in defective regulation of glutamatergic neurotransmission and the excitatory/inhibitory balance in the brain, which lowers the threshold for cortical spreading depression, a wave of cortical depolarization thought to be involved in headache initiation mechanisms. Other putative genes for monogenic migraine include KCKN18, PRRT2, and CSNK1D, which can also be involved with other disorders. There are a number of primarily vascular disorders caused by mutations in single genes, which are often accompanied by migraine symptoms. Mutations in NOTCH3 causes cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebrovascular disease that leads to ischemic strokes and dementia, but in which migraine is often present, sometimes long before the onset of other symptoms. Mutations in the TREX1 and COL4A1 also cause vascular disorders, but often feature migraine. With respect to common polygenic migraine, genome-wide association studies have now identified single nucleotide polymorphisms at 38 loci significantly associated with migraine risk. Functions assigned to the genes in proximity to these loci suggest that both neuronal and vascular pathways also contribute to the pathophysiology of common

  12. Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder.

    PubMed

    Trent, Simon; Dean, Rachel; Veit, Bonnie; Cassano, Tommaso; Bedse, Gaurav; Ojarikre, Obah A; Humby, Trevor; Davies, William

    2013-08-01

    Chromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,X(Y*)O mice, which lack the murine orthologue of the Xp22.3 ADHD candidate gene STS (encoding steroid sulfatase), exhibit behavioural phenotypes relevant to such disorders (e.g. hyperactivity), elevated hippocampal serotonin (5-HT) levels, and reduced serum levels of dehydroepiandrosterone (DHEA). Here we initially show that 39,X(Y*)O mice are also deficient for the recently-characterised murine orthologue of the Xp22.3 autism candidate gene ASMT (encoding acetylserotonin-O-methyltransferase). Subsequently, to specify potential behavioural correlates of elevated hippocampal 5-HT arising due to the genetic lesion, we compared 39,X(Y*)O MF1 mice to 40,XY MF1 mice on behavioural tasks taxing hippocampal and/or 5-HT function (a 'foraging' task, an object-location task, and the 1-choice serial reaction time task of impulsivity). Although Sts/Asmt deficiency did not influence foraging behaviour, reactivity to familiar objects in novel locations, or 'ability to wait', it did result in markedly increased response rates; these rates correlated with hippocampal 5-HT levels and are likely to index behavioural perseveration, a frequent feature of neurodevelopmental disorders. Additionally, we show that whilst there was no systematic relationship between serum DHEA levels and hippocampal 5-HT levels across 39,X(Y*)O and 40,XY mice, there was a significant inverse linear correlation between serum DHEA levels and activity. Our data suggest that deficiency for genes within Xp22.3 could influence core behavioural features of neurodevelopmental disorders via dissociable effects on hippocampal neurochemistry and steroid hormone levels, and that the mediating neurobiological mechanisms may be investigated in the 39,X(Y*)O model.

  13. Therapeutic siRNAs for dominant genetic skin disorders including pachyonychia congenita.

    PubMed

    Leachman, Sancy A; Hickerson, Robyn P; Hull, Peter R; Smith, Frances J D; Milstone, Leonard M; Lane, E Birgitte; Bale, Sherri J; Roop, Dennis R; McLean, W H Irwin; Kaspar, Roger L

    2008-09-01

    The field of science and medicine has experienced a flood of data and technology associated with the human genome project. Over 10,000 human diseases have been genetically defined, but little progress has been made with respect to the clinical application of this knowledge. A notable exception to this exists for pachyonychia congenita (PC), a rare, dominant-negative keratin disorder. The establishment of a non-profit organization, PC Project, has led to an unprecedented coalescence of patients, scientists, and physicians with a unified vision of developing novel therapeutics for PC. Utilizing the technological by-products of the human genome project, such as RNA interference (RNAi) and quantitative RT-PCR (qRT-PCR), physicians and scientists have collaborated to create a candidate siRNA therapeutic that selectively inhibits a mutant allele of KRT6A, the most commonly affected PC keratin. In vitro investigation of this siRNA demonstrates potent inhibition of the mutant allele and reversal of the cellular aggregation phenotype. In parallel, an allele-specific quantitative real-time RT-PCR assay has been developed and validated on patient callus samples in preparation for clinical trials. If clinical efficacy is ultimately demonstrated, this "first-in-skin" siRNA may herald a paradigm shift in the treatment of dominant-negative genetic disorders.

  14. Genetic and Environmental Structure of DSM-IV Criteria for Antisocial Personality Disorder: A Twin Study.

    PubMed

    Rosenström, Tom; Ystrom, Eivind; Torvik, Fartein Ask; Czajkowski, Nikolai Olavi; Gillespie, Nathan A; Aggen, Steven H; Krueger, Robert F; Kendler, Kenneth S; Reichborn-Kjennerud, Ted

    2017-01-21

    Results from previous studies on DSM-IV and DSM-5 Antisocial Personality Disorder (ASPD) have suggested that the construct is etiologically multidimensional. To our knowledge, however, the structure of genetic and environmental influences in ASPD has not been examined using an appropriate range of biometric models and diagnostic interviews. The 7 ASPD criteria (section A) were assessed in a population-based sample of 2794 Norwegian twins by a structured interview for DSM-IV personality disorders. Exploratory analyses were conducted at the phenotypic level. Multivariate biometric models, including both independent and common pathways, were compared. A single phenotypic factor was found, and the best-fitting biometric model was a single-factor common pathway model, with common-factor heritability of 51% (95% CI 40-67%). In other words, both genetic and environmental correlations between the ASPD criteria could be accounted for by a single common latent variable. The findings support the validity of ASPD as a unidimensional diagnostic construct.

  15. Strong genetic correlation between interview-assessed internalizing disorders and a brief self-report symptom scale.

    PubMed

    Gjerde, Line C; Røysamb, Espen; Czajkowski, Nikolai; Reichborn-Kjennerud, Ted; Orstavik, Ragnhild E; Kendler, Kenneth S; Tambs, Kristian

    2011-02-01

    Self-report scales for symptoms of anxiety and depression are frequently used for screening and research purposes. A moderate phenotypic association between disorders measured by diagnostic interviews and symptoms of anxiety and depression measured by self-report scales has been shown, but little is known about the overlap in these phenotypes' genetic and environmental variance. In the present study, we used twin modeling to identify common genetic and environmental liabilities underlying the phenotypic association between the self-report Symptom Checklist-5 (SCL-5) and lifetime internalizing disorders derived from the Composite International Diagnostic Interview (CIDI). The sample consisted of 7,992 young adult twins from the Norwegian Institute of Public Health Twin Panel (NIPHT), who all responded to a questionnaire. A subset of 2,793 individuals later underwent structured interviews. The best fitting model showed a strong genetic correlation of 0.82 (95% confidence interval; 0.61-1.0) between current self-report symptoms of anxiety and depression, and lifetime internalizing disorders, which suggests an almost complete overlap in genetic liability. The correlation between environmental factors was much lower: 0.16 (0.00-0.34, 95% CI). This implies that brief self-report scales capture genetic variance that is highly overlapping with the genetic variance common to internalizing disorder diagnoses. It thus follows that SCL-5 and similar instruments may be used as screening instruments for genetic risk factors that influence liability to internalizing disorders. In addition, existing data on self-report symptoms of anxiety and depression can be used with increased confidence to specify models including effects from genes coding for internalizing disorders.

  16. Characterization of Movement Disorder Phenomenology in Genetically Proven, Familial Frontotemporal Lobar Degeneration: A Systematic Review and Meta-Analysis

    PubMed Central

    Gasca-Salas, Carmen; Masellis, Mario; Khoo, Edwin; Shah, Binit B.; Fisman, David; Lang, Anthony E.; Kleiner-Fisman, Galit

    2016-01-01

    Background Mutations in granulin (PGRN) and tau (MAPT), and hexanucleotide repeat expansions near the C9orf72 genes are the most prevalent genetic causes of frontotemporal lobar degeneration. Although behavior, language and movement presentations are common, the relationship between genetic subgroup and movement disorder phenomenology is unclear. Objective We conducted a systematic review and meta-analysis of the literature characterizing the spectrum and prevalence of movement disorders in genetic frontotemporal lobar degeneration. Methods Electronic databases were searched using terms related to frontotemporal lobar degeneration and movement disorders. Articles were included when cases had a proven genetic cause. Study-specific prevalence estimates for clinical features were transformed using Freeman-Tukey arcsine transformation, allowing for pooled estimates of prevalence to be generated using random-effects models. Results The mean age at onset was earlier in those with MAPT mutations compared to PGRN (p<0.001) and C9orf72 (p = 0.024). 66.5% of subjects had an initial non-movement presentation that was most likely a behavioral syndrome (35.7%). At any point during the disease, parkinsonism was the most common movement syndrome reported in 79.8% followed by progressive supranuclear palsy (PSPS) and corticobasal (CBS) syndromes in 12.2% and 10.7%, respectively. The prevalence of movement disorder as initial presentation was higher in MAPT subjects (35.8%) compared to PGRN subjects (10.1). In those with a non-movement presentation, language disorder was more common in PGRN subjects (18.7%) compared to MAPT subjects (5.4%). Summary This represents the first systematic review and meta-analysis of the occurrence of movement disorder phenomenology in genetic frontotemporal lobar degeneration. Standardized prospective collection of clinical information in conjunction with genetic characterization will be crucial for accurate clinico-genetic correlation. PMID:27100392

  17. Health-Related Quality of Life Measures in Genetic Disorders: an Outcome Variable for Consideration in Clinical Trials

    PubMed Central

    Stevenson, David A.; Carey, John C.

    2009-01-01

    The field of medical genetics is rapidly advancing, and therapeutic options to treat genetic syndromes are becoming increasingly available. An understanding of the pathophysiology of various genetic disorders has provided researchers the opportunity to propose and test pharmacologic agents in preclinical murine models with hopes of translation to human trials. The development of clinical trials can be costly and time consuming, particularly for rare conditions. Pilot feasibility studies should be performed when designing clinical trials for genetic disorders. The development and selection of appropriate outcome measures are particularly paramount in the implementation of clinical trials. The selection of inappropriate outcome measures can lead to non-measurable differences or clinically insignificant findings. In addition, just as age appropriate measures are needed, some instruments may not apply to populations with specific genetic disorders that have significant cognitive and physical impairment, as the measures may not be sensitive enough to identify clinically significant changes. .In the last decade health-related quality of life measures (HRQOL) have been increasingly included as an outcome measure in clinical trials. While traditional clinical outcomes are important, these newly developed instruments should be considered along with clinical indicators as measures of effect in clinical trials of interventions in genetic disorders. PMID:19621444

  18. Multivariate genetic determinants of EEG oscillations in schizophrenia and psychotic bipolar disorder from the BSNIP study

    PubMed Central

    Narayanan, B; Soh, P; Calhoun, V D; Ruaño, G; Kocherla, M; Windemuth, A; Clementz, B A; Tamminga, C A; Sweeney, J A; Keshavan, M S; Pearlson, G D

    2015-01-01

    Schizophrenia (SZ) and psychotic bipolar disorder (PBP) are disabling psychiatric illnesses with complex and unclear etiologies. Electroencephalogram (EEG) oscillatory abnormalities in SZ and PBP probands are heritable and expressed in their relatives, but the neurobiology and genetic factors mediating these abnormalities in the psychosis dimension of either disorder are less explored. We examined the polygenic architecture of eyes-open resting state EEG frequency activity (intrinsic frequency) from 64 channels in 105 SZ, 145 PBP probands and 56 healthy controls (HCs) from the multisite BSNIP (Bipolar-Schizophrenia Network on Intermediate Phenotypes) study. One million single-nucleotide polymorphisms (SNPs) were derived from DNA. We assessed eight data-driven EEG frequency activity derived from group-independent component analysis (ICA) in conjunction with a reduced subset of 10 422 SNPs through novel multivariate association using parallel ICA (para-ICA). Genes contributing to the association were examined collectively using pathway analysis tools. Para-ICA extracted five frequency and nine SNP components, of which theta and delta activities were significantly correlated with two different gene components, comprising genes participating extensively in brain development, neurogenesis and synaptogenesis. Delta and theta abnormality was present in both SZ and PBP, while theta differed between the two disorders. Theta abnormalities were also mediated by gene clusters involved in glutamic acid pathways, cadherin and synaptic contact-based cell adhesion processes. Our data suggest plausible multifactorial genetic networks, including novel and several previously identified (DISC1) candidate risk genes, mediating low frequency delta and theta abnormalities in psychoses. The gene clusters were enriched for biological properties affecting neural circuitry and involved in brain function and/or development. PMID:26101851

  19. Preimplantation Genetic Diagnosis (PGD) for Monogenic Disorders: the Value of Concurrent Aneuploidy Screening.

    PubMed

    Goldman, Kara N; Nazem, Taraneh; Berkeley, Alan; Palter, Steven; Grifo, Jamie A

    2016-12-01

    Pre-implantation genetic diagnosis (PGD) has changed the landscape of clinical genetics by helping families reduce the transmission of monogenic disorders. However, given the high prevalence of embryonic aneuploidy, particularly in patients of advanced reproductive age, unaffected embryos remain at high risk of implantation failure or pregnancy loss due to aneuploidy. 24-chromosome aneuploidy screening has become widely utilized in routine in vitro fertilization (IVF) to pre-select embryos with greater pregnancy potential, but concurrent 24-chromosome aneuploidy screening has not become standard practice in embryos biopsied for PGD. We performed a retrospective cohort study of patients who underwent PGD with or without 24-chromosome aneuploidy screening to explore the value of concurrent screening. Among the PGD + aneuploidy-screened group (n = 355 blastocysts), only 25.6 % of embryos were both Single Gene Disorder (SGD)-negative (or carriers) and euploid; thus the majority of embryos were ineligible for transfer due to the high prevalence of aneuploidy. Despite a young mean age (32.4 ± 5.9y), 49.9 % of Blastocysts were aneuploid. The majority of patients (53.2 %) had ≥1 blastocyst that was Single Gene Disorder (SGD)-unaffected but aneuploid; without screening, these unaffected but aneuploid embryos would likely have been transferred resulting in implantation failure, pregnancy loss, or a pregnancy affected by chromosomal aneuploidy. Despite the transfer of nearly half the number of embryos in the aneuploidy-screened group (1.1 ± 0.3 vs. 1.9 ± 0.6, p < 0.0001), the implantation rate was higher (75 % vs. 53.3 %) and miscarriage rate lower (20 % vs. 40 %) (although not statistically significant). 24-chromosome aneuploidy screening when performed concurrently with PGD provides valuable information for embryo selection, and notably improves single embryo transfer rates.

  20. Polygenic risk assessment reveals pleiotropy between sarcoidosis and inflammatory disorders in the context of genetic ancestry.

    PubMed

    Lareau, C A; DeWeese, C F; Adrianto, I; Lessard, C J; Gaffney, P M; Iannuzzi, M C; Rybicki, B A; Levin, A M; Montgomery, C G

    2017-03-09

    Sarcoidosis is a complex disease of unknown etiology characterized by the presence of granulomatous inflammation. Though various immune system pathways have been implicated in disease, the relationship between the genetic determinants of sarcoidosis and other inflammatory disorders has not been characterized. Herein, we examined the degree of genetic pleiotropy common to sarcoidosis and other inflammatory disorders to identify shared pathways and disease systems pertinent to sarcoidosis onset. To achieve this, we quantify the association of common variant polygenic risk scores from nine complex inflammatory disorders with sarcoidosis risk. Enrichment analyses of genes implicated in pleiotropic associations were further used to elucidate candidate pathways. In European-Americans, we identify significant pleiotropy between risk of sarcoidosis and risk of asthma (R(2)=2.03%; P=8.89 × 10(-9)), celiac disease (R(2)=2.03%; P=8.21 × 10(-9)), primary biliary cirrhosis (R(2)=2.43%; P=2.01 × 10(-10)) and rheumatoid arthritis (R(2)=4.32%; P=2.50 × 10(-17)). These associations validate in African Americans only after accounting for the proportion of genome-wide European ancestry, where we demonstrate similar effects of polygenic risk for African-Americans with the highest levels of European ancestry. Variants and genes implicated in European-American pleiotropic associations were enriched for pathways involving interleukin-12, interleukin-27 and cell adhesion molecules, corroborating the hypothesized immunopathogenesis of disease.Genes and Immunity advance online publication, 9 March 2017; doi:10.1038/gene.2017.3.

  1. Multivariate genetic determinants of EEG oscillations in schizophrenia and psychotic bipolar disorder from the BSNIP study.

    PubMed

    Narayanan, B; Soh, P; Calhoun, V D; Ruaño, G; Kocherla, M; Windemuth, A; Clementz, B A; Tamminga, C A; Sweeney, J A; Keshavan, M S; Pearlson, G D

    2015-06-23

    Schizophrenia (SZ) and psychotic bipolar disorder (PBP) are disabling psychiatric illnesses with complex and unclear etiologies. Electroencephalogram (EEG) oscillatory abnormalities in SZ and PBP probands are heritable and expressed in their relatives, but the neurobiology and genetic factors mediating these abnormalities in the psychosis dimension of either disorder are less explored. We examined the polygenic architecture of eyes-open resting state EEG frequency activity (intrinsic frequency) from 64 channels in 105 SZ, 145 PBP probands and 56 healthy controls (HCs) from the multisite BSNIP (Bipolar-Schizophrenia Network on Intermediate Phenotypes) study. One million single-nucleotide polymorphisms (SNPs) were derived from DNA. We assessed eight data-driven EEG frequency activity derived from group-independent component analysis (ICA) in conjunction with a reduced subset of 10,422 SNPs through novel multivariate association using parallel ICA (para-ICA). Genes contributing to the association were examined collectively using pathway analysis tools. Para-ICA extracted five frequency and nine SNP components, of which theta and delta activities were significantly correlated with two different gene components, comprising genes participating extensively in brain development, neurogenesis and synaptogenesis. Delta and theta abnormality was present in both SZ and PBP, while theta differed between the two disorders. Theta abnormalities were also mediated by gene clusters involved in glutamic acid pathways, cadherin and synaptic contact-based cell adhesion processes. Our data suggest plausible multifactorial genetic networks, including novel and several previously identified (DISC1) candidate risk genes, mediating low frequency delta and theta abnormalities in psychoses. The gene clusters were enriched for biological properties affecting neural circuitry and involved in brain function and/or development.

  2. FKBP5 genetic variation: association with selective serotonin reuptake inhibitor treatment outcomes in major depressive disorder

    PubMed Central

    Ellsworth, Katarzyna A.; Moon, Irene; Eckloff, Bruce W.; Fridley, Brooke L.; Jenkins, Gregory D.; Batzler, Anthony; Biernacka, Joanna M.; Abo, Ryan; Brisbin, Abra; Ji, Yuan; Hebbring, Scott; Wieben, Eric D.; Mrazek, David A.; Weinshilboum, Richard M.; Wang, Liewei

    2013-01-01

    Objectives FKBP51 (51 kDa immunophilin) acts as a modulator of the glucocorticoid receptor and a negative regulator of the Akt pathway. Genetic variation in FKBP5 plays a role in antidepressant response. The aim of this study was to comprehensively assess the role of genetic variation in FKBP5, identified by both Sanger and Next Generation DNA resequencing, as well as genome-wide single nucleotide polymorphisms (SNPs) associated with FKBP5 expression in the response to the selective serotonin reuptake inhibitor (SSRI) treatment of major depressive disorder. Methods We identified 657 SNPs in FKBP5 by Next Generation sequencing of 96 DNA samples from white patients, and 149 SNPs were selected for the genotyping together with 235 SNPs that were trans-associated with variation in FKBP5 expression in lymphoblastoid cells. A total of 529 DNA samples from the Mayo Clinic PGRN-SSRI Pharmacogenomic trial for which genome-wide SNPs had already been obtained were genotyped for these 384 SNPs, and associations with treatment outcomes were determined. The most significant SNPs were genotyped using 96 DNA samples from white non-Hispanic patients of the NIMH-supported Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study to attempt replication, followed by functional genomic studies. Results Genotype–phenotype association analysis indicated that rs352428 was associated with both 8-week treatment response in the Mayo study (odds ratio =0.49; P = 0.003) and 6-week response in the STAR*D replication study (odds ratio = 0.74; P =0.05). The electrophoresis mobility shift assay and the reporter gene assay confirmed the possible role of this SNP in transcription regulation. Conclusion This comprehensive FKBP5 sequence study provides insight into the role of common genetic polymorphisms that might influence SSRI treatment outcomes in major depressive disorder patients. PMID:23324805

  3. The genetics of attention deficit/hyperactivity disorder in adults, a review

    PubMed Central

    Franke, B; Faraone, S V; Asherson, P; Buitelaar, J; Bau, C H D; Ramos-Quiroga, J A; Mick, E; Grevet, E H; Johansson, S; Haavik, J; Lesch, K-P; Cormand, B; Reif, A

    2012-01-01

    The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30–40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood. PMID:22105624

  4. The genetics of attention deficit/hyperactivity disorder in adults, a review.

    PubMed

    Franke, B; Faraone, S V; Asherson, P; Buitelaar, J; Bau, C H D; Ramos-Quiroga, J A; Mick, E; Grevet, E H; Johansson, S; Haavik, J; Lesch, K-P; Cormand, B; Reif, A

    2012-10-01

    The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30-40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood.

  5. Distinct Muscle Biopsy Findings in Genetically Defined Adult-Onset Motor Neuron Disorders.

    PubMed

    Jokela, Manu; Huovinen, Sanna; Raheem, Olayinka; Lindfors, Mikaela; Palmio, Johanna; Penttilä, Sini; Udd, Bjarne

    2016-01-01

    The objective of this study was to characterize and compare muscle histopathological findings in 3 different genetic motor neuron disorders. We retrospectively re-assessed muscle biopsy findings in 23 patients with autosomal dominant lower motor neuron disease caused by p.G66V mutation in CHCHD10 (SMAJ), 10 X-linked spinal and bulbar muscular atrophy (SBMA) and 11 autosomal dominant c9orf72-mutated amyotrophic lateral sclerosis (c9ALS) patients. Distinct large fiber type grouping consisting of non-atrophic type IIA muscle fibers were 100% specific for the late-onset spinal muscular atrophies (SMAJ and SBMA) and were never observed in c9ALS. Common, but less specific findings included small groups of highly atrophic rounded type IIA fibers in SMAJ/SBMA, whereas in c9ALS, small group atrophies consisting of small-caliber angular fibers involving both fiber types were more characteristic. We also show that in the 2 slowly progressive motor neuron disorders (SMAJ and SBMA) the initial neurogenic features are often confused with considerable secondary "myopathic" changes at later disease stages, such as rimmed vacuoles, myofibrillar aggregates and numerous fibers reactive for fetal myosin heavy chain (dMyHC) antibodies. Based on our findings, muscle biopsy may be valuable in the diagnostic work-up of suspected motor neuron disorders in order to avoid a false ALS diagnosis in patients without clear findings of upper motor neuron lesions.

  6. Comparing ESC and iPSC—Based Models for Human Genetic Disorders

    PubMed Central

    Halevy, Tomer; Urbach, Achia

    2014-01-01

    Traditionally, human disorders were studied using animal models or somatic cells taken from patients. Such studies enabled the analysis of the molecular mechanisms of numerous disorders, and led to the discovery of new treatments. Yet, these systems are limited or even irrelevant in modeling multiple genetic diseases. The isolation of human embryonic stem cells (ESCs) from diseased blastocysts, the derivation of induced pluripotent stem cells (iPSCs) from patients’ somatic cells, and the new technologies for genome editing of pluripotent stem cells have opened a new window of opportunities in the field of disease modeling, and enabled studying diseases that couldn’t be modeled in the past. Importantly, despite the high similarity between ESCs and iPSCs, there are several fundamental differences between these cells, which have important implications regarding disease modeling. In this review we compare ESC-based models to iPSC-based models, and highlight the advantages and disadvantages of each system. We further suggest a roadmap for how to choose the optimal strategy to model each specific disorder. PMID:26237596

  7. Distinct Muscle Biopsy Findings in Genetically Defined Adult-Onset Motor Neuron Disorders

    PubMed Central

    Jokela, Manu; Huovinen, Sanna; Raheem, Olayinka; Lindfors, Mikaela; Palmio, Johanna; Penttilä, Sini; Udd, Bjarne

    2016-01-01

    The objective of this study was to characterize and compare muscle histopathological findings in 3 different genetic motor neuron disorders. We retrospectively re-assessed muscle biopsy findings in 23 patients with autosomal dominant lower motor neuron disease caused by p.G66V mutation in CHCHD10 (SMAJ), 10 X-linked spinal and bulbar muscular atrophy (SBMA) and 11 autosomal dominant c9orf72-mutated amyotrophic lateral sclerosis (c9ALS) patients. Distinct large fiber type grouping consisting of non-atrophic type IIA muscle fibers were 100% specific for the late-onset spinal muscular atrophies (SMAJ and SBMA) and were never observed in c9ALS. Common, but less specific findings included small groups of highly atrophic rounded type IIA fibers in SMAJ/SBMA, whereas in c9ALS, small group atrophies consisting of small-caliber angular fibers involving both fiber types were more characteristic. We also show that in the 2 slowly progressive motor neuron disorders (SMAJ and SBMA) the initial neurogenic features are often confused with considerable secondary “myopathic” changes at later disease stages, such as rimmed vacuoles, myofibrillar aggregates and numerous fibers reactive for fetal myosin heavy chain (dMyHC) antibodies. Based on our findings, muscle biopsy may be valuable in the diagnostic work-up of suspected motor neuron disorders in order to avoid a false ALS diagnosis in patients without clear findings of upper motor neuron lesions. PMID:26999347

  8. Mitochondrial genetic analyses suggest selection against maternal lineages in bipolar affective disorder.

    PubMed Central

    Kirk, R; Furlong, R A; Amos, W; Cooper, G; Rubinsztein, J S; Walsh, C; Paykel, E S; Rubinsztein, D C

    1999-01-01

    Previous reports of preferential transmission of bipolar affective disorder (BP) from the maternal versus the paternal lines in families suggested that this disorder may be caused by mitochondrial DNA mutations. We have sequenced the mitochondrial genome in 25 BP patients with family histories of psychiatric disorder that suggest matrilineal inheritance. No polymorphism identified more than once in this sequencing showed any significant association with BP in association studies using 94 cases and 94 controls. To determine whether our BP sample showed evidence of selection against the maternal lineage, we determined genetic distances between all possible pairwise comparisons within the BP and control groups, based on multilocus mitochondrial polymorphism haplotypes. These analyses revealed fewer closely related haplotypes in the BP group than in the matched control group, suggesting selection against maternal lineages in this disease. Such selection is compatible with recurrent mitochondrial mutations, which are associated with slightly decreased fitness. Although such mismatch distribution comparisons have been used previously for analyses of population histories, this is, as far as we are aware, the first report of this method being used to study disease. PMID:10417293

  9. Transitions in genetic toggle switches driven by dynamic disorder in rate coefficients

    NASA Astrophysics Data System (ADS)

    Chen, Hang; Thill, Peter; Cao, Jianshu

    2016-05-01

    In biochemical systems, intrinsic noise may drive the system switch from one stable state to another. We investigate how kinetic switching between stable states in a bistable network is influenced by dynamic disorder, i.e., fluctuations in the rate coefficients. Using the geometric minimum action method, we first investigate the optimal transition paths and the corresponding minimum actions based on a genetic toggle switch model in which reaction coefficients draw from a discrete probability distribution. For the continuous probability distribution of the rate coefficient, we then consider two models of dynamic disorder in which reaction coefficients undergo different stochastic processes with the same stationary distribution. In one, the kinetic parameters follow a discrete Markov process and in the other they follow continuous Langevin dynamics. We find that regulation of the parameters modulating the dynamic disorder, as has been demonstrated to occur through allosteric control in bistable networks in the immune system, can be crucial in shaping the statistics of optimal transition paths, transition probabilities, and the stationary probability distribution of the network.

  10. Utility of genetically modified mice for understanding the neurobiology of substance use disorders.

    PubMed

    Fowler, Christie D; Kenny, Paul J

    2012-06-01

    Advances in our ability to modify the mouse genome have enhanced our understanding of the genetic and neurobiological mechanisms contributing to addiction-related behaviors underlying substance use and abuse. These experimentally induced manipulations permit greater spatial and temporal specificity for modification of gene expression within specific cellular populations and during select developmental time periods. In this review, we consider the current mouse genetic model systems that have been employed to understand aspects of addiction and highlight significant conceptual advances achieved related to substance use and abuse. The mouse models reviewed herein include conventional knock-out and knock-in, conditional knockout, transgenic, inducible transgenic, mice suitable for optogenetic control of discrete neuronal populations, and phenotype-selected mice. By establishing a reciprocal investigatory relationship between genetic findings in humans and genomic manipulations in mice, a far better understanding of the discrete neuromechanisms underlying addiction can be achieved, which is likely to provide a strong foundation for developing and validating novel therapeutics for the treatment of substance abuse disorders.

  11. Integrating behavioral economics and behavioral genetics: delayed reward discounting as an endophenotype for addictive disorders.

    PubMed

    MacKillop, James

    2013-01-01

    Delayed reward discounting is a behavioral economic index of impulsivity, referring to how much an individual devalues a reward based on its delay in time. As a behavioral process that varies considerably across individuals, delay discounting has been studied extensively as a model for self-control, both in the general population and in clinical samples. There is growing interest in genetic influences on discounting and, in particular, the prospect of discounting as an endophenotype for addictive disorders (i.e., a heritable mechanism partially responsible for conferring genetic risk). This review assembles and critiques the evidence supporting this hypothesis. Via numerous cross-sectional studies and a small number of longitudinal studies, there is considerable evidence that impulsive discounting is associated with addictive behavior and appears to play an etiological role. Moreover, there is increasing evidence from diverse methodologies that impulsive delay discounting is temporally stable, heritable, and that elevated levels are present in nonaffected family members. These findings suggest that impulsive discounting meets the criteria for being considered an endophenotype. In addition, recent findings suggest that genetic variation related to dopamine neurotransmission is significantly associated with variability in discounting preferences. A significant caveat, however, is that the literature is modest in some domains and, in others, not all the findings have been supportive or consistent. In addition, important methodological considerations are necessary in future studies. Taken together, although not definitive, there is accumulating support for the hypothesis of impulsive discounting as an endophenotype for addictive behavior and a need for further systematic investigation.

  12. Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders.

    PubMed

    Arloth, Janine; Bogdan, Ryan; Weber, Peter; Frishman, Goar; Menke, Andreas; Wagner, Klaus V; Balsevich, Georgia; Schmidt, Mathias V; Karbalai, Nazanin; Czamara, Darina; Altmann, Andre; Trümbach, Dietrich; Wurst, Wolfgang; Mehta, Divya; Uhr, Manfred; Klengel, Torsten; Erhardt, Angelika; Carey, Caitlin E; Conley, Emily Drabant; Ruepp, Andreas; Müller-Myhsok, Bertram; Hariri, Ahmad R; Binder, Elisabeth B

    2015-06-03

    Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain.

  13. Population-based study of genetic variation in individuals with autism spectrum disorders from Croatia

    PubMed Central

    2010-01-01

    Background Genome-wide studies on autism spectrum disorders (ASDs) have mostly focused on large-scale population samples, but examination of rare variations in isolated populations may provide additional insights into the disease pathogenesis. Methods As a first step in the genetic analysis of ASD in Croatia, we characterized genetic variation in a sample of 103 subjects with ASD and 203 control individuals, who were genotyped using the Illumina HumanHap550 BeadChip. We analyzed the genetic diversity of the Croatian population and its relationship to other populations, the degree of relatedness via Runs of Homozygosity (ROHs), and the distribution of large (>500 Kb) copy number variations. Results Combining the Croatian cohort with several previously published populations in the FastME analysis (an alternative to Neighbor Joining) revealed that Croatian subjects cluster, as expected, with Southern Europeans; in addition, individuals from the same geographic region within Europe cluster together. Whereas Croatian subjects could be separated from a sample of healthy control subjects of European origin from North America, Croatian ASD cases and controls are well mixed. A comparison of runs of homozygosity indicated that the number and the median length of regions of homozygosity are higher for ASD subjects than for controls (p = 6 × 10-3). Furthermore, analysis of copy number variants found a higher frequency of large chromosomal rearrangements (>2 Mb) in ASD cases (5/103) than in ethnically matched control subjects (1/197, p = 0.019). Conclusions Our findings illustrate the remarkable utility of high-density genotype data for subjects from a limited geographic area in dissecting genetic heterogeneity with respect to population and disease related variation. PMID:20858243

  14. The cognitive genetics of attention deficit hyperactivity disorder (ADHD): sustained attention as a candidate phenotype.

    PubMed

    Bellgrove, Mark A; Hawi, Ziarih; Gill, Michael; Robertson, Ian H

    2006-08-01

    Here we describe the application of cognitive genetics to the study of attention deficit hyperactivity disorder (ADHD). Cognitive genetics owes much to the pioneering work of cognitive neuropsychologists such as John Marshall, whose careful observations of cognitive dissociations between brain-lesioned patients greatly advanced the theoretical understanding of normal cognitive function. These theories have in turn helped to constrain linkages between candidate genes and cognitive processes and thus help to drive the relatively new field of cognitive genetics in a hypothesis-driven fashion. We examined the relationship between sustained attention deficits in ADHD and genetic variation in a catecholamine-related gene, dopamine beta hydroxylase (DbetaH). DBH encodes the enzyme that converts dopamine to noradrenaline and is crucial to catecholamine regulation. A polymorphism with the DBH gene has been associated with ADHD. In fifty-two children with ADHD, we examined whether variation in the Taq I DBH gene polymorphism was related to sustained attention performance. Participants performed the Sustained Attention to Response Test (SART). Performance on the SART discriminates ADHD from control children, and in imaging work, is associated with right frontoparietal activation. A significant effect of DBH genotype was found on SART performance measures. Children possessing two copies of the ADHD-associated risk allele (A2) had significantly poorer sustained attention than those ADHD children who did not possess this allele or a non-genotyped control group. The DBH gene may contribute to the susceptibility for ADHD, in part because of its varying effects on the development of brain mechanisms mediating sustained attention.

  15. Joubert syndrome: A model for untangling recessive disorders with extreme genetic heterogeneity

    PubMed Central

    R, Bachmann-Gagescu; JC, Dempsey; IG, Phelps; BJ, O’Roak; DM, Knutzen; TC, Rue; GE, Ishak; CR, Isabella; N, Gorden; J, Adkins; EA, Boyle; N, de Lacy; D, O’Day; A, Alswaid; AR, Devi; L, Lingappa; C, Lourenço; L, Martorell; À, Garcia-Cazorla; H, Ozyürek; G, Haliloğlu; B, Tuysuz; M, Topçu; P, Chance; MA, Parisi; I, Glass; J, Shendure; D, Doherty

    2016-01-01

    Background Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances, and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS. Methods We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion (CADD) algorithm with an optimized score cut-off. Results We identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a “pure JS” phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS-subtypes. Conclusion This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes, and enable gene-specific treatments in the future. PMID:26092869

  16. The Structure of Genetic and Environmental Risk Factors for Syndromal and Subsyndromal Common DSM-IV Axis I and All Axis II Disorders

    PubMed Central

    Kendler, Kenneth S.; Aggen, Steven H.; Knudsen, Gun Peggy; Røysamb, Espen; Neale, Michael C.; Reichborn-Kjennerud, Ted

    2011-01-01

    Objective The authors sought to clarify the structure of the genetic and environmental risk factors for 22 DSM-IV disorders: 12 common axis I disorders and all 10 axis II disorders. Method The authors examined syndromal and subsyndromal axis I diagnoses and five categories reflecting number of endorsed criteria for axis II disorders in 2,111 personally interviewed young adult members of the Norwegian Institute of Public Health Twin Panel. Results Four correlated genetic factors were identified: axis I internalizing, axis II internalizing, axis I externalizing, and axis II externalizing. Factors 1 and 2 and factors 3 and 4 were moderately correlated, supporting the importance of the internalizing-externalizing distinction. Five disorders had substantial loadings on two factors: borderline personality disorder (factors 3 and 4), somatoform disorder (factors 1 and 2), paranoid and dependent personality disorders (factors 2 and 4), and eating disorders (factors 1 and 4). Three correlated environmental factors were identified: axis II disorders, axis I internalizing disorders, and externalizing disorders versus anxiety disorders. Conclusions Common axis I and II psychiatric disorders have a coherent underlying genetic structure that reflects two major dimensions: internalizing versus externalizing, and axis I versus axis II. The underlying structure of environmental influences is quite different. The organization of common psychiatric disorders into coherent groups results largely from genetic, not environmental, factors. These results should be interpreted in the context of unavoidable limitations of current statistical methods applied to this number of diagnostic categories. PMID:20952461

  17. Genetic inactivation of glutamate neurons in the rat sublaterodorsal tegmental nucleus recapitulates REM sleep behaviour disorder.

    PubMed

    Valencia Garcia, Sara; Libourel, Paul-Antoine; Lazarus, Michael; Grassi, Daniela; Luppi, Pierre-Hervé; Fort, Patrice

    2017-02-01

    SEE SCHENCK AND MAHOWALD DOI101093/AWW329 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Idiopathic REM sleep behaviour disorder is characterized by the enactment of violent dreams during paradoxical (REM) sleep in the absence of normal muscle atonia. Accumulating clinical and experimental data suggest that REM sleep behaviour disorder might be due to the neurodegeneration of glutamate neurons involved in paradoxical sleep and located within the pontine sublaterodorsal tegmental nucleus. The purpose of the present work was thus to functionally determine first, the role of glutamate sublaterodorsal tegmental nucleus neurons in paradoxical sleep and second, whether their genetic inactivation is sufficient for recapitulating REM sleep behaviour disorder in rats. For this goal, we first injected two retrograde tracers in the intralaminar thalamus and ventral medulla to disentangle neuronal circuits in which sublaterodorsal tegmental nucleus is involved; second we infused bilaterally in sublaterodorsal tegmental nucleus adeno-associated viruses carrying short hairpin RNAs targeting Slc17a6 mRNA [which encodes vesicular glutamate transporter 2 (vGluT2)] to chronically impair glutamate synaptic transmission in sublaterodorsal tegmental nucleus neurons. At the neuroanatomical level, sublaterodorsal tegmental nucleus neurons specifically activated during paradoxical sleep hypersomnia send descending efferents to glycine/GABA neurons within the ventral medulla, but not ascending projections to the intralaminar thalamus. These data suggest a crucial role of sublaterodorsal tegmental nucleus neurons rather in muscle atonia than in paradoxical sleep generation. In line with this hypothesis, 30 days after adeno-associated virus injections into sublaterodorsal tegmental nucleus rats display a decrease of 30% of paradoxical sleep daily quantities, and a significant increase of muscle tone during paradoxical sleep concomitant to a tremendous increase of abnormal motor dream

  18. Dopamine and serotonin genetic risk scores predicting substance and nicotine use in attention deficit/hyperactivity disorder.

    PubMed

    Groenman, Annabeth P; Greven, Corina U; van Donkelaar, Marjolein M J; Schellekens, Arnt; van Hulzen, Kimm J E; Rommelse, Nanda; Hartman, Catharina A; Hoekstra, Pieter J; Luman, Marjolein; Franke, Barbara; Faraone, Stephen V; Oosterlaan, Jaap; Buitelaar, Jan K

    2016-07-01

    Individuals with attention deficit/hyperactivity disorder (ADHD) are at increased risk of developing substance use disorders (SUDs) and nicotine dependence. The co-occurrence of ADHD and SUDs/nicotine dependence may in part be mediated by shared genetic liability. Several neurobiological pathways have been implicated in both ADHD and SUDs, including dopamine and serotonin pathways. We hypothesized that variations in dopamine and serotonin neurotransmission genes were involved in the genetic liability to develop SUDs/nicotine dependence in ADHD. The current study included participants with ADHD (n = 280) who were originally part of the Dutch International Multicenter ADHD Genetics study. Participants were aged 5-15 years and attending outpatient clinics at enrollment in the study. Diagnoses of ADHD, SUDs, nicotine dependence, age of first nicotine and substance use, and alcohol use severity were based on semi-structured interviews and questionnaires. Genetic risk scores were created for both serotonergic and dopaminergic risk genes previously shown to be associated with ADHD and SUDs and/or nicotine dependence. The serotonin genetic risk score significantly predicted alcohol use severity. No significant serotonin × dopamine risk score or effect of stimulant medication was found. The current study adds to the literature by providing insight into genetic underpinnings of the co-morbidity of ADHD and SUDs. While the focus of the literature so far has been mostly on dopamine, our study suggests that serotonin may also play a role in the relationship between these disorders.

  19. Keith R. Porter Lecture, 1996. Of mice and men: genetic disorders of the cytoskeleton.

    PubMed Central

    Fuchs, E

    1997-01-01

    Since the time when I was a postdoctoral fellow under the supervision of Dr. Howard Green, then at the Massachusetts Institute of Technology, I have been interested in understanding the molecular mechanisms underlying growth, differentiation, and development in the mammalian ectoderm. The ectoderm gives rise to epidermal keratinocytes and to neurons, which are the only two cell types of the body that devote most of their protein-synthesizing machinery to developing an elaborate cytoskeletal architecture composed of 10-nm intermediate filaments (IFs). Our interest is in understanding the architecture of the cytoskeleton in keratinocytes and in neurons, and in elucidating how perturbations in this architecture can lead to degenerative diseases of the skin and the nervous system. I will concentrate on the intermediate filament network of the skin and its associated genetic disorders, since this has been a long-standing interest of my laboratory at the University of Chicago. Images PMID:9190201

  20. Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease

    PubMed Central

    Hoban, Megan D.; Bauer, Daniel E.

    2016-01-01

    Effective medical management for sickle cell disease (SCD) remains elusive. As a prevalent and severe monogenic disorder, SCD has been long considered a logical candidate for gene therapy. Significant progress has been made in moving toward this goal. These efforts have provided substantial insight into the natural regulation of the globin genes and illuminated challenges for genetic manipulation of the hematopoietic system. The initial γ-retroviral vectors, next-generation lentiviral vectors, and novel genome engineering and gene regulation approaches each share the goal of preventing erythrocyte sickling. After years of preclinical studies, several clinical trials for SCD gene therapies are now open. This review focuses on progress made toward achieving gene therapy, the current state of the field, consideration of factors that may determine clinical success, and prospects for future development. PMID:26758916

  1. Peabody Picture Vocabulary Test: Proxy for Verbal IQ in Genetic Studies of Autism Spectrum Disorder.

    PubMed

    Krasileva, Kate E; Sanders, Stephan J; Bal, Vanessa Hus

    2017-04-01

    This study assessed the utility of a brief assessment (the Peabody Picture Vocabulary Test-4th Edition; PPVT4) as a proxy for verbal IQ (VIQ) in large-scale studies of autism spectrum disorder (ASD). In a sample of 2,420 proband with ASD, PPVT4:IQ correlations were strong. PPVT4 scores were, on average, 5.46 points higher than VIQ; 79% of children had PPVT4 scores within one standard deviation (+/-15) of their VIQ and 90% were similarly classified as having abilities above or below 70 on both measures. Distributions of PPVT4 and VIQ by de novo mutation status were highly similar. These results strongly support the utility of PPVT4 as a proxy for VIQ in large-scale ASD studies, particularly for genetic investigations.

  2. To grow or not to grow: hair morphogenesis and human genetic hair disorders.

    PubMed

    Duverger, Olivier; Morasso, Maria I

    2014-01-01

    Mouse models have greatly helped in elucidating the molecular mechanisms involved in hair formation and regeneration. Recent publications have reviewed the genes involved in mouse hair development based on the phenotype of transgenic, knockout and mutant animal models. While much of this information has been instrumental in determining molecular aspects of human hair development and cycling, mice exhibit a specific pattern of hair morphogenesis and hair distribution throughout the body that cannot be directly correlated to human hair. In this mini-review, we discuss specific aspects of human hair follicle development and present an up-to-date summary of human genetic disorders associated with abnormalities in hair follicle morphogenesis, structure or regeneration.

  3. Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease.

    PubMed

    Hoban, Megan D; Orkin, Stuart H; Bauer, Daniel E

    2016-02-18

    Effective medical management for sickle cell disease (SCD) remains elusive. As a prevalent and severe monogenic disorder, SCD has been long considered a logical candidate for gene therapy. Significant progress has been made in moving toward this goal. These efforts have provided substantial insight into the natural regulation of the globin genes and illuminated challenges for genetic manipulation of the hematopoietic system. The initial γ-retroviral vectors, next-generation lentiviral vectors, and novel genome engineering and gene regulation approaches each share the goal of preventing erythrocyte sickling. After years of preclinical studies, several clinical trials for SCD gene therapies are now open. This review focuses on progress made toward achieving gene therapy, the current state of the field, consideration of factors that may determine clinical success, and prospects for future development.

  4. To grow or not to grow: Hair morphogenesis and human genetic hair disorders

    PubMed Central

    Duverger, Olivier; Morasso, Maria I.

    2014-01-01

    Mouse models have greatly helped in elucidating the molecular mechanisms involved in hair formation and regeneration. Recent publications have reviewed the genes involved in mouse hair development based on the phenotype of transgenic, knockout and mutant animal models. While much of this information has been instrumental in determining molecular aspects of human hair development and cycling, mice exhibit a specific pattern of hair morphogenesis and hair distribution throughout the body that cannot be directly correlated to human hair. In this mini-review, we discuss specific aspects of human hair follicle development and present an up-to-date summary of human genetic disorders associated with abnormalities in hair follicle morphogenesis, structure or regeneration. PMID:24361867

  5. Genetic Controls Balancing Excitatory and Inhibitory Synaptogenesis in Neurodevelopmental Disorder Models

    PubMed Central

    Gatto, Cheryl L.; Broadie, Kendal

    2010-01-01

    Proper brain function requires stringent balance of excitatory and inhibitory synapse formation during neural circuit assembly. Mutation of genes that normally sculpt and maintain this balance results in severe dysfunction, causing neurodevelopmental disorders including autism, epilepsy and Rett syndrome. Such mutations may result in defective architectural structuring of synaptic connections, molecular assembly of synapses and/or functional synaptogenesis. The affected genes often encode synaptic components directly, but also include regulators that secondarily mediate the synthesis or assembly of synaptic proteins. The prime example is Fragile X syndrome (FXS), the leading heritable cause of both intellectual disability and autism spectrum disorders. FXS results from loss of mRNA-binding FMRP, which regulates synaptic transcript trafficking, stability and translation in activity-dependent synaptogenesis and plasticity mechanisms. Genetic models of FXS exhibit striking excitatory and inhibitory synapse imbalance, associated with impaired cognitive and social interaction behaviors. Downstream of translation control, a number of specific synaptic proteins regulate excitatory versus inhibitory synaptogenesis, independently or combinatorially, and loss of these proteins is also linked to disrupted neurodevelopment. The current effort is to define the cascade of events linking transcription, translation and the role of specific synaptic proteins in the maintenance of excitatory versus inhibitory synapses during neural circuit formation. This focus includes mechanisms that fine-tune excitation and inhibition during the refinement of functional synaptic circuits, and later modulate this balance throughout life. The use of powerful new genetic models has begun to shed light on the mechanistic bases of excitation/inhibition imbalance for a range of neurodevelopmental disease states. PMID:21423490

  6. Common genetic variants on 5p14.1 associate with autism spectrum disorders

    PubMed Central

    Wang, Kai; Zhang, Haitao; Ma, Deqiong; Bucan, Maja; Glessner, Joseph T.; Abrahams, Brett S.; Salyakina, Daria; Imielinski, Marcin; Bradfield, Jonathan P.; Sleiman, Patrick M. A.; Kim, Cecilia E.; Hou, Cuiping; Frackelton, Edward; Chiavacci, Rosetta; Takahashi, Nagahide; Sakurai, Takeshi; Rappaport, Eric; Lajonchere, Clara M.; Munson, Jeffrey; Estes, Annette; Korvatska, Olena; Piven, Joseph; Sonnenblick, Lisa I.; Retuerto, Ana I. Alvarez; Herman, Edward I.; Dong, Hongmei; Hutman, Ted; Sigman, Marian; Ozonoff, Sally; Klin, Ami; Owley, Thomas; Sweeney, John A.; Brune, Camille W.; Cantor, Rita M.; Bernier, Raphael; Gilbert, John R.; Cuccaro, Michael L.; McMahon, William M.; Miller, Judith; State, Matthew W.; Wassink, Thomas H.; Coon, Hilary; Levy, Susan E.; Schultz, Robert T.; Nurnberger, John I.; Haines, Jonathan L.; Sutcliffe, James S.; Cook, Edwin H.; Minshew, Nancy J.; Buxbaum, Joseph D.; Dawson, Geraldine; Grant, Struan F. A.; Geschwind, Daniel H.; Pericak-Vance, Margaret A.; Schellenberg, Gerard D.; Hakonarson, Hakon

    2009-01-01

    Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10−8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10−8 to 2.1 × 10−10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs. PMID:19404256

  7. Fetal alcohol spectrum disorders and their transmission through genetic and epigenetic mechanisms

    PubMed Central

    Mead, Edward A.; Sarkar, Dipak K.

    2014-01-01

    Fetal alcohol spectrum disorders (FASD) are a group of related conditions that arise from prenatal exposure to maternal consumption of the teratogen, ethanol. It has been estimated that roughly 1% of children in the US suffer from FASD (Sampson etal., 1997), though in some world populations, such as inhabitants of some poorer regions of South Africa, the rate can climb to as high as 20% (May etal., 2013). FASD are the largest cause of mental retardation in U.S. neonates, and ironically, are entirely preventable. FASD have been linked to major changes in the hypothalamic-pituitary-adrenal (HPA) axis, resulting in lifelong impairments through mental disorders, retardation, and sensitivity to stress. FASD are linked to an impaired immune system which consequently leads to an elevated risk of cancer and other diseases. FASD arise from a complex interplay of genetic and epigenetic factors. Here, we review current literature on the topic to tease apart what is known in these areas particularly emphasizing HPA axis dysfunction and how this ties into new studies of transgenerational inheritance in FASD. PMID:24917878

  8. Fetal alcohol spectrum disorders and their transmission through genetic and epigenetic mechanisms.

    PubMed

    Mead, Edward A; Sarkar, Dipak K

    2014-01-01

    Fetal alcohol spectrum disorders (FASD) are a group of related conditions that arise from prenatal exposure to maternal consumption of the teratogen, ethanol. It has been estimated that roughly 1% of children in the US suffer from FASD (Sampson etal., 1997), though in some world populations, such as inhabitants of some poorer regions of South Africa, the rate can climb to as high as 20% (May etal., 2013). FASD are the largest cause of mental retardation in U.S. neonates, and ironically, are entirely preventable. FASD have been linked to major changes in the hypothalamic-pituitary-adrenal (HPA) axis, resulting in lifelong impairments through mental disorders, retardation, and sensitivity to stress. FASD are linked to an impaired immune system which consequently leads to an elevated risk of cancer and other diseases. FASD arise from a complex interplay of genetic and epigenetic factors. Here, we review current literature on the topic to tease apart what is known in these areas particularly emphasizing HPA axis dysfunction and how this ties into new studies of transgenerational inheritance in FASD.

  9. [Perspectives of genetic research in eating disorders using the example of anorexia nervosa].

    PubMed

    Hinney, Anke; Volckmar, Anna-Lena

    2015-01-01

    Genetic mechanisms are relevant for both body weight regulation and eating disorders (e.g. anorexia nervosa, AN). Although genome-wide association studies (GWAS) have so far identified about 100 chromosomal regions that influence body weight, only a small part of the variance could be explained by molecular genetic factors. For AN GWAS up to now did not reveal genome-wide significant loci. There are first hints for epigenetic mechanisms involved in the described phenotypes. Epigenomics can improve our understanding of the regulation of body weight including hunger (AN) and overnutrition (obesity). Since the prenatal phase is characterized by dramatic epigenetic changes, it can be regarded as vulnerable period for the epigenotype. Adult health and disease depend on prenatal and early postnatal development. Gene expression markers that are imprinted during this phase can be heritable at the cellular level. These markers can be altered by environmental factors. Altered epigenetic profiles had been described for obese individuals. In mice it was shown that an epigenetic modification of an obesity gene locus had been transferred to the next generation. The year to come will show whether the combined analysis of epigenomic and GWAS data will deepen our understanding of the underlying biological mechanisms.

  10. Approaches to Managing Autoimmune Cytopenias in Novel Immunological Disorders with Genetic Underpinnings Like Autoimmune Lymphoproliferative Syndrome.

    PubMed

    Rao, V Koneti

    2015-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of apoptosis. It is frequently caused by mutations in FAS (TNFRSF6) gene. Unlike most of the self-limiting autoimmune cytopenias sporadically seen in childhood, multi lineage cytopenias due to ALPS are often refractory, as their inherited genetic defect is not going to go away. Historically, more ALPS patients have died due to overwhelming sepsis following splenectomy to manage their chronic cytopenias than due to any other cause, including malignancies. Hence, current recommendations underscore the importance of avoiding splenectomy in ALPS, by long-term use of corticosteroid-sparing immunosuppressive agents like mycophenolate mofetil and sirolimus. Paradigms learnt from managing ALPS patients in recent years is highlighted here and can be extrapolated to manage refractory cytopenias in patients with as yet undetermined genetic bases for their ailments. It is also desirable to develop international registries for children with rare and complex immune problems associated with chronic multilineage cytopenias in order to elucidate their natural history and long-term comorbidities due to the disease and its treatments.

  11. Genetic variation at the TPH2 gene influences impulsivity in addition to eating disorders.

    PubMed

    Slof-Op't Landt, Margarita C T; Bartels, Meike; Middeldorp, Christel M; van Beijsterveldt, Catherina E M; Slagboom, P Eline; Boomsma, Dorret I; van Furth, Eric F; Meulenbelt, Ingrid

    2013-01-01

    Genes are involved in eating disorders (EDs) and self-induced vomiting (SV), a key symptom of different types of EDs. Perfectionism and impulsivity are potential risk factors for EDs. TPH2 (tryptophan hydroxylase 2) SNP rs1473473 was previously associated with anorexia nervosa and EDs characterized by SV. Could perfectionism or impulsivity be underlying the association between rs1473473 and EDs? Genetic association between TPH2 SNP rs1473473 and perfectionism or impulsivity was first evaluated in a random control group (N = 512). The associations obtained in this control group were subsequently tested in a group of patients with an ED (N = 267). The minor allele of rs1473473 (OR = 1.49) was more frequent in impulsive controls, but also in impulsive patients with an ED (OR = 1.83). The largest effect was found in the patients with an ED characterized by SV (OR = 2.51, p = 0.02). Genetic variation at the TPH2 gene appeared to affect impulsivity which, in turn, might predispose to the SV phenotype.

  12. Contributions of endocannabinoid signaling to psychiatric disorders in humans: Genetic and biochemical evidence

    PubMed Central

    Hillard, Cecilia J.; Weinlander, Kenneth M.; Stuhr, Kara L.

    2011-01-01

    The endocannabinoid signaling system is a widespread, neuromodulatory system in brain and is also widely utilized in the periphery to modulate metabolic functions and the immune system. Preclinical data demonstrate that endocannabinoid signaling is an important stress buffer and modulates emotional and cognitive functions. These data suggest the hypothesis that endocannabinoid signaling could be dysfunctional in a number of mental disorders. Genetic polymorphisms in the human genes for two important proteins of the endocannabinoid signaling system, the CB1 cannabinoid receptor (CB1R) and fatty acid amide hydrolase (FAAH), have been explored in the context of normal and pathological conditions. In the case the gene for FAAH, the mechanistic relationships among the common genetic polymorphism, the expression of the FAAH protein and its likely impact on endocannabinoid signaling are understood. However, multiple polymorphisms in the gene for the CB1R occur and are associated with human phenotypic differences without an understanding of the functional relationships among the gene, mRNA, protein and protein function. The endocannabinoid ligands are found in the circulation and several studies have identified changes in their concentrations under various conditions. These data are reviewed for the purpose of generating hypotheses and to encourage further studies in this very interesting and important area. PMID:22123166

  13. Mechanism and evidence of nonsense suppression therapy for genetic eye disorders.

    PubMed

    Richardson, Rose; Smart, Matthew; Tracey-White, Dhani; Webster, Andrew R; Moosajee, Mariya

    2017-02-01

    Between 5 and 70% of genetic disease is caused by in-frame nonsense mutations, which introduce a premature termination codon (PTC) within the disease-causing gene. Consequently, during translation, non-functional or gain-of-function truncated proteins of pathological significance, are formed. Approximately 50% of all inherited retinal disorders have been associated with PTCs, highlighting the importance of novel pharmacological or gene correction therapies in ocular disease. Pharmacological nonsense suppression of PTCs could delineate a therapeutic strategy that treats the mutation in a gene- and disease-independent manner. This approach aims to suppress the fidelity of the ribosome during protein synthesis so that a near-cognate aminoacyl-tRNA, which shares two of the three nucleotides of the PTC, can be inserted into the peptide chain, allowing translation to continue, and a full-length functional protein to be produced. Here we discuss the mechanisms and evidence of nonsense suppression agents, including the small molecule drug ataluren (or PTC124) and next generation 'designer' aminoglycosides, for the treatment of genetic eye disease.

  14. Genetic landscape of T- and NK-cell post-transplant lymphoproliferative disorders

    PubMed Central

    Margolskee, Elizabeth; Jobanputra, Vaidehi; Jain, Preti; Chen, Jinli; Ganapathi, Karthik; Nahum, Odelia; Levy, Brynn; Morscio, Julie; Murty, Vundavalli; Tousseyn, Thomas; Alobeid, Bachir

    2016-01-01

    Post-transplant lymphoproliferative disorders of T- or NK-cell origin (T/NK-PTLD) are rare entities and their genetic basis is unclear. We performed targeted sequencing of 465 cancer-related genes and high-resolution copy number analysis in 17 T-PTLD and 2 NK-PTLD cases. Overall, 377 variants were detected, with an average of 20 variants per case. Mutations of epigenetic modifier genes (TET2, KMT2C, KMT2D, DNMT3A, ARID1B, ARID2, KDM6B, n=11). and inactivation of TP53 by mutation and/or deletion(n=6) were the most frequent alterations, seen across disease subtypes, followed by mutations of JAK/STAT pathway genes (n=5). Novel variants, including mutations in TBX3 (n=3), MED12 (n=3) and MTOR (n=1), were observed as well. High-level microsatellite instability was seen in 1 of 14 (7%) cases, which had a heterozygous PMS2 mutation. Complex copy number changes were detected in 8 of 16 (50%) cases and disease subtype-specific aberrations were also identified. In contrast to B-cell PTLDs, the molecular and genomic alterations observed in T/NK-PTLD appear similar to those reported for peripheral T-cell lymphomas occurring in immunocompetent hosts, which may suggest common genetic mechanisms of lymphoma development. PMID:27203213

  15. Effect of genetic variation in the nicotinic receptor genes on risk for posttraumatic stress disorder

    PubMed Central

    Kimbrel, Nathan A.; Garrett, Melanie E.; Dennis, Michelle F.; Liu, Yutao; Patanam, Ilyas; Ashley-Koc, Allison E.; Hauser, Michael A.; Beckham, Jean C.

    2015-01-01

    The present study examined the association between genetic variation in the nicotinic receptor gene family (CHRNA2, CHRNA3, CHRNA4, CHRNA5, CHRNA6, CHRNA7, CHRNA9, CHRNA10, CHRNB2, CHRNB3, CHRNB4) and the occurrence of posttraumatic stress disorder (PTSD). Clinical interviews were used to diagnose PTSD in 925 non-Hispanic Black (NHB) and 743 non-Hispanic White (NHW) participants. Trauma history and smoking status were assessed with self-report. No significant main effects or single nucleotide polymorphism (SNP) * smoking interactions were observed among NHB participants; however, among NHW participants, a novel association between rs12898919 in the cholinergic receptor nicotinic alpha-5 (CHRNA5) gene and PTSD was observed. No other significant main effects or SNP * smoking interactions were identified among NHW participants. While preliminary, these findings provide continued support for the hypothesis that the CHRNA5 gene is associated with increased risk for PTSD. Limitations of the present study include cross-sectional design, relatively small sample sizes for genetic research, use of self-report to assess smoking status, and use of different methods to diagnose PTSD. Additional research in other samples of trauma-exposed participants is needed to identify the specific functional variant(s) responsible for the association observed between CHRNA5 and PTSD risk in the present study. PMID:26184988

  16. Approaches to Managing Autoimmune Cytopenias in Novel Immunological Disorders with Genetic Underpinnings Like Autoimmune Lymphoproliferative Syndrome

    PubMed Central

    Rao, V. Koneti

    2015-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of apoptosis. It is frequently caused by mutations in FAS (TNFRSF6) gene. Unlike most of the self-limiting autoimmune cytopenias sporadically seen in childhood, multi lineage cytopenias due to ALPS are often refractory, as their inherited genetic defect is not going to go away. Historically, more ALPS patients have died due to overwhelming sepsis following splenectomy to manage their chronic cytopenias than due to any other cause, including malignancies. Hence, current recommendations underscore the importance of avoiding splenectomy in ALPS, by long-term use of corticosteroid-sparing immunosuppressive agents like mycophenolate mofetil and sirolimus. Paradigms learnt from managing ALPS patients in recent years is highlighted here and can be extrapolated to manage refractory cytopenias in patients with as yet undetermined genetic bases for their ailments. It is also desirable to develop international registries for children with rare and complex immune problems associated with chronic multilineage cytopenias in order to elucidate their natural history and long-term comorbidities due to the disease and its treatments. PMID:26258116

  17. Do nightmares and generalized anxiety disorder in childhood and adolescence have a common genetic origin?

    PubMed

    Coolidge, Frederick L; Segal, Daniel L; Coolidge, Christa M; Spinath, Frank M; Gottschling, Juliana

    2010-05-01

    The present study investigated the prevalence and heritability of nightmares and their comorbidity with psychopathology in a sample (N = 1,318) of children, adolescents, and child and adolescent twins ranging in age from 4 to 17 years old. The prevalence of terrible nightmares was estimated to be 6.4%, which is similar to previous studies. There were marginal gender differences in this rate (7.7% for boys; 5.1% in girls), contrary to previous studies that purport higher rates for girls. There was little evidence for prevalence changes across age. Nightmares were highly heritable and attributed to an additive genetic influence (51%) and nonshared environmental effects (49%). There was little evidence for a shared genetic correlation for nightmares and generalized waking anxiety (Overanxious Disorder of Childhood). There was also a substantial and pervasive comorbid psychopathology for those parents who reported Strongly True on Item 59: My child has terrible nightmares on the 200-item parent-as-respondent, Coolidge Personality and Neuropsychological Inventory. Issues in estimating prevalence rates of nightmares were identified.

  18. Symptom dimensions as alternative phenotypes to address genetic heterogeneity in schizophrenia and bipolar disorder.

    PubMed

    Labbe, Aurélie; Bureau, Alexandre; Moreau, Isabel; Roy, Marc-André; Chagnon, Yvon; Maziade, Michel; Merette, Chantal

    2012-11-01

    This study introduces a novel way to use the lifetime ratings of symptoms of psychosis, mania and depression in genetic linkage analysis of schizophrenia (SZ) and bipolar disorder (BP). It suggests using a latent class model developed for family data to define more homogeneous symptom subtypes that are influenced by a smaller number of genes that will thus be more easily detectable. In a two-step approach, we proposed: (i) to form homogeneous clusters of subjects based on the symptom dimensions and (ii) to use the information from these homogeneous clusters in linkage analysis. This framework was applied to a unique SZ and BP sample composed of 1278 subjects from 48 large kindreds from the Eastern Quebec population. The results suggest that our strategy has the power to increase linkage signals previously obtained using the diagnosis as phenotype and allows for a better characterization of the linkage signals. This is the case for a linkage signal, which we formerly obtained in chromosome 13q and enhanced using the dimension mania. The analysis also suggests that the methods may detect new linkage signals not previously uncovered by using diagnosis alone, as in chromosomes 2q (delusion), 15q (bizarre behavior), 7p (anhedonia) and 9q (delusion). In the case of the 15q and 2q region, the results coincide with linkage signals detected in other studies. Our results support the view that dissecting phenotypic heterogeneity by modeling symptom dimensions may provide new insights into the genetics of SZ and BP.

  19. Genetic overlap between personality and risk for disordered gambling: evidence from a national community-based Australian twin study.

    PubMed

    Slutske, Wendy S; Cho, Seung Bin; Piasecki, Thomas M; Martin, Nicholas G

    2013-02-01

    Using data from a large Australian twin sample we examined the extent to which genetic variation in the Big Three personality dimensions (positive emotionality, negative emotionality, and constraint) and their lower-order components explained genetic variation in the risk for disordered gambling (DG) among men and women. Genetic influences contributing to individual differences in normal-range personality traits explained over 40% of the genetic risk for DG, with a larger contribution among women than among men. The largest and most robust contributions came from the higher-order personality dimension of negative emotionality and its two lower-order dimensions of alienation and aggression. Surprisingly, low self-control was associated with the genetic risk for DG only among women, and risk-taking/sensation-seeking did not explain genetic risk for DG in either sex. The results of this study have implications for the causes of comorbidity between DG and other psychiatric disorders, the search for genes associated with DG risk, and the possibility of sex differences in the etiology of DG. Using a broad-band inventory of personality supports the conclusion that there probably is a substantial proportion of genetic variation in DG that cannot be explained by individual differences in personality.

  20. Multiple-trait estimates of genetic parameters for metabolic disease traits, fertility disorders, and their predictors in Canadian Holsteins.

    PubMed

    Jamrozik, J; Koeck, A; Kistemaker, G J; Miglior, F

    2016-03-01

    Producer-recorded health data for metabolic disease traits and fertility disorders on 35,575 Canadian Holstein cows were jointly analyzed with selected indicator traits. Metabolic diseases included clinical ketosis (KET) and displaced abomasum (DA); fertility disorders were metritis (MET) and retained placenta (RP); and disease indicators were fat-to-protein ratio, milk β-hydroxybutyrate, and body condition score (BCS) in the first lactation. Traits in first and later (up to fifth) lactations were treated as correlated in the multiple-trait (13 traits in total) animal linear model. Bayesian methods with Gibbs sampling were implemented for the analysis. Estimates of heritability for disease incidence were low, up to 0.06 for DA in first lactation. Among disease traits, the environmental herd-year variance constituted 4% of the total variance for KET and less for other traits. First- and later-lactation disease traits were genetically correlated (from 0.66 to 0.72) across all traits, indicating different genetic backgrounds for first and later lactations. Genetic correlations between KET and DA were relatively strong and positive (up to 0.79) in both first- and later-lactation cows. Genetic correlations between fertility disorders were slightly lower. Metritis was strongly genetically correlated with both metabolic disease traits in the first lactation only. All other genetic correlations between metabolic and fertility diseases were statistically nonsignificant. First-lactation KET and MET were strongly positively correlated with later-lactation performance for these traits due to the environmental herd-year effect. Indicator traits were moderately genetically correlated (from 0.30 to 0.63 in absolute values) with both metabolic disease traits in the first lactation. Smaller and mostly nonsignificant genetic correlations were among indicators and metabolic diseases in later lactations. The only significant genetic correlations between indicators and fertility

  1. Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing

    PubMed Central

    Jiang, Yong-hui; Yuen, Ryan K.C.; Jin, Xin; Wang, Mingbang; Chen, Nong; Wu, Xueli; Ju, Jia; Mei, Junpu; Shi, Yujian; He, Mingze; Wang, Guangbiao; Liang, Jieqin; Wang, Zhe; Cao, Dandan; Carter, Melissa T.; Chrysler, Christina; Drmic, Irene E.; Howe, Jennifer L.; Lau, Lynette; Marshall, Christian R.; Merico, Daniele; Nalpathamkalam, Thomas; Thiruvahindrapuram, Bhooma; Thompson, Ann; Uddin, Mohammed; Walker, Susan; Luo, Jun; Anagnostou, Evdokia; Zwaigenbaum, Lonnie; Ring, Robert H.; Wang, Jian; Lajonchere, Clara; Wang, Jun; Shih, Andy; Szatmari, Peter; Yang, Huanming; Dawson, Geraldine; Li, Yingrui; Scherer, Stephen W.

    2013-01-01

    Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms. PMID:23849776

  2. Genetic Evidence for Elevated Pathogenicity of Mitochondrial DNA Heteroplasmy in Autism Spectrum Disorder.

    PubMed

    Wang, Yiqin; Picard, Martin; Gu, Zhenglong

    2016-10-01

    Increasing clinical and biochemical evidence implicate mitochondrial dysfunction in the pathophysiology of Autism Spectrum Disorder (ASD), but little is known about the biological basis for this connection. A possible cause of ASD is the genetic variation in the mitochondrial DNA (mtDNA) sequence, which has yet to be thoroughly investigated in large genomic studies of ASD. Here we evaluated mtDNA variation, including the mixture of different mtDNA molecules in the same individual (i.e., heteroplasmy), using whole-exome sequencing data from mother-proband-sibling trios from simplex families (n = 903) where only one child is affected by ASD. We found that heteroplasmic mutations in autistic probands were enriched at non-polymorphic mtDNA sites (P = 0.0015), which were more likely to confer deleterious effects than heteroplasmies at polymorphic mtDNA sites. Accordingly, we observed a ~1.5-fold enrichment of nonsynonymous mutations (P = 0.0028) as well as a ~2.2-fold enrichment of predicted pathogenic mutations (P = 0.0016) in autistic probands compared to their non-autistic siblings. Both nonsynonymous and predicted pathogenic mutations private to probands conferred increased risk of ASD (Odds Ratio, OR[95% CI] = 1.87[1.14-3.11] and 2.55[1.26-5.51], respectively), and their influence on ASD was most pronounced in families with probands showing diminished IQ and/or impaired social behavior compared to their non-autistic siblings. We also showed that the genetic transmission pattern of mtDNA heteroplasmies with high pathogenic potential differed between mother-autistic proband pairs and mother-sibling pairs, implicating developmental and possibly in utero contributions. Taken together, our genetic findings substantiate pathogenic mtDNA mutations as a potential cause for ASD and synergize with recent work calling attention to their unique metabolic phenotypes for diagnosis and treatment of children with ASD.

  3. Genetic Evidence for Elevated Pathogenicity of Mitochondrial DNA Heteroplasmy in Autism Spectrum Disorder

    PubMed Central

    Wang, Yiqin; Picard, Martin; Gu, Zhenglong

    2016-01-01

    Increasing clinical and biochemical evidence implicate mitochondrial dysfunction in the pathophysiology of Autism Spectrum Disorder (ASD), but little is known about the biological basis for this connection. A possible cause of ASD is the genetic variation in the mitochondrial DNA (mtDNA) sequence, which has yet to be thoroughly investigated in large genomic studies of ASD. Here we evaluated mtDNA variation, including the mixture of different mtDNA molecules in the same individual (i.e., heteroplasmy), using whole-exome sequencing data from mother-proband-sibling trios from simplex families (n = 903) where only one child is affected by ASD. We found that heteroplasmic mutations in autistic probands were enriched at non-polymorphic mtDNA sites (P = 0.0015), which were more likely to confer deleterious effects than heteroplasmies at polymorphic mtDNA sites. Accordingly, we observed a ~1.5-fold enrichment of nonsynonymous mutations (P = 0.0028) as well as a ~2.2-fold enrichment of predicted pathogenic mutations (P = 0.0016) in autistic probands compared to their non-autistic siblings. Both nonsynonymous and predicted pathogenic mutations private to probands conferred increased risk of ASD (Odds Ratio, OR[95% CI] = 1.87[1.14–3.11] and 2.55[1.26–5.51], respectively), and their influence on ASD was most pronounced in families with probands showing diminished IQ and/or impaired social behavior compared to their non-autistic siblings. We also showed that the genetic transmission pattern of mtDNA heteroplasmies with high pathogenic potential differed between mother-autistic proband pairs and mother-sibling pairs, implicating developmental and possibly in utero contributions. Taken together, our genetic findings substantiate pathogenic mtDNA mutations as a potential cause for ASD and synergize with recent work calling attention to their unique metabolic phenotypes for diagnosis and treatment of children with ASD. PMID:27792786

  4. Integrating Behavioral Economics and Behavioral Genetics: Delayed Reward Discounting as an Endophenotype for Addictive Disorders

    PubMed Central

    MacKillop, James

    2013-01-01

    Delayed reward discounting is a behavioral economic index of impulsivity, referring to how much an individual devalues a reward based on its delay in time. As a behavioral process that varies considerably across individuals, delay discounting has been studied extensively as a model for self-control, both in the general population and in clinical samples. There is growing interest in genetic influences on discounting and, in particular, the prospect of discounting as an endophenotype for addictive disorders (i.e., a heritable mechanism partially responsible for conferring genetic risk). This review assembles and critiques the evidence supporting this hypothesis. Via numerous cross-sectional studies and a small number of longitudinal studies, there is considerable evidence that impulsive discounting is associated with addictive behavior and appears to play an etiological role. Moreover, there is increasing evidence from diverse methodologies that impulsive delay discounting is temporally stable, heritable, and that elevated levels are present in nonaffected family members. These findings suggest that impulsive discounting meets the criteria for being considered an endophenotype. In addition, recent findings suggest that genetic variation related to dopamine neurotransmission is significantly associated with variability in discounting preferences. A significant caveat, however, is that the literature is modest in some domains and, in others, not all the findings have been supportive or consistent. In addition, important methodological considerations are necessary in future studies. Taken together, although not definitive, there is accumulating support for the hypothesis of impulsive discounting as an endophenotype for addictive behavior and a need for further systematic investigation. PMID:23344986

  5. Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility.

    PubMed

    Skakkebaek, Niels E; Rajpert-De Meyts, Ewa; Buck Louis, Germaine M; Toppari, Jorma; Andersson, Anna-Maria; Eisenberg, Michael L; Jensen, Tina Kold; Jørgensen, Niels; Swan, Shanna H; Sapra, Katherine J; Ziebe, Søren; Priskorn, Lærke; Juul, Anders

    2016-01-01

    It is predicted that Japan and European Union will soon experience appreciable decreases in their populations due to persistently low total fertility rates (TFR) below replacement level (2.1 child per woman). In the United States, where TFR has also declined, there are ethnic differences. Caucasians have rates below replacement, while TFRs among African-Americans and Hispanics are higher. We review possible links between TFR and trends in a range of male reproductive problems, including testicular cancer, disorders of sex development, cryptorchidism, hypospadias, low testosterone levels, poor semen quality, childlessness, changed sex ratio, and increasing demand for assisted reproductive techniques. We present evidence that several adult male reproductive problems arise in utero and are signs of testicular dysgenesis syndrome (TDS). Although TDS might result from genetic mutations, recent evidence suggests that it most often is related to environmental exposures of the fetal testis. However, environmental factors can also affect the adult endocrine system. Based on our review of genetic and environmental factors, we conclude that environmental exposures arising from modern lifestyle, rather than genetics, are the most important factors in the observed trends. These environmental factors might act either directly or via epigenetic mechanisms. In the latter case, the effects of exposures might have an impact for several generations post-exposure. In conclusion, there is an urgent need to prioritize research in reproductive physiology and pathophysiology, particularly in highly industrialized countries facing decreasing populations. We highlight a number of topics that need attention by researchers in human physiology, pathophysiology, environmental health sciences, and demography.

  6. Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility

    PubMed Central

    Skakkebaek, Niels E.; Rajpert-De Meyts, Ewa; Buck Louis, Germaine M.; Toppari, Jorma; Andersson, Anna-Maria; Eisenberg, Michael L.; Jensen, Tina Kold; Jørgensen, Niels; Swan, Shanna H.; Sapra, Katherine J.; Ziebe, Søren; Priskorn, Lærke; Juul, Anders

    2015-01-01

    It is predicted that Japan and European Union will soon experience appreciable decreases in their populations due to persistently low total fertility rates (TFR) below replacement level (2.1 child per woman). In the United States, where TFR has also declined, there are ethnic differences. Caucasians have rates below replacement, while TFRs among African-Americans and Hispanics are higher. We review possible links between TFR and trends in a range of male reproductive problems, including testicular cancer, disorders of sex development, cryptorchidism, hypospadias, low testosterone levels, poor semen quality, childlessness, changed sex ratio, and increasing demand for assisted reproductive techniques. We present evidence that several adult male reproductive problems arise in utero and are signs of testicular dysgenesis syndrome (TDS). Although TDS might result from genetic mutations, recent evidence suggests that it most often is related to environmental exposures of the fetal testis. However, environmental factors can also affect the adult endocrine system. Based on our review of genetic and environmental factors, we conclude that environmental exposures arising from modern lifestyle, rather than genetics, are the most important factors in the observed trends. These environmental factors might act either directly or via epigenetic mechanisms. In the latter case, the effects of exposures might have an impact for several generations post-exposure. In conclusion, there is an urgent need to prioritize research in reproductive physiology and pathophysiology, particularly in highly industrialized countries facing decreasing populations. We highlight a number of topics that need attention by researchers in human physiology, pathophysiology, environmental health sciences, and demography. PMID:26582516

  7. Genetic and epigenetic methylation defects and implication of the ERMN gene in autism spectrum disorders.

    PubMed

    Homs, A; Codina-Solà, M; Rodríguez-Santiago, B; Villanueva, C M; Monk, D; Cuscó, I; Pérez-Jurado, L A

    2016-07-12

    Autism spectrum disorders (ASD) are highly heritable and genetically complex conditions. Although highly penetrant mutations in multiple genes have been identified, they account for the etiology of <1/3 of cases. There is also strong evidence for environmental contribution to ASD, which can be mediated by still poorly explored epigenetic modifications. We searched for methylation changes on blood DNA of 53 male ASD patients and 757 healthy controls using a methylomic array (450K Illumina), correlated the variants with transcriptional alterations in blood RNAseq data, and performed a case-control association study of the relevant findings in a larger cohort (394 cases and 500 controls). We found 700 differentially methylated CpGs, most of them hypomethylated in the ASD group (83.9%), with cis-acting expression changes at 7.6% of locations. Relevant findings included: (1) hypomethylation caused by rare genetic variants (meSNVs) at six loci (ERMN, USP24, METTL21C, PDE10A, STX16 and DBT) significantly associated with ASD (q-value <0.05); and (2) clustered epimutations associated to transcriptional changes in single-ASD patients (n=4). All meSNVs and clustered epimutations were inherited from unaffected parents. Resequencing of the top candidate genes also revealed a significant load of deleterious mutations affecting ERMN in ASD compared with controls. Our data indicate that inherited methylation alterations detectable in blood DNA, due to either genetic or epigenetic defects, can affect gene expression and contribute to ASD susceptibility most likely in an additive manner, and implicate ERMN as a novel ASD gene.

  8. Understanding the Covariation among Childhood Externalizing Symptoms: Genetic and Environmental Influences on Conduct Disorder, Attention Deficit Hyperactivity Disorder, and Oppositional Defiant Disorder Symptoms.

    ERIC Educational Resources Information Center

    Dick, Danielle M.; Viken, Richard J.; Kaprio, Jaakko; Pulkkinen, Lea; Rose, Richard J.

    2005-01-01

    Conduct disorder (CD), attention deficit hyperactivity disorder (ADHD), and oppositional defiant disorder (ODD) are common childhood externalizing disorders that frequently co-occur. However, the causes of their comorbidity are not well understood. To address that question, we analyzed data from >600 Finnish twin pairs, who completed standardized…

  9. Genetic Syndromes, Maternal Diseases and Antenatal Factors Associated with Autism Spectrum Disorders (ASD)

    PubMed Central

    Ornoy, Asher; Weinstein- Fudim, Liza; Ergaz, Zivanit

    2016-01-01

    Autism spectrum disorder (ASD) affecting about 1% of all children is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal, and postnatal etiologies. In addition, ASD is often an important clinical presentation of some well-known genetic syndromes in human. We discuss these syndromes as well as the role of the more important prenatal factors affecting the fetus throughout pregnancy which may also be associated with ASD. Among the genetic disorders we find Fragile X, Rett syndrome, tuberous sclerosis, Timothy syndrome, Phelan–McDermid syndrome, Hamartoma tumor syndrome, Prader-Willi and Angelman syndromes, and a few others. Among the maternal diseases in pregnancy associated with ASD are diabetes mellitus (PGDM and/or GDM), some maternal autoimmune diseases like antiphospholipid syndrome (APLS) with anti-β2GP1 IgG antibodies and thyroid disease with anti-thyroid peroxidase (TPO) antibodies, preeclampsia and some other autoimmune diseases with IgG antibodies that might affect fetal brain development. Other related factors are maternal infections (rubella and CMV with fetal brain injuries, and possibly Influenza with fever), prolonged fever and maternal inflammation, especially with changes in a variety of inflammatory cytokines and antibodies that cross the placenta and affect the fetal brain. Among the drugs are valproic acid, thalidomide, misoprostol, and possibly SSRIs. β2-adrenergic receptor agonists and paracetamol have also lately been associated with increased rate of ASD but the data is too preliminary and inconclusive. Associations were also described with ethanol, cocaine, and possibly heavy metals, heavy smoking, and folic acid deficiency. Recent studies show that heavy exposure to pesticides and air pollution, especially particulate matter < 2.5 and 10 μm in diameter (PM2.5 and PM10) during pregnancy is also associated with ASD. Finally, we have to remember that many of the associations mentioned in this review are

  10. Psychological Factors Associated with Genetic Test Decision-Making among Parents of Children with Autism Spectrum Disorders in Taiwan

    ERIC Educational Resources Information Center

    Xu, Lei; Richman, Alice R.

    2015-01-01

    Making decisions to undergo Autism Spectrum Disorders (ASD) genetic testing can be challenging. It is important to understand how the perceptions of affected individuals might influence testing decision-making. Although evidence has shown that psychological factors are important in predicting testing decisions, affect-type variables have been…

  11. Genetic association studies of glutamate, GABA and related genes in schizophrenia and bipolar disorder: a decade of advance.

    PubMed

    Cherlyn, Suat Ying Tan; Woon, Puay San; Liu, Jian Jun; Ong, Wei Yi; Tsai, Guo Chuan; Sim, Kang

    2010-05-01

    Schizophrenia (SZ) and bipolar disorder (BD) are debilitating neurobehavioural disorders likely influenced by genetic and non-genetic factors and which can be seen as complex disorders of synaptic neurotransmission. The glutamatergic and GABAergic neurotransmission systems have been implicated in both diseases and we have reviewed extensive literature over a decade for evidence to support the association of glutamate and GABA genes in SZ and BD. Candidate-gene based population and family association studies have implicated some ionotrophic glutamate receptor genes (GRIN1, GRIN2A, GRIN2B and GRIK3), metabotropic glutamate receptor genes (such as GRM3), the G72/G30 locus and GABAergic genes (e.g. GAD1 and GABRB2) in both illnesses to varying degrees, but further replication studies are needed to validate these results. There is at present no consensus on specific single nucleotide polymorphisms or haplotypes associated with the particular candidate gene loci in these illnesses. The genetic architecture of glutamate systems in bipolar disorder need to be better studied in view of recent data suggesting an overlap in the genetic aetiology of SZ and BD. There is a pressing need to integrate research platforms in genomics, epistatic models, proteomics, metabolomics, neuroimaging technology and translational studies in order to allow a more integrated understanding of glutamate and GABAergic signalling processes and aberrations in SZ and BD as well as their relationships with clinical presentations and treatment progress over time.

  12. The Genetic Intersection of Neurodevelopmental Disorders and Shared Medical Comorbidities – Relations that Translate from Bench to Bedside

    PubMed Central

    Plummer, Jasmine T.; Gordon, Alexis J.; Levitt, Pat

    2016-01-01

    Most psychiatric disorders are considered neurodevelopmental, and the associated genes often are expressed in tissues outside of the brain. This suggests a biological relatedness with medical co-occurrences that could have broad clinical implications for diagnosis and patient management over a lifetime. A qualitative integration of public data from genetic consortia of psychiatric disorders and medical comorbidities explores the question of whether genetically associated psychiatric illnesses present with co-occurring disturbances can be used to define specific mental–physical health relations. Novel patterns of gene-disorder relations appear with approximately one-third of conservatively defined, consortia-generated candidate risk genes with multiple psychiatric diagnoses. Moreover, nearly as many genes overlap with non-psychiatric phenotypes, including cardiovascular, renal, respiratory, and metabolic disturbances. While the landscape of genetic risk will change as study populations are expanded and biological confirmations accrue, the current relationships suggest that a mostly siloed perspective of gene relatedness to one categorical psychiatric diagnosis is not clinically useful. The future holds the promise that once candidates are fully validated, genome screening and mutation identification will bring more precision for predicting the risk for complex health conditions. Our view is that as genetic data are refined, continuing to decipher a shared pattern of genetic risk for brain and peripheral organ pathophysiology is not simply an academic exercise. Rather, determining relatedness will impact predictions of multifaceted health risks, patient treatment, and management. PMID:27597832

  13. Catabolism of N-glycoproteins in mammalian cells: Molecular mechanisms and genetic disorders related to the processes.

    PubMed

    Suzuki, Tadashi

    2016-10-01

    N-glycans on glycoproteins serve as one of the most important co- and post-translational modifications of proteins, and it has been well established that they play pivotal roles in controlling the physicochemical and/or physiological properties of the carrier proteins. The biosynthetic/processing pathways for N-glycans have been well characterized in mammalian cells. There are, however, issues that remain to be clarified concerning aspects of their degradation. While the molecular mechanism of the lysosomal degradation for N-glycoproteins has been well studied in relation to genetic disorders, which are collectively referred to as lysosomal storage disorders, evidence exists to suggest that there are also "non-lysosomal" degradation processes, which are now known to occur widely in eukaryotic cells. In this review, our current knowledge of the lysosomal/non-lysosomal degradation of N-glycoproteins in mammalian cells, as well as in human genetic disorders caused by the defects of these processes, is reviewed.

  14. Diagnosis of Attention-Deficit/Hyperactivity Disorder and Its Behavioral, Neurological, and Genetic Roots

    ERIC Educational Resources Information Center

    Mueller, Kathryn L.; Tomblin, J. Bruce

    2012-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is a common developmental disorder often associated with other developmental disorders including speech, language, and reading disorders. Here, we review the principal features of ADHD and current diagnostic standards for the disorder. We outline the ADHD subtypes, which are based upon the dimensions…

  15. Brain imaging genetics in ADHD and beyond - mapping pathways from gene to disorder at different levels of complexity.

    PubMed

    Klein, Marieke; Onnink, Marten; van Donkelaar, Marjolein; Wolfers, Thomas; Harich, Benjamin; Shi, Yan; Dammers, Janneke; Arias-Va Squez, Alejandro; Hoogman, Martine; Franke, Barbara

    2017-01-31

    Attention-deficit/hyperactivity disorder (ADHD) is a common and often persistent neurodevelopmental disorder. Beyond gene-finding, neurobiological parameters, such as brain structure, connectivity, and function, have been used to link genetic variation to ADHD symptomatology. We performed a systematic review of brain imaging genetics studies involving 62 ADHD candidate genes in childhood and adult ADHD cohorts. Fifty-one eligible research articles described studies of 13 ADHD candidate genes. Almost exclusively, single genetic variants were studied, mostly focussing on dopamine-related genes. While promising results have been reported, imaging genetics studies are thus far hampered by methodological differences in study design and analysis methodology, as well as limited sample sizes. Beyond reviewing imaging genetics studies, we also discuss the need for complementary approaches at multiple levels of biological complexity and emphasize the importance of combining and integrating findings across levels for a better understanding of biological pathways from gene to disease. These may include multi-modal imaging genetics studies, bioinformatic analyses, and functional analyses of cell and animal models.

  16. Immunodeficiency disorders in horses.

    PubMed

    Crisman, Mark V; Scarratt, W Kent

    2008-08-01

    Immunodeficiencies are characterized as primary (genetic) or secondary (acquired). Primary immunodeficiencies are relatively uncommon; however, clinically, they present a significant challenge to the practitioner, especially if the underlying disorder goes unrecognized. Secondary immunodeficiencies may present at any age, but failure of passive transfer in neonatal foals is most commonly encountered. This article provides a general overview of clinical signs and diagnosis of primary and secondary immunodeficiencies currently recognized in horses.

  17. Social engagement with parents in 11-month-old siblings at high and low genetic risk for autism spectrum disorder.

    PubMed

    Campbell, Susan B; Leezenbaum, Nina B; Mahoney, Amanda S; Day, Taylor N; Schmidt, Emily N

    2015-11-01

    Infant siblings of children with an autism spectrum disorder are at heightened genetic risk to develop autism spectrum disorder. We observed high risk (n = 35) and low risk (n = 27) infants at 11 months during free play with a parent. Children were assessed for autism spectrum disorder in toddlerhood. High-risk infants with a later diagnosis (n = 10) were less socially engaged with their parents than were low-risk infants. Parent behavior during play did not vary by group. Within the high-risk group, ratings of social reciprocity at 11 months predicted Autism Diagnostic Observation Schedule severity scores at follow-up, suggesting that systematic observations of parent-infant play may be a useful addition to early assessments of emerging autism spectrum disorder.

  18. Genetic Background, Adipocytokines, and Metabolic Disorders in Postmenopausal Overweight and Obese Women.

    PubMed

    Grygiel-Górniak, Bogna; Kaczmarek, Elżbieta; Mosor, Maria; Przysławski, Juliusz; Bogacz, Anna

    2016-10-01

    The relationship between the genetic background, adipocytokines, and metabolic state in postmenopausal women has not yet been fully described. The aim of this study was to determine the relationship between PPAR gamma-2 (Pro12Ala, C1431T) and ADRB3 (Trp64Arg) polymorphisms and serum adipocytokines (adiponectin, visfatin, and resistin) and metabolic disorders in 176 postmenopausal women with increased body mass (BMI ≥ 25 kg m(-2)). The distributions of selected alleles and genotype frequencies were determined with the PCR-RFLP method. The bioimpedance method was used to determine nutritional status, and enzyme-linked immunosorbent assays were applied to determine serum concentrations of adipocytokines. Viscerally obese postmenopausal women had higher body mass, body fat content, serum glucose, insulin, total cholesterol, LDL, triglycerides, uric acid, and HOMA-IR and a higher prevalence of the Ala12 allele. In models based on cytokine concentration, higher body mass and glucose concentration (visfatin model, p = 0.008) and higher insulin and triglyceride levels (resistin model, p = 0.002) were observed in visceral fat deposition and this was potentiated by the presence of the T1431 allele. In resistin models, co-existence of Ala12/X polymorphisms with the T1431 allele was associated with higher resistin and triglyceride concentrations (p = 0.045). In postmenopausal women, metabolic parameters are mainly determined by the distribution of body fat, but Ala12/X polymorphism may increase the metabolic disorders and this effect can be enhanced by the T1431 allele.

  19. Oxytocin and Vasopressin Are Dysregulated in Williams Syndrome, a Genetic Disorder Affecting Social Behavior

    PubMed Central

    Dai, Li; Carter, C. Sue; Ying, Jian; Bellugi, Ursula; Pournajafi-Nazarloo, Hossein; Korenberg, Julie R.

    2012-01-01

    The molecular and neural mechanisms regulating human social-emotional behaviors are fundamentally important but largely unknown; unraveling these requires a genetic systems neuroscience analysis of human models. Williams Syndrome (WS), a condition caused by deletion of ∼28 genes, is associated with a gregarious personality, strong drive to approach strangers, difficult peer interactions, and attraction to music. WS provides a unique opportunity to identify endogenous human gene-behavior mechanisms. Social neuropeptides including oxytocin (OT) and arginine vasopressin (AVP) regulate reproductive and social behaviors in mammals, and we reasoned that these might mediate the features of WS. Here we established blood levels of OT and AVP in WS and controls at baseline, and at multiple timepoints following a positive emotional intervention (music), and a negative physical stressor (cold). We also related these levels to standardized indices of social behavior. Results revealed significantly higher median levels of OT in WS versus controls at baseline, with a less marked increase in AVP. Further, in WS, OT and AVP increased in response to music and to cold, with greater variability and an amplified peak release compared to controls. In WS, baseline OT but not AVP, was correlated positively with approach, but negatively with adaptive social behaviors. These results indicate that WS deleted genes perturb hypothalamic-pituitary release not only of OT but also of AVP, implicating more complex neuropeptide circuitry for WS features and providing evidence for their roles in endogenous regulation of human social behavior. The data suggest a possible biological basis for amygdalar involvement, for increased anxiety, and for the paradox of increased approach