The National Stroke Strategy - is it achievable?

PubMed

Reid, T D; Finney, L J; Hedges, A R

2009-11-01

Timing of intervention in symptomatic carotid disease is critical. The UK Department of Health's National Stroke Strategy published in December 2007 recommends urgent carotid intervention within 48 h, in appropriate patients, who have suffered a transient ischaemic attack (TIA), amaurosis fugax or minor stroke. Despite the running of a rapid-access clinic for patients with symptoms of TIA, the time from symptom to surgery is rarely less than 2 weeks. To date, there has been little published research on the UK public response to the symptoms of TIA, and no study at all of the response of primary care to such patients. The aim of this study was to ascertain both these responses to see whether a 48-h target is achievable. A total of 402 men attending our aortic aneurysm screening sessions were asked to complete a questionnaire requesting their most likely response to an episode of amaurosis fugax or TIA. All 45 GP practices in the hospital catchment area were asked how they would respond to patients requesting to be seen with the symptoms used in the questionnaire. Nearly one in six patients would ignore the symptom unless it recurred, approximately half would request a GP appointment and a third would see an optician if they had amaurosis fugax. The mean waiting time to see a GP was 2 days for a routine appointment and within 24 h for an emergency appointment. It is clear that a significant number of people would ignore the first symptom of carotid ischaemia; for those with amaurosis fugax, nearly a third would initially seek help from their optician. Those given a routine GP appointment would have to wait a minimum of 2 days. If the Department of Health is serious about reducing the incidence of stroke and introducing a target of 48 h from symptom to treatment, then there needs to be a wide-spread public and healthcare education programme, in particular alerting opticians and GP receptionists that these symptoms constitute a medical emergency.

[Gonorrheal proctitis imitating proctalgia fugax].

PubMed

Nechvátal, A; Masek, T; Hoch, J; Hercogová, J

2004-01-01

Proctalgia fugax is usually a source of many diagnostic and therapeutic problems. It is often very difficult to find the cause of the pain. Case-report of a 27-year-old patient who was examined by surgeons on cramp-like pain localized to the rectum. The careful history and laboratory examination confirmed gonorrheal proctitis. She was then successfully treated with ceftriaxon.

Use of botulinum A toxin for proctalgia fugax-a case report of successful treatment.

PubMed

Grigoriou, Marios; Ioannidis, Aristeidis; Kofina, Konstantinia; Efthimiadis, Christoforos

2017-11-01

Proctalgia fugax is considered as intermittent anal pain of unknown etiology; a variety of treatments have been used, without, however, permanent results. Injection of botulinum A toxin is recently suggested as an alternative option. We present the case of a woman presenting proctalgia fugax that was untreatable through other current forms of treatment. After two administrations of botulinum A toxin, 80 units and 100 units each, the patient remained asymptomatic on 8-month follow-up control. Botulinum A toxin injection can reduce internal anal sphincter pressure, leading to relief of symptoms, and seems a promising option with minimal morbidity in cases on proctalgia fugax that does not respond to other current treatments.

Anorectal function and morphology in patients with sporadic proctalgia fugax.

PubMed

Eckardt, V F; Dodt, O; Kanzler, G; Bernhard, G

1996-07-01

The pathophysiology of sporadic proctalgia fugax remains unknown. This study investigates whether patients with this syndrome exhibit alterations in anal function and morphology. Eighteen patients with sporadic proctalgia fugax and 18 sex-matched and age-matched healthy controls were studied. Manometric studies investigated anal resting and squeeze pressures, the rectoanal inhibitory reflex, rectal compliance, and smooth muscle response to edrophonium chloride administration. External and internal sphincter thickness was measured endosonographically. Patients had slightly higher (P = 0.0291) anal resting pressures (65.5 +/- 11.4 mmHg) than controls (56 +/- 9.9 mmHg). However, anal squeeze pressure, sphincter relaxation during rectal distention, and rectal compliance were similar in both groups, and no alterations were detected in external and internal anal sphincter thickness. Edrophonium chloride administration was followed by sharp postrelaxation contractions in two patients, whereas anal function remained unaltered in controls. Acute episodes of proctalgia, which occurred in two patients while under study, were associated with a rise in anal resting tone and an increase in slow wave amplitude. In the resting state, patients with proctalgia fugax have normal anorectal function and morphology. However, they may exhibit a motor abnormality of the anal smooth muscle during an acute attack.

Epicrania Fugax.

PubMed

Cuadrado, María Luz; Guerrero, Angel L; Pareja, Juan A

2016-04-01

Epicrania fugax (EF) is a primary headache of recent description. EF essentially consists of brief paroxysms of pain describing a linear or zigzag trajectory across the surface of one hemicranium, commencing and terminating in the territories of different nerves. The pain of forward EF originates in a particular area of the occipital, parietal or temporal regions and moves anteriorly, whereas the pain of backward EF originates in the frontal area, the eye or the nose and moves posteriorly. Some patients have ocular or nasal autonomic accompaniments, and some have triggers. Between attacks, many patients have continuous or intermittent pain and/or tenderness at the stemming area. Pain frequency is extremely variable and some patients have spontaneous remissions. Preventive therapy is required when the paroxysms are frequent and non-remitting. Neuromodulators, indomethacin, amitryptiline, nerve anesthetic blockades, and trochlear steroid injections have been used in different cases, with partial or complete response.

Paroxysmal anal hyperkinesis: a characteristic feature of proctalgia fugax.

PubMed

Rao, S S; Hatfield, R A

1996-10-01

Proctalgia fugax is a common problem, yet its pathophysiology is poorly understood. The objective was to characterise colorectal disturbances in a paraplegic patient with a 10 year history of proctalgia fugax that began two years after an attack of transverse myelitis. Standard anorectal manometry and prolonged 33 hour ambulatory colonic manometry at six sites in the colon were performed together with myoelectrical recording of the anus. Provocative tests designed to simulate psychological and physical stress and two types of meals were included. Anorectal manometry showed normal internal sphincter tone and normal rectoanal inhibitory reflex but an inability to squeeze or to bear down or to expel a simulated stool. Rectal sensation (up to 360 ml inflation) was absent. Pudendal nerve latency was prolonged (4.5 ms (normal < 2.2 ms). During colonic manometry, the patient reported 27 episodes of pain, of which 23 (85%) were associated with bursts (1-60 min) of a high amplitude (0.5 to > 3.2 mv), high frequency (5-50/min) anal myoelectrical activity, particularly after stress tests, meals, and at night. The myoelectrical disturbance only occurred with proctalgia. Intermittently, 16 bursts of 3 cycles/ min phasic rectal contractions were seen, but only six were associated with proctalgia. Colonic motility was reduced compared with normal subjects. The temporal association between a high amplitude, high frequency myoelectrical activity of the anal sphincter, and the occurrence of proctalgia suggests that paroxysmal hyperkinesis of the anus may cause proctalgia fugax.

Paroxysmal anal hyperkinesis: a characteristic feature of proctalgia fugax.

PubMed Central

Rao, S S; Hatfield, R A

1996-01-01

BACKGROUND AND AIMS: Proctalgia fugax is a common problem, yet its pathophysiology is poorly understood. The objective was to characterise colorectal disturbances in a paraplegic patient with a 10 year history of proctalgia fugax that began two years after an attack of transverse myelitis. METHODS: Standard anorectal manometry and prolonged 33 hour ambulatory colonic manometry at six sites in the colon were performed together with myoelectrical recording of the anus. Provocative tests designed to simulate psychological and physical stress and two types of meals were included. RESULTS: Anorectal manometry showed normal internal sphincter tone and normal rectoanal inhibitory reflex but an inability to squeeze or to bear down or to expel a simulated stool. Rectal sensation (up to 360 ml inflation) was absent. Pudendal nerve latency was prolonged (4.5 ms (normal < 2.2 ms). During colonic manometry, the patient reported 27 episodes of pain, of which 23 (85%) were associated with bursts (1-60 min) of a high amplitude (0.5 to > 3.2 mv), high frequency (5-50/min) anal myoelectrical activity, particularly after stress tests, meals, and at night. The myoelectrical disturbance only occurred with proctalgia. Intermittently, 16 bursts of 3 cycles/ min phasic rectal contractions were seen, but only six were associated with proctalgia. Colonic motility was reduced compared with normal subjects. CONCLUSIONS: The temporal association between a high amplitude, high frequency myoelectrical activity of the anal sphincter, and the occurrence of proctalgia suggests that paroxysmal hyperkinesis of the anus may cause proctalgia fugax. PMID:8944574

[Treatment of proctalgia fugax with botulinum toxin: results in 5 patients].

PubMed

Sánchez Romero, A M; Arroyo Sebastián, A; Pérez Vicente, F A; Serrano Paz, P; Candela Polo, F; Calpena Rico, R

2006-03-01

Proctalgia fugax can be defined as transitory but recurrent anal pain. Although its etiology remains unknown, an internal anal sphincter spasm seems to be the most likely, so that the different treatments focus on reducing the pressure of the internal anal sphincter. This study is aimed at evaluating the effectiveness of botulinum A toxin in the treatment of proctalgia fugax. Prospective clinical trial of patients with proctalgia fugax treated with botulinum A toxin at the Outpatient Clinic attached to the Coloproctogy Unit, University Hospital of Elche, from January 1999 to January 2002. The patients included in the study underwent rectal digital examination, anuscopy, rectoscopy, anal manometry and ultrasonography, barium enema and pelvic CT scan to rule out any organic cause for anal pain. The treatment consisted of 25 IU of botulinum A toxin, with a supplementary dose of 50 IU in those patients with persistence of anal pain episodes within the next two months. The patients were reviewed on the first week, second month, sixth month and first and second year. Anal pain was measured by the patients, using a linear analogue scale from 0 to 10, and continence was assessed at every visit using the Cleveland Continence Grading Scale. Five patients were recluted for the study, with a predominance of females (4 vs. 1). Mean age was 45 years. Length of symptoms prior to the treatment was 13 months (range: 6-18 months). Only one female patient required a second dose of botulinum A toxin to handle the anal pain. All the patients healed and remained free of pain up to finishing the follow-up. There were no local complications. Anal manometry showed an increased MRP (mean resting pressure) in comparison to a control group of patients (114 mmHg vs. 66 mmHg; p < 0.001) that restore to normal values after the treatment (75.65 mmHg). As for the MSP (mean squeeze pressure), it showed no difference with respect to the control group nor did it vary after the treatment. Botulinum A

Annual Research Progress Report. Fiscal Year 2003. Volume’s 1 and 2

DTIC Science & Technology

2003-01-01

transient ischemic attack, amaurosis fugax or stroke in the cerebral distribution of the operated side, 3) the occurrence of criteria for reoperation...Functional Severity and Recovery of Motor Limbs in Acute Brain Injury KEYWORDS: Stroke /Diagnostic assessment. PRINCIPAL INVESTIGATOR: LTC...A Randomized Trial. (1/16/2001) 02-86002 655Knapik, Joseph, PhD DAC. Injury Control and Running Footwear. (3/12/2002) CHPPM 02-98001E

Transcriptomics analysis of the flowering regulatory genes involved in the herbicide resistance of Asia minor bluegrass (Polypogon fugax).

PubMed

Zhou, Fengyan; Zhang, Yong; Tang, Wei; Wang, Mei; Gao, Tongchun

2017-12-06

Asia minor bluegrass (Polypogon fugax, P. fugax), a weed that is both distributed across China and associated with winter crops, has evolved resistance to acetyl-CoA carboxylase (ACCase) herbicides, but the resistance mechanism remains unclear. The goal of this study was to analyze the transcriptome between resistant and sensitive populations of P. fugax at the flowering stage. Populations resistant and susceptible to clodinafop-propargyl showed distinct transcriptome profiles. A total of 206,041 unigenes were identified; 165,901 unique sequences were annotated using BLASTX alignment databases. Among them, 5904 unigenes were classified into 58 transcription factor families. Nine families were related to the regulation of plant growth and development and to stress responses. Twelve unigenes were differentially expressed between the clodinafop-propargyl-sensitive and clodinafop-propargyl-resistant populations at the early flowering stage; among those unigenes, three belonged to the ABI3VP1, BHLH, and GRAS families, while the remaining nine belonged to the MADS family. Compared with the clodinafop-propargyl-sensitive plants, the resistant plants exhibited different expression pattern of these 12 unigenes. This study identified differentially expressed unigenes related to ACCase-resistant P. fugax and thus provides a genomic resource for understanding the molecular basis of early flowering.

[Proctalgia fugax. Differential diagnosis and therapy of fleeting anal cramp].

PubMed

Staude, G

1992-05-30

Proctalgia fugax--short-lived anal spasm--is a common, extremely unpleasant, painful condition that occurs completely unexpectedly, often waking the victim at night. Scientific assessment is difficult on account of the functional nature of the condition and its multifactorial genesis. Before the patient is labeled "anal neurotic", however, he/she should be investigated by a specialist. The results of treating the rarely absent pathological organic findings give rise to optimism.

Proctalgia fugax: demographic and clinical characteristics. What every doctor should know from a prospective study of 54 patients.

PubMed

de Parades, Vincent; Etienney, Isabelle; Bauer, Pierre; Taouk, Milad; Atienza, Patrick

2007-06-01

This prospective study was designed to describe a typical attack of proctalgia fugax. Patients were recruited from May 2003 to June 2004. Whatever the reason for consultation, they were systematically asked: "Do you ever suffer intermittent and recurring anorectal pain lasting for at least three seconds?" If the answer was yes, they were interviewed with a questionnaire and had a proctologic examination. The criterion for proctalgia fugax was a positive answer with a negative examination. The study included 1,809 patients. Fifty-four of these patients (3 percent) had proctalgia fugax and 83 percent of them had never sought medical advice for this problem. The mean age was 51 (range, 18-87) years. Thirty-seven patients were females (69 percent). The onset of pain was sudden and without a trigger factor in 85 percent of cases. Attacks occurred in the daytime (33 percent) as well as at night (35 percent). The pain was described as cramping, spasm-like, or stabbing in 76 percent of cases. It did not radiate in 93 percent of cases. There were no concomitant symptoms in 81 percent of cases. Attacks stopped spontaneously in 67 percent of cases. The average duration was 15 minutes (range, 5 seconds to 90 minutes). The average annual number of attacks was 13 (range, 1-180). Proctalgia fugax affects twice as many females as males at approximately aged 50 years. Commonly the roughly once-monthly attack occurs as a sudden pain with no trigger factor, diurnally as often as nocturnally. The nonradiating cramp, spasm, or stabbing pain, without concomitant symptoms, is most severe on average after 15 minutes and declines spontaneously.

Prevention of Leber congenital amaurosis through preimplantation genetic diagnosis.

PubMed

Kodsi, Sylvia R; Bristow, Sara L; Fox, Joyce E; Hershlag, Avner

2018-06-01

Preimplantation genetic diagnosis can allow a family with a hereditary genetic mutation to conceive a disease-free child. We report the first published case of a child born without Leber congenital amaurosis through preimplantation genetic testing to a couple who had a son with a homozygous mutation in the GUCY2D gene. Copyright © 2018 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.

[Proctalgia Fugax--what's new over the last 100 years?].

PubMed

Amosi, Doron; Werbin, Nachum; Skornick, Yehuda; Greenberg, Ron

2004-05-01

Proctalgia Fugax is a benign, self-limiting disease characterized by episodes of intense pain in the anorectal area occurring at infrequent intervals. It is common, but most suffers do not seek medical advice. Although its classical symptomatology was describe more than a century ago, the etiology is unclear. Theories regarding the etiology have centered on alteration in the internal anal sphincter function and morphology. For most patients after gathering a detailed history, reassurance and warm baths will suffice. In persistent cases therapies that induce internal anal sphincter relaxation are the main treatment modalities.

Intracranial meningioma causing partial amaurosis in a cat.

PubMed

Goulle, Frédéric; Meige, Frédéric; Durieux, Franck; Malet, Christophe; Toulza, Olivier; Isard, Pierre-François; Peiffer, Robert L; Dulaurent, Thomas

2011-09-01

To describe a case of intracranial meningioma causing visual impairment in a cat, successfully treated by surgery. An adult neutered male domestic cat was referred with a 10-month history of progressive visual impairment and altered behavior. Investigations included physical, ophthalmologic and neurological examinations as well as hematology, serum biochemistry and CT scan of the head. The menace response was absent in the left eye and decreased in the right eye. Electroretinograms were normal on both eyes, as was ophthalmic examination, ruling out an ocular cause and allowing a presumptive diagnosis of partial amaurosis due to a post-retinal lesion. CT scan demonstrated a large sessile extra axial mass along the right parietal bone and thickening of the adjacent bone. Cerebrospinal fluid was not collected because high intracranial pressure represented a risk for brain herniation. A right rostrotentorial craniectomy was performed to remove the tumor. Ten days after surgery, vision was improved, neurological examination was normal and normal behavior was restored. Ten months after surgery, ophthalmological examination showed no visual deficit and CT scan did not reveal any sign of recurrence. Advanced imaging techniques allow veterinarians to detect early cerebral diseases and to provide specific treatment when it is possible. In cases of feline amaurosis due to intracranial meningioma, the vital prognosis is good while the visual prognosis is more uncertain, but recovery of normal vision and normal behavior is possible as demonstrated in the present case. © 2011 American College of Veterinary Ophthalmologists.

Anorectal pain and irritation: anal fissure, levator syndrome, proctalgia fugax, and pruritus ani.

PubMed

Vincent, C

1999-03-01

Anal fissures, proctalgia fugax, levator ani syndrome, and pruritus ani are common causes of anorectal pain and irritation. The clinician who obtains a thorough history and performs a complete examination can accurately diagnose these disorders. Ancillary tests seldom are helpful and rarely are necessary. Most patients suffering from these conditions readily respond to conservative therapy provided in the primary care practitioner's office.

Central amaurosis induced by an intraocular, posttraumatic fibrosarcoma in a cat.

PubMed

Barrett, P M; Merideth, R E; Alarcon, F L

1995-01-01

A 12-year-old, castrated male, domestic shorthair cat with a previous penetrating trauma to the left globe which progressed to a phthisical eye presented for acute blindness. Ophthalmic examination and electroretinography of the right eye were found to be normal. Following euthanasia, gross and microscopic examinations were completed. A left intraocular, posttraumatic fibrosarcoma with extension to the optic nerve and chiasm and induced right optic nerve fiber degeneration at the optic chiasm with necrosis leading to central amaurosis were diagnosed.

Hereditary vacuolar internal anal sphincter myopathy causing proctalgia fugax and constipation: a new case contribution.

PubMed

de la Portilla, Fernando; Borrero, Juan José; Rafel, Enrique

2005-03-01

Hereditary anal sphincter myopathy is rare. We present a family with one affected member with proctalgia fugax, constipation and internal anal sphincter hypertrophy. Ultrastructural findings show vacuolization of smooth muscle cells without the characteristic polyglucosan inclusion. Further relief of symptoms was obtained using an oral calcium antagonist. Based on clinical presentation, endosonography and morphological findings, we consider our case is a histological variant of the vacuolar myopathy originally described.

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

PubMed Central

Jonsson, Frida; Burstedt, Marie S; Sandgren, Ola; Norberg, Anna; Golovleva, Irina

2013-01-01

This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C>T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T>C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773+3A>G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors. PMID:23443024

Hereditary proctalgia fugax and constipation: report of a second family.

PubMed Central

Celik, A F; Katsinelos, P; Read, N W; Khan, M I; Donnelly, T C

1995-01-01

A second family with hereditary proctalgia fugax and internal anal sphincter hypertrophy associated with constipation is described. Anorectal ultrasonography, manometry, and sensory tests were conducted in two symptomatic and one asymptomatic subjects within the same family and further clinical information was obtained from other family members. The inheritance would correspond to an autosomal dominant condition with incomplete penetration, presenting after the second decade of life. Physiological studies showed deep, ultraslow waves and an absence of internal anal sphincter relaxation on rectal distension in the two most severely affected family members, suggesting the possibility of a neuropathic origin. Both of these patients had an abnormally high blood pressure. After treatment with a sustained release formulation of the calcium antagonist, nifedipine, their blood pressure returned to normal, anal tone was reduced, and the frequency and intensity of anal pain was suppressed. These together improved the quality of the patients' sleep, which had previously been very troubled because of night time attacks of anal pain. PMID:7737568

Hereditary proctalgia fugax and constipation: report of a second family.

PubMed

Celik, A F; Katsinelos, P; Read, N W; Khan, M I; Donnelly, T C

1995-04-01

A second family with hereditary proctalgia fugax and internal anal sphincter hypertrophy associated with constipation is described. Anorectal ultrasonography, manometry, and sensory tests were conducted in two symptomatic and one asymptomatic subjects within the same family and further clinical information was obtained from other family members. The inheritance would correspond to an autosomal dominant condition with incomplete penetration, presenting after the second decade of life. Physiological studies showed deep, ultraslow waves and an absence of internal anal sphincter relaxation on rectal distension in the two most severely affected family members, suggesting the possibility of a neuropathic origin. Both of these patients had an abnormally high blood pressure. After treatment with a sustained release formulation of the calcium antagonist, nifedipine, their blood pressure returned to normal, anal tone was reduced, and the frequency and intensity of anal pain was suppressed. These together improved the quality of the patients' sleep, which had previously been very troubled because of night time attacks of anal pain.

Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial

PubMed Central

Maguire, Albert M; High, Katherine A; Auricchio, Alberto; Wright, J Fraser; Pierce, Eric A; Testa, Francesco; Mingozzi, Federico; Bennicelli, Jeannette L; Ying, Gui-shuang; Rossi, Settimio; Fulton, Ann; Marshall, Kathleen A; Banfi, Sandro; Chung, Daniel C; Morgan, Jessica IW; Hauck, Bernd; Zelenaia, Olga; Zhu, Xiaosong; Raffini, Leslie; Coppieters, Frauke; De Baere, Elfride; Shindler, Kenneth S; Volpe, Nicholas J; Surace, Enrico M; Acerra, Carmela; Lyubarsky, Arkady; Redmond, T Michael; Stone, Edwin; Sun, Junwei; McDonnell, Jennifer Wellman; Leroy, Bart P; Simonelli, Francesca; Bennett, Jean

2015-01-01

Summary Background Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber’s congenital amaurosis. Methods We assessed the retinal and visual function in 12 patients (aged 8–44 years) with RPE65-associated Leber’s congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1·5×1010 vector genomes), medium (4·8×1010 vector genomes), or high dose (1·5×1011 vector genomes) for up to 2 years. Findings AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477. Interpretation The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain. Funding Center for Cellular and Molecular Therapeutics at the Children’s Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for

Proctalgia fugax, an evidence-based management pathway.

PubMed

Jeyarajah, Santhini; Chow, Andre; Ziprin, Paul; Tilney, Henry; Purkayastha, Sanjay

2010-09-01

Proctalgia fugax (PF) is a benign anorectal condition which has been described in the literature since the nineteenth century commonly presenting to general surgeons. There is little high level evidence on the subject and its therapeutic modalities. We aimed through this systematic literature review to outline the definition and diagnostic criteria of this condition, the aetiology and differential diagnoses and describe the different treatment modalities that have been attempted and their success. A literature search of Google Scholar and Medline using Pubmed as the search engine was used to identify all studies directly related to the definition, aetiology and treatment options for this condition (latest at 12 August 2008) was performed. The search produced 61 references with three others obtained from the references of these papers. The prevalence of PF in the general population ranges from 4% to 18%. The diagnosis is based on the presence of characteristic symptoms as defined by Rome III guidelines and physical examination. The mainstay of treatment is reassurance and careful counselling with evidence in the literature for warm baths, topical treatment with glyceryl trinitrate or diltiazem and salbutamol inhalation. In persistent cases, local anaesthetic blocks, clonidine or Botox injections can be considered after clarification of risk and benefit. Based on this we suggest that diagnosis should be made through exclusion of common organic causes such as haemorrhoids, anal fissure or anorectal carcinoma and on the fulfillment of Rome III criteria. The main treatment for this benign condition remains reassurance and topical treatment.

Safety and Efficacy of Gene Transfer for Leber’s Congenital Amaurosis

PubMed Central

Maguire, Albert M.; Simonelli, Francesca; Pierce, Eric A.; Pugh, Edward N.; Mingozzi, Federico; Bennicelli, Jeannette; Banfi, Sandro; Marshall, Kathleen A.; Testa, Francesco; Surace, Enrico M.; Rossi, Settimio; Lyubarsky, Arkady; Arruda, Valder R.; Konkle, Barbara; Stone, Edwin; Sun, Junwei; Jacobs, Jonathan; Dell’Osso, Lou; Hertle, Richard; Ma, Jian-xing; Redmond, T. Michael; Zhu, Xiaosong; Hauck, Bernd; Zelenaia, Olga; Shindler, Kenneth S.; Maguire, Maureen G.; Wright, J. Fraser; Volpe, Nicholas J.; McDonnell, Jennifer Wellman; Auricchio, Alberto; High, Katherine A.; Bennett, Jean

2010-01-01

SUMMARY Leber’s congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium–specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) (ClinicalTrials.gov number, NCT00516477). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2.hRPE65v2. Each patient had a modest improvement in measures of retinal function on subjective tests of visual acuity. In one patient, an asymptomatic macular hole developed, and although the occurrence was considered to be an adverse event, the patient had some return of retinal function. Although the follow-up was very short and normal vision was not achieved, this study provides the basis for further gene therapy studies in patients with LCA. PMID:18441370

Gene therapy for eye as regenerative medicine? Lessons from RPE65 gene therapy for Leber's Congenital Amaurosis.

PubMed

Rakoczy, Elizabeth P; Narfström, Kristina

2014-11-01

Recombinant virus mediated gene therapy of Leber's Congenital Amaurosis has provided a wide range of data on the utility of gene replacement therapy for recessive diseases. Studies to date demonstrate that gene therapy in the eye is safe and can result in long-term recovery of visual function, but they also highlight that further research is required to identify optimum intervention time-points, target populations and the compatibility of associate therapies. This article is part of a directed issue entitled: Regenerative Medicine: the challenge of translation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Dysthyroid Orbitopathy Presenting with Gaze-Evoked Amaurosis: Case Report and Review of the Literature.

PubMed

Orlans, Harry O; Bremner, Fion D

2015-01-01

Gaze-evoked amaurosis (GEA) describes visual loss associated with eccentric gaze that recovers when the eye is returned to primary position. Here we describe an unusual case of bilateral GEA as the presenting feature of dysthyroid orbitopathy. This is only the third such case to be reported in the literature and the first to feature bilateral GEA in all positions of gaze without accompanying proptosis or ophthalmoplegia. A 50-year-old man who had recently commenced treatment for thyrotoxicosis presented with a 3-week history of typical GEA in both eyes in all positions of gaze. He subsequently developed a bilateral compressive optic neuropathy which was only partially responsive to high dose steroid therapy. Although an uncommon presenting feature of dysthyroid orbitopathy, GEA is an ominous symptom that may precede sight-threatening optic nerve compromise. When present, early immunosuppressive and/or decompressive treatment should be considered.

Internal anal sphincter myopathy causing proctalgia fugax and constipation: further clinical and radiological characterization in a patient.

PubMed

Guy, R J; Kamm, M A; Martin, J E

1997-02-01

We report a case of a distinctive familial internal anal sphincter myopathy with unique histological and radiological features. A 67-year-old woman presented with a 20-year history of proctalgia fugax and outlet obstruction; other family members were similarly affected. Computed tomograpy and magnetic resonance imaging demonstrated a grossly hypertrophied internal anal sphincter. Strip myectomy of the sphincter was carried out with improvement in evacuation but little relief of proctalgia. Further relief of symptoms was obtained using oral and transdermal nitrates and a calcium antagonist. Histological examination of the excised muscle revealed hypertrophy and an abnormal arrangement of fibres in whorls; many fibres contained vacuoles with inclusion bodies positive for periodic acid-Schiff. This description of a specific anal sphincter myopathy illustrates the potential importance of histopathological studies of smooth muscle in functional disorders of the gut.

Autosomal-dominant Leber Congenital Amaurosis Caused by a Heterozygous CRX Mutation in a Father and Son.

PubMed

Arcot Sadagopan, Karthikeyan; Battista, Robert; Keep, Rosanne B; Capasso, Jenina E; Levin, Alex V

2015-06-01

Leber congenital amaurosis (LCA) is most often an autosomal recessive disorder. We report a father and son with autosomal dominant LCA due to a mutation in the CRX gene. DNA screening using an allele specific assay of 90 of the most common LCA-causing variations in the coding sequences of AIPL1, CEP290, CRB1, CRX, GUCY2D, RDH12 and RPE65 was performed on the father. Automated DNA sequencing of his son examining exon 3 of the CRX gene was subsequently performed. Both father and son have a heterozygous single base pair deletion of an adenine at codon 153 in the coding sequence of the CRX gene resulting in a frameshift mutation. Mutations involving the CRX gene may demonstrate an autosomal dominant inheritance pattern for LCA.

[Irritable bowel syndrome, levator ani syndrome, proctalgia fugax and chronic pelvic and perineal pain].

PubMed

Watier, Alain; Rigaud, Jérôme; Labat, Jean-Jacques

2010-11-01

To define functional gastrointestinal pain, irritable bowel syndrome (IBS), levator ani syndrome, proctalgia fugax, the pathophysiology of these syndromes and the treatments that can be proposed. Review of articles published on the theme based on a Medline (PubMed) search and consensus conferences selected according to their scientific relevance. IBS is very common. Patients report abdominal pain and/or discomfort, bloating, and abnormal bowel habit (diarrhoea, constipation or both), in the absence of any structural or biochemical abnormalities. IBS has a complex, multifactorial pathophysiology, involving biological and psychosocial interactions resulting in dysregulation of the brain-gut axis associated with disorders of intestinal motility, hyperalgesia, immune disorders and disorders of the intestinal bacterial microflora and autonomic and hormonal dysfunction. Many treatments have been proposed, ranging from diet to pharmacology and psychotherapy. Patients with various types of chronic pelvic and perineal pain, especially those seen in urology departments, very often report associated IBS. This syndrome is also part of a global and integrated concept of pelviperineal dysfunction, avoiding a rigorous distinction between the posterior segment and the midline and anterior segments of the perineum. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Proctalgia fugax in patients with the irritable bowel, peptic ulcer, or inflammatory bowel disease.

PubMed

Thompson, W G

1984-06-01

One hundred forty-eight patients with gastrointestinal disease, 50 patients with the irritable bowel syndrome (IBS) and 49 each with peptic ulcer and inflammatory bowel disease, were interviewed to determine if they had proctalgia fugax (PF) and if the symptom was associated with the IBS. One-third of the patients had PF. It occurred in 51% of females and 12% of males (p less than 0.001). When corrected for sex, PF was no more prevalent in IBS than in peptic ulcer or inflammatory bowel disease. Only two of six previously described IBS symptoms were more prevalent in the PF patients. Attacks occurred in the day in 94%, and one-third of sufferers related them to defecation. The pain was localized in the anus in 90%, occurred less than five times a year in 51%, and lasted less than 1 min in 57%. In most, activity was not interrupted by this pain and only 20% had ever reported it to a physician. PF is very common among patients with abdominal symptoms, but is not related to the IBS. Since it is infrequent, benign, and transient, PF is usually not mentioned to the physician.

[Evidence of pudendal neuropathy in Proctalgia Fugax: perineal neurophysiological assessment in 55 patients].

PubMed

Damphousse, M; Jousse, M; Verollet, D; Guinet, A; Le Breton, F; Lacroix, P; Sheik Ismael, S; Amarenco, G

2012-04-01

Proctalgia fugax (PF) is a very common condition especially in women. Causes and pathophysiological mechanisms of PF are unknown. Recently, a pudendal neuropathy was clinically suspected in women with PF. The goal of our study was to demonstrate, or not, such abnormalities by means electrophysiological testing. Fifty-five patients with PF (45 female and 10 male, mean age 50.2 years) were evaluated. EMG testing with motor unit potential analysis of pelvic floor muscles (bulbocavernosus muscle and striated external anal sphincter), study of bulbocavernosus reflex and pudendal nerve terminal motor latencies (PNTML) were performed. EMG testing was altered in two males out of 10 (20%) and 29/45 females (64%). In women, denervation was found bilateral in 25/29 (86%). Sacral latency was delayed in eight out of 29 (bilateral in five cases, unilateral in three cases) and PNTML altered in 17 cases (13 bilateral alteration, four unilateral). A significant difference (P<0.002 Chi(2) test) was demonstrated between male and female concerning pelvic floor muscles denervation. Pelvic floor muscles denervation was a common feature in women suffering from PF, due to a stretch bilateral pudendal neuropathy. Distal lesions of the pudendal nerves, principally due to a stretch perineal neuropathy, can be imagined as a factor or co-factor of PF. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Sequential treatment for proctalgia fugax. Mid-term follow-up.

PubMed

Gracia Solanas, J A; Ramírez Rodríguez, J M; Elía Guedea, M; Aguilella Diago, V; Martínez Díez, M

2005-07-01

Proctalgia fugax (PF) is a benign, self-limiting disease characterized by episodes of intense anorectal pain at frequent intervals in the absence of organic proctological disease. Even though PF was described more than a century ago, its etiology remains unclear. Currently there is no information available. Few papers quoting many ways of management have been published. The aim of this study was to investigate patients complaining of this condition and to treat them with sequential therapy. We devised a descriptive, prospective study of patients complaining of acute perianal pain--duration less than 30 minutes--without organic disease or previous perianal surgery since 1996 to 2002 in our Department. We treated these patients using a three-step treatment (1: information, hip bath, benzodiazepines; 2: sublingual nifedipine 10 mg, or topic 0.1% nitroglycerin on demand; 3: internal anal sphincterotomy if hypertrophy of the internal anal sphincter was demonstrated by anal ultrasonography and no improvement was confirmed with the previous steps of treatment). We defined remarkable improvement as a decrease in the number of episodes by half or in pain intensity by 50%. Fifteen patients with an average follow-up of 4 years. Anal endosonography confirmed a grossly thickened internal anal sphincter (IAS) in 5 cases. After the first step of treatment 7 patients improved and 1 patient was cured; after the second step of treatment 3 patients improved and 1 was cured; the third step was applied to 3 patients with a thickened IAS; 1 patient improved and 1 patient was cured. A total resolution of PF is not always possible, but we may improve symptoms and their frequency. Almost 50% of patients in our series improved with the first step of treatment; 30% of our patients had IAS hypertrophy. Anal endosonography can help in the diagnosis of organic diseases or IAS hypertrophy, for which we can perform an internal anal sphincter myectomy.

[Gene therapy for vision restoration in patients with Leber congenital amaurosis (LCA) due to RPE65 gene mutations: beginning the phase IV trial].

PubMed

Chacón-Camacho, Óscar Francisco; Zenteno, Juan Carlos

This is a significant time moment in the field of gene therapy in humans. Recently, results from a phase III clinical trial were published, demonstrating the first gene therapy success for a genetic disease. A clinical trial was carried out in patients suffering a hereditary blindness disease named Leber congenital amaurosis, caused by mutations in the RPE65 gene. Participating subjects received a subretinal injection of the normal RPE65 gene and one year after exhibited a significant improvement in visual acuity. It is expected that this gene therapy treatment will be approved by the FDA and commercialized in the USA in 2017.

Diagnostic application of clinical exome sequencing in Leber congenital amaurosis.

PubMed

Han, Jinu; Rim, John Hoon; Hwang, In Sik; Kim, Jieun; Shin, Saeam; Lee, Seung-Tae; Choi, Jong Rak

2017-01-01

Leber congenital amaurosis (LCA) is a hereditary retinal dystrophy with wide genetic heterogeneity. Next-generation sequencing (NGS) targeting multiple genes can be a good option for the diagnosis of LCA, and we tested a clinical exome panel in patients with LCA. A total of nine unrelated Korean patients with LCA were sequenced using the Illumina TruSight One panel, which targets 4,813 clinically associated genes, followed by confirmation using Sanger sequencing. Patients' clinical information and familial study results were obtained and used for comprehensive interpretation. In all nine patients, we identified pathogenic variations in LCA-associated genes: NMNAT1 (n=3), GUCY2D (n=2), RPGRIP1 (n=2), CRX (n=1), and CEP290 or SPATA7 . Six patients had one or two mutations in accordance with inheritance patterns, all consistent with clinical phenotypes. Two patients had only one pathogenic mutation in recessive genes ( NMNAT1 and RPGRIP1 ), and the clinical features were specific to disorders associated with those genes. Six patients were solved for genetic causes, and it remains unclear for three patients with the clinical exome panel. With subsequent targeted panel sequencing with 113 genes associated with infantile nystagmus syndrome, a likely pathogenic allele in CEP290 was detected in one patient. Interestingly, one pathogenic variant (p.Arg237Cys) in NMNAT1 was present in three patients, and it had a high allele frequency (0.24%) in the general Korean population, suggesting that NMNAT1 could be a major gene responsible for LCA in Koreans. We confirmed that a commercial clinical exome panel can be effectively used in the diagnosis of LCA. Careful interpretation and clinical correlation could promote the successful implementation of clinical exome panels in routine diagnoses of retinal dystrophies, including LCA.

Hereditary internal anal sphincter myopathy causing proctalgia fugax and constipation. A newly identified condition.

PubMed

Kamm, M A; Hoyle, C H; Burleigh, D E; Law, P J; Swash, M; Martin, J E; Nicholls, R J; Northover, J M

1991-03-01

A newly identified myopathy of the internal anal sphincter is described. In the affected family, at least one member from each of five generations had severe proctalgia fugax; onset was usually in the third to fifth decades of life. Three members of the family have been studied in detail. Each had severe pain intermittently during the day and hourly during the night. Constipation was an associated symptom, in particular difficulty with rectal evacuation. Clinically the internal anal sphincter was thickened and of decreased compliance. The maximum anal canal pressure was usually increased with marked ultraslow wave activity. Anal endosonography confirmed a grossly thickened internal anal sphincter. Two patients were treated by internal anal sphincter strip myectomy; one showed marked improvement and one was relieved of the constipation but had only slight improvement of the pain. The hypertrophied muscle in two of the patients showed unique myopathic changes, consisting of vacuolar changes with periodic acid-Schiff-positive polyglycosan bodies in the smooth muscle fibers and increased endomysial fibrosis. In vitro organ-bath studies showed insensitivity of the muscle to noradrenaline, isoprenaline, carbachol, dimethylpiperazinium, and electrical-field stimulation. Immunohistochemical studies for substance P, calcitonin gene-related peptide, galanin, neuropeptide Y, and vasoactive intestinal peptide showed staining in a similar distribution to that in control tissue. A specific autosomal-dominant inherited myopathy of the internal anal sphincter that causes anal pain and constipation has been identified and characterized.

Leber congenital amaurosis associated with Chiari I malformation: Two cases and a review of the literature

PubMed Central

Petraglia, Anthony L.; Chengazi, Harris U.; Chung, Mina M.; Silberstein, Howard J.

2012-01-01

Objective: Leber congenital amaurosis (LCA) is a rare, clinically and genetically heterogeneous disorder characterized by severe loss of vision in the first year of life, affecting approximately 3000 people in the United States. Some LCA patients manifest developmental abnormalities of the central nervous system (CNS) and neuroradiological studies have revealed a variety of cerebral anomalies in association with LCA; however, Chiari I malformations (CMI) have never been described. Case Description: We report two sisters who were referred to the pediatric neurosurgery clinic for evaluation of CMI. The elder sister presented with convergence nystagmus from 3 months of age and magnetic resonance imaging (MRI) demonstrated evidence of significant CMI. Her younger sister began developing nystagmus at 4 months of age. Both had symptomatic progression and underwent suboccipital decompression. Both were subsequently diagnosed with LCA. Case specifics and imaging findings are presented. Conclusions: CMI have been found in association with several genetic syndromes, but not with LCA. These patients represent the first reported cases of CMI with LCA and suggest an additional potential CNS anomaly. The unique occurrence in siblings and the association with another inherited disorder are suggestive of a genetic basis for CMI. PMID:22347674

Severe Loss of Tritan Color Discrimination in RPE65 Associated Leber Congenital Amaurosis

PubMed Central

Kumaran, Neruban; Ripamonti, Caterina; Kalitzeos, Angelos; Rubin, Gary S.; Bainbridge, James W. B.

2018-01-01

Purpose RPE65-associated Leber congenital amaurosis (RPE65-LCA) is a progressive severe retinal dystrophy with early profound dysfunction of rod photoreceptors followed by progressive cone photoreceptor degeneration. We aim to provide detailed information about how cone dysfunction affects color discrimination. Methods Seven adults (aged 16–21) with RPE65-LCA underwent monocular color discrimination assessment using the Trivector and Ellipse versions of three computerized tests: Cambridge Colour Test (CCT), low vision version of the Cambridge Colour Test (lvvCCT), and the Universal Colour Discrimination Test (UCDT). For comparison, subjects were also tested using the American Optical Hardy Rand Rittler (AO-HRR) plates. Each assessment was repeated three times. Results The Trivector version of the tests demonstrated that color discrimination along the tritan axis was undetectable in four subjects, and severely reduced in three subjects. These findings were confirmed by the Ellipse version of the tests. Color discrimination along the protan and deutan axes was evident but reduced in six of seven subjects. Four of seven subjects were unable to read any of the HRR plates. Conclusions The computerized color vision tests adopted in this study provide detailed information about color discrimination in adult RPE65-LCA patients. The condition is associated with severe impairment of color discrimination, particularly along the tritan axis indicating possible early involvement of S-cones, with additional protan and deutan loss to a lesser extent. This psychophysical assessment strategy is likely to be valuable in measuring the impact of therapeutic intervention on cone function. PMID:29332120

Chemical Chaperone TUDCA Preserves Cone Photoreceptors in a Mouse Model of Leber Congenital Amaurosis

PubMed Central

Zhang, Tao; Baehr, Wolfgang; Fu, Yingbin

2012-01-01

Purpose. Mutations in either retinoid isomerase (RPE65) or lecithin-retinol acyltransferase (LRAT) lead to Leber congenital amaurosis (LCA). By using the Lrat–/– mouse model, previous studies have shown that the rapid cone degeneration in LCA was caused by endoplasmic reticulum (ER) stress induced by S-opsin aggregation. The purpose of this study is to examine the efficacy of an ER chemical chaperone, tauroursodeoxycholic acid (TUDCA), in preserving cones in the Lrat–/– model. Methods. Lrat–/– mice were systemically administered with TUDCA and vehicle (0.15 M NaHCO3) every 3 days from P9 to P28. Cone cell survival was determined by counting cone cells on flat-mounted retinas. The expression and subcellular localization of cone-specific proteins were analyzed by western blotting and immunohistochemistry, respectively. Results. TUDCA treatment reduced ER stress and apoptosis in Lrat–/– retina. It significantly slowed down cone degeneration in Lrat–/– mice, resulting in a ∼3-fold increase in cone density in the ventral and central retina as compared with the vehicle-treated mice at P28. Furthermore, TUDCA promoted the degradation of cone membrane–associated proteins by enhancing the ER-associated protein degradation pathway. Conclusions. Systemic injection of TUDCA is effective in reducing ER stress, preventing apoptosis, and preserving cones in Lrat–/– mice. TUDCA has the potential to lead to the development of a new class of therapeutic drugs for treating LCA. PMID:22531707

Long-Term Effect of Gene Therapy on Leber’s Congenital Amaurosis

PubMed Central

Bainbridge, J.W.B.; Mehat, M.S.; Sundaram, V.; Robbie, S.J.; Barker, S.E.; Ripamonti, C.; Georgiadis, A.; Mowat, F.M.; Beattie, S.G.; Gardner, P.J.; Feathers, K.L.; Luong, V.A.; Yzer, S.; Balaggan, K.; Viswanathan, A.; de Ravel, T.J.L.; Casteels, I.; Holder, G.E.; Tyler, N.; Fitzke, F.W.; Weleber, R.G.; Nardini, M.; Moore, A.T.; Thompson, D.A.; Petersen-Jones, S.M.; Michaelides, M.; van den Born, L.I.; Stockman, A.; Smith, A.J.; Rubin, G.; Ali, R.R.

2015-01-01

BACKGROUND Mutations in RPE65 cause Leber’s congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. METHODS We performed a phase 1–2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. RESULTS Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG. CONCLUSIONS Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; ClinicalTrials.gov number, NCT00643747.) PMID:25938638

Mouse Models as Tools to Identify Genetic Pathways for Retinal Degeneration, as Exemplified by Leber's Congenital Amaurosis.

PubMed

Chang, Bo

2016-01-01

Leber's congenital amaurosis (LCA) is an inherited retinal degenerative disease characterized by severe loss of vision in the first year of life. In addition to early vision loss, a variety of other eye-related abnormalities including roving eye movements, deep-set eyes, and sensitivity to bright light also occur with this disease. Many animal models of LCA are available and the study them has led to a better understanding of the pathology of the disease, and has led to the development of therapeutic strategies aimed at curing or slowing down LCA. Mouse models, with their well-developed genetics and similarity to human physiology and anatomy, serve as powerful tools with which to investigate the etiology of human LCA. Such mice provide reproducible, experimental systems for elucidating pathways of normal development, function, designing strategies and testing compounds for translational research and gene-based therapies aimed at delaying the diseases progression. In this chapter, I describe tools used in the discovery and evaluation of mouse models of LCA including a Phoenix Image-Guided Optical Coherence Tomography (OCT) and a Diagnosys Espion Visual Electrophysiology System. Three mouse models are described, the rd3 mouse model for LCA12 and LCA1, the rd12 mouse model for LCA2, and the rd16 mouse model for LCA10.

Plasticity of the human visual system after retinal gene therapy in patients with Leber’s congenital amaurosis

PubMed Central

Ashtari, Manzar; Zhang, Hui; Cook, Philip A.; Cyckowski, Laura L.; Shindler, Kenneth S.; Marshall, Kathleen A.; Aravand, Puya; Vossough, Arastoo; Gee, James C.; Maguire, Albert M.; Baker, Chris I.; Bennett, Jean

2015-01-01

Much of our knowledge of the mechanisms underlying plasticity in the visual cortex in response to visual impairment, vision restoration, and environmental interactions comes from animal studies. We evaluated human brain plasticity in a group of patients with Leber’s congenital amaurosis (LCA), who regained vision through gene therapy. Using non-invasive multimodal neuroimaging methods, we demonstrated that reversing blindness with gene therapy promoted long-term structural plasticity in the visual pathways emanating from the treated retina of LCA patients. The data revealed improvements and normalization along the visual fibers corresponding to the site of retinal injection of the gene therapy vector carrying the therapeutic gene in the treated eye compared to the visual pathway for the untreated eye of LCA patients. After gene therapy, the primary visual pathways (for example, geniculostriate fibers) in the treated retina were similar to those of sighted control subjects, whereas the primary visual pathways of the untreated retina continued to deteriorate. Our results suggest that visual experience, enhanced by gene therapy, may be responsible for the reorganization and maturation of synaptic connectivity in the visual pathways of the treated eye in LCA patients. The interactions between the eye and the brain enabled improved and sustained long-term visual function in patients with LCA after gene therapy. PMID:26180100

Society of vascular surgery vascular registry comparison of carotid artery stenting outcomes for atherosclerotic vs nonatherosclerotic carotid artery disease.

PubMed

White, Rodney A; Sicard, Gregorio A; Zwolak, Robert M; Sidawy, Anton N; Schermerhorn, Marc L; Shackelton, Rebecca J; Siami, Flora Sandra

2010-05-01

The Vascular Registry (VR) on carotid procedures collects long-term outcomes on carotid artery stenting (CAS) and carotid endarterectomy (CEA) patients. The purpose of this report is to describe in-hospital and 30-day CAS outcomes in patients with atherosclerotic carotid artery disease (CAD; atherosclerosis [ATH]) compared to recurrent carotid stenosis (RES) and radiation-induced stenosis (RAD). The VR collects provider-reported data on CAS using a Web-based data management system. For this report, data were analyzed at the preprocedure, procedure, predischarge, and 30-day intervals. As of November 20, 2008, there were 4017 patients with CAS with discharge data, of which 72% were due to ATH. A total of 2321 patients were available for 30-day outcomes analysis (1623 ATH, 529 restenosis, 119 radiation, 17 dissection, 3 trauma, and 30 other). Baseline demographics showed that ATH occurred in older patients (72-years-old), had the greatest history of coronary artery disease (CAD; 62%), myocardial infarction (MI; 24%), valvular heart disease (8%), arrhythmia (16%), congestive heart failure (CHF; 16%), diabetes mellitus (DM; 35%), and chronic obstructive pulmonary disease (COPD; 20%). RES had a higher degree of baseline stenosis (87.0 vs 85.8 ATH; P = .010), were less likely to be symptomatic (35.5% vs 46.3% ATH; P < .001), but had a greater history of hypertension, peripheral vascular disease (PVD), and smoking. RAD was seen in younger patients (66.6 vs 71.7 ATH; P < .001), were more likely to be male (78.2% vs 60.9% ATH; P < .001), and had less comorbidities overall, with the exception of amaurosis fugax, smoking, and cancer. The only statistically significant difference in perioperative rates was in transient ischemic attack (TIA; 2.7% ATH vs 0.9% RES; P = .02). There were no statistically significant differences in in-hospital death/stroke/MI (ATH 5.4%, RES 3.8%, RAD 4.2%) or at 30 days (ATH 7.1%, RES 5.1%, RAD 5.0%). Even after adjusting for age, gender

Variations in NPHP5 in Patients With Nonsyndromic Leber Congenital Amaurosis and Senior-Loken Syndrome

PubMed Central

Stone, Edwin M.; Cideciyan, Artur V.; Aleman, Tomas S.; Scheetz, Todd E.; Sumaroka, Alexander; Ehlinger, Mary A.; Schwartz, Sharon B.; Fishman, Gerald A.; Traboulsi, Elias I.; Lam, Byron L.; Fulton, Anne B.; Mullins, Robert F.; Sheffield, Val C.; Jacobson, Samuel G.

2014-01-01

Objective To investigate whether mutations in NPHP5 can cause Leber congenital amaurosis (LCA) without early-onset renal disease. Methods DNA samples from 276 individuals with non-syndromic LCA were screened for variations in the NPHP5 gene. Each had been previously screened for mutations in 8 known LCA genes without identifying a disease-causing genotype. Results Nine of the 276 LCA probands (3.2%) harbored 2 plausible disease-causing mutations (7 different alleles) in NPHP5. Four of these have been previously reported in patients with Senior-Loken syndrome (F141del, R461X, H506del, and R489X) and 3 are novel (A111del, E346X, and R455X). All 9 patients had severe visual loss from early childhood but none had overt renal disease in the first decade of life. Two patients were diagnosed with nephronophthisis in the second decade. Retinal imaging studies showed retained photoreceptor nuclei and retinal pigment epithelium integrity mainly in the cone-rich central retina, a phenotype with strong similarities to that of NPHP6 disease. Conclusions Mutations in NPHP5 can cause LCA without early-onset renal disease. Abnormalities observed in the photoreceptor outer segments (a cilial structure) may explain the severe visual loss in NPHP5-associated LCA. Clinical Relevance The persistence of central photoreceptor nuclei despite severe visual loss in NPHP5 disease is encouraging for future therapeutic interventions. PMID:21220633

Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions.

PubMed

Kumaran, Neruban; Moore, Anthony T; Weleber, Richard G; Michaelides, Michel

2017-09-01

Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by severe congenital/early infancy visual loss, nystagmus, amaurotic pupils and markedly reduced/absent full-field electroretinograms. The vast genetic heterogeneity of inherited retinal disease has been established over the last 10 - 20 years, with disease-causing variants identified in 25 genes to date associated with LCA/EOSRD, accounting for 70-80% of cases, with thereby more genes yet to be identified. There is now far greater understanding of the structural and functional associations seen in the various LCA/EOSRD genotypes. Subsequent development/characterisation of LCA/EOSRD animal models has shed light on the underlying pathogenesis and allowed the demonstration of successful rescue with gene replacement therapy and pharmacological intervention in multiple models. These advancements have culminated in more than 12 completed, ongoing and anticipated phase I/II and phase III gene therapy and pharmacological human clinical trials. This review describes the clinical and genetic characteristics of LCA/EOSRD and the differential diagnoses to be considered. We discuss in further detail the diagnostic clinical features, pathophysiology, animal models and human treatment studies and trials, in the more common genetic subtypes and/or those closest to intervention. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Plasticity of the human visual system after retinal gene therapy in patients with Leber's congenital amaurosis.

PubMed

Ashtari, Manzar; Zhang, Hui; Cook, Philip A; Cyckowski, Laura L; Shindler, Kenneth S; Marshall, Kathleen A; Aravand, Puya; Vossough, Arastoo; Gee, James C; Maguire, Albert M; Baker, Chris I; Bennett, Jean

2015-07-15

Much of our knowledge of the mechanisms underlying plasticity in the visual cortex in response to visual impairment, vision restoration, and environmental interactions comes from animal studies. We evaluated human brain plasticity in a group of patients with Leber's congenital amaurosis (LCA), who regained vision through gene therapy. Using non-invasive multimodal neuroimaging methods, we demonstrated that reversing blindness with gene therapy promoted long-term structural plasticity in the visual pathways emanating from the treated retina of LCA patients. The data revealed improvements and normalization along the visual fibers corresponding to the site of retinal injection of the gene therapy vector carrying the therapeutic gene in the treated eye compared to the visual pathway for the untreated eye of LCA patients. After gene therapy, the primary visual pathways (for example, geniculostriate fibers) in the treated retina were similar to those of sighted control subjects, whereas the primary visual pathways of the untreated retina continued to deteriorate. Our results suggest that visual experience, enhanced by gene therapy, may be responsible for the reorganization and maturation of synaptic connectivity in the visual pathways of the treated eye in LCA patients. The interactions between the eye and the brain enabled improved and sustained long-term visual function in patients with LCA after gene therapy. Copyright © 2015, American Association for the Advancement of Science.

Reversal of blindness in animal models of leber congenital amaurosis using optimized AAV2-mediated gene transfer.

PubMed

Bennicelli, Jeannette; Wright, John Fraser; Komaromy, Andras; Jacobs, Jonathan B; Hauck, Bernd; Zelenaia, Olga; Mingozzi, Federico; Hui, Daniel; Chung, Daniel; Rex, Tonia S; Wei, Zhangyong; Qu, Guang; Zhou, Shangzhen; Zeiss, Caroline; Arruda, Valder R; Acland, Gregory M; Dell'Osso, Lou F; High, Katherine A; Maguire, Albert M; Bennett, Jean

2008-03-01

We evaluated the safety and efficacy of an optimized adeno-associated virus (AAV; AAV2.RPE65) in animal models of the RPE65 form of Leber congenital amaurosis (LCA). Protein expression was optimized by addition of a modified Kozak sequence at the translational start site of hRPE65. Modifications in AAV production and delivery included use of a long stuffer sequence to prevent reverse packaging from the AAV inverted-terminal repeats, and co-injection with a surfactant. The latter allows consistent and predictable delivery of a given dose of vector. We observed improved electroretinograms (ERGs) and visual acuity in Rpe65 mutant mice. This has not been reported previously using AAV2 vectors. Subretinal delivery of 8.25 x 10(10) vector genomes in affected dogs was well tolerated both locally and systemically, and treated animals showed improved visual behavior and pupillary responses, and reduced nystagmus within 2 weeks of injection. ERG responses confirmed the reversal of visual deficit. Immunohistochemistry confirmed transduction of retinal pigment epithelium cells and there was minimal toxicity to the retina as judged by histopathologic analysis. The data demonstrate that AAV2.RPE65 delivers the RPE65 transgene efficiently and quickly to the appropriate target cells in vivo in animal models. This vector holds great promise for treatment of LCA due to RPE65 mutations.

Reversal of Blindness in Animal Models of Leber Congenital Amaurosis Using Optimized AAV2-mediated Gene Transfer

PubMed Central

Bennicelli, Jeannette; Wright, John Fraser; Komaromy, Andras; Jacobs, Jonathan B; Hauck, Bernd; Zelenaia, Olga; Mingozzi, Federico; Hui, Daniel; Chung, Daniel; Rex, Tonia S; Wei, Zhangyong; Qu, Guang; Zhou, Shangzhen; Zeiss, Caroline; Arruda, Valder R; Acland, Gregory M; Dell’Osso, Lou F; High, Katherine A; Maguire, Albert M; Bennett, Jean

2010-01-01

We evaluated the safety and efficacy of an optimized adeno-associated virus (AAV; AAV2.RPE65) in animal models of the RPE65 form of Leber congenital amaurosis (LCA). Protein expression was optimized by addition of a modified Kozak sequence at the translational start site of hRPE65. Modifications in AAV production and delivery included use of a long stuffer sequence to prevent reverse packaging from the AAV inverted-terminal repeats, and co-injection with a surfactant. The latter allows consistent and predictable delivery of a given dose of vector. We observed improved electroretinograms (ERGs) and visual acuity in Rpe65 mutant mice. This has not been reported previously using AAV2 vectors. Subretinal delivery of 8.25 × 1010 vector genomes in affected dogs was well tolerated both locally and systemically, and treated animals showed improved visual behavior and pupillary responses, and reduced nystagmus within 2 weeks of injection. ERG responses confirmed the reversal of visual deficit. Immunohistochemistry confirmed transduction of retinal pigment epithelium cells and there was minimal toxicity to the retina as judged by histopathologic analysis. The data demonstrate that AAV2.RPE65 delivers the RPE65 transgene efficiently and quickly to the appropriate target cells in vivo in animal models. This vector holds great promise for treatment of LCA due to RPE65 mutations. PMID:18209734

Antisense Oligonucleotide (AON)-based Therapy for Leber Congenital Amaurosis Caused by a Frequent Mutation in CEP290

PubMed Central

Collin, Rob WJ; den Hollander, Anneke I; van der Velde-Visser, Saskia D; Bennicelli, Jeannette; Bennett, Jean; Cremers, Frans PM

2012-01-01

Leber congenital amaurosis (LCA) is the most severe form of inherited retinal degeneration, with an onset in the first year of life. The most frequent mutation that causes LCA, present in at least 10% of individuals with LCA from North-American and Northern-European descent, is an intronic mutation in CEP290 that results in the inclusion of an aberrant exon in the CEP290 mRNA. Here, we describe a genetic therapy approach that is based on antisense oligonucleotides (AONs), small RNA molecules that are able to redirect normal splicing of aberrantly processed pre-mRNA. Immortalized lymphoblastoid cells of individuals with LCA homozygously carrying the intronic CEP290 mutation were transfected with several AONs that target the aberrant exon that is incorporated in the mutant CEP290 mRNA. Subsequent RNA isolation and reverse transcription-PCR analysis revealed that a number of AONs were capable of almost fully redirecting normal CEP290 splicing, in a dose-dependent manner. Other AONs however, displayed no effect on CEP290 splicing at all, indicating that the rescue of aberrant CEP290 splicing shows a high degree of sequence specificity. Together, our data show that AON-based therapy is a promising therapeutic approach for CEP290-associated LCA that warrants future research in animal models to develop a cure for this blinding disease. PMID:23343883

The Protective Effects of Lycium Barbarum Polysaccharides on Transient Retinal Ischemia

PubMed Central

Yang, Di; Li, Suk-Yee; Yeung, Chung-Man; Yu, Wing-Yan; Chang, Raymond Chuen-Chung; So, Kwok-Fai; Wong, David; Lo, Amy C. Y.

2011-01-01

Retinal ischemia/reperfusion (I/R) injury leads to irreversible neuronal death, glial activation, retinal swelling and oxidative stress. It is a common feature in various ocular diseases, such as glaucoma, diabetic retinopathy and amaurosis fugax. In the present study, we aimed to evaluate the effects of Lycium Barbarum Polysaccharides (LBP) in a murine retinal I/R model. Mice were orally treated with either vehicle (PBS) or LBP (1mg/kg) daily for 1 week before induction of retinal ischemia. Retinae were collected after 2 hours ischemia and 22 hours reperfusion. Paraffin-embedded sections were prepared for immunohistochemical analyses. Significantly fewer viable cells were found in vehicle-treated retinae comparing to LBP group. This finding was further confirmed by TUNEL assay where significantly fewer apoptotic cells were identified in LBP-treated retinae. Additionally, retinal swelling induced by retinal I/R injury in the vehicle-treated group was not observed in LBP-treated group. Moreover, intense GFAP immunoreactivity and IgG extravasation were observed in vehicle-treated group but not in LBP treated group. The results showed that pre-treatment with LBP was protective in retinal I/R injury via reducing neuronal death, apoptosis, retinal swelling, GFAP activation and blood vessel leakage. LBP may be used as a preventive agent for retinal ischemia diseases.

Altered Expression of Retinal Molecular Markers in the Canine RPE65 Model of Leber Congenital Amaurosis

PubMed Central

Hernández, Maria; Pearce-Kelling, Susan E.; Rodriguez, F. David; Aguirre, Gustavo D.; Vecino, Elena

2010-01-01

Purpose. Leber congenital amaurosis (LCA) is a group of childhood-onset retinal diseases characterized by severe visual impairment or blindness. One form is caused by mutations in the RPE65 gene, which encodes the retinal pigment epithelium (RPE) isomerase. In this study, the retinal structure and expression of molecular markers for different retinal cell types were characterized, and differences between control and RPE65 mutant dogs during the temporal evolution of the disease were analyzed. Methods. Retinas from normal and mutant dogs of different ages were examined by immunofluorescence with a panel of 16 different antibodies. Results. Cones and rods were preserved in the mutant retinas, and the number of cones was normal. However, there was altered expression of cone arrestin and delocalization of rod opsin. The ON bipolar cells showed sprouting of the dendritic arbors toward the outer nuclear layer (ONL) and retraction of their axons in the inner nuclear layer (INL). A decreased expression of GABA, and an increased expression of intermediate filament glial markers was also found in the mutant retinas. These changes were more evident in the adult than the young mutant retinas. Conclusions. The structure of the retina is well preserved in the mutant retina, but several molecular changes take place in photoreceptors and in bipolar and amacrine cells. Some of these changes are structural, whereas others reflect a change in localization of the examined proteins. This study provides new information that can be applied to the interpretation of outcomes of retinal gene therapy in animal models and humans. PMID:20671290

Comprehensive analysis of genetic variations in strictly-defined Leber congenital amaurosis with whole-exome sequencing in Chinese.

PubMed

Wang, Shi-Yuan; Zhang, Qi; Zhang, Xiang; Zhao, Pei-Quan

2016-01-01

To make a comprehensive analysis of the potential pathogenic genes related with Leber congenital amaurosis (LCA) in Chinese. LCA subjects and their families were retrospectively collected from 2013 to 2015. Firstly, whole-exome sequencing was performed in patients who had underwent gene mutation screening with nothing found, and then homozygous sites was selected, candidate sites were annotated, and pathogenic analysis was conducted using softwares including Sorting Tolerant from Intolerant (SIFT), Polyphen-2, Mutation assessor, Condel, and Functional Analysis through Hidden Markov Models (FATHMM). Furthermore, Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of pathogenic genes were performed followed by co-segregation analysis using Fisher exact Test. Sanger sequencing was used to validate single-nucleotide variations (SNVs). Expanded verification was performed in the rest patients. Totally 51 LCA families with 53 patients and 24 family members were recruited. A total of 104 SNVs (66 LCA-related genes and 15 co-segregated genes) were submitted for expand verification. The frequencies of homozygous mutation of KRT12 and CYP1A1 were simultaneously observed in 3 families. Enrichment analysis showed that the potential pathogenic genes were mainly enriched in functions related to cell adhesion, biological adhesion, retinoid metabolic process, and eye development biological adhesion. Additionally, WFS1 and STAU2 had the highest homozygous frequencies. LCA is a highly heterogeneous disease. Mutations in KRT12, CYP1A1, WFS1, and STAU2 may be involved in the development of LCA.

ACUTE RETINAL ARTERIAL OCCLUSIVE DISORDERS

PubMed Central

Hayreh, Sohan Singh

2011-01-01

The initial section deals with basic sciences; among the various topics briefly discussed are the anatomical features of ophthalmic, central retinal and cilioretinal arteries which may play a role in acute retinal arterial ischemic disorders. Crucial information required in the management of central retinal artery occlusion (CRAO) is the length of time the retina can survive following that. An experimental study shows that CRAO for 97 minutes produces no detectable permanent retinal damage but there is a progressive ischemic damage thereafter, and by 4 hours the retina has suffered irreversible damage. In the clinical section, I discuss at length various controversies on acute retinal arterial ischemic disorders. Classification of acute retinal arterial ischemic disorders These are of 4 types: CRAO, branch retinal artery occlusion (BRAO), cotton wools spots and amaurosis fugax. Both CRAO and BRAO further comprise multiple clinical entities. Contrary to the universal belief, pathogenetically, clinically and for management, CRAO is not one clinical entity but 4 distinct clinical entities – non-arteritic CRAO, non-arteritic CRAO with cilioretinal artery sparing, arteritic CRAO associated with giant cell arteritis (GCA) and transient non-arteritic CRAO. Similarly, BRAO comprises permanent BRAO, transient BRAO and cilioretinal artery occlusion (CLRAO), and the latter further consists of 3 distinct clinical entities - non-arteritic CLRAO alone, non-arteritic CLRAO associated with central retinal vein occlusion and arteritic CLRAO associated with GCA. Understanding these classifications is essential to comprehend fully various aspects of these disorders. Central retinal artery occlusion The pathogeneses, clinical features and management of the various types of CRAO are discussed in detail. Contrary to the prevalent belief, spontaneous improvement in both visual acuity and visual fields does occur, mainly during the first 7 days. The incidence of spontaneous visual

Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement.

PubMed

Cideciyan, Artur V; Jacobson, Samuel G; Beltran, William A; Sumaroka, Alexander; Swider, Malgorzata; Iwabe, Simone; Roman, Alejandro J; Olivares, Melani B; Schwartz, Sharon B; Komáromy, András M; Hauswirth, William W; Aguirre, Gustavo D

2013-02-05

Leber congenital amaurosis (LCA) associated with retinal pigment epithelium-specific protein 65 kDa (RPE65) mutations is a severe hereditary blindness resulting from both dysfunction and degeneration of photoreceptors. Clinical trials with gene augmentation therapy have shown partial reversal of the dysfunction, but the effects on the degeneration are not known. We evaluated the consequences of gene therapy on retinal degeneration in patients with RPE65-LCA and its canine model. In untreated RPE65-LCA patients, there was dysfunction and degeneration of photoreceptors, even at the earliest ages. Examined serially over years, the outer photoreceptor nuclear layer showed progressive thinning. Treated RPE65-LCA showed substantial visual improvement in the short term and no detectable decline from this new level over the long term. However, retinal degeneration continued to progress unabated. In RPE65-mutant dogs, the first one-quarter of their lifespan showed only dysfunction, and there was normal outer photoreceptor nuclear layer thickness retina-wide. Dogs treated during the earlier dysfunction-only stage showed improved visual function and dramatic protection of treated photoreceptors from degeneration when measured 5-11 y later. Dogs treated later during the combined dysfunction and degeneration stage also showed visual function improvement, but photoreceptor loss continued unabated, the same as in human RPE65-LCA. The results suggest that, in RPE65 disease treatment, protection from visual function deterioration cannot be assumed to imply protection from degeneration. The effects of gene augmentation therapy are complex and suggest a need for a combinatorial strategy in RPE65-LCA to not only improve function in the short term but also slow retinal degeneration in the long term.

Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing

PubMed Central

Wang, Xia; Wang, Hui; Sun, Vincent; Tuan, Han-Fang; Keser, Vafa; Wang, Keqing; Ren, Huanan; Lopez, Irma; Zaneveld, Jacques E; Siddiqui, Sorath; Bowles, Stephanie; Khan, Ayesha; Salvo, Jason; Jacobson, Samuel G; Iannaccone, Alessandro; Wang, Feng; Birch, David; Heckenlively, John R; Fishman, Gerald A; Traboulsi, Elias I; Li, Yumei; Wheaton, Dianna; Koenekoop, Robert K; Chen, Rui

2014-01-01

Background Leber congenital amaurosis (LCA) and juvenile retinitis pigmentosa (RP) are inherited retinal diseases that cause early onset severe visual impairment. An accurate molecular diagnosis can refine the clinical diagnosis and allow gene specific treatments. Methods We developed a capture panel that enriches the exonic DNA of 163 known retinal disease genes. Using this panel, we performed targeted next generation sequencing (NGS) for a large cohort of 179 unrelated and prescreened patients with the clinical diagnosis of LCA or juvenile RP. Systematic NGS data analysis, Sanger sequencing validation, and segregation analysis were utilised to identify the pathogenic mutations. Patients were revisited to examine the potential phenotypic ambiguity at the time of initial diagnosis. Results Pathogenic mutations for 72 patients (40%) were identified, including 45 novel mutations. Of these 72 patients, 58 carried mutations in known LCA or juvenile RP genes and exhibited corresponding phenotypes, while 14 carried mutations in retinal disease genes that were not consistent with their initial clinical diagnosis. We revisited patients in the latter case and found that homozygous mutations in PRPH2 can cause LCA/juvenile RP. Guided by the molecular diagnosis, we reclassified the clinical diagnosis in two patients. Conclusions We have identified a novel gene and a large number of novel mutations that are associated with LCA/juvenile RP. Our results highlight the importance of molecular diagnosis as an integral part of clinical diagnosis. PMID:23847139

Comprehensive analysis of genetic variations in strictly-defined Leber congenital amaurosis with whole-exome sequencing in Chinese

PubMed Central

Wang, Shi-Yuan; Zhang, Qi; Zhang, Xiang; Zhao, Pei-Quan

2016-01-01

AIM To make a comprehensive analysis of the potential pathogenic genes related with Leber congenital amaurosis (LCA) in Chinese. METHODS LCA subjects and their families were retrospectively collected from 2013 to 2015. Firstly, whole-exome sequencing was performed in patients who had underwent gene mutation screening with nothing found, and then homozygous sites was selected, candidate sites were annotated, and pathogenic analysis was conducted using softwares including Sorting Tolerant from Intolerant (SIFT), Polyphen-2, Mutation assessor, Condel, and Functional Analysis through Hidden Markov Models (FATHMM). Furthermore, Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of pathogenic genes were performed followed by co-segregation analysis using Fisher exact Test. Sanger sequencing was used to validate single-nucleotide variations (SNVs). Expanded verification was performed in the rest patients. RESULTS Totally 51 LCA families with 53 patients and 24 family members were recruited. A total of 104 SNVs (66 LCA-related genes and 15 co-segregated genes) were submitted for expand verification. The frequencies of homozygous mutation of KRT12 and CYP1A1 were simultaneously observed in 3 families. Enrichment analysis showed that the potential pathogenic genes were mainly enriched in functions related to cell adhesion, biological adhesion, retinoid metabolic process, and eye development biological adhesion. Additionally, WFS1 and STAU2 had the highest homozygous frequencies. CONCLUSION LCA is a highly heterogeneous disease. Mutations in KRT12, CYP1A1, WFS1, and STAU2 may be involved in the development of LCA. PMID:27672588

Venous Thromboembolism and Cerebrovascular Events in Patients with Giant Cell Arteritis: A Population-Based Retrospective Cohort Study

PubMed Central

Crowson, Cynthia S.; Makol, Ashima; Ytterberg, Steven R.; Saitta, Antonino; Salvarani, Carlo; Matteson, Eric L.; Warrington, Kenneth J.

2016-01-01

Objective To investigate the incidence of venous thromboembolism (VTE) and cerebrovascular events in a community-based incidence cohort of patients with giant cell arteritis (GCA) compared to the general population. Methods A population-based inception cohort of patients with incident GCA between January 1, 1950 and December 31, 2009 in Olmsted County, Minnesota and a cohort of non-GCA subjects from the same population were assembled and followed until December 31, 2013. Confirmed VTE and cerebrovascular events were identified through direct medical record review. Results The study population included 244 patients with GCA with a mean ± SD age at diagnosis of 76.2 ± 8.2 years (79% women) and an average length of follow-up of 10.2 ± 6.8 years. Compared to non-GCA subjects of similar age and sex, patients diagnosed with GCA had a higher incidence (%) of amaurosis fugax (cumulative incidence ± SE: 2.1 ± 0.9 versus 0, respectively; p = 0.014) but similar rates of stroke, transient ischemic attack (TIA), and VTE. Among patients with GCA, neither baseline characteristics nor laboratory parameters at diagnosis reliably predicted risk of VTE or cerebrovascular events. Conclusion In this population-based study, the incidence of VTE, stroke and TIA was similar in patients with GCA compared to non-GCA subjects. PMID:26901431

Clinical results of carotid artery stenting versus carotid endarterectomy

PubMed Central

Akinci, Tuba; Derle, Eda; Kibaroğlu, Seda; Harman, Ali; Kural, Feride; Cınar, Pınar; Kilinc, Munire; Akay, Hakki T.; Can, Ufuk; Benli, Ulku S.

2016-01-01

Objective: To review our results of carotid artery stenting (CAS) and carotid endarterectomy (CEA). Methods: We evaluated the medical records of patients undergoing carotid artery revascularization procedure, between 2001 and 2013 in Baskent University Hospital, Ankara, Turkey. Carotid artery stenting or CEA procedures were performed in patients with asymptomatic carotid stenosis (≥70%) or symptomatic stenosis (≥50%). Demographic data, procedural details, and clinical outcomes were recorded. Primary outcome measures were in 30-day stroke/transient ischemic attacks (TIA)/amaurosis fugax or death. Secondary outcome measures were nerve injury, bleeding complications, length of stay in hospital, stroke, restenosis (ICA patency), and all-cause death during long-term follow-up. Results: One hundred ninety-four CEA and 115 CAS procedures were performed for symptomatic and/or asymptomatic carotid artery stenosis. There is no significant differences 30-day mortality and neurologic morbidity between CAS (13%) and CEA procedures (7.7%). Length of stay in hospital were significantly longer in CEA group (p=0.001). In the post-procedural follow up, only in symptomatic patients, restenosis rate was higher in the CEA group (p=.045). The other endpoints did not differ significantly. Conclusions: Endovascular stent treatment of carotid artery atherosclerotic disease is an alternative for vascular surgery, especially for patients that are high risk for standard CEA. The increasing experience, development of cerebral protection systems and new treatment protocols increases CAS feasibility. PMID:27744460

Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families

PubMed Central

Srilekha, Sundaramurthy; Arokiasamy, Tharigopala; Srikrupa, Natarajan N.; Umashankar, Vetrivel; Meenakshi, Swaminathan; Sen, Parveen; Kapur, Suman; Soumittra, Nagasamy

2015-01-01

Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are retinal degenerative diseases which cause severe retinal dystrophy affecting the photoreceptors. LCA is predominantly inherited as an autosomal recessive trait and contributes to 5% of all retinal dystrophies; whereas RP is inherited by all the Mendelian pattern of inheritance and both are leading causes of visual impairment in children and young adults. Homozygosity mapping is an efficient strategy for mapping both known and novel disease loci in recessive conditions, especially in a consanguineous mating, exploiting the fact that the regions adjacent to the disease locus will also be homozygous by descent in such inbred children. Here we have studied eleven consanguineous LCA and one autosomal recessive RP (arRP) south Indian families to know the prevalence of mutations in known genes and also to know the involvement of novel loci, if any. Complete ophthalmic examination was done for all the affected individuals including electroretinogram, fundus photograph, fundus autofluorescence, and optical coherence tomography. Homozygosity mapping using Affymetrix 250K HMA GeneChip on eleven LCA families followed by screening of candidate gene(s) in the homozygous block identified mutations in ten families; AIPL1 – 3 families, RPE65- 2 families, GUCY2D, CRB1, RDH12, IQCB1 and SPATA7 in one family each, respectively. Six of the ten (60%) mutations identified are novel. Homozygosity mapping using Affymetrix 10K HMA GeneChip on the arRP family identified a novel nonsense mutation in MERTK. The mutations segregated within the family and was absent in 200 control chromosomes screened. In one of the eleven LCA families, the causative gene/mutation was not identified but many homozygous blocks were noted indicating that a possible novel locus/gene might be involved. The genotype and phenotype features, especially the fundus changes for AIPL1, RPE65, CRB1, RDH12 genes were as reported earlier. PMID:26147992

Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families.

PubMed

Srilekha, Sundaramurthy; Arokiasamy, Tharigopala; Srikrupa, Natarajan N; Umashankar, Vetrivel; Meenakshi, Swaminathan; Sen, Parveen; Kapur, Suman; Soumittra, Nagasamy

2015-01-01

Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are retinal degenerative diseases which cause severe retinal dystrophy affecting the photoreceptors. LCA is predominantly inherited as an autosomal recessive trait and contributes to 5% of all retinal dystrophies; whereas RP is inherited by all the Mendelian pattern of inheritance and both are leading causes of visual impairment in children and young adults. Homozygosity mapping is an efficient strategy for mapping both known and novel disease loci in recessive conditions, especially in a consanguineous mating, exploiting the fact that the regions adjacent to the disease locus will also be homozygous by descent in such inbred children. Here we have studied eleven consanguineous LCA and one autosomal recessive RP (arRP) south Indian families to know the prevalence of mutations in known genes and also to know the involvement of novel loci, if any. Complete ophthalmic examination was done for all the affected individuals including electroretinogram, fundus photograph, fundus autofluorescence, and optical coherence tomography. Homozygosity mapping using Affymetrix 250K HMA GeneChip on eleven LCA families followed by screening of candidate gene(s) in the homozygous block identified mutations in ten families; AIPL1 - 3 families, RPE65- 2 families, GUCY2D, CRB1, RDH12, IQCB1 and SPATA7 in one family each, respectively. Six of the ten (60%) mutations identified are novel. Homozygosity mapping using Affymetrix 10K HMA GeneChip on the arRP family identified a novel nonsense mutation in MERTK. The mutations segregated within the family and was absent in 200 control chromosomes screened. In one of the eleven LCA families, the causative gene/mutation was not identified but many homozygous blocks were noted indicating that a possible novel locus/gene might be involved. The genotype and phenotype features, especially the fundus changes for AIPL1, RPE65, CRB1, RDH12 genes were as reported earlier.

Molecular genetics of Leber congenital amaurosis in Chinese: New data from 66 probands and mutation overview of 159 probands.

PubMed

Xu, Yan; Xiao, Xueshan; Li, Shiqiang; Jia, Xiaoyun; Xin, Wei; Wang, Panfeng; Sun, Wenmin; Huang, Li; Guo, Xiangming; Zhang, Qingjiong

2016-08-01

Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy. We have previously performed a mutational analysis of the known LCA-associated genes in probands with LCA by both Sanger and whole exome sequencing. In this study, whole exome sequencing was carried out on 66 new probabds with LCA. In conjunction with these data, the present study provides a comprehensive analysis of the spectrum and frequency of all known genes associated with retinal dystrophy in a total of 159 Chinese probands with LCA. The known genes responsible for all forms hereditary retinal dystrophy were included based on information from RetNet. The candidate variants were filtered by bioinformatics analysis and confirmed by Sanger sequencing. Potentially causative mutations were further validated in available family members. Overall, a total of 118 putative pathogenic mutations from 23 genes were identified in 56.6% (90/159) of probands. These mutations were harbored in 13 LCA-associated genes and in ten genes related to other forms of retinal dystrophy. The most frequently mutated gene in probands with LCA was GUCY2D (10.7%, 17/159). A series of mutational analyses suggests that all known genes associated with retinal dystrophy account for 56.6% of Chinese patients with LCA. A comprehensive molecular genetic analysis of Chinese patients with LCA provides an overview of the spectrum and frequency of ethno-specific mutations of all known genes, as well as indications about other unknown genes in the remaining probands who lacked identified mutations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Involvement of LCA5 in Leber congenital amaurosis and retinitis pigmentosa in the Spanish population.

PubMed

Corton, Marta; Avila-Fernandez, Almudena; Vallespín, Elena; López-Molina, María Isabel; Almoguera, Berta; Martín-Garrido, Esther; Tatu, Sorina D; Khan, M Imran; Blanco-Kelly, Fiona; Riveiro-Alvarez, Rosa; Brión, María; García-Sandoval, Blanca; Cremers, Frans P M; Carracedo, Angel; Ayuso, Carmen

2014-01-01

We aimed to identify novel genetic defects in the LCA5 gene underlying Leber congenital amaurosis (LCA) in the Spanish population and to describe the associated phenotype. Case series. A cohort of 217 unrelated Spanish families affected by autosomal recessive or isolated retinal dystrophy, that is, 79 families with LCA and 138 families with early-onset retinitis pigmentosa (EORP). A total of 100 healthy, unrelated Spanish individuals were screened as controls. High-resolution homozygosity mapping was performed in 44 patients with LCA using genome-wide single nucleotide polymorphism (SNP) microarrays. Direct sequencing of the LCA5 gene was performed in 5 patients who showed homozygous regions at chromosome 6 and in 173 unrelated individuals with LCA or EORP. The ophthalmic history of 8 patients carrying LCA5 mutations was reviewed and additional examinations were performed, including electroretinography (ERG), optical coherence tomography (OCT), and fundus photography. Single nucleotide polymorphism genotyping, identity-by-descent (IBD) regions, LCA5 mutations, best-corrected visual acuity, visual field assessments, fundus appearance, ERG, and OCT findings. Four novel and 2 previously reported LCA5 mutations have been identified in 6 unrelated families with LCA by homozygosity mapping or Sanger sequencing. Thus, LCA5 mutations have a frequency of 7.6% in the Spanish population. However, no LCA5 mutations were found in 138 patients with EORP. Although most of the identified LCA5 mutations led to a truncated protein, a likely pathogenic missense variant was identified for the first time as a cause of LCA, segregating in 2 families. We also have characterized a novel splicing site mutation at the RNA level, demonstrating that the mutant LCA5 transcript was absent in a patient. All patients carrying LCA5 mutations presented nystagmus, night blindness, and progressive loss of visual acuity and visual field leading to blindness toward the third decade of life. Fundoscopy

Correlation of calcified carotid plaques detected by panoramic radiograph with risk factors for stroke development.

PubMed

Griniatsos, John; Damaskos, Spyros; Tsekouras, Nikolaos; Klonaris, Chris; Georgopoulos, Sotirios

2009-10-01

The aim was to evaluate whether patients with calcifications in the carotid region detectable by panoramic radiograph differ in the prevalence of risk factors for stroke development compared with those without calcifications. Forty consecutive individuals suffering from proven carotid artery atherosclerotic occlusive disease were submitted to carotid endarterectomy. Seventeen patients were symptomatic at the time of referral, having suffered at least 1 episode of ischemic cerebral event during the preceding 6 months, mainly transient ischemic attacks or amaurosis fugax, and the remaining 23 patients were asymptomatic and the diagnosis was reached during a thorough investigation of coexisting coronary or peripheral vascular disease. Preoperatively, all patients had undergone panoramic radiograph examination, as the presurgical protocol commanded. Based on the panoramic radiograph results, patients in whom calcifications were detected either unilaterally (n = 10) or bilaterally (n = 18) constituted group A (n = 28) and patients in whom no calcifications were detected constituted group B (n = 12) of this study. Univariate analysis among several risk factors for stroke development between the 2 groups of patients disclosed a stastistically significant lower incidence of diabetes mellitus (P = .005) but a higher incidence of symptomatic plaques (P < .030) in the group of patients with detectable calcifications in the panoramic radiograph. Patients with calcified carotid plaques detectable by panoramic radiography are more likely to have suffered cerebrovascular events. Therefore, patients with detectable carotid plaque in panoramic radiographs require referral to their physician for further investigation.

Variogram methods for texture classification of atherosclerotic plaque ultrasound images

NASA Astrophysics Data System (ADS)

Jeromin, Oliver M.; Pattichis, Marios S.; Pattichis, Constantinos; Kyriacou, Efthyvoulos; Nicolaides, Andrew

2006-03-01

Stroke is the third leading cause of death in the western world and the major cause of disability in adults. The type and stenosis of extracranial carotid artery disease is often responsible for ischemic strokes, transient ischemic attacks (TIAs) or amaurosis fugax (AF). The identification and grading of stenosis can be done using gray scale ultrasound scans. The appearance of B-scan pictures containing various granular structures makes the use of texture analysis techniques suitable for computer assisted tissue characterization purposes. The objective of this study is to investigate the usefulness of variogram analysis in the assessment of ultrasound plague morphology. The variogram estimates the variance of random fields, from arbitrary samples in space. We explore stationary random field models based on the variogram, which can be applied in ultrasound plaque imaging leading to a Computer Aided Diagnosis (CAD) system for the early detection of symptomatic atherosclerotic plaques. Non-parametric tests on the variogram coefficients show that the cofficients coming from symptomatic versus asymptomatic plaques come from distinct distributions. Furthermore, we show significant improvement in class separation, when a log point-transformation is applied to the images, prior to variogram estimation. Model fitting using least squares is explored for anisotropic variograms along specific directions. Comparative classification results, show that variogram coefficients can be used for the early detection of symptomatic cases, and also exhibit the largest class distances between symptomatic and asymptomatic plaque images, as compared to over 60 other texture features, used in the literature.

Use of botulinum A toxin for proctalgia fugax—a case report of successful treatment

PubMed Central

Grigoriou, Marios; Ioannidis, Aristeidis; Efthimiadis, Christoforos

2017-01-01

Abstract Proctalgia fugax is considered as intermittent anal pain of unknown etiology; a variety of treatments have been used, without, however, permanent results. Injection of botulinum A toxin is recently suggested as an alternative option. We present the case of a woman presenting proctalgia fugax that was untreatable through other current forms of treatment. After two administrations of botulinum A toxin, 80 units and 100 units each, the patient remained asymptomatic on 8-month follow-up control. Botulinum A toxin injection can reduce internal anal sphincter pressure, leading to relief of symptoms, and seems a promising option with minimal morbidity in cases on proctalgia fugax that does not respond to other current treatments. PMID:29218214

Pharmacological and rAAV Gene Therapy Rescue of Visual Functions in a Blind Mouse Model of Leber Congenital Amaurosis

PubMed Central

Batten, Matthew L; Imanishi, Yoshikazu; Tu, Daniel C; Doan, Thuy; Zhu, Li; Pang, Jijing; Glushakova, Lyudmila; Moise, Alexander R; Baehr, Wolfgang; Van Gelder, Russell N.; Hauswirth, William W; Rieke, Fred; Palczewski, Krzysztof

2005-01-01

Background Leber congenital amaurosis (LCA), a heterogeneous early-onset retinal dystrophy, accounts for ~15% of inherited congenital blindness. One cause of LCA is loss of the enzyme lecithin:retinol acyl transferase (LRAT), which is required for regeneration of the visual photopigment in the retina. Methods and Findings An animal model of LCA, the Lrat −/− mouse, recapitulates clinical features of the human disease. Here, we report that two interventions—intraocular gene therapy and oral pharmacologic treatment with novel retinoid compounds—each restore retinal function to Lrat −/− mice. Gene therapy using intraocular injection of recombinant adeno-associated virus carrying the Lrat gene successfully restored electroretinographic responses to ~50% of wild-type levels (p < 0.05 versus wild-type and knockout controls), and pupillary light responses (PLRs) of Lrat −/− mice increased ~2.5 log units (p < 0.05). Pharmacological intervention with orally administered pro-drugs 9-cis-retinyl acetate and 9-cis-retinyl succinate (which chemically bypass the LRAT-catalyzed step in chromophore regeneration) also caused long-lasting restoration of retinal function in LRAT-deficient mice and increased ERG response from ~5% of wild-type levels in Lrat −/− mice to ~50% of wild-type levels in treated Lrat −/− mice (p < 0.05 versus wild-type and knockout controls). The interventions produced markedly increased levels of visual pigment from undetectable levels to 600 pmoles per eye in retinoid treated mice, and ~1,000-fold improvements in PLR and electroretinogram sensitivity. The techniques were complementary when combined. Conclusion Intraocular gene therapy and pharmacologic bypass provide highly effective and complementary means for restoring retinal function in this animal model of human hereditary blindness. These complementary methods offer hope of developing treatment to restore vision in humans with certain forms of hereditary congenital blindness

Gene therapy using self-complementary Y733F capsid mutant AAV2/8 restores vision in a model of early onset Leber congenital amaurosis.

PubMed

Ku, Cristy A; Chiodo, Vince A; Boye, Sanford L; Goldberg, Andrew F X; Li, Tiansen; Hauswirth, William W; Ramamurthy, Visvanathan

2011-12-01

Defects in the photoreceptor-specific gene aryl hydrocarbon receptor interacting protein-like 1 (Aipl1) are associated with Leber congenital amaurosis (LCA), a childhood blinding disease with early-onset retinal degeneration and vision loss. Furthermore, Aipl1 defects are characterized at the most severe end of the LCA spectrum. The rapid photoreceptor degeneration and vision loss observed in the LCA patient population are mimicked in a mouse model lacking AIPL1. Using this model, we evaluated if gene replacement therapy using recent advancements in adeno-associated viral vectors (AAV) provides advantages in preventing rapid retinal degeneration. Specifically, we demonstrated that the novel self-complementary Y733F capsid mutant AAV2/8 (sc-Y733F-AAV) provided greater preservation of photoreceptors and functional vision in Aipl1 null mice compared with single-stranded AAV2/8. The benefits of sc-Y733F-AAV were evident following viral administration during the active phase of retinal degeneration, where only sc-Y733F-AAV treatment achieved functional vision rescue. This result was likely due to higher and earlier onset of Aipl1 expression. Based on our studies, we conclude that the sc-Y733F-AAV2/8 viral vector, to date, achieves the best rescue for rapid retinal degeneration in Aipl1 null mice. Our results provide important considerations for viral vectors to be used in future gene therapy clinical trials targeting a wider severity spectrum of inherited retinal dystrophies.

[Stroke. are there any difference between patients with or without patent foramen ovale in left atrial appendage systolic function?].

PubMed

Contreras, Alejandro E; Perrote, Federico; Concari, Ignacio; Brenna, Eduardo J; Lucero, Cecilia

2012-01-01

The aim of this study was to evaluate the systolic function of the left atrial appendage (LAA) in a group with and without patent foramen ovale (PFO) who suffered ischemic cerebrovascular events. Between September 2010 and October 2011, 17 patients were referred for transesophageal echocardiography (TEE) after suffering a stroke. PFO was defined as the passage of at least one bubble through atrial septum with bubble test. We compared systolic velocity in the appendage between patients with and without PFO and a control group. Were 8 women and 9 men, mean age 54.1 ± 19.5 years and 8 patients were under 55 years of age. All patients had suffered a ischemic cerebrovascular events, 41.2% had stroke, 52.9% transient ischemic attack and amaurosis fugax 5.9%. In the assessment of TEE, 11.8% had atrial septal aneurysm and 35.3% PFO. Mean LAA systolic velocity was 66.3 ± 20.3 cm / sec. There was no difference in systolic velocity of the LAA between patients with and without PFO (67.5 ± 11.8 cm / sec vs 65.7 ± 24.3 cm / sec respectively, p = 0.87). The control group of 8 patients, 5 women and 3 men, mean age 39.5 ± 18 years, had a LAA systolic velocity of 77.6 ± 28.9 cm / sec, no significant differences with ischemic patients. There were no differences in systolic function of the LAA between patients with and without PFO with ischemic cerebrovascular event.

Do elderly patients call 911 when presented with clinical scenarios suggestive of acute stroke? A cross-sectional study.

PubMed

Caruso, Diego; Perez Akly, Manuel; Costantini, Pablo Daniel; Fridman, Sebastian; Esnaola, Maria Martha

2015-01-01

Among patients with acute stroke symptoms, delay in hospital admission is the main obstacle for the use of thrombolytic therapy and other interventions associated with decreased mortality and disability. The primary aim of this study was to assess whether an elderly clinical population correctly endorsed the response to call for emergency services when presented with signs and symptoms of stroke using a standardized questionnaire. We performed a cross-sectional study among elderly out-patients (≥60 years) in Buenos Aires, Argentina randomly recruited from a government funded health clinic. The correct endorsement of intention to call 911 was assessed with the Stroke Action Test and the cut-off point was set at ≥75%. Knowledge of stroke and clinical and socio-demographic indicators were also collected and evaluated as predictors of correct endorsement using logistic regression. Among 367 elderly adults, 14% correctly endorsed intention to call 911. Presented with the most typical signs and symptoms, only 65% reported that they would call an ambulance. Amaurosis Fugax was the symptom for which was called the least (15%). On average, the correct response was chosen only 37% of the time. Compared to lower levels of education, higher levels were associated to correctly endorsed intention to call 911 (secondary School adjusted OR 3.53, 95% CI 1.59-7.86 and Tertiary/University adjusted OR 3.04, 95% CI 1.12-8.21). These results suggest the need to provide interventions that are specifically designed to increase awareness of potential stroke signs and symptoms and appropriate subsequent clinical actions. © 2015 S. Karger AG, Basel.

Pharmacological Amelioration of Cone Survival and Vision in a Mouse Model for Leber Congenital Amaurosis

PubMed Central

Li, Songhua; Samardzija, Marijana; Yang, Zhihui; Grimm, Christian

2016-01-01

RPE65, an abundant membrane-associate protein in the retinal pigment epithelium (RPE), is a key retinoid isomerase of the visual cycle necessary for generating 11-cis-retinal that functions not only as a molecular switch for activating cone and rod visual pigments in response to light stimulation, but also as a chaperone for normal trafficking of cone opsins to the outer segments. Many mutations in RPE65 are associated with Leber congenital amaurosis (LCA). A R91W substitution, the most frequent LCA-associated mutation, results in a severe decrease in protein level and enzymatic activity of RPE65, causing cone opsin mislocalization and early cone degeneration in the mutation knock-in mouse model of LCA. Here we show that R91W RPE65 undergoes ubiquitination-dependent proteasomal degradation in the knock-in mouse RPE due to misfolding. The 26S proteasome non-ATPase regulatory subunit 13 mediated degradation specifically of misfolded R91W RPE65. The mutation disrupted membrane-association and colocalization of RPE65 with lecithin:retinol acyltransferase (LRAT) that provides the hydrophobic substrate for RPE65. Systemic administration of sodium 4-phenylbutyrate (PBA), a chemical chaperone, increased protein stability, enzymatic activity, membrane-association, and colocalization of R91W RPE65 with LRAT. This rescue effect increased synthesis of 11-cis-retinal and 9-cis-retinal, a functional iso-chromophore of the visual pigments, led to alleviation of S-opsin mislocalization and cone degeneration in the knock-in mice. Importantly, PBA-treatment also improved cone-mediated vision in the mutant mice. These results indicate that PBA, a U.S. Food and Drug Administration-approved safe oral medication, may provide a noninvasive therapeutic intervention that delays daylight vision loss in patients with RPE65 mutations. SIGNIFICANCE STATEMENT LCA is a severe early onset retinal dystrophy. Recent clinical trials of gene therapy have implicated the need of an alternative or

Clinical and genetic findings in a family with NMNAT1-associated Leber congenital amaurosis: case report and review of the literature.

PubMed

Hedergott, A; Volk, A E; Herkenrath, P; Thiele, H; Fricke, J; Altmüller, J; Nürnberg, P; Kubisch, C; Neugebauer, A

2015-12-01

Leber congenital amaurosis (LCA) is a severe retinal dystrophy, typically manifesting in the first year of life. Mutations in more than 18 genes have been reported to date. In recent studies, biallelic mutations in NMNAT1 encoding nicotinamide mononucleotide adenylyltransferase 1 have been found to cause LCA. To broaden the knowledge regarding the phenotype of NMNAT1-associated LCA. Clinical ophthalmologic examinations were performed in two sisters with LCA. Whole exome sequencing was performed in one of the affected girls, with subsequent segregation analysis in the affected sister and unaffected parents. The literature was reviewed for reports of NMNAT1-associated LCA. Exome sequencing revealed the known NMNAT1 mutation c.25G>A (p.Val9Met) in a homozygous state. Segregation analysis showed the same homozygous mutation in the affected younger sister. Both parents were found to be heterozygous carriers of the mutation. The two girls both presented with severe visual impairment, nystagmus, central atrophy of the pigment epithelium, and pigment clumping in the periphery before the age of 6 months. Retinal vessels were attenuated. Both children were hyperopic. In the older sister, differential diagnosis included an inflammatory origin, but electrophysiology in her as well as her sister confirmed a diagnosis of LCA. Pallor of the optic nerve head was not present at birth but developed progressively. We confirmed a diagnosis of NMNAT1-associated LCA in two siblings through identification of the mutation (c.25G>A [p. Val9Met]) in a homozygous state. In infants with non-detectable electroretinogram (ERG), along with severe congenital visual dysfunction or blindness and central pigment epithelium atrophy with pigment clumping resembling scarring due to chorioretinitis, LCA due to NMNAT1 mutations should be considered.

Antisense Oligonucleotide-Based Splicing Correction in Individuals with Leber Congenital Amaurosis due to Compound Heterozygosity for the c.2991+1655A>G Mutation in CEP290.

PubMed

Duijkers, Lonneke; van den Born, L Ingeborgh; Neidhardt, John; Bax, Nathalie M; Pierrache, Laurence H M; Klevering, B Jeroen; Collin, Rob W J; Garanto, Alejandro

2018-03-07

Leber congenital amaurosis (LCA) is a rare inherited retinal disorder affecting approximately 1:50,000 people worldwide. So far, mutations in 25 genes have been associated with LCA, with CEP290 (encoding the Centrosomal protein of 290 kDa) being the most frequently mutated gene. The most recurrent LCA-causing CEP290 mutation, c.2991+1655A>G, causes the insertion of a pseudoexon into a variable proportion of CEP290 transcripts. We previously demonstrated that antisense oligonucleotides (AONs) have a high therapeutic potential for patients homozygously harbouring this mutation, although to date, it is unclear whether rescuing one single allele is enough to restore CEP290 function. Here, we assessed the AON efficacy at RNA, protein and cellular levels in samples that are compound heterozygous for this mutation, together with a protein-truncating mutation in CEP290 . We demonstrate that AONs can efficiently restore splicing and increase protein levels. However, due to a high variability in ciliation among the patient-derived cell lines, the efficacy of the AONs was more difficult to assess at the cellular level. This observation points towards the importance of the severity of the second allele and possibly other genetic variants present in each individual. Overall, AONs seem to be a promising tool to treat CEP290 -associated LCA, not only in homozygous but also in compound heterozygous carriers of the c.2991+1655A>G variant.

Leber Congenital Amaurosis Associated with Mutations in CEP290, Clinical Phenotype, and Natural History in Preparation for Trials of Novel Therapies.

PubMed

Sheck, Leo; Davies, Wayne I L; Moradi, Phillip; Robson, Anthony G; Kumaran, Neruban; Liasis, Alki C; Webster, Andrew R; Moore, Anthony T; Michaelides, Michel

2018-06-01

To investigate and describe in detail the demographics, functional and anatomic characteristics, and clinical course of Leber congenital amaurosis (LCA) associated with mutations in the CEP290 gene (LCA-CEP290) in a large cohort of adults and children. Retrospective case series. Patients with mutations in CEP290 identified at a single UK referral center. Review of case notes and results of retinal imaging (color fundus photography, fundus autofluorescence [FAF] imaging, OCT), electrophysiologic assessment, and molecular genetic testing. Molecular genetic testing, clinical findings including visual acuity and retinal imaging, and electrophysiologic assessment. Forty patients with LCA-CEP290 were identified. The deep intronic mutation c.2991+1655 A>G was the most common disease-causing variant (23/40 patients) identified in the compound heterozygous state in 20 patients (50%) and homozygous in 2 patients (5%). Visual acuity (VA) varied from 6/9 to no perception of light, and only 2 of 12 patients with longitudinal VA data showed deterioration in VA in their better-seeing eye over time. A normal fundus was found at diagnosis in younger patients (mean age, 1.9 years), with older patients showing white flecks (mean age, 5.9 years) or pigmentary retinopathy (mean age, 21.7 years). Eleven of 12 patients (92%) with OCT imaging had preservation of foveal architecture. Ten of 12 patients (83%) with FAF imaging had a perifoveal hyperautofluorescent ring. Having 2 nonsense CEP290 mutations was associated with worse final VA and the presence of nonocular features. Detailed analysis of the clinical phenotype of LCA-CEP290 in a large cohort confirms that there is a window of opportunity in childhood for therapeutic intervention based on relative structural preservation in the central cone-rich retina in a significant proportion of patients, with the majority harboring the deep intronic variant potentially tractable to several planned gene editing approaches. Copyright © 2018

Gene Therapy Rescues Cone Structure and Function in the 3-Month-Old rd12 Mouse: A Model for Midcourse RPE65 Leber Congenital Amaurosis

PubMed Central

Li, Xia; Li, Wensheng; Dai, Xufeng; Kong, Fansheng; Zheng, Qinxiang; Zhou, Xiangtian; Lü, Fan; Chang, Bo; Rohrer, Bärbel; Hauswirth, William. W.; Qu, Jia; Pang, Ji-jing

2011-01-01

Purpose. RPE65 function is necessary in the retinal pigment epithelium (RPE) to generate chromophore for all opsins. Its absence results in vision loss and rapid cone degeneration. Recent Leber congenital amaurosis type 2 (LCA with RPE65 mutations) phase I clinical trials demonstrated restoration of vision on RPE65 gene transfer into RPE cells overlying cones. In the rd12 mouse, a naturally occurring model of RPE65-LCA early cone degeneration was observed; however, some peripheral M-cones remained. A prior study showed that AAV-mediated RPE65 expression can prevent early cone degeneration. The present study was conducted to test whether the remaining cones in older rd12 mice can be rescued. Methods. Subretinal treatment with the scAAV5-smCBA-hRPE65 vector was initiated at postnatal day (P)14 and P90. After 2 months, electroretinograms were recorded, and cone morphology was analyzed by using cone-specific peanut agglutinin and cone opsin–specific antibodies. Results. Cone degeneration started centrally and spread ventrally, with cells losing cone-opsin staining before that for the PNA-lectin–positive cone sheath. Gene therapy starting at P14 resulted in almost wild-type M- and S-cone function and morphology. Delaying gene-replacement rescued the remaining M-cones, and most important, more M-cone opsin–positive cells were identified than were present at the onset of gene therapy, suggesting that opsin expression could be reinitiated in cells with cone sheaths. Conclusions. The results support and extend those of the previous study that gene therapy can stop early cone degeneration, and, more important, they provide proof that delayed treatment can restore the function and morphology of the remaining cones. These results have important implications for the ongoing LCA2 clinical trials. PMID:21169527

Leber Congenital Amaurosis

MedlinePlus

... Campaign to End Blindness Other Ways to Fight Blindness Corporate Support Volunteer Take Action You are here ... become narrow and constricted. A variety of pigmentary (color) changes can also occur in the retinal pigment ...

Functional disorders of the anus and rectum

PubMed Central

Whitehead, W; Wald, A; Diamant, N; Enck, P; Pemberton, J; Rao, S

1999-01-01

In this report the functional anorectal disorders, the etiology of which is currently unknown or related to the abnormal functioning of normally innervated and structurally intact muscles, are discussed. These disorders include functional fecal incontinence, functional anorectal pain, including levator ani syndrome and proctalgia fugax, and pelvic floor dyssynergia. The epidemiology of each disorder is defined and discussed, their pathophysiology is summarized and diagnostic approaches and treatment are suggested. Some suggestions for the direction of future research on these disorders are also given.


Keywords: fecal incontinence; pelvic floor dyssynergia; anismus; proctalgia fugax; levator ani syndrome; constipation; Rome II PMID:10457046

Clinical and genetic characteristics of Leber congenital amaurosis with novel mutations in known genes based on a Chinese eastern coast Han population.

PubMed

Wang, Shiyuan; Zhang, Qi; Zhang, Xiang; Wang, Zhaoyang; Zhao, Peiquan

2016-11-01

To study the genotype-phenotype characteristics of Leber congenital amaurosis (LCA) in the Chinese eastern coast Han population. Children with strictly defined LCA with novel mutations of known LCA genes identified by targeted next-generation sequencing (NGS) and a prediction of pathogenicity (in silico) were included in this study (2013-2015). Mutations were confirmed using Sanger sequencing and segregation analysis. The clinical findings were recorded, including visual function, refractive error, fundus changes, and electroretinograms (ERGs). Spectral-domain optical coherence tomography (SD-OCT) examination, fundus fluorescein angiography (FFA), and ultra-wide field scanning laser ophthalmoscopy (UWF SLO) were performed on children when available. A total of 65 patients underwent NGS for mutation screening and 45 patients were identified as carrying known LCA genes. Of these, 36(80 %) children harbored novel mutations, and they were all from the eastern coast of China. A total of 50 novel variants were identified, which covered 15 known LCA genes. GUCY2D (17 %), CEP290 (14 %), NMNAT1 (14 %), AIPL1 (11 %) and RPGRIP1 (11 %) were the five most frequently mutated genes with novel mutations. A total of four (11 %) patients with AIPL1 mutations harbored the same novel mutated allele (c.C241T p.Q81X), which was homozygous in patients 1 and 2. Unusual manifestations were detected in patient 16 who had novel mutations in CRB1 with a dense proliferative membrane adhering to the posterior retina of the right eye with numerous fine glistening crystals spreading over the retina of both eyes. Ten (40 %) of the 25 available patients who underwent SD-OCT showed a normal macular appearance using fundus photography but an abnormal macular structure using OCT imaging, most of whom presented with a thickened fovea with maldevelopment of the inner and outer retinal laminae. There may be a high frequency of AIPL1 novel mutations and a founder mutation of p.Q81X in the Chinese

Determining consequences of retinal membrane guanylyl cyclase (RetGC1) deficiency in human Leber congenital amaurosis en route to therapy: residual cone-photoreceptor vision correlates with biochemical properties of the mutants

PubMed Central

Jacobson, Samuel G.; Cideciyan, Artur V.; Peshenko, Igor V.; Sumaroka, Alexander; Olshevskaya, Elena V.; Cao, Lihui; Schwartz, Sharon B.; Roman, Alejandro J.; Olivares, Melani B.; Sadigh, Sam; Yau, King-Wai; Heon, Elise; Stone, Edwin M.; Dizhoor, Alexander M.

2013-01-01

The GUCY2D gene encodes retinal membrane guanylyl cyclase (RetGC1), a key component of the phototransduction machinery in photoreceptors. Mutations in GUCY2D cause Leber congenital amaurosis type 1 (LCA1), an autosomal recessive human retinal blinding disease. The effects of RetGC1 deficiency on human rod and cone photoreceptor structure and function are currently unknown. To move LCA1 closer to clinical trials, we characterized a cohort of patients (ages 6 months—37 years) with GUCY2D mutations. In vivo analyses of retinal architecture indicated intact rod photoreceptors in all patients but abnormalities in foveal cones. By functional phenotype, there were patients with and those without detectable cone vision. Rod vision could be retained and did not correlate with the extent of cone vision or age. In patients without cone vision, rod vision functioned unsaturated under bright ambient illumination. In vitro analyses of the mutant alleles showed that in addition to the major truncation of the essential catalytic domain in RetGC1, some missense mutations in LCA1 patients result in a severe loss of function by inactivating its catalytic activity and/or ability to interact with the activator proteins, GCAPs. The differences in rod sensitivities among patients were not explained by the biochemical properties of the mutants. However, the RetGC1 mutant alleles with remaining biochemical activity in vitro were associated with retained cone vision in vivo. We postulate a relationship between the level of RetGC1 activity and the degree of cone vision abnormality, and argue for cone function being the efficacy outcome in clinical trials of gene augmentation therapy in LCA1. PMID:23035049

Symptomatic carotid stenosis and stroke risk in patients with transient ischemic attack according to the tissue-based definition.

PubMed

Al-Khaled, Mohamed; Scheef, Björn

2016-10-01

Symptomatic carotid stenosis (sCS), a common cause of transient ischemic attack (TIA), is correlated with higher stroke risk. We investigated the frequency and associated factors of sCS in patients with TIA and the association between sCS and stroke risk following TIA. Over a three-year period (2011-2013), 861 consecutive patients with TIA, who were admitted to the Department of Neurology at the University of Lübeck, Germany, were included in a monocenter study and prospectively evaluated. Diagnosis of TIA was in accordance with the tissue-based definition (transient neurological symptoms without evidence of infarction by brain imaging). Of 827 patients (mean age, 70 ± 13.2 years; 49.7% women), 64 patients (7.7%; 95% confidence interval [CI], 5.9%-9.7%) exhibited sCS and 3 patients (0.3%) showed an occlusion of the corresponding internal carotid artery. Logistic regression revealed that sCS was associated with male sex (odds ratio [OR], 2.7; 95% CI, 1.2-3.6; p = 0.012), amaurosis fugax (OR, 8.1; 95% CI, 3.4-19-4; p < 0.001), unilateral weakness (OR, 3.4; 95% CI, 1.9-6.1; p < 0.001), symptom duration less than 1 h (OR, 2.0; 95% CI, 1.1-3.4; p = 0.019) and previous stroke (OR, 2.7; 95% CI, 1.5-4.7; p = 0.001). During hospitalization (mean, 6.6 days), five patients (0.6%; 95% CI, 0.1%-1.2%) suffered from stroke. The stroke risk was higher in patients with sCS than in those without sCS (6.3% vs. 0.1%; p < 0.001), whereas the recurrent TIA risk (2.6%) did not differ between the groups (4.7% vs. 2.5%; p = 0.29). SCS appears to be associated with a higher risk of stroke in patients with TIA defined according to the tissue-based definition.

[Kniest's syndrome (author's transl)].

PubMed

Kniest, W; Leiber, B

1977-12-01

The clinical picture of the Kniest's syndrome is described. The syndrome is a rare hereditary condition with generalized bone dysplasia, disproportional dwarfism, conduction deafness and severe myopia, retinal detachment, cataract and amaurosis.

Metformin and sitAgliptin in patients with impAired glucose tolerance and a recent TIA or minor ischemic Stroke (MAAS): study protocol for a randomized controlled trial.

PubMed

Osei, Elizabeth; Fonville, Susanne; Zandbergen, Adrienne A M; Brouwers, Paul J A M; Mulder, Laus J M M; Lingsma, Hester F; Dippel, Diederik W J; Koudstaal, Peter J; den Hertog, Heleen M

2015-08-05

Impaired glucose tolerance is present in one third of patients with a TIA or ischemic stroke and is associated with a two-fold risk of recurrent stroke. Metformin improves glucose tolerance, but often leads to side effects. The aim of this study is to explore the feasibility, safety, and effects on glucose metabolism of metformin and sitagliptin in patients with TIA or minor ischemic stroke and impaired glucose tolerance. We will also assess whether a slow increase in metformin dose and better support and information on this treatment will reduce the incidence of side effects in these patients. The Metformin and sitAgliptin in patients with impAired glucose tolerance and a recent TIA or minor ischemic Stroke trial (MAAS trial) is a phase II, multicenter, randomized, controlled, open-label trial with blinded outcome assessment. Non-diabetic patients (n = 100) with a recent (<6 months) TIA, amaurosis fugax or minor ischemic stroke (modified Rankin scale ≤ 3) and impaired glucose tolerance, defined as 2-hour post-load glucose levels between 7.8 and 11.0 mmol/L after repeated standard oral glucose tolerance test, will be included. Patients with renal or liver impairment, heart failure, chronic hypoxic lung disease stage III-IV, history of lactate acidosis or diabetic ketoacidosis, pregnancy or breastfeeding, pancreatitis and use of digoxin will be excluded. The patients will be randomly assigned in a 1:1:2 ratio to metformin, sitagliptin or "no treatment." Patients allocated to metformin will start with 500 mg twice daily, which will be slowly increased during a 6-week period to a twice daily dose of 1000 mg. Patients allocated to sitagliptin will be treated with a daily fixed dose of 100 mg. The study has been registered as NTR 3196 in The Netherlands Trial Register. Primary outcomes include percentage still on treatment, percentage of (serious) adverse events, and the baseline adjusted difference in 2-hour post-load glucose levels at 6 months. This study will give

What was Glaucoma Called Before the 20th Century?

PubMed Central

Leffler, Christopher T.; Schwartz, Stephen G.; Giliberti, Francesca M.; Young, Matthew T.; Bermudez, Dennis

2015-01-01

Glaucoma involves a characteristic optic neuropathy, often with elevated intraocular pressure. Before 1850, poor vision with a normal eye appearance, as occurs in primary open-angle glaucoma, was termed amaurosis, gutta serena, or black cataract. Few observers noted palpable hardness of the eye in amaurosis. On the other hand, angle-closure glaucoma can produce a green or gray pupil, and therefore was called, variously, glaucoma (derived from the Greek for glaucous, a nonspecific term connoting blue, green, or light gray) and viriditate oculi. Angle closure, with palpable hardness of the eye, mydriasis, and anterior prominence of the lens, was described in greater detail in the 18th and 19th centuries. The introduction of the ophthalmoscope in 1850 permitted the visualization of the excavated optic neuropathy in eyes with a normal or with a dilated greenish-gray pupil. Physicians developed a better appreciation of the role of intraocular pressure in both conditions, which became subsumed under the rubric “glaucoma”. PMID:26483611

Patient characteristics and treatment outcome in functional anorectal pain.

PubMed

Atkin, Gary K; Suliman, Amna; Vaizey, Carolynne J

2011-07-01

Functional anorectal pain occurs in the absence of any clinical abnormality. It is common and disabling; it has previously been reported in only a few studies involving small patient numbers. This study aimed to report the clinical characteristics and treatment outcomes for patients with functional anorectal pain. Patient demographics, clinical history, and tests results for all referrals for anorectal physiological testing between 1997 and 2009 were prospectively recorded. For patients with functional anorectal pain, further information was gained from clinical notes. Clinical history, anorectal physiology, and radiological imaging data were recorded for all patients; treatment outcome was noted for patients treated and followed up at the present unit. One hundred seventy patients, 99 female, with a median age of 48 years (range, 18-86), were studied. Patients were classified as having chronic proctalgia (pain duration ≥20 min, 158 patients) or proctalgia fugax (pain duration <20 min, 12 patients). The pain was most commonly located in the anal canal (90%) and aggravated by defecation or sitting (66%). A third of patients had a history of psychological disturbance. Internal anal sphincter thickness correlated with resting anal pressures. Patients with proctalgia fugax had a higher internal anal sphincter thickness and resting pressure than patients with chronic proctalgia, whereas patients with a family history of similar symptoms were more likely to have proctalgia fugax and higher resting pressures and internal anal sphincter thickness compared with those without a family history of these symptoms. Patients referred for treatment underwent a range of interventions including biofeedback (29 patients, 17 improved), tricyclic antidepressants (26 patients, 10 improved), Botox injection (9 patients, 5 improved), and sacral nerve stimulation (3 patients, 2 improved). Biofeedback had the greatest treatment effect, especially in patients with defecatory dysfunction

Leber congenital amaurosis: from darkness to spotlight.

PubMed

Kaplan, Josseline

2008-09-01

Almost 150 years ago, Theodor Leber described a severe form of vision loss at or near birth which was later given his name. During the century that followed this description, ophthalmologists dedicated efforts to give an accurate definition of the disease but patients were neglected because of the inability of physicians to provide them with treatment. In the 90s, at the time of the Golden Age of Linkage, the first LCA locus was mapped to a human chromosome and shortly after identified as the gene for guanylate cyclase. This discovery was the spark that made the disease emerge from the shadows as illustrated by the flood of LCA genes identified in the following ten-year period. During the same time period, the clinical variability of the disease was rediscovered and an unexpected physiopathological heterogeneity demonstrated. In the beginning of the third millennium, LCA came out definitively from the tunnel to shine under the bright spotlights with the RPE65 gene therapy trial that succeeded to restore vision in a dog model and opened the door to gene therapy trials in humans.

Frequency of functional bowel disorders among healthy volunteers in Mexico City.

PubMed

Schmulson, Max; Ortíz, Orianna; Santiago-Lomeli, Mariana; Gutiérrez-Reyes, Gabriela; Gutiérrez-Ruiz, María Concepción; Robles-Díaz, Guillermo; Morgan, Douglas

2006-01-01

The frequency of functional bowel disorders (FBD) in Mexico using the Rome II criteria is unknown. The Rome II Modular Questionnaire (RII-MQ) was translated into Spanish in coordination with the Rome Committee and their Latin American program. Volunteers were recruited by advertisement in Mexico City, and administered the RII-MQ. The study population consisted of 324 healthy volunteers, with a mean age of 35.7; 66% were female. The most prevalent disorders were heartburn 35%, irritable bowel syndrome (IBS) 35%, functional bloating 21%, proctalgia fugax 21%, and functional constipation 19%. Based on gender, IBS-C was 4 times more frequent in females than males (19 vs. 4.6%) and functional bloating 3 times more frequent (10 vs. 3.7%). Differences according to occupation included a higher prevalence of ulcer-like dyspepsia (p = 0.04), IBS-C (p = 0.018) and proctalgia fugax (p = 0.034) among students. This is the first study to use RII-MQ to determine the prevalence of FBD in urban Mexico. The prevalence of IBS was significant and is related to a number of factors, including the stress of living in an overpopulated city. Selection bias is likely operative. A community-based study is warranted. Copyright 2006 S. Karger AG, Basel

Common anorectal disorders.

PubMed

Foxx-Orenstein, Amy E; Umar, Sarah B; Crowell, Michael D

2014-05-01

Anorectal disorders result in many visits to healthcare specialists. These disorders include benign conditions such as hemorrhoids to more serious conditions such as malignancy; thus, it is important for the clinician to be familiar with these disorders as well as know how to conduct an appropriate history and physical examination. This article reviews the most common anorectal disorders, including hemorrhoids, anal fissures, fecal incontinence, proctalgia fugax, excessive perineal descent, and pruritus ani, and provides guidelines on comprehensive evaluation and management.

Common Anorectal Disorders

PubMed Central

Foxx-Orenstein, Amy E.; Umar, Sarah B.; Crowell, Michael D.

2014-01-01

Anorectal disorders result in many visits to healthcare specialists. These disorders include benign conditions such as hemorrhoids to more serious conditions such as malignancy; thus, it is important for the clinician to be familiar with these disorders as well as know how to conduct an appropriate history and physical examination. This article reviews the most common anorectal disorders, including hemorrhoids, anal fissures, fecal incontinence, proctalgia fugax, excessive perineal descent, and pruritus ani, and provides guidelines on comprehensive evaluation and management. PMID:24987313

Inherited Retinal Degenerative Disease Registry

ClinicalTrials.gov

2017-09-13

Eye Diseases Hereditary; Retinal Disease; Achromatopsia; Bardet-Biedl Syndrome; Bassen-Kornzweig Syndrome; Batten Disease; Best Disease; Choroidal Dystrophy; Choroideremia; Cone Dystrophy; Cone-Rod Dystrophy; Congenital Stationary Night Blindness; Enhanced S-Cone Syndrome; Fundus Albipunctatus; Goldmann-Favre Syndrome; Gyrate Atrophy; Juvenile Macular Degeneration; Kearns-Sayre Syndrome; Leber Congenital Amaurosis; Refsum Syndrome; Retinitis Pigmentosa; Retinitis Punctata Albescens; Retinoschisis; Rod-Cone Dystrophy; Rod Dystrophy; Rod Monochromacy; Stargardt Disease; Usher Syndrome

[Acute anal pain].

PubMed

Pittet, Olivier; Demartines, Nicolas; Hahnloser, Dieter

2013-07-01

Acute anal pain is a common proctological problem. A detailed history together with the clinical examination are crucial for the diagnosis. An acute perianal vein thrombosis can be successfully excised within the first 72 hours. Acute anal fissures are best treated conservatively using stool regulation and topical medications reducing the sphincter spasm. A chronic anal fissure needs surgery. Perianal abscesses can very often be incised and drained in local anesthesia. Proctalgia fugax and the levator ani syndrome are exclusion diagnoses and are treated symptomatically.

Restenosis after carotid artery stenting and endarterectomy: a secondary analysis of CREST, a randomised controlled trial.

PubMed

Lal, Brajesh K; Beach, Kirk W; Roubin, Gary S; Lutsep, Helmi L; Moore, Wesley S; Malas, Mahmoud B; Chiu, David; Gonzales, Nicole R; Burke, J Lee; Rinaldi, Michael; Elmore, James R; Weaver, Fred A; Narins, Craig R; Foster, Malcolm; Hodgson, Kim J; Shepard, Alexander D; Meschia, James F; Bergelin, Robert O; Voeks, Jenifer H; Howard, George; Brott, Thomas G

2012-09-01

In the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), the composite primary endpoint of stroke, myocardial infarction, or death during the periprocedural period or ipsilateral stroke thereafter did not differ between carotid artery stenting and carotid endarterectomy for symptomatic or asymptomatic carotid stenosis. A secondary aim of this randomised trial was to compare the composite endpoint of restenosis or occlusion. Patients with stenosis of the carotid artery who were asymptomatic or had had a transient ischaemic attack, amaurosis fugax, or a minor stroke were eligible for CREST and were enrolled at 117 clinical centres in the USA and Canada between Dec 21, 2000, and July 18, 2008. In this secondary analysis, the main endpoint was a composite of restenosis or occlusion at 2 years. Restenosis and occlusion were assessed by duplex ultrasonography at 1, 6, 12, 24, and 48 months and were defined as a reduction in diameter of the target artery of at least 70%, diagnosed by a peak systolic velocity of at least 3·0 m/s. Studies were done in CREST-certified laboratories and interpreted at the Ultrasound Core Laboratory (University of Washington). The frequency of restenosis was calculated by Kaplan-Meier survival estimates and was compared during a 2-year follow-up period. We used proportional hazards models to assess the association between baseline characteristics and risk of restenosis. Analyses were per protocol. CREST is registered with ClinicalTrials.gov, number NCT00004732. 2191 patients received their assigned treatment within 30 days of randomisation and had eligible ultrasonography (1086 who had carotid artery stenting, 1105 who had carotid endarterectomy). In 2 years, 58 patients who underwent carotid artery stenting (Kaplan-Meier rate 6·0%) and 62 who had carotid endarterectomy (6·3%) had restenosis or occlusion (hazard ratio [HR] 0·90, 95% CI 0·63-1·29; p=0·58). Female sex (1·79, 1·25-2·56), diabetes (2·31, 1·61-3·31

Transient Amaurosis and Diplopia After Inferior Alveolar Nerve Block.

PubMed

Odabaşi, Onur; Şahin, Onur; Polat, Mehmet Emrah

2017-10-01

A 40-year-old female patient was admitted to the authors' oral and maxillofacial clinic for removal of her lower left second molar under local anesthesia. The patient's medical history revealed that she had cardiac arhythmia and hypertension. Inferior alveolar nerve block was achieved using 2 mL of sefacaine (%3 mepivacaine HCL, without epinephrine). The patient complained of loss of vision in her left eye. All procedures were stopped immediately. Within 2 minutes the patient reported diplopia. All of the symptoms disappeared about 5 minutes after initial observation. Follow-up after 1 day revealed no complications. The procedure was then performed uneventfully.

Progress toward the maintenance and repair of degenerating retinal circuitry.

PubMed

Vugler, Anthony A

2010-01-01

Retinal diseases such as age-related macular degeneration and retinitis pigmentosa remain major causes of severe vision loss in humans. Clinical trials for treatment of retinal degenerations are underway and advancements in our understanding of retinal biology in health/disease have implications for novel therapies. A review of retinal biology is used to inform a discussion of current strategies to maintain/repair neural circuitry in age-related macular degeneration, retinitis pigmentosa, and Type 2 Leber congenital amaurosis. In age-related macular degeneration/retinitis pigmentosa, a progressive loss of rods/cones results in corruption of bipolar cell circuitry, although retinal output neurons/photoreceptive melanopsin cells survive. Visual function can be stabilized/enhanced after treatment in age-related macular degeneration, but in advanced degenerations, reorganization of retinal circuitry may preclude attempts to restore cone function. In Type 2 Leber congenital amaurosis, useful vision can be restored by gene therapy where central cones survive. Remarkable progress has been made in restoring vision to rodents using light-responsive ion channels inserted into bipolar cells/retinal ganglion cells. Advances in genetic, cellular, and prosthetic therapies show varying degrees of promise for treating retinal degenerations. While functional benefits can be obtained after early therapeutic interventions, efforts should be made to minimize circuitry changes as soon as possible after rod/cone loss. Advances in retinal anatomy/physiology and genetic technologies should allow refinement of future reparative strategies.

Restenosis after carotid artery stenting and endarterectomy: a secondary analysis of CREST, a randomised controlled trial

PubMed Central

Lal, Brajesh K.; Beach, Kirk W.; Roubin, Gary S.; Lutsep, Helmi L.; Moore, Wesley S.; Malas, Mahmoud B.; Chiu, David; Gonzales, Nicole R.; Burke, J. Lee; Rinaldi, Michael; Elmore, James R.; Weaver, Fred A.; Narins, Craig R.; Foster, Malcolm; Hodgson, Kim J.; Shepard, Alexander D.; Meschia, James F.; Bergelin, Robert O.; Voeks, Jenifer H.; Howard, George; Brott, Thomas G.

2012-01-01

Background In the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), the composite primary endpoint of stroke, myocardial infarction, or death during the periprocedural period or ipsilateral stroke thereafter did not differ between carotid artery stenting and carotid endarterectomy for symptomatic or asymptomatic carotid stenosis. A secondary aim of this randomised trial was to compare the composite endpoint of restenosis or occlusion. Methods Patients with stenosis of the carotid artery who were asymptomatic or had had a transient ischaemic attack, amaurosis fugax, or a minor stroke were eligible for CREST and were enrolled at 117 clinical centres in the USA and Canada between Dec 21, 2000, and July 18, 2008. In this secondary analysis, the main endpoint was a composite of restenosis or occlusion at 2 years. Restenosis and occlusion were assessed by duplex ultrasonography at 1, 6, 12, 24, and 48 months and were defined as a reduction in diameter of the target artery of at least 70%, diagnosed by a peak systolic velocity of at least 3·0 m/s. Studies were done in CREST-certified laboratories and interpreted at the Ultrasound Core Laboratory (University of Washington). The frequency of restenosis was calculated by Kaplan-Meier survival estimates and was compared during a 2-year follow-up period. We used proportional hazards models to assess the association between baseline characteristics and risk of restenosis. Analyses were per protocol. CREST is registered with ClinicalTrials.gov, number NCT00004732. Findings 2191 patients received their assigned treatment within 30 days of randomisation and had eligible ultrasonography (1086 who had carotid artery stenting, 1105 who had carotid endarterectomy). In 2 years, 58 patients who underwent carotid artery stenting (Kaplan-Meier rate 6·0%) and 62 who had carotid endarterectomy (6·3%) had restenosis or occlusion (hazard ratio [HR] 0·90, 95% CI 0·63–1·29; p=0·58). Female sex (1·79, 1·25–2�

Common anorectal disorders: diagnosis and treatment.

PubMed

Lacy, Brian E; Weiser, Kirsten

2009-10-01

Anorectal disorders affect men and women of all ages. Their management is not limited to the evaluation and treatment of hemorrhoids. Rather, a spectrum of anorectal disorders ranges from benign and irritating (pruritus ani) to potentially life-threatening (anorectal cancer). Symptoms are nonspecific, which can make the evaluation of patients difficult. In addition, treatment can be frustrating because clinicians are hamstrung by a lack of well-designed, prospective, clinical trials. Some of the most common anorectal disorders include fecal incontinence, pelvic floor dyssynergia, anal fissures, pruritus ani, proctalgia fugax, and solitary rectal ulcer syndrome. This article provides an update on the evaluation and treatment of common anorectal disorders.

Diplopia after inferior alveolar nerve block: case report and related physiology.

PubMed

You, Tae Min

2015-06-01

Although inferior alveolar nerve block is one of the most common procedures performed at dental clinics, complications or adverse effects can still occur. On rare occasions, ocular disturbances, such as diplopia, blurred vision, amaurosis, mydriasis, abnormal pupillary light reflex, retrobulbar pain, miosis, and enophthalmos, have also been reported after maxillary and mandibular anesthesia. Generally, these symptoms are temporary but they can be rather distressing to both patients and dental practitioners. Herein, we describe a case of diplopia caused by routine inferior alveolar nerve anesthesia, its related physiology, and management.

Diplopia after inferior alveolar nerve block: case report and related physiology

PubMed Central

2015-01-01

Although inferior alveolar nerve block is one of the most common procedures performed at dental clinics, complications or adverse effects can still occur. On rare occasions, ocular disturbances, such as diplopia, blurred vision, amaurosis, mydriasis, abnormal pupillary light reflex, retrobulbar pain, miosis, and enophthalmos, have also been reported after maxillary and mandibular anesthesia. Generally, these symptoms are temporary but they can be rather distressing to both patients and dental practitioners. Herein, we describe a case of diplopia caused by routine inferior alveolar nerve anesthesia, its related physiology, and management. PMID:28879264

Investor Outlook: Focus on Upcoming LCA2 Gene Therapy Phase III Results.

PubMed

Schimmer, Joshua; Breazzano, Steven

2015-09-01

Investor interest in gene therapy has increased substantially over the past few years, and the next major catalyst for the field is likely to be Spark Therapeutics's phase III trial for the treatment of visual impairment caused by RPE65 gene mutations (often referred to as Leber congenital amaurosis type 2, or LCA2, but may include other retinal disorders). Analysis of the approach from the basic genetics, underlying visual mechanisms, clinical data, and commercialization considerations helps frame investor expectations and the potential implications for the broader field.

[The migraine of Immanual Kant].

PubMed

Podoll, K; Hoff, P; Sass, H

2000-07-01

The German philosopher Immanuel Kant (1724-1804) suffered, since his forties, from a migraine with aura which showed a significant exacerbation in his seventies, coinciding with the onset of symptoms of a senile dementia of Alzheimer's type. Recorded symptoms of Kant's migraine include recurrent scintillating scotomas, one episode of diplopia, two episodes of complete amaurosis and frequent headaches described as oppressions of the head. The said symptoms of Kant's migraine can be traced not only in his letters and in accounts of his contemporary biographers, but also in the philosopher's published work.

[Progress in research on pathogenic genes and gene therapy for inherited retinal diseases].

PubMed

Zhu, Ling; Cao, Cong; Sun, Jiji; Gao, Tao; Liang, Xiaoyang; Nie, Zhipeng; Ji, Yanchun; Jiang, Pingping; Guan, Minxin

2017-02-10

Inherited retinal diseases (IRDs), including retinitis pigmentosa, Usher syndrome, Cone-Rod degenerations, inherited macular dystrophy, Leber's congenital amaurosis, Leber's hereditary optic neuropathy are the most common and severe types of hereditary ocular diseases. So far more than 200 pathogenic genes have been identified. With the growing knowledge of the genetics and mechanisms of IRDs, a number of gene therapeutic strategies have been developed in the laboratory or even entered clinical trials. Here the progress of IRD research on the pathogenic genes and therapeutic strategies, particularly gene therapy, are reviewed.

[Molecular genetics of pigmentary retinopathies: identification of mutations in CHM, RDS, RHO, RPE65, USH2A and XLRS1 genes].

PubMed

Hamel, C P; Griffoin, J M; Bazalgette, C; Lasquellec, L; Duval, P A; Bareil, C; Beaufrère, L; Bonnet, S; Eliaou, C; Marlhens, F; Schmitt-Bernard, C F; Tuffery, S; Claustres, M; Arnaud, B

2000-12-01

To evaluate the occurrence and inheritance of various types of pigmentary retinopathy in patients followed at the outpatient clinic in the university hospital, Montpellier, France. To characterize genes and mutations causing these conditions. Ophthalmic examination and various visual tests were performed. Mutations were sought from genomic DNA by PCR amplification of exons associated with single-strand conformation analysis and/or direct sequencing. Among 315 patients over an 8-year period, cases of retinitis pigmentosa (63.2%), Usher's syndrome (10.2%), Stargardt's disease (5.4%), choroideremia (3.2%), Leber's congenital amaurosis (3.2%), congenital stationary night blindness (2.9%), cone dystrophy (2.5%), dominant optic atrophy (1.9%), X-linked juvenile retinoschisis (1.6%), Best's disease (1.6%), and others (4.3%) were diagnosed. In retinitis pigmentosa, inheritance could be determined in 54.2% of the cases including dominant autosomic (26.6%), recessive autosomic (22.6%), and X-linked cases (5%) while it could not be confirmed in 45.7% of the cases (simplex cases in the majority). For the 6 examined genes, mutations were found in 22 out of 182 propositus (12.1%). Analysis of phenotype-genotype correlations indicates that in retinitis pigmentosa, RDS is more frequently associated with macular involvement and retinal flecks, RHO with regional disease, and RPE65 with the great severity of the disease with some cases of Leber's congenital amaurosis. Identification of genes may help in diagnosis and in genetic counseling, especially in simplex cases with retinitis pigmentosa. In this latter condition, molecular diagnosis will be necessary to rationalize future treatments.

Improvement and Decline in Vision with Gene Therapy in Childhood Blindness

PubMed Central

Jacobson, Samuel G.; Cideciyan, Artur V.; Roman, Alejandro J.; Sumaroka, Alexander; Schwartz, Sharon B.; Heon, Elise; Hauswirth, William W.

2015-01-01

Summary Retinal gene therapy for Leber’s congenital amaurosis, an autosomal recessive childhood blindness, has been widely considered to be safe and efficacious. Three years after therapy, improvement in vision was maintained, but the rate of loss of photoreceptors in the treated retina was the same as that in the untreated retina. Here we describe long-term follow-up data from three treated patients. Topographic maps of visual sensitivity in treated regions, nearly 6 years after therapy for two of the patients and 4.5 years after therapy for the third patient, indicate progressive diminution of the areas of improved vision. PMID:25936984

CRB2 in immature photoreceptors determines the superior-inferior symmetry of the developing retina to maintain retinal structure and function.

PubMed

Quinn, Peter M; Alves, C Henrique; Klooster, Jan; Wijnholds, Jan

2018-06-08

The mammalian apical-basal determinant Crumbs homolog-1 (CRB1) plays a crucial role in retinal structure and function by the maintenance of adherens junctions between photoreceptors and Müller glial cells. Patients with mutations in the CRB1 gene develop retinal dystrophies, including early-onset retinitis pigmentosa and Leber congenital amaurosis. Previously, we showed that Crb1 knockout mice developed a slow-progressing retinal phenotype at foci in the inferior retina, whiles specific ablation of Crb2 in immature photoreceptors lead to an early-onset phenotype throughout the retina. Here, we conditionally disrupted one or both alleles of Crb2 in immature photoreceptors, on a genetic background lacking Crb1, and studied the retinal dystrophies thereof. Our data showed that disruption of one allele of Crb2 in immature photoreceptors caused a substantial aggravation of the Crb1 phenotype in the entire inferior retina. The photoreceptor layer showed early-onset progressive thinning limited to the inferior retina while the superior retina maintained intact. Surprisingly, disruption of both alleles of Crb2 in immature photoreceptors further aggravated the phenotype. Throughout the retina, photoreceptor synapses were disrupted and photoreceptor nuclei intermingled with nuclei of the inner nuclear layer. In the superior retina, the ganglion cell layer appeared thicker due to ectopic nuclei of photoreceptors. In conclusion, the data suggest that CRB2 is required to maintain retinal progenitor and photoreceptor cell adhesion and prevent photoreceptor ingression into the immature inner retina. We hypothesise, from these animal models, that decreased levels of CRB2 in immature photoreceptors adjust retinitis pigmentosa due to loss of CRB1 into Leber congenital amaurosis phenotype.

The Status of RPE65 Gene Therapy Trials: Safety and Efficacy

PubMed Central

Pierce, Eric A.; Bennett, Jean

2015-01-01

Several groups have reported the results of clinical trials of gene augmentation therapy for Leber congenital amaurosis (LCA) because of mutations in the RPE65 gene. These studies have used subretinal injection of adeno-associated virus (AAV) vectors to deliver the human RPE65 cDNA to the retinal pigment epithelial (RPE) cells of the treated eyes. In all of the studies reported to date, this approach has been shown to be both safe and effective. The successful clinical trials of gene augmentation therapy for retinal degeneration caused by mutations in the RPE65 gene sets the stage for broad application of gene therapy to treat retinal degenerative disorders. PMID:25635059

Expanded Retinal Disease Spectrum Associated With Autosomal Recessive Mutations in GUCY2D.

PubMed

Stunkel, Maria L; Brodie, Scott E; Cideciyan, Artur V; Pfeifer, Wanda L; Kennedy, Elizabeth L; Stone, Edwin M; Jacobson, Samuel G; Drack, Arlene V

2018-06-01

GUCY2D has been associated with autosomal recessive Leber congenital amaurosis and autosomal dominant cone-rod dystrophy. This report expands the phenotype of autosomal recessive mutations to congenital night blindness, which may slowly progress to mild retinitis pigmentosa. Retrospective case series. Multicenter study of 5 patients (3 male, 2 female). All patients presented with night blindness since childhood. Age at referral was 9-45 years. Length of follow-up was 1-7 years. Best-corrected visual acuity at presentation ranged from 20/15 to 20/30 and at most recent visit averaged 20/25. No patient had nystagmus or high refractive error. ISCEV standard electroretinography revealed nondetectable dark-adapted dim flash responses and reduced amplitude but not electronegative dark-adapted bright flash responses with similar waveforms to the reduced-amplitude light-adapted single flash responses. The 30 Hz flicker responses were relatively preserved. Macular optical coherence tomography revealed normal lamination in 3 patients, with abnormalities in 2. Goldmann visual fields were normal at presentation in children but constricted in 1 adult. One child showed loss of midperipheral fields over time. Fundus appearance was normal in childhood; the adult had sparse bone spicule-like pigmentation. Full-field stimulus testing (FST) revealed markedly decreased retinal sensitivity to light. Dark adaptation demonstrated lack of rod-cone break. Two patients had tritanopia. All 5 had compound heterozygous mutations in GUCY2D. Three of the 5 patients harbor the Arg768Trp mutation reported in GUCY2D-associated Leber congenital amaurosis. Autosomal recessive GUCY2D mutations may cause congenital night blindness with normal acuity and refraction, and unique electroretinography. Progression to mild retinitis pigmentosa may occur. Copyright © 2018 Elsevier Inc. All rights reserved.

Loss of lysophosphatidylcholine acyltransferase 1 leads to photoreceptor degeneration in rd11 mice

PubMed Central

Friedman, James S.; Chang, Bo; Krauth, Daniel S.; Lopez, Irma; Waseem, Naushin H.; Hurd, Ron E.; Feathers, Kecia L.; Branham, Kari E.; Shaw, Manessa; Thomas, George E.; Brooks, Matthew J.; Liu, Chunqiao; Bakeri, Hirva A.; Campos, Maria M.; Maubaret, Cecilia; Webster, Andrew R.; Rodriguez, Ignacio R.; Thompson, Debra A.; Bhattacharya, Shomi S.; Koenekoop, Robert K.; Heckenlively, John R.; Swaroop, Anand

2010-01-01

Retinal degenerative diseases, such as retinitis pigmentosa and Leber congenital amaurosis, are a leading cause of untreatable blindness with substantive impact on the quality of life of affected individuals and their families. Mouse mutants with retinal dystrophies have provided a valuable resource to discover human disease genes and helped uncover pathways critical for photoreceptor function. Here we show that the rd11 mouse mutant and its allelic strain, B6-JR2845, exhibit rapid photoreceptor dysfunction, followed by degeneration of both rods and cones. Using linkage analysis, we mapped the rd11 locus to mouse chromosome 13. We then identified a one-nucleotide insertion (c.420–421insG) in exon 3 of the Lpcat1 gene. Subsequent screening of this gene in the B6-JR2845 strain revealed a seven-nucleotide deletion (c.14–20delGCCGCGG) in exon 1. Both sequence changes are predicted to result in a frame-shift, leading to premature truncation of the lysophosphatidylcholine acyltransferase-1 (LPCAT1) protein. LPCAT1 (also called AYTL2) is a phospholipid biosynthesis/remodeling enzyme that facilitates the conversion of palmitoyl-lysophosphatidylcholine to dipalmitoylphosphatidylcholine (DPPC). The analysis of retinal lipids from rd11 and B6-JR2845 mice showed substantially reduced DPPC levels compared with C57BL/6J control mice, suggesting a causal link to photoreceptor dysfunction. A follow-up screening of LPCAT1 in retinitis pigmentosa and Leber congenital amaurosis patients did not reveal any obvious disease-causing mutations. Previously, LPCAT1 has been suggested to be critical for the production of lung surfactant phospholipids and biosynthesis of platelet-activating factor in noninflammatory remodeling pathway. Our studies add another dimension to an essential role for LPCAT1 in retinal photoreceptor homeostasis. PMID:20713727

[ERG diagnosis and differential diagnosis: results of examination over 6 years].

PubMed

Stemeyer, G; Stähli, P

1996-05-01

This study reviews the patient material first from the point of view of referral diagnosis. Secondly, we focus on difficulties in selective differential diagnoses. 1501 patients underwent electroretinographic (ERG) testing from 1989 to 1994, amounting to 1815 ERG recordings, including follow-up examinations. The technique applied is full-field, single flash ERG with selective stimulation of the rod- and of the cone-systems. In 3.8% (57 cases) the ERG was performed under general anesthesia in outpatients. Tapetoretinal degenerations, toxic retinal side effects, inflammatory disease and ocular trauma represented, in this order, the major groups of referral diagnoses aside from unclear visual loss. The documentation or the exclusion of tapetoretinal degeneration represented the largest share (57%) of the application of the diagnostic procedure. 171 cases of isolated retinitis pigmentosa (RP) and 33 cases of syndromic RP were identified. Frequent and rare diagnostic entities and their differential diagnoses within this group are discussed. Inevitably, a number of diagnostic decisions remain problematic, in particular at the first examination. These diagnostic difficulties are addressed also and include the differentiation between RP sine pigmento and congenital amaurosis Leber in infants, RP with macular involvement vs. cone-rod degeneration, unilateral RP vs. postinflammatory conditions, and progressive cone dystrophy vs. achromatopsia, cone-rod degeneration or Stargardt's disease. Frequent and meaningful indications for ERG recording and difficult diagnostic decisions arise from this review of a relatively large group of patients. A number of diagnoses can hardly, if not at all be established without ERG testing. These include retinal cause of visual loss in infants, congenital amaurosis Leber, RP sine pigmento, early stages of RP, carrier status in XL RP and in choroideremia, progressive cone dystrophy, toxic retinopathy without fundus changes, retinal involvement

Let There Be Light: Gene and Cell Therapy for Blindness.

PubMed

Dalkara, Deniz; Goureau, Olivier; Marazova, Katia; Sahel, José-Alain

2016-02-01

Retinal degenerative diseases are a leading cause of irreversible blindness. Retinal cell death is the main cause of vision loss in genetic disorders such as retinitis pigmentosa, Stargardt disease, and Leber congenital amaurosis, as well as in complex age-related diseases such as age-related macular degeneration. For these blinding conditions, gene and cell therapy approaches offer therapeutic intervention at various disease stages. The present review outlines advances in therapies for retinal degenerative disease, focusing on the progress and challenges in the development and clinical translation of gene and cell therapies. A significant body of preclinical evidence and initial clinical results pave the way for further development of these cutting edge treatments for patients with retinal degenerative disorders.

Keratoconus presenting with bilateral simultaneous acute corneal hydrops.

PubMed

Bilgin, Burak; Unal, Betül; Unal, Mustafa; Doğan, Erkan; Cetinkaya, Aslı; Akyol, Mahmut; Yücel, Iclal; Akar, Yusuf; Apaydın, Cemil; Ilhan, Deniz

2013-04-01

To report a case of unknown keratoconus presenting with bilateral simultaneous acute corneal hydrops. Case report. A case of a 12-year-old male patient with Leber congenital amaurosis (LCA) presented with sudden whitening and lacrimation for 2 days in both eyes simultaneously. At the initial examination, there were bilateral acute corneal hydrops, enophthalmic eyes and roving nystagmus. Ultrasonography revealed clear crystalline lenses and attached retina. Initial management consisted of topical hypertonic solutions, steroids and artificial tears. Bilateral simultaneous acute corneal hydrops has not been reported before in the literature. It may be the presenting sign of keratoconus. Copyright © 2012 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Regenerative Medicine: Solution in Sight.

PubMed

Wang, Qingjie; Stern, Jeffrey H; Temple, Sally

2016-01-01

The retina, like other central nervous system tissues, has poor regenerative properties in humans. Therefore, diseases that cause retinal cell loss, such as Age-related macular degeneration (AMD), retinitis pigmentosa (RP), Leber congenital amaurosis, Usher syndrome, glaucoma, and diabetic retinopathy, typically result in permanent visual impairment. Stem cell technologies have revolutionized our ability to produce neural cells in abundant supply. Much stem cell research effort is focused on producing the required cell types for cell replacement, or to generate disease-in-a-dish models to elucidate novel disease mechanisms for therapeutic development. Here we review the recent advances in stem cell studies relevant to producing RPE and retinal cells, and highlight future directions.

Chronic perineal pain: current pathophysiological aspects, diagnostic approaches and treatment.

PubMed

Andromanakos, Nikolaos P; Kouraklis, Grigorios; Alkiviadis, Kostakis

2011-01-01

Chronic perineal pain is the anorectal and perineal pain without underlying organic disease, anorectal or endopelvic, which has been excluded by careful physical examination, radiological and endoscopic investigations. A variety of neuromuscular disorders of the pelvic floor lead to the different pathological conditions such as anorectal incontinence, urinary incontinence and constipation of obstructed defecation, sexual dysfunction and pain syndromes. The most common functional disorders of the pelvic floor muscles, accompanied by perineal pain are levator ani syndrome, proctalgia fugax, myofascial syndrome and coccygodynia. In the diagnosis of these syndromes, contributing to a thorough history, physical examination, selected specialized investigations and the exclusion of organic disease with proctalgia is carried out. Accurate diagnosis of the syndromes helps in choosing an appropriate treatment and in avoiding unnecessary and ineffective surgical procedures, which often are performed in an attempt to alleviate the patient's symptoms.

An eye for discovery

PubMed Central

Stahl, Andreas; Smith, Lois E.H.

2010-01-01

Vision research has often led to significant advances in our understanding of biology. There has also been particular success in translating basic research in the eye into breakthrough clinical therapies that mark important milestones for ophthalmology and also for medical research. Anti-VEGF therapy for age-related macular degeneration was named as one of the top ten science advancements of the year 2006. Only two years later, successful transfer of the RPE65 gene into retinal pigment epithelium of patients with Leber congenital amaurosis was noted as one of the most important clinical applications of gene therapy. The articles in this Review series outline current developments in vision research and highlight its continued importance in ophthalmology and medicine. PMID:20811156

Investor Outlook: Significance of the Positive LCA2 Gene Therapy Phase III Results.

PubMed

Schimmer, Joshua; Breazzano, Steven

2015-12-01

Spark Therapeutics recently reported positive phase III results for SPK-RPE65 targeting the treatment of visual impairment caused by RPE65 gene mutations (often referred to as Leber congenital amaurosis type 2, or LCA2, but may include other retinal disorders), marking an important inflection point for the field of gene therapy. The results highlight the ability to successfully design and execute a randomized trial of a gene therapy and also reinforce the potentially predictive nature of early preclinical and clinical data. The results are expected to pave the way for the first approved gene therapy product in the United States and should sustain investor interest and confidence in gene therapy for many approaches, including retina targeting and beyond.

Let There Be Light: Gene and Cell Therapy for Blindness

PubMed Central

Dalkara, Deniz; Goureau, Olivier; Marazova, Katia; Sahel, José-Alain

2016-01-01

Retinal degenerative diseases are a leading cause of irreversible blindness. Retinal cell death is the main cause of vision loss in genetic disorders such as retinitis pigmentosa, Stargardt disease, and Leber congenital amaurosis, as well as in complex age-related diseases such as age-related macular degeneration. For these blinding conditions, gene and cell therapy approaches offer therapeutic intervention at various disease stages. The present review outlines advances in therapies for retinal degenerative disease, focusing on the progress and challenges in the development and clinical translation of gene and cell therapies. A significant body of preclinical evidence and initial clinical results pave the way for further development of these cutting edge treatments for patients with retinal degenerative disorders. PMID:26751519

CRISPR-mediated Ophthalmic Genome Surgery.

PubMed

Cho, Galaxy Y; Abdulla, Yazeed; Sengillo, Jesse D; Justus, Sally; Schaefer, Kellie A; Bassuk, Alexander G; Tsang, Stephen H; Mahajan, Vinit B

2017-09-01

Clustered regularly interspaced short palindromic repeats (CRISPR) is a genome engineering system with great potential for clinical applications due to its versatility and programmability. This review highlights the development and use of CRISPR-mediated ophthalmic genome surgery in recent years. Diverse CRISPR techniques are in development to target a wide array of ophthalmic conditions, including inherited and acquired conditions. Preclinical disease modeling and recent successes in gene editing suggest potential efficacy of CRISPR as a therapeutic for inherited conditions. In particular, the treatment of Leber congenital amaurosis with CRISPR-mediated genome surgery is expected to reach clinical trials in the near future. Treatment options for inherited retinal dystrophies are currently limited. CRISPR-mediated genome surgery methods may be able to address this unmet need in the future.

[Anorectal pain in children: rare or rarely recognised?].

PubMed

Sonneveld, Laura J H; Engelberts, Adèle C; van den Elzen, Annette P M

2016-01-01

Anorectal pain is a common symptom, often as part of functional gastrointestinal disorders. Children seldom present with this complaint. Proctalgia fugax and chronic proctalgia are both anorectal pain syndromes but differ in duration and frequency of episodes and in pain characteristics. No research has been conducted on anorectal pain syndromes in children. We present two patients. Firstly, an 8-year-old girl who suffered from anorectal cramps. We found no underlying cause apart from constipation. The symptoms disappeared spontaneously. The second concerned an 8-year-old boy who presented with recurrent anorectal cramps. He was diagnosed with celiac disease. Anorectal dysfunction and visceral hypersensitivity have been described in adult celiac patients. Symptoms of anorectal pain in children are rare probably because it often remains unrecognised. Noninvasive diagnostic methods and interventions are preferred in paediatric medicine. Screening for celiac disease in children with anorectal pain episodes should be considered.

Applications of CRISPR/Cas9 in retinal degenerative diseases

PubMed Central

Peng, Ying-Qian; Tang, Luo-Sheng; Yoshida, Shigeo; Zhou, Ye-Di

2017-01-01

Gene therapy is a potentially effective treatment for retinal degenerative diseases. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has been developed as a new genome-editing tool in ophthalmic studies. Recent advances in researches showed that CRISPR/Cas9 has been applied in generating animal models as well as gene therapy in vivo of retinitis pigmentosa (RP) and leber congenital amaurosis (LCA). It has also been shown as a potential attempt for clinic by combining with other technologies such as adeno-associated virus (AAV) and induced pluripotent stem cells (iPSCs). In this review, we highlight the main points of further prospect of using CRISPR/Cas9 in targeting retinal degeneration. We also emphasize the potential applications of this technique in treating retinal degenerative diseases. PMID:28503441

Perianal pain as a presentation of lumbosacral neurofibroma: a case report.

PubMed

Moghaddasi, Mehdi; Aghaii, Mahboubeh; Mamarabadi, Mansoureh

2014-12-01

Rectal and perianal pain is a common problem. Most people have experienced it at least once in their lifetime. It usually manifests as mild discomfort, but sometimes the pain can be so severe that it is incapacitating. A 59-year-old woman admitted with a 2-year history of paroxysmal perianal pain underwent a full work-up including proctoscopy, sigmoidoscopy, full colonoscopy, and barium enema that were unremarkable. Lumbosacral magnetic resonance imaging with and without gadolinium showed an intradural-extramedullary lesion at the level of L5. The pathologic diagnosis was a neurofibroma. She underwent surgery, and after a few weeks she felt well and medication was no longer needed for her paroxysmal pain. Although one should consider the usual causes of colorectal pain such as hemorrhoids, anal fissure, proctalgia fugax, and chronic perianal pain syndrome, we should keep in mind that some referral pain may mimic local pathologies and should be evaluated properly.

Perianal Pain as a Presentation of Lumbosacral Neurofibroma: A Case Report

PubMed Central

Moghaddasi, Mehdi; Aghaii, Mahboubeh; Mamarabadi, Mansoureh

2014-01-01

Rectal and perianal pain is a common problem. Most people have experienced it at least once in their lifetime. It usually manifests as mild discomfort, but sometimes the pain can be so severe that it is incapacitating. A 59-year-old woman admitted with a 2-year history of paroxysmal perianal pain underwent a full work-up including proctoscopy, sigmoidoscopy, full colonoscopy, and barium enema that were unremarkable. Lumbosacral magnetic resonance imaging with and without gadolinium showed an intradural-extramedullary lesion at the level of L5. The pathologic diagnosis was a neurofibroma. She underwent surgery, and after a few weeks she felt well and medication was no longer needed for her paroxysmal pain. Although one should consider the usual causes of colorectal pain such as hemorrhoids, anal fissure, proctalgia fugax, and chronic perianal pain syndrome, we should keep in mind that some referral pain may mimic local pathologies and should be evaluated properly. PMID:25485211

[Postoperative cortical blindness after right upper lung lobectomy].

PubMed

Bausili, M; Abreu, S; Unzueta, M C; García Álvarez, M; Crespí, J; Moral, M V

2012-03-01

Changes in vision after non-ophthalmic surgery are a serious complication that can have devastating consequences due to its potential irreversibility. This not only leads to medical problems, but also legal ones. Many causes that affect sight during the peri-operative period have been identified, whether due to optic nerve damage or of extra-ocular origin (in the neuro-optic pathways and/or cerebral cortex). AU these may have a multifactorial origin, and there is still controversy as regards it pathogenesis and treatment. We present the case of a thoracic surgery patient who had a bilateral amaurosis in the post-operative period, which had a favourable outcome. Copyright © 2010 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Published by Elsevier España.. All rights reserved.

Unilateral Vision Loss after a Dental Visit

PubMed Central

Khattab, Mohammed H.; Wiegand, Annette; Storch, Marcus; Hoerauf, Hans; Feltgen, Nicolas

2018-01-01

Intraoral local anesthetics are widely used for performing painless dental treatments; however, in some cases, they may cause ocular complications such as meiosis, diplopia, nystagmus, ophthalmoplegia, ptosis, and amaurosis. Mostly, the symptoms disappear after several hours; rarely, they have a prolonged character. We describe the case of a 38-year-old young man who had reduced vision in the left eye 5 days after having received intraoral local anesthesia. A diagnosis of cilioretinal artery occlusion with optic disc swelling was made. Ten weeks later, the patient's visual acuity had increased to 20/20, and the swelling of the optic disc had subsided. Although various possible mechanisms for ocular complications after intraoral local anesthetic administration were suggested in the literature, the exact etiology remains unclear. In this case, inadvertent intravascular injection is believed to be the cause. PMID:29681838

Using Stem Cells to Model Diseases of the Outer Retina.

PubMed

Yvon, Camille; Ramsden, Conor M; Lane, Amelia; Powner, Michael B; da Cruz, Lyndon; Coffey, Peter J; Carr, Amanda-Jayne F

2015-01-01

Retinal degeneration arises from the loss of photoreceptors or retinal pigment epithelium (RPE). It is one of the leading causes of irreversible blindness worldwide with limited effective treatment options. Generation of induced pluripotent stem cell (IPSC)-derived retinal cells and tissues from individuals with retinal degeneration is a rapidly evolving technology that holds a great potential for its use in disease modelling. IPSCs provide an ideal platform to investigate normal and pathological retinogenesis, but also deliver a valuable source of retinal cell types for drug screening and cell therapy. In this review, we will provide some examples of the ways in which IPSCs have been used to model diseases of the outer retina including retinitis pigmentosa (RP), Usher syndrome (USH), Leber congenital amaurosis (LCA), gyrate atrophy (GA), juvenile neuronal ceroid lipofuscinosis (NCL), Best vitelliform macular dystrophy (BVMD) and age related macular degeneration (AMD).

Nanoparticles for Retinal Gene Therapy

PubMed Central

Conley, Shannon M.; Naash, Muna I.

2010-01-01

Ocular gene therapy is becoming a well-established field. Viral gene therapies for the treatment of Leber’s congentinal amaurosis (LCA) are in clinical trials, and many other gene therapy approaches are being rapidly developed for application to diverse ophthalmic pathologies. Of late, development of non-viral gene therapies has been an area of intense focus and one technology, polymer-compacted DNA nanoparticles, is especially promising. However, development of pharmaceutically and clinically viable therapeutics depends not only on having an effective and safe vector but also on a practical treatment strategy. Inherited retinal pathologies are caused by mutations in over 220 genes, some of which contain over 200 individual disease-causing mutations, which are individually very rare. This review will focus on both the progress and future of nanoparticles and also on what will be required to make them relevant ocular pharmaceutics. PMID:20452457

[Ocular complications of local anaesthesia in dentistry].

PubMed

Steenen, S A; Dubois, L; de Lange, J

2017-03-01

An estimated 1 in 1,000 local anaesthetic injections in the maxilla or the mandible lead to unwanted effects on the ipsilateral eye. We have seen a case with diplopia and lateral rectus palsy following bimaxillary anaesthesia. A systematic literature review of reports on this type of complication resulted in a total of 144 documented cases published between 1936 and 2016. The most frequently reported symptoms included diplopia (72%), partial or full ophthalmoplegia (26%), ptosis (22%), mydriasis (18%), amaurosis (13%) and orbital pain (12%). This type of complication is best understood by pathophysiological hypotheses that include intra-arterial injection, intravenous injection, autonomic dysregulation, or deep injection and diffusion. If ocular symptoms appear after local intraoral anaesthesia, the patient should be reassured. In the case of diplopia, the eye should be covered with a gauze dressing, and the patient should be instructed about associated safety risks. If symptoms persist or when vision deteriorates, referral to an ophthalmologist is advisable.

Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness

PubMed Central

Kmoch, S.; Majewski, J.; Ramamurthy, V.; Cao, S.; Fahiminiya, S.; Ren, H.; MacDonald, I.M.; Lopez, I.; Sun, V.; Keser, V.; Khan, A.; Stránecký, V.; Hartmannová, H.; Přistoupilová, A.; Hodaňová, K.; Piherová, L.; Kuchař, L.; Baxová, A.; Chen, R.; Barsottini, O.G.P.; Pyle, A.; Griffin, H.; Splitt, M.; Sallum, J.; Tolmie, J.L.; Sampson, J.R.; Chinnery, P.; Canada, Care4Rare; Banin, E.; Sharon, D.; Dutta, S.; Grebler, R.; Helfrich-Foerster, C.; Pedroso, J.L.; Kretzschmar, D.; Cayouette, M.; Koenekoop, R.K.

2015-01-01

Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. Mutations in PNPLA6 also cause human spastic paraplegia characterized by motor neuron degeneration. Here we identify PNPLA6 mutations in childhood blindness in seven families with retinal degeneration, including Leber congenital amaurosis and Oliver McFarlane syndrome. PNPLA6 localizes mostly at the inner segment plasma membrane in photo-receptors and mutations in Drosophila PNPLA6 lead to photoreceptor cell death. We also report that lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness. PMID:25574898

Potential of Gene Editing and Induced Pluripotent Stem Cells (iPSCs) in Treatment of Retinal Diseases.

PubMed

Chuang, Katherine; Fields, Mark A; Del Priore, Lucian V

2017-12-01

The advent of gene editing has introduced the ability to make changes to the genome of cells, thus allowing for correction of genetic mutations in patients with monogenic diseases. Retinal diseases are particularly suitable for the application of this new technology because many retinal diseases, such as Stargardt disease, retinitis pigmentosa (RP), and Leber congenital amaurosis (LCA), are monogenic. Moreover, gene delivery techniques such as the use of adeno-associated virus (AAV) vectors have been optimized for intraocular use, and phase III trials are well underway to treat LCA, a severe form of inherited retinal degeneration, with gene therapy. This review focuses on the use of gene editing techniques and another relatively recent advent, induced pluripotent stem cells (iPSCs), and their potential for the study and treatment of retinal disease. Investment in these technologies, including overcoming challenges such as off-target mutations and low transplanted cell integration, may allow for future treatment of many debilitating inherited retinal diseases.

NMNAT1 variants cause cone and cone-rod dystrophy.

PubMed

Nash, Benjamin M; Symes, Richard; Goel, Himanshu; Dinger, Marcel E; Bennetts, Bruce; Grigg, John R; Jamieson, Robyn V

2018-03-01

Cone and cone-rod dystrophies (CD and CRD, respectively) are degenerative retinal diseases that predominantly affect the cone photoreceptors. The underlying disease gene is not known in approximately 75% of autosomal recessive cases. Variants in NMNAT1 cause a severe, early-onset retinal dystrophy called Leber congenital amaurosis (LCA). We report two patients where clinical phenotyping indicated diagnoses of CD and CRD, respectively. NMNAT1 variants were identified, with Case 1 showing an extremely rare homozygous variant c.[271G > A] p.(Glu91Lys) and Case 2 compound heterozygous variants c.[53 A > G];[769G > A] p.(Asn18Ser);(Glu257Lys). The detailed variant analysis, in combination with the observation of an associated macular atrophy phenotype, indicated that these variants were disease-causing. This report demonstrates that the variants in NMNAT1 may cause CD or CRD associated with macular atrophy. Genetic investigations of the patients with CD or CRD should include NMNAT1 in the genes examined.

Greek mythology: the eye, ophthalmology, eye disease, and blindness.

PubMed

Trompoukis, Constantinos; Kourkoutas, Dimitrios

2007-06-01

In distant eras, mythology was a form of expression used by many peoples. A study of the Greek myths reveals concealed medical knowledge, in many cases relating to the eye. An analysis was made of the ancient Greek texts for mythological references relating to an understanding of vision, visual abilities, the eye, its congenital and acquired abnormalities, blindness, and eye injuries and their treatment. The Homeric epics contain anatomical descriptions of the eyes and the orbits, and an elementary knowledge of physiology is also apparent. The concept of the visual field can be seen in the myth of Argos Panoptes. Many myths describe external eye disease ("knyzosis"), visual disorders (amaurosis), and cases of blinding that, depending on the story, are ascribed to various causes. In addition, ocular motility abnormalities, congenital anomalies (cyclopia), injuries, and special treatments, such as the "licking" method, are mentioned. The study of mythological references to the eye reveals reliable medical observations of the ancient Greeks, which are concealed within the myths.

Synthetic 9-cis-beta-carotene inhibits photoreceptor degeneration in cultures of eye cups from rpe65rd12 mouse model of retinoid cycle defect.

PubMed

Sher, Ifat; Tzameret, Adi; Peri-Chen, Sara; Edelshtain, Victoria; Ioffe, Michael; Sayer, Alon; Buzhansky, Ludmila; Gazit, Ehud; Rotenstreich, Ygal

2018-04-17

The retinoid cycle enzymes regenerate the visual chromophore 11-cis retinal to enable vision. Mutations in the genes encoding the proteins of the retinoid cycle are the leading cause for recessively inherited retinal dystrophies such as retinitis pigmentosa, Leber congenital amaurosis, congenital cone-rod dystrophy and fundus albipunctatus. Currently there is no treatment for these blinding diseases. In previous studies we demonstrated that oral treatment with the 9-cis-β-carotene rich Dunaliella Bardawil algae powder significantly improved visual and retinal functions in patients with retinitis pigmentosa and fundus albipunctatus. Here we developed a convenient and economical synthetic route for biologically active 9-cis-β-carotene from inexpensive building materials and demonstrated that the molecule is stable for at least one month. Synthetic 9-cis-β-carotene rescued cone photoreceptors from degeneration in eye cup cultures of mice with a retinoid cycle genetic defect. This study suggests that synthetic 9-cis-β-carotene may serve as an effective treatment for retinal dystrophies involving the retinoid cycle.

Anorectal and Pelvic Pain

PubMed Central

Bharucha, Adil E.; Lee, Tae Hee

2016-01-01

Although pelvic pain is a symptom of several structural anorectal and pelvic disorders (eg, anal fissure, endometriosis, and pelvic inflammatory disease), this comprehensive review will focus on the three most common nonstructural, or functional, disorders associated with pelvic pain: functional anorectal pain (ie, levator ani syndrome, unspecified anorectal pain, and proctalgia fugax), interstitial cystitis/bladder pain syndrome, and chronic prostatitis/chronic pelvic pain syndrome. The first two conditions occur in both sexes, while the latter occurs only in men. They are defined by symptoms, supplemented with levator tenderness (levator ani syndrome) and bladder mucosal inflammation (interstitial cystitis). Although distinct, these conditions share several similarities, including associations with dysfunctional voiding or defecation, comorbid conditions (eg, fibromyalgia, depression), impaired quality of life, and increased health care utilization. Several factors, including pelvic floor muscle tension, peripheral inflammation, peripheral and central sensitization, and psychosocial factors, have been implicated in the pathogenesis. The management is tailored to symptoms, is partly supported by clinical trials, and includes multidisciplinary approaches such as lifestyle modifications and pharmacologic, behavioral, and physical therapy. Opioids should not be avoided, and surgery has a limited role, primarily in refractory interstitial cystitis. PMID:27712641

Hereditary internal anal sphincter myopathy causing proctalgia fugax and constipation: further clinical and histological characterization in a patient.

PubMed

König, P; Ambrose, N S; Scott, N

2000-01-01

Hereditary internal anal sphincter myopathy is a very rare condition, only three families have so far been described in the literature. In this case report further clinical and histological findings of one affected member of one of the above families are presented.

Gene therapy and genome surgery in the retina.

PubMed

DiCarlo, James E; Mahajan, Vinit B; Tsang, Stephen H

2018-06-01

Precision medicine seeks to treat disease with molecular specificity. Advances in genome sequence analysis, gene delivery, and genome surgery have allowed clinician-scientists to treat genetic conditions at the level of their pathology. As a result, progress in treating retinal disease using genetic tools has advanced tremendously over the past several decades. Breakthroughs in gene delivery vectors, both viral and nonviral, have allowed the delivery of genetic payloads in preclinical models of retinal disorders and have paved the way for numerous successful clinical trials. Moreover, the adaptation of CRISPR-Cas systems for genome engineering have enabled the correction of both recessive and dominant pathogenic alleles, expanding the disease-modifying power of gene therapies. Here, we highlight the translational progress of gene therapy and genome editing of several retinal disorders, including RPE65-, CEP290-, and GUY2D-associated Leber congenital amaurosis, as well as choroideremia, achromatopsia, Mer tyrosine kinase- (MERTK-) and RPGR X-linked retinitis pigmentosa, Usher syndrome, neovascular age-related macular degeneration, X-linked retinoschisis, Stargardt disease, and Leber hereditary optic neuropathy.

Clustered Regularly Interspaced Short Palindromic Repeats: Challenges in Treating Retinal Disease.

PubMed

Chrenek, Micah A; Nickerson, John M; Boatright, Jeffrey H

2016-01-01

Ophthalmic researchers and clinicians arguably have led the way for safe, effective gene therapy, most notably with adeno-associated viral gene supplementation in the treatment for patients with Leber congenital amaurosis type 2 with mutations in the RPE65 gene. These successes notwithstanding, most other genetic retinal disease will be refractory to supplementation. The ideal gene therapy approach would correct gene mutations to restore normal function in the affected cells. Gene editing in which a mutant allele is inactivated or converted to sequence that restores normal function is hypothetically one such approach. Such editing involves site-specific digestion of mutant genomic DNA followed by repair. Previous experimental approaches were hampered by inaccurate and high rates of off-site lesioning and by overall low digestion rates. A new tool, clustered regularly interspaced short palindromic repeats coupled with the nuclease Cas9, may address both shortcomings. Some of the many challenges that must be addressed in moving clustered regularly interspaced short palindromic repeats coupled with the nuclease Cas9 therapies to the ophthalmic clinic are discussed here.

[Gene Therapy for Inherited RETINAL AND OPTIC NERVE Disorders: Current Knowledge].

PubMed

Ďuďáková, Ľ; Kousal, B; Kolářová, H; Hlavatá, L; Lišková, P

The aim of this review is to provide a comprehensive summary of current gene therapy clinical trials for monogenic and optic nerve disorders.The number of genes for which gene-based therapies are being developed is growing. At the time of writing this review gene-based clinical trials have been registered for Leber congenital amaurosis 2 (LCA2), retinitis pigmentosa 38, Usher syndrome 1B, Stargardt disease, choroideremia, achromatopsia, Leber hereditary optic neuropathy (LHON) and X-linked retinoschisis. Apart from RPE65 gene therapy for LCA2 and MT-ND4 for LHON which has reached phase III, all other trials are in investigation phase I and II, i.e. testing the efficacy and safety.Because of the relatively easy accessibility of the retina and its ease of visualization which allows monitoring of efficacy, gene-based therapies for inherited retinal disorders represent a very promising treatment option. With the development of novel therapeutic approaches, the importance of establishing not only clinical but also molecular genetic diagnosis is obvious.Key words: gene therapy, monogenic retinal diseases, optic nerve atrophy, mitochondrial disease.

Gene therapy: light is finally in the tunnel.

PubMed

Cao, Huibi; Molday, Robert S; Hu, Jim

2011-12-01

After two decades of ups and downs, gene therapy has recently achieved a milestone in treating patients with Leber's congenital amaurosis (LCA). LCA is a group of inherited blinding diseases with retinal degeneration and severe vision loss in early infancy. Mutations in several genes, including RPE65, cause the disease. Using adeno-associated virus as a vector, three independent teams of investigators have recently shown that RPE65 can be delivered to retinal pigment epithelial cells of LCA patients by subretinal injections resulting in clinical benefits without side effects. However, considering the whole field of gene therapy, there are still major obstacles to clinical applications for other diseases. These obstacles include innate and immune barriers to vector delivery, toxicity of vectors and the lack of sustained therapeutic gene expression. Therefore, new strategies are needed to overcome these hurdles for achieving safe and effective gene therapy. In this article, we shall review the major advancements over the past two decades and, using lung gene therapy as an example, discuss the current obstacles and possible solutions to provide a roadmap for future gene therapy research.

Cytospora species from Populus and Salix in China with C. davidiana sp. nov.

PubMed

Wang, Yan-Li; Lu, Quan; Decock, Cony; Li, Yong-Xia; Zhang, Xing-Yao

2015-05-01

Poplar and willow plantations have become widespread in China, in order to meet national economic and environmental needs. The emergence of several pathogens is enhanced by climatic change and associated human factors. Species of Cytospora are well-known pathogens on poplar and willow, and cause stem cankers and diebacks. In the present study, we conducted a survey of Cytospora species occurring on Populus spp. and Salix spp. in China. We used morphological examination and phylogenetic inferences, based on the DNA sequence data from the internal transcribed spacer regions (ITS1, 5.8S rDNA, and ITS2) and partial β-tubulin gene, to identify six Cytospora species occurring on poplar and willow. Five of these species belonged to known taxa, viz. Cytospora chrysosperma (asexual state of Valsa sordida), Cytospora translucens (asexual state of Leucostoma translucens), Cytospora fugax (asexual state of Valsa salicina), Cytospora atrocirrhata, and Cytospora kantschavelii. Our study yielded a new species, Cytospora davidiana sp. nov., on poplar. The new species is characterized by typical torsellioid conidiomata. An additional Cytospora sp. 1, which formed a distinct clade in the phylogenetic inferences, remains unnamed; the paucity of available materials prevented phenotypical characterization. Copyright © 2015 The British Mycological Society. Published by Elsevier Ltd. All rights reserved.

Anorectal Disorders

PubMed Central

Rao, Satish S. C.; Bharucha, Adil E.; Chiarioni, Giuseppe; Felt-Bersma, Richelle; Knowles, Charles; Malcolm, Allison; Wald, Arnold

2016-01-01

This report defines criteria and reviews the epidemiology, pathophysiology, and management of the following common anorectal disorders: fecal incontinence (FI), functional anorectal pain, and functional defecation disorders. FI is defined as the recurrent uncontrolled passage of fecal material for at least 3 months. The clinical features of FI are useful for guiding diagnostic testing and therapy. Anorectal manometry and imaging are useful for evaluating anal and pelvic floor structure and function. Education, antidiarrheals, and biofeedback therapy are the mainstay of management; surgery may be useful in refractory cases. Functional anorectal pain syndromes are defined by clinical features and categorized into 3 subtypes. In proctalgia fugax, the pain is typically fleeting and lasts for seconds to minutes. In levator ani syndrome and unspecified anorectal pain, the pain lasts more than 30 minutes, but in levator ani syndrome there is puborectalis tenderness. Functional defecation disorders are defined by ≥2 symptoms of chronic constipation or irritable bowel syndrome with constipation, and with ≥2 features of impaired evacuation, that is, abnormal evacuation pattern on manometry, abnormal balloon expulsion test, or impaired rectal evacuation by imaging. It includes 2 subtypes: dyssynergic defecation and inadequate defecatory propulsion. Pelvic floor biofeedback therapy is effective for treating levator ani syndrome and defecatory disorders. PMID:27144630

Anorectal and Pelvic Pain.

PubMed

Bharucha, Adil E; Lee, Tae Hee

2016-10-01

Although pelvic pain is a symptom of several structural anorectal and pelvic disorders (eg, anal fissure, endometriosis, and pelvic inflammatory disease), this comprehensive review will focus on the 3 most common nonstructural, or functional, disorders associated with pelvic pain: functional anorectal pain (ie, levator ani syndrome, unspecified anorectal pain, and proctalgia fugax), interstitial cystitis/bladder pain syndrome, and chronic prostatitis/chronic pelvic pain syndrome. The first 2 conditions occur in both sexes, while the latter occurs only in men. They are defined by symptoms, supplemented with levator tenderness (levator ani syndrome) and bladder mucosal inflammation (interstitial cystitis). Although distinct, these conditions share several similarities, including associations with dysfunctional voiding or defecation, comorbid conditions (eg, fibromyalgia, depression), impaired quality of life, and increased health care utilization. Several factors, including pelvic floor muscle tension, peripheral inflammation, peripheral and central sensitization, and psychosocial factors, have been implicated in the pathogenesis. The management is tailored to symptoms, is partly supported by clinical trials, and includes multidisciplinary approaches such as lifestyle modifications and pharmacological, behavioral, and physical therapy. Opioids should be avoided, and surgical treatment has a limited role, primarily in refractory interstitial cystitis. Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Functional Anorectal Disorders.

PubMed

Rao, Satish Sc; Bharucha, Adil E; Chiarioni, Giuseppe; Felt-Bersma, Richelle; Knowles, Charles; Malcolm, Allison; Wald, Arnold

2016-03-25

This report defines criteria and reviews the epidemiology, pathophysiology, and management of common anorectal disorders: fecal incontinence (FI), functional anorectal pain and functional defecation disorders. FI is defined as the recurrent uncontrolled passage of fecal material for at least 3 months. The clinical features of FI are useful for guiding diagnostic testing and therapy. Anorectal manometry and imaging are useful for evaluating anal and pelvic floor structure and function. Education, antidiarrheals and biofeedback therapy are the mainstay of management; surgery may be useful in refractory cases. Functional anorectal pain syndromes are defined by clinical features and categorized into three subtypes. In proctalgia fugax, the pain is typically fleeting and lasts for seconds to minutes. In levator ani syndrome (LAS) and unspecified anorectal pain the pain lasts more than 30 minutes, but in LAS there is puborectalis tenderness. Functional defecation disorders are defined by >2 symptoms of chronic constipation or irritable bowel syndrome with constipation, and with >2 features of impaired evacuation i.e., abnormal evacuation pattern on manometry, abnormal balloon expulsion test or impaired rectal evacuation by imaging. It includes two subtypes; dyssynergic defecation and inadequate defecatory propulsion. Pelvic floor biofeedback therapy is effective for treating LAS and defecatory disorders. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

Ophthalmologic complications after intraoral local anesthesia.

PubMed

von Arx, Thomas; Lozanoff, Scott; Zinkernagel, Martin

2014-01-01

The first ophthalmologic complication in conjunction with a dental anesthesia was reported in 1936. The objective of the present study was a detailed analysis of case reports about that topic. After conducting a literature search in PubMed this study analyzed 108 ophthalmologic complications following intraoral local anesthesia in 65 case reports with respect to patient-, anesthesia-, and complication- related factors. The mean age of the patients was 33.8 years and females predominated (72.3%). The most commonly reported complication was diplopia (39.8%), mostly resulting from paralysis of the lateral rectus muscle. Other relatively frequent complications included ptosis (16.7%), mydriasis (14.8%) and amaurosis (13%). Ophthalmologic complications were mainly associated with block anesthesia of the inferior alveolar nerve (45.8%) or the posterior superior alveolar nerve (40.3%). Typically, the ophthalmologic complications in conjunction with intraoral local anesthesia had an immediate to short onset, and disappeared as the anesthesia subsided. The increased number of ophthalmologic complications after intraoral local anesthesia in females may suggest a gender effect. Double vision (diplopia) is the most frequently described complication, which is usually completely reversible like the other reported ophthalmologic complications.

Gene therapy for inherited retinal and optic nerve degenerations.

PubMed

Moore, Nicholas A; Morral, Nuria; Ciulla, Thomas A; Bracha, Peter

2018-01-01

The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight blood-ocular barrier, the ability to non-invasively monitor for functional and anatomic outcomes, as well as its relative immune privileged state.Vectors currently used in IRD clinical trials include adeno-associated virus (AAV), small single-stranded DNA viruses, and lentivirus, RNA viruses of the retrovirus family. Both can transduce non-dividing cells, but AAV are non-integrating, while lentivirus integrate into the host cell genome, and have a larger transgene capacity. Areas covered: This review covers Leber's congenital amaurosis, choroideremia, retinitis pigmentosa, Usher syndrome, Stargardt disease, Leber's hereditary optic neuropathy, Achromatopsia, and X-linked retinoschisis. Expert opinion: Despite great potential, gene therapy for IRD raises many questions, including the potential for less invasive intravitreal versus subretinal delivery, efficacy, safety, and longevity of response, as well as acceptance of novel study endpoints by regulatory bodies, patients, clinicians, and payers. Also, ultimate adoption of gene therapy for IRD will require widespread genetic screening to identify and diagnose patients based on genotype instead of phenotype.

Improvement in vision: a new goal for treatment of hereditary retinal degenerations

PubMed Central

Jacobson, Samuel G; Cideciyan, Artur V; Aguirre, Gustavo D; Roman, Alejandro J; Sumaroka, Alexander; Hauswirth, William W; Palczewski, Krzysztof

2015-01-01

Introduction: Inherited retinal degenerations (IRDs) have long been considered untreatable and incurable. Recently, one form of early-onset autosomal recessive IRD, Leber congenital amaurosis (LCA) caused by mutations in RPE65 (retinal pigment epithelium-specific protein 65 kDa) gene, has responded with some improvement of vision to gene augmentation therapy and oral retinoid administration. This early success now requires refinement of such therapeutics to fully realize the impact of these major scientific and clinical advances. Areas covered: Progress toward human therapy for RPE65-LCA is detailed from the understanding of molecular mechanisms to preclinical proof-of-concept research to clinical trials. Unexpected positive and complicating results in the patients receiving treatment are explained. Logical next steps to advance the clinical value of the therapeutics are suggested. Expert opinion: The first molecularly based early-phase therapies for an IRD are remarkably successful in that vision has improved and adverse events are mainly associated with surgical delivery to the subretinal space. Yet, there are features of the gene augmentation therapeutic response, such as slowed kinetics of night vision, lack of foveal cone function improvement and relentlessly progressive retinal degeneration despite therapy, that still require research attention. PMID:26246977

[Pro731Ser mutation in the β-myosin heavy chain and hypertrophic cardiomyopathy in a Chinese pedigree].

PubMed

Zhao, Xintao; Wu, Yajie; Chen, Yi; Feng, Xinxing; Song, Ying; Wang, Yilu; Zou, Yubao; Wang, Jizheng; Shao, Yibing; Hui, Rutai; Song, Lei; Wang, Xu

2014-07-01

To identify the casual mutation of a Chinese pedigree with hypertrophic cardiomyopathy (HCM), and to analyze the genotype-phenotype relationship. The coding exons of 26 reported disease genes were sequenced by targeted resequencing in the proband and the identified mutation were detected with bi-directional Sanger sequencing in all family members and 307 healthy controls. The genotype-phenotype correlation was analyzed in the family. A missense mutation (c.2191C > T, p. Pro731Ser) in the 20th exon of MYH7 gene was identified. This mutation was absent in 307 healthy controls and predicted to be pathogenic by PolyPhen-HCM. Totally 13 family members carried this mutation, including 10 patients with HCM and 3 asymptomatic mutation carriers. The proband manifested severe congestive heart failure and 8 patients expressed various clinical manifestations of heart failure, including dyspnea, palpitations, chest pain, amaurosis or syncope. Five patients were diagnosed as HCM at the age of 16 or younger. One family member suffered sudden cardiac death. The Pro731Ser of MYH7 gene mutation is a causal and malignant mutation linked with familiar HCM.

KMeyeDB: a graphical database of mutations in genes that cause eye diseases.

PubMed

Kawamura, Takashi; Ohtsubo, Masafumi; Mitsuyama, Susumu; Ohno-Nakamura, Saho; Shimizu, Nobuyoshi; Minoshima, Shinsei

2010-06-01

KMeyeDB (http://mutview.dmb.med.keio.ac.jp/) is a database of human gene mutations that cause eye diseases. We have substantially enriched the amount of data in the database, which now contains information about the mutations of 167 human genes causing eye-related diseases including retinitis pigmentosa, cone-rod dystrophy, night blindness, Oguchi disease, Stargardt disease, macular degeneration, Leber congenital amaurosis, corneal dystrophy, cataract, glaucoma, retinoblastoma, Bardet-Biedl syndrome, and Usher syndrome. KMeyeDB is operated using the database software MutationView, which deals with various characters of mutations, gene structure, protein functional domains, and polymerase chain reaction (PCR) primers, as well as clinical data for each case. Users can access the database using an ordinary Internet browser with smooth user-interface, without user registration. The results are displayed on the graphical windows together with statistical calculations. All mutations and associated data have been collected from published articles. Careful data analysis with KMeyeDB revealed many interesting features regarding the mutations in 167 genes that cause 326 different types of eye diseases. Some genes are involved in multiple types of eye diseases, whereas several eye diseases are caused by different mutations in one gene.

FiberNet--a new embolic protection device for carotid artery stenting.

PubMed

Bauer, C; Franke, J; Bertog, S C; Woerner, V; Ghasemzadeh-Asl, S; Sievert, H

2014-05-01

Though distal filter protection during carotid stenting reduces the risk of cerebrovascular events, periprocedural stroke remains a risk despite their broad usage. This observation may be related to the pore size of common filters. The FiberNet distal filter system is unique by its very small pore size (40 µm) as well as its low profile and flexibility. Little data is available regarding the clinical performance and safety of this device. The aim was the evaluation of the safety of the FiberNet embolic protection system during carotid artery stenting. All consecutive patients treated with carotid stenting at our institution using the FiberNet device were systematically followed. Primary endpoint was the rate of all death and stroke within 30 days of the procedure. Carotid artery stenting using the FiberNet embolic protection system was performed in 54 patients. The procedure was technical successful in all patients. Three patients (5.5%) had a TIA. Amauosis fugax occurred in two patients (3.7%). One patient (1.9%) had a minor stroke with hemiparesis of the left arm and face which resolved completely within 48 hr after the procedure. No patient died or suffered a major stroke. The safety and feasibility of the FiberNet distal protection system appears to be at least equivalent to that reported in studies using conventional distal filter protection. Copyright © 2013 Wiley Periodicals, Inc.

Diurnal and twenty-four hour patterning of human diseases: acute and chronic common and uncommon medical conditions.

PubMed

Smolensky, Michael H; Portaluppi, Francesco; Manfredini, Roberto; Hermida, Ramon C; Tiseo, Ruana; Sackett-Lundeen, Linda L; Haus, Erhard L

2015-06-01

The symptom intensity and mortality of human diseases, conditions, and syndromes exhibit diurnal or 24 h patterning, e.g., skin: atopic dermatitis, urticaria, psoriasis, and palmar hyperhidrosis; gastrointestinal: esophageal reflux, peptic ulcer (including perforation and hemorrhage), cyclic vomiting syndrome, biliary colic, hepatic variceal hemorrhage, and proctalgia fugax; infection: susceptibility, fever, and mortality; neural: frontal, parietal, temporal, and occipital lobe seizures, Parkinson's and Alzheimer's disease, hereditary progressive dystonia, and pain (cancer, post-surgical, diabetic neuropathic and foot ulcer, tooth caries, burning mouth and temporomandibular syndromes, fibromyalgia, sciatica, intervertebral vacuum phenomenon, multiple sclerosis muscle spasm, and migraine, tension, cluster, hypnic, and paroxysmal hemicranial headache); renal: colic and nocturnal enuresis and polyuria; ocular: bulbar conjunctival redness, keratoconjunctivitis sicca, intraocular pressure and anterior ischemic optic neuropathy, and recurrent corneal erosion syndrome; psychiatric/behavioral: major and seasonal affective depressive disorders, bipolar disorder, parasuicide and suicide, dementia-associated agitation, and addictive alcohol, tobacco, and heroin cravings and withdrawal phenomena; plus autoimmune and musculoskeletal: rheumatoid arthritis, osteoarthritis, axial spondylarthritis, gout, Sjögren's syndrome, and systemic lupus erythematosus. Knowledge of these and other 24 h patterns of human pathophysiology informs research of their underlying circadian and other endogenous mechanisms, external temporal triggers, and more effective patient care entailing clinical chronopreventive and chronotherapeutic strategies. Copyright © 2014 Elsevier Ltd. All rights reserved.

Gene therapy delivery systems for enhancing viral and nonviral vectors for cardiac diseases: current concepts and future applications.

PubMed

Katz, Michael G; Fargnoli, Anthony S; Williams, Richard D; Bridges, Charles R

2013-11-01

Gene therapy is one of the most promising fields for developing new treatments for the advanced stages of ischemic and monogenetic, particularly autosomal or X-linked recessive, cardiomyopathies. The remarkable ongoing efforts in advancing various targets have largely been inspired by the results that have been achieved in several notable gene therapy trials, such as the hemophilia B and Leber's congenital amaurosis. Rate-limiting problems preventing successful clinical application in the cardiac disease area, however, are primarily attributable to inefficient gene transfer, host responses, and the lack of sustainable therapeutic transgene expression. It is arguable that these problems are directly correlated with the choice of vector, dose level, and associated cardiac delivery approach as a whole treatment system. Essentially, a delicate balance exists in maximizing gene transfer required for efficacy while remaining within safety limits. Therefore, the development of safe, effective, and clinically applicable gene delivery techniques for selected nonviral and viral vectors will certainly be invaluable in obtaining future regulatory approvals. The choice of gene transfer vector, dose level, and the delivery system are likely to be critical determinants of therapeutic efficacy. It is here that the interactions between vector uptake and trafficking, delivery route means, and the host's physical limits must be considered synergistically for a successful treatment course.

Gene Therapy Delivery Systems for Enhancing Viral and Nonviral Vectors for Cardiac Diseases: Current Concepts and Future Applications

PubMed Central

Katz, Michael G.; Fargnoli, Anthony S.; Williams, Richard D.

2013-01-01

Abstract Gene therapy is one of the most promising fields for developing new treatments for the advanced stages of ischemic and monogenetic, particularly autosomal or X-linked recessive, cardiomyopathies. The remarkable ongoing efforts in advancing various targets have largely been inspired by the results that have been achieved in several notable gene therapy trials, such as the hemophilia B and Leber's congenital amaurosis. Rate-limiting problems preventing successful clinical application in the cardiac disease area, however, are primarily attributable to inefficient gene transfer, host responses, and the lack of sustainable therapeutic transgene expression. It is arguable that these problems are directly correlated with the choice of vector, dose level, and associated cardiac delivery approach as a whole treatment system. Essentially, a delicate balance exists in maximizing gene transfer required for efficacy while remaining within safety limits. Therefore, the development of safe, effective, and clinically applicable gene delivery techniques for selected nonviral and viral vectors will certainly be invaluable in obtaining future regulatory approvals. The choice of gene transfer vector, dose level, and the delivery system are likely to be critical determinants of therapeutic efficacy. It is here that the interactions between vector uptake and trafficking, delivery route means, and the host's physical limits must be considered synergistically for a successful treatment course. PMID:24164239

Mutation analysis of Leber congenital amaurosis‑associated genes in patients with retinitis pigmentosa.

PubMed

Shen, Tao; Guan, Liping; Li, Shiqiang; Zhang, Jianguo; Xiao, Xueshan; Jiang, Hui; Yang, Jianhua; Guo, Xiangming; Wang, Jun; Zhang, Qingjiong

2015-03-01

The genetic defects underlying approximately half of all retinitis pigmentosa (RP) cases are unknown. A number of genes responsible for Leber congenital amaurosis (LCA) may also cause RP when they are mutated. Our previous study revealed that variants in the most frequently mutated nine exons accounted for approximately half of the mutations detected in a cohort of patients with LCA. The aim of the present study was to detect mutations in LCA-associated genes in patients with RP using two different strategies. Sanger sequencing was used to screen mutations in the nine exons in 293 patients with RP and exome sequencing was used to detect variants in 12 LCA-associated genes in 157 of the 293 patients with RP and then to validate the variants by Sanger sequencing. Potential pathogenic mutations were identified in four patients with early onset RP, including homozygous CRB1 mutations in two patients, compound heterozygous CRB1 mutations in one patient and compound heterozygous CEP290 mutations in one patient. The present study indicated that mutations in CEP290 may also be associated with RP but not with LCA. With the exception of CEP290, the remaining 11 genes known to be associated with LCA but not with RP are unlikely to be a common cause of RP.

Republished review: Gene therapy for ocular diseases.

PubMed

Liu, Melissa M; Tuo, Jingsheng; Chan, Chi-Chao

2011-07-01

The eye is an easily accessible, highly compartmentalised and immune-privileged organ that offers unique advantages as a gene therapy target. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been implicated as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of-concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis. This review describes current developments and future prospects for ocular gene therapy. Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirus-mediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future.

Gene therapy for ocular diseases.

PubMed

Liu, Melissa M; Tuo, Jingsheng; Chan, Chi-Chao

2011-05-01

The eye is an easily accessible, highly compartmentalised and immune-privileged organ that offers unique advantages as a gene therapy target. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been implicated as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of-concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis. This review describes current developments and future prospects for ocular gene therapy. Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirus-mediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future.

Gene therapy for the eye focus on mutation-independent approaches.

PubMed

Dalkara, Deniz; Duebel, Jens; Sahel, José-Alain

2015-02-01

This review will discuss retinal gene therapy strategies with a focus on mutation-independent approaches to treat a large number of patients without knowledge of the mutant gene. These approaches rely on the secretion of neurotrophic factors to slow down retinal degeneration and the use of optogenetics to restore vision in late-stage disease. Success in clinical application of adeno-associated virus (AAV)-mediated gene therapy for Leber's congenital amaurosis established the feasibility of retinal gene therapy. More clinical trials are currently on their way for recessive diseases with known mutations. However, the genetic and mechanistic diversity of the retinal diseases presents an enormous obstacle for the development of gene therapies tailored to each patient-specific mutation. To extend gene therapy's promise to a large number of patients, evidence suggests retina-specific trophic factors, such as rod-derived cone viability factor, can be used to slow down loss of cone cells responsible for our high acuity vision. In parallel, it has been shown that microbial opsins are able to restore light sensitivity when expressed in blind retinas. Recent findings imply that using the viral technology that has been demonstrated as well tolerated in patients, there are opportunities to develop widely applicable gene therapeutic interventions in clinical ophthalmology.

The human visual cortex responds to gene therapy–mediated recovery of retinal function

PubMed Central

Ashtari, Manzar; Cyckowski, Laura L.; Monroe, Justin F.; Marshall, Kathleen A.; Chung, Daniel C.; Auricchio, Alberto; Simonelli, Francesca; Leroy, Bart P.; Maguire, Albert M.; Shindler, Kenneth S.; Bennett, Jean

2011-01-01

Leber congenital amaurosis (LCA) is a rare degenerative eye disease, linked to mutations in at least 14 genes. A recent gene therapy trial in patients with LCA2, who have mutations in RPE65, demonstrated that subretinal injection of an adeno-associated virus (AAV) carrying the normal cDNA of that gene (AAV2-hRPE65v2) could markedly improve vision. However, it remains unclear how the visual cortex responds to recovery of retinal function after prolonged sensory deprivation. Here, 3 of the gene therapy trial subjects, treated at ages 8, 9, and 35 years, underwent functional MRI within 2 years of unilateral injection of AAV2-hRPE65v2. All subjects showed increased cortical activation in response to high- and medium-contrast stimuli after exposure to the treated compared with the untreated eye. Furthermore, we observed a correlation between the visual field maps and the distribution of cortical activations for the treated eyes. These data suggest that despite severe and long-term visual impairment, treated LCA2 patients have intact and responsive visual pathways. In addition, these data suggest that gene therapy resulted in not only sustained and improved visual ability, but also enhanced contrast sensitivity. PMID:21606598

Successful gene therapy in older Rpe65-deficient dogs following subretinal injection of an adeno-associated vector expressing RPE65.

PubMed

Annear, Matthew J; Mowat, Freya M; Bartoe, Joshua T; Querubin, Janice; Azam, Selina A; Basche, Mark; Curran, Paul G; Smith, Alexander J; Bainbridge, James W B; Ali, Robin R; Petersen-Jones, Simon M

2013-10-01

Young Rpe65-deficient dogs have been used as a model for human RPE65 Leber congenital amaurosis (RPE65-LCA) in proof-of-concept trials of recombinant adeno-associated virus (rAAV) gene therapy. However, there are relatively few reports of the outcome of rAAV gene therapy in Rpe65-deficient dogs older than 2 years of age. The purpose of this study was to investigate the success of this therapy in older Rpe65-deficient dogs. Thirteen eyes were treated in dogs between 2 and 6 years old. An rAAV2 vector expressing the human RPE65 cDNA driven by the human RPE65 promoter was delivered by subretinal injection. Twelve of the 13 eyes had improved retinal function as assessed by electroretinography, and all showed improvement in vision at low lighting intensities. Histologic examination of five of the eyes was performed but found no correlation between electroretinogram (ERG) rescue and numbers of remaining photoreceptors. We conclude that functional rescue is still possible in older dogs and that the use of older Rpe65-deficient dogs, rather than young Rpe65-deficient dogs that have very little loss of photoreceptors, more accurately models the situation when treating human RPE65-LCA patients.

Complications associated with prone positioning in elective spinal surgery.

PubMed

DePasse, J Mason; Palumbo, Mark A; Haque, Maahir; Eberson, Craig P; Daniels, Alan H

2015-04-18

Complications associated with prone surgical positioning during elective spine surgery have the potential to cause serious patient morbidity. Although many of these complications remain uncommon, the range of possible morbidities is wide and includes multiple organ systems. Perioperative visual loss (POVL) is a well described, but uncommon complication that may occur due to ischemia to the optic nerve, retina, or cerebral cortex. Closed-angle glaucoma and amaurosis have been reported as additional etiologies for vision loss following spinal surgery. Peripheral nerve injuries, such as those caused by prolonged traction to the brachial plexus, are more commonly encountered postoperative events. Myocutaneous complications including pressure ulcers and compartment syndrome may also occur after prone positioning, albeit rarely. Other uncommon positioning complications such as tongue swelling resulting in airway compromise, femoral artery ischemia, and avascular necrosis of the femoral head have also been reported. Many of these are well-understood and largely avoidable through thoughtful attention to detail. Other complications, such as POVL, remain incompletely understood and thus more difficult to predict or prevent. Here, the current literature on the complications of prone positioning for spine surgery is reviewed to increase awareness of the spectrum of potential complications and to inform spine surgeons of strategies to minimize the risk of prone patient morbidity.

Complications associated with prone positioning in elective spinal surgery

PubMed Central

DePasse, J Mason; Palumbo, Mark A; Haque, Maahir; Eberson, Craig P; Daniels, Alan H

2015-01-01

Complications associated with prone surgical positioning during elective spine surgery have the potential to cause serious patient morbidity. Although many of these complications remain uncommon, the range of possible morbidities is wide and includes multiple organ systems. Perioperative visual loss (POVL) is a well described, but uncommon complication that may occur due to ischemia to the optic nerve, retina, or cerebral cortex. Closed-angle glaucoma and amaurosis have been reported as additional etiologies for vision loss following spinal surgery. Peripheral nerve injuries, such as those caused by prolonged traction to the brachial plexus, are more commonly encountered postoperative events. Myocutaneous complications including pressure ulcers and compartment syndrome may also occur after prone positioning, albeit rarely. Other uncommon positioning complications such as tongue swelling resulting in airway compromise, femoral artery ischemia, and avascular necrosis of the femoral head have also been reported. Many of these are well-understood and largely avoidable through thoughtful attention to detail. Other complications, such as POVL, remain incompletely understood and thus more difficult to predict or prevent. Here, the current literature on the complications of prone positioning for spine surgery is reviewed to increase awareness of the spectrum of potential complications and to inform spine surgeons of strategies to minimize the risk of prone patient morbidity. PMID:25893178

Assessment of different virus-mediated approaches for retinal gene therapy of Usher 1B.

PubMed

Lopes, Vanda S; Diemer, Tanja; Williams, David S

2014-01-01

Usher syndrome type 1B, which is characterized by congenital deafness and progressive retinal degeneration, is caused by the loss of the function of MYO7A. Prevention of the retinal degeneration should be possible by delivering functional MYO7A to retinal cells. Although this approach has been used successfully in clinical trials for Leber congenital amaurosis (LCA2), it remains a challenge for Usher 1B because of the large size of the MYO7A cDNA. Different viral vectors have been tested for use in MYO7A gene therapy. Here, we review approaches with lentiviruses, which can accommodate larger genes, as well as attempts to use adeno-associated virus (AAV), which has a smaller packaging capacity. In conclusion, both types of viral vector appear to be effective. Despite concerns about the ability of lentiviruses to access the photoreceptor cells, a phenotype of the photoreceptors of Myo7a-mutant mice can be corrected. And although MYO7A cDNA is significantly larger than the nominal carrying capacity of AAV, AAV-MYO7A in single vectors also corrected Myo7a-mutant phenotypes in photoreceptor and RPE cells. Interestingly, however, a dual AAV vector approach was found to be much less effective.

Epidemiology of uninvestigated gastrointestinal symptoms in adolescents: a population-based study applying the Rome II questionnaire.

PubMed

Sohrabi, Sahand; Nouraie, Mehdi; Khademi, Hooman; Baghizadeh, Somayyeh; Nasseri-Moghaddam, Siavosh; Malekzadeh, Reza

2010-07-01

: Gastrointestinal (GI) disorders in early life contribute to a lower quality of life and more persistent GI symptoms during the rest of life. Epidemiologic data on adolescence GI disorders are scarce. We aimed to perform a population-based study to assess the prevalence of GI symptoms in adolescents and their relation to sex, age, and socioeconomic status. : A multistage random sample of Tehran middle and high school students (ages 14-19 years) was selected. A validated Persian version of the Rome II questionnaire was used to measure the frequency of different GI disorders as well as demographic socioeconomic variables. : A total of 1436 participants were enrolled in the study, 736 (51.3%) of whom were men. Mean (SD) age was 16.9 (1.8) years. The frequency of at least 1 GI symptom was 32.4%. The 4 most prevalent GI symptoms were bloating (16.9%), heartburn (4.9%), incontinence (4.3%), and irritable bowel syndrome (4.1%). Bloating, irritable bowel syndrome, and proctalgia fugax were significantly more common in girls (P < 0.05). Incontinence was significantly more prevalent in lower socioeconomic status levels (P = 0.01). In logistic regression, age was a risk factor for abdominal bloating and dysphagea and a protective factor for incontinence. : Our study indicates that GI symptoms are common among adolescents. Girls are more prone to these disorders. Special psychological and medical interventions are necessary for high-risk groups.

Functional anorectal disorders.

PubMed

Bharucha, Adil E; Wald, Arnold; Enck, Paul; Rao, Satish

2006-04-01

This report defines criteria for diagnosing functional anorectal disorders (ie, fecal incontinence, anorectal pain, and disorders of defecation). Functional fecal incontinence is defined as the uncontrolled passage of fecal material recurring for > or =3 months in an individual with a developmental age of > or =4 years that is associated with: (1) abnormal functioning of normally innervated and structurally intact muscles, and/or (2) no or minor abnormalities of sphincter structure and/or innervation insufficient to explain fecal incontinence, and/or (3) normal or disordered bowel habits (ie, fecal retention or diarrhea), and/or (4) psychological causes. However, conditions wherein structural and/or neurogenic abnormalities explain the symptom, or are part of a generalized process (eg, diabetic neuropathy) are not included within functional fecal incontinence. Functional fecal incontinence is a common, but underrecognized symptom, which is equally prevalent in men and women, and can often cause considerable distress. The clinical features are useful for guiding diagnostic testing and therapy. Functional anorectal pain syndromes include proctalgia fugax (fleeting pain) and chronic proctalgia; chronic proctalgia may be subdivided into levator ani syndrome and unspecified anorectal pain, which are defined by arbitrary clinical criteria. Functional defecation disorders are characterized by 2 or more symptoms of constipation, with > or =2 of the following features during defecation: impaired evacuation, inappropriate contraction of the pelvic floor muscles, and inadequate propulsive forces. Functional disorders of defecation may be amenable to pelvic floor retraining by biofeedback therapy (such as dyssynergic defecation).

Chronic idiopathic anal pain. Results of a diagnostic-therapeutic protocol in a colorectal referral unit.

PubMed

Armañanzas, Laura; Arroyo, Antonio; Ruiz-Tovar, Jaime; López, Alberto; Santos, Jair; Moya, Pedro; Gómez, María Amparo; Candela, Fernando; Calpena, Rafael

2015-01-01

Chronic idiopathic anal pain (CIAP) remains a diagnosis of exclusion. Its study and management still lack a standardized protocol. The aim of this study is to evaluate the results obtained with the diagnostic-therapeutic protocol established in our service. We performed a retrospective study of patients diagnosed with CIAP at the Colorectal Unit of the General University Hospital of Elche, between 2005 and 2011. We evaluated 57 patients with a diagnosis of chronic anal pain for functional anorectal disease (FAD). After the application of our diagnostic protocol, final diagnosis of chronic anal pain (CAP) was achieved in 43 cases (75%), including 22 cases of descending perineum syndrome, 12 of proctalgia fugax, 2 of pudendal neuritis and 7 of coccydynia. In 14 patients exclusion diagnosis of CIAP was established. Among the therapies used on patients with CIAP, biofeedback combined with conservative measures improved symptoms in 43% of the cases. Sacral nerve stimulation was assessed in patients who did not respond to other treatments. Through proper anamnesis, physical examination and complementary tests, a specific diagnosis of the cause of CAP by FAD can be achieved, reducing exclusion diagnosis of CIAP to 25% of cases. Conservative measures combined with biofeedback achieved an improvement in pain in more than 40% of the cases of CIAP in our study. Sacral nerve stimulation can be considered as a treatment option in refractory cases. Copyright © 2013 AEC. Publicado por Elsevier España, S.L.U. All rights reserved.

Pharmacotherapy of retinal disease with visual cycle modulators.

PubMed

Hussain, Rehan M; Gregori, Ninel Z; Ciulla, Thomas A; Lam, Byron L

2018-04-01

Pharmacotherapy with visual cycle modulators (VCMs) is under investigation for retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Stargardt macular dystrophy (SMD) and nonexudative age-related macular degeneration (AMD), all blinding diseases that lack effective treatment options. Areas covered: The authors review investigational VCMs, including oral retinoids, 9-cis-retinyl-acetate (zuretinol) and 9-cis-β-carotene, which restore 11-cis-retinal levels in RP and LCA caused by LRAT and RPE65 gene mutations, and may improve visual acuity and visual fields. Therapies for SMD aiming to decrease accumulation of toxic Vitamin A dimers and lipofuscin in the retina and retinal pigment epithelium (RPE) include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Mouse models of SMD show promising data for these treatments, though proof of efficacy in humans is currently lacking. Fenretinide and emixustat are investigational VCMs for dry AMD, though neither has been shown to reduce geographic atrophy or improve vision in human trials. A1120 prevents retinol transport into the RPE and may spare the side effects typically seen in VCMs (nyctalopia and chromatopsia) per mouse studies. Expert opinion: Oral VCMs may be feasible treatment options for degenerative retinal diseases based on pre-clinical and some early clinical studies. Further trials are warranted to assess their efficacy and safety in humans.

Hidden Genetic Variation in LCA9-Associated Congenital Blindness Explained by 5'UTR Mutations and Copy-Number Variations of NMNAT1.

PubMed

Coppieters, Frauke; Todeschini, Anne Laure; Fujimaki, Takuro; Baert, Annelot; De Bruyne, Marieke; Van Cauwenbergh, Caroline; Verdin, Hannah; Bauwens, Miriam; Ongenaert, Maté; Kondo, Mineo; Meire, Françoise; Murakami, Akira; Veitia, Reiner A; Leroy, Bart P; De Baere, Elfride

2015-12-01

Leber congenital amaurosis (LCA) is a severe autosomal-recessive retinal dystrophy leading to congenital blindness. A recently identified LCA gene is NMNAT1, located in the LCA9 locus. Although most mutations in blindness genes are coding variations, there is accumulating evidence for hidden noncoding defects or structural variations (SVs). The starting point of this study was an LCA9-associated consanguineous family in which no coding mutations were found in the LCA9 region. Exploring the untranslated regions of NMNAT1 revealed a novel homozygous 5'UTR variant, c.-70A>T. Moreover, an adjacent 5'UTR variant, c.-69C>T, was identified in a second consanguineous family displaying a similar phenotype. Both 5'UTR variants resulted in decreased NMNAT1 mRNA abundance in patients' lymphocytes, and caused decreased luciferase activity in human retinal pigment epithelial RPE-1 cells. Second, we unraveled pseudohomozygosity of a coding NMNAT1 mutation in two unrelated LCA patients by the identification of two distinct heterozygous partial NMNAT1 deletions. Molecular characterization of the breakpoint junctions revealed a complex Alu-rich genomic architecture. Our study uncovered hidden genetic variation in NMNAT1-associated LCA and emphasized a shift from coding to noncoding regulatory mutations and repeat-mediated SVs in the molecular pathogenesis of heterogeneous recessive disorders such as hereditary blindness. © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

Sleep quality and functional gastrointestinal disorders. A psychological issue.

PubMed

Bouchoucha, Michel; Mary, Florence; Bon, Cyriaque; Bejou, Bakhtiar; Airinei, Gheorghe; Benamouzig, Robert

2018-02-01

Sleep disorders are often associated with functional gastrointestinal disorders (FGIDs). This study aims to evaluate the association of sleep disorders with specific FGIDs and to assess the related importance of psychological disorders. We included 1009 consecutive patients with FGIDs (70.9% females). The patients completed a Rome III questionnaire and after a psychological evaluation on anxiety and depression they were classified according to their sleep disorders using a 7-point grading scale: Groups 1-3, drowsiness (severe, moderate, mild); Group 4, no change; Groups 5-7, insomnia (mild, moderate, severe). Multinomial logistic regression using sleep group as a dependent variable with no sleep change as reference and body mass index, FGIDs, anxiety and depression as independent variables were used for statistical analysis. Altogether 667 (66.1%) patients reported changes in sleep disorders, of whom 487 (48.3%) had decreased sleep and 180 (17.8%) had increased sleep while 342 (33.9%) reported no change. Depression was lower in patients with no change in sleep pattern and increased with the severity of their sleep disorder (P < 0.001). State-anxiety is associated with moderate drowsiness (P = 0.024), while trait anxiety is associated with mild insomnia (P = 0.048). FGIDs associated with sleep disorders included chest pain, epigastric pain syndrome, irritable bowel syndrome with constipation, diarrhea, bloating, fecal incontinence and proctalgia fugax. Sleep disorders are associated with FGIDs, especially in the presence of depressive symptoms. © 2018 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Presacral abscess as a rare complication of sacral nerve stimulator implantation.

PubMed

Gumber, A; Ayyar, S; Varia, H; Pettit, S

2017-03-01

A 50-year-old man with intractable anal pain attributed to proctalgia fugax underwent insertion of a sacral nerve stimulator via the right S3 vertebral foramen for pain control with good symptomatic relief. Thirteen months later, he presented with signs of sepsis. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a large presacral abscess. MRI demonstrated increased enhancement along the pathway of the stimulator electrode, indicating that the abscess was caused by infection introduced at the time of sacral nerve stimulator placement. The patient was treated with broad spectrum antibiotics, and the sacral nerve stimulator and electrode were removed. Attempts were made to drain the abscess transrectally using minimally invasive techniques but these were unsuccessful and CT guided transperineal drainage was then performed. Despite this, the presacral abscess progressed, developing enlarging gas locules and extending to the pelvic brim to involve the aortic bifurcation, causing hydronephrosis and radiological signs of impending sacral osteomyelitis. MRI showed communication between the rectum and abscess resulting from transrectal drainage. In view of the progressive presacral sepsis, a laparotomy was performed with drainage of the abscess, closure of the upper rectum and formation of a defunctioning end sigmoid colostomy. Following this, the presacral infection resolved. Presacral abscess formation secondary to an infected sacral nerve stimulator electrode has not been reported previously. Our experience suggests that in a similar situation, the optimal management is to perform laparotomy with drainage of the presacral abscess together with simultaneous removal of the sacral nerve stimulator and electrode.

Presacral abscess as a rare complication of sacral nerve stimulator implantation

PubMed Central

Gumber, A; Ayyar, S; Varia, H

2017-01-01

A 50-year-old man with intractable anal pain attributed to proctalgia fugax underwent insertion of a sacral nerve stimulator via the right S3 vertebral foramen for pain control with good symptomatic relief. Thirteen months later, he presented with signs of sepsis. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a large presacral abscess. MRI demonstrated increased enhancement along the pathway of the stimulator electrode, indicating that the abscess was caused by infection introduced at the time of sacral nerve stimulator placement. The patient was treated with broad spectrum antibiotics, and the sacral nerve stimulator and electrode were removed. Attempts were made to drain the abscess transrectally using minimally invasive techniques but these were unsuccessful and CT guided transperineal drainage was then performed. Despite this, the presacral abscess progressed, developing enlarging gas locules and extending to the pelvic brim to involve the aortic bifurcation, causing hydronephrosis and radiological signs of impending sacral osteomyelitis. MRI showed communication between the rectum and abscess resulting from transrectal drainage. In view of the progressive presacral sepsis, a laparotomy was performed with drainage of the abscess, closure of the upper rectum and formation of a defunctioning end sigmoid colostomy. Following this, the presacral infection resolved. Presacral abscess formation secondary to an infected sacral nerve stimulator electrode has not been reported previously. Our experience suggests that in a similar situation, the optimal management is to perform laparotomy with drainage of the presacral abscess together with simultaneous removal of the sacral nerve stimulator and electrode. PMID:28071947

Epidemiology of the functional gastrointestinal disorders diagnosed according to Rome II criteria: an Australian population-based study.

PubMed

Boyce, P M; Talley, N J; Burke, C; Koloski, N A

2006-01-01

Population-based studies of the prevalence of all functional gastrointestinal disorders (FGID) using the Rome II criteria are lacking. It is also not certain whether subjects who meet the Rome II criteria for an FGID are different in terms of demographic and psychological characteristics from those subjects meeting exclusively the more restrictive Rome I criteria. To determine whether using the more restrictive Rome I criteria would result in a more biologically determined group of FGID than when the Rome II is applied. Subjects included individuals aged 18 years and older (n = 1,225) from the Penrith population who were initially surveyed with the Penrith District Health Survey in 1997. Subjects were sent a self-report questionnaire that contained items on gastrointestinal symptoms applying the Rome II criteria. Subjects were also assessed on psychological and personality factors and on physical and mental functioning. A total of 36.1% (n = 275) of respondents was diagnosed with an FGID according to Rome II criteria. The five most prevalent FGID were functional heartburn (10.4%), irritable bowel syndrome (8.9%), functional incontinence (7.6%), proctalgia fugax (6.5%) and functional chest pain (5.1%). Subjects meeting Rome II only criteria for FGID scored significantly higher on measures of psychological caseness and emotionality than Rome I only subjects, and these were independently associated with meeting Rome I only versus Rome II only criteria for FGID. The Rome II criteria FGID are common and do not appear to identify a vastly different group of FGID sufferers compared with the earlier Rome I criteria.

The CRB1 Complex: Following the Trail of Crumbs to a Feasible Gene Therapy Strategy.

PubMed

Quinn, Peter M; Pellissier, Lucie P; Wijnholds, Jan

2017-01-01

Once considered science fiction, gene therapy is rapidly becoming scientific reality, targeting a growing number of the approximately 250 genes linked to hereditary retinal disorders such as retinitis pigmentosa and Leber's congenital amaurosis. Powerful new technologies have emerged, leading to the development of humanized models for testing and screening these therapies, bringing us closer to the goal of personalized medicine. These tools include the ability to differentiate human induced pluripotent stem cells (iPSCs) to create a "retina-in-a-dish" model and the self-formed ectodermal autonomous multi-zone, which can mimic whole eye development. In addition, highly specific gene-editing tools are now available, including the CRISPR/Cas9 system and the recently developed homology-independent targeted integration approach, which allows gene editing in non-dividing cells. Variants in the CRB1 gene have long been associated with retinopathies, and more recently the CRB2 gene has also been shown to have possible clinical relevance with respect to retinopathies. In this review, we discuss the role of the CRB protein complex in patients with retinopathy. In addition, we discuss new opportunities provided by stem cells and gene-editing tools, and we provide insight into how the retinal therapeutic pipeline can be improved. Finally, we discuss the current state of adeno-associated virus-mediated gene therapy and how it can be applied to treat retinopathies associated with mutations in CRB1 .

RPE65 gene therapy slows cone loss in Rpe65-deficient dogs.

PubMed

Mowat, F M; Breuwer, A R; Bartoe, J T; Annear, M J; Zhang, Z; Smith, A J; Bainbridge, J W B; Petersen-Jones, S M; Ali, R R

2013-05-01

Recent clinical trials of retinal pigment epithelium gene (RPE65) supplementation therapy in Leber congenital amaurosis type 2 patients have demonstrated improvements in rod and cone function, but it may be some years before the effects of therapy on photoreceptor survival become apparent. The Rpe65-deficient dog is a very useful pre-clinical model in which to test efficacy of therapies, because the dog has a retina with a high degree of similarity to that of humans. In this study, we evaluated the effect of RPE65 gene therapy on photoreceptor survival in order to predict the potential benefit and limitations of therapy in patients. We examined the retinas of Rpe65-deficient dogs after RPE65 gene therapy to evaluate the preservation of rods and cone photoreceptor subtypes. We found that gene therapy preserves both rods and cones. While the moderate loss of rods in the Rpe65-deficient dog retina is slowed by gene therapy, S-cones are lost extensively and gene therapy can prevent that loss, although only within the treated area. Although LM-cones are not lost extensively, cone opsin mislocalization indicates that they are stressed, and this can be partially reversed by gene therapy. Our results suggest that gene therapy may be able to slow cone degeneration in patients if intervention is sufficiently early and also that it is probably important to treat the macula in order to preserve central function.

[Role of physical, psychological and sexual abuse in functional digestive disorders. A case-controls trial.].

PubMed

Remes-Troche, J M; Cid-Juárez, S; Campos-Ramos, I; Ramos-de la Medina, A; Galmiche, A; Schmulson-Wasserman, M; Roesch-Dietlen, F

2008-01-01

Abuse has been considered a significant factor on the development of functional gastrointestinal disorders (FGID), especially for severe and treatment-refractory patients. The aim of our study was to evaluate the presence of all FGID according to Rome II criteria, in a group of women with history of physical, psychological and/or sexual abuse. A cross sectional study was performed in 96 women (37 +/- 12 years of age) with history of physical, psychological and/or sexual abuse (cases); and 96 open population women (36 +/- 14 years of age) (controls). The following evaluations were administered: Rome II questionnaire, a self-administered instrument to evaluate history of physical (beating), psychological(insults, public humiliation) and/or sexual abuse (rape, coercion), and HAD questionnaire. Among 96 women with history of abuse,91 (95%) reported to have suffered psychological abuse, 72 (75%) physical abuse, and 24 (25%)sexual abuse. Women with history of abuse had a higher prevalence of rumination (6% vs. 0%, p= 0.02), functional heartburn (26% vs. 13%, p =0.04), aerofagia (17% vs. 5%, p = 0.019), irritable bowel syndrome (38% vs. 18%, p = 0.002), fecalin continence (16% vs. 4%, p = 0.01), elevator anisyndrome (5% vs. 0%, p = 0.05), and proctalgia fugax (29% vs. 15%, p = 0.02) compared to controls. There was a positive correlation between anxiety (r = 0.5, p = 0.001) and depression scores(r = 0.45, p = 0.001), and the number of FGID. We demonstrated a high prevalence of FGID among women with history of physical,psychological, and/or sexual abuse. In this association,concomitant anxiety and depression play a significant role.

Autofluorescence Imaging With Near-Infrared Excitation:Normalization by Reflectance to Reduce Signal From Choroidal Fluorophores

PubMed Central

Cideciyan, Artur V.; Swider, Malgorzata; Jacobson, Samuel G.

2015-01-01

Purpose. We previously developed reduced-illuminance autofluorescence imaging (RAFI) methods involving near-infrared (NIR) excitation to image melanin-based fluorophores and short-wavelength (SW) excitation to image lipofuscin-based flurophores. Here, we propose to normalize NIR-RAFI in order to increase the relative contribution of retinal pigment epithelium (RPE) fluorophores. Methods. Retinal imaging was performed with a standard protocol holding system parameters invariant in healthy subjects and in patients. Normalized NIR-RAFI was derived by dividing NIR-RAFI signal by NIR reflectance point-by-point after image registration. Results. Regions of RPE atrophy in Stargardt disease, AMD, retinitis pigmentosa, choroideremia, and Leber congenital amaurosis as defined by low signal on SW-RAFI could correspond to a wide range of signal on NIR-RAFI depending on the contribution from the choroidal component. Retinal pigment epithelium atrophy tended to always correspond to high signal on NIR reflectance. Normalizing NIR-RAFI reduced the choroidal component of the signal in regions of atrophy. Quantitative evaluation of RPE atrophy area showed no significant differences between SW-RAFI and normalized NIR-RAFI. Conclusions. Imaging of RPE atrophy using lipofuscin-based AF imaging has become the gold standard. However, this technique involves bright SW lights that are uncomfortable and may accelerate the rate of disease progression in vulnerable retinas. The NIR-RAFI method developed here is a melanin-based alternative that is not absorbed by opsins and bisretinoid moieties, and is comfortable to view. Further development of this method may result in a nonmydriatic and comfortable imaging method to quantify RPE atrophy extent and its expansion rate. PMID:26024124

Focus on Kir7.1: physiology and channelopathy

PubMed Central

Kumar, Mohit; Pattnaik, Bikash R

2014-01-01

Genetic studies have linked alterations in Kir7.1 channel to diverse pathologies. We summarize functional relevance of Kir7.1 channel in retinal pigment epithelium (RPE), regulation of channel function by various cytoplasmic metabolites, and mutations that cause channelopathies. At the apical membrane of RPE, K+ channels contribute to subretinal K+ homeostasis and support Na+/K+ pump and Na+-K+-2Cl− cotransporter function by providing a pathway for K+ secretion. Electrophysiological studies have established that barium- and cesium-sensitive inwardly rectifying K+ (Kir) channels make up a major component of the RPE apical membrane K+ conductance. Native human RPE expresses transcripts for Kir1.1, Kir2.1, Kir2.2, Kir3.1, Kir3.4, Kir4.2, and Kir6.1, albeit at levels at least 50-fold lower than Kir7.1. Kir7.1 is structurally similar to other Kir channels, consisting of 2 trans-membrane domains, a pore-forming loop that contains the selectivity filter, and 2 cytoplasmic polar tails. Within the cytoplasmic structure, clusters of amino acid sequences form regulatory domains that interact with cellular metabolites and control the opening and closing of the channel. Recent evidence indicated that intrinsic sequence motifs present in Kir7.1 control surface expression. Mutant Kir7.1 channels are associated with inherited eye pathologies such as Snowflake Vitreoretinal Degeneration (SVD) and Lebers Congenital Amaurosis (LCA16). Based on the current evidence, mutations implicated in channelopathies have the potential to be used for genetic testing to diagnose blindness due to Kir7.1. PMID:25558901

Braille use among Norwegian children from 1967 to 2007: trends in the underlying causes.

PubMed

Augestad, Liv Berit; Klingenberg, Oliv; Fosse, Per

2012-08-01

The aim of the study was to estimate the occurrence, diagnoses and time trends among Norwegian children that have received education in braille from 1967 to 2007. We used a retrospective population-based study design. The health care system is free for all inhabitants in Norway. We included all children that had received braille education the last four decades. From each student's record, we abstracted year born, country of birth, gender, year diagnosed, diagnosis, classification of visual impairment and type of reading media. We identified 287 children (137 girls and 150 boys) that had received braille education over the last 40 years. Of these, 262 (91.3%) children were born in Norway, 145 (53.7%) were diagnosed within the first year of life and 59 (20.6%) from age of one to five. The most frequent diagnoses were Retinopathy of Prematurity (ROP), Juvenile Ceroid Lipofuscinoses (JNCL), Lebers Congenital Amaurosis (LCA) and Retinitis Pigmentosa (RP). Among the children, 63% (N = 170) used braille only, 9% (N = 25) braille and print, but priority braille, and 27% (N = 73) braille and print, priority print. The number of children with ROP using braille had a peak in 1977, then the number declined. The number diagnosed with LCA increased from 1987 to 1992. The number of braille users among children diagnosed with JNCL tended to increase substantially after 1992. Braille education seemed to be dependent of trends in diagnoses as well as trends in recommendations from professional educators. © 2011 The Authors. Acta Ophthalmologica © 2011 Acta Ophthalmologica Scandinavica Foundation.

Using CRISPR-Cas9 to Generate Gene-Corrected Autologous iPSCs for the Treatment of Inherited Retinal Degeneration.

PubMed

Burnight, Erin R; Gupta, Manav; Wiley, Luke A; Anfinson, Kristin R; Tran, Audrey; Triboulet, Robinson; Hoffmann, Jeremy M; Klaahsen, Darcey L; Andorf, Jeaneen L; Jiao, Chunhua; Sohn, Elliott H; Adur, Malavika K; Ross, Jason W; Mullins, Robert F; Daley, George Q; Schlaeger, Thorsten M; Stone, Edwin M; Tucker, Budd A

2017-09-06

Patient-derived induced pluripotent stem cells (iPSCs) hold great promise for autologous cell replacement. However, for many inherited diseases, treatment will likely require genetic repair pre-transplantation. Genome editing technologies are useful for this application. The purpose of this study was to develop CRISPR-Cas9-mediated genome editing strategies to target and correct the three most common types of disease-causing variants in patient-derived iPSCs: (1) exonic, (2) deep intronic, and (3) dominant gain of function. We developed a homology-directed repair strategy targeting a homozygous Alu insertion in exon 9 of male germ cell-associated kinase (MAK) and demonstrated restoration of the retinal transcript and protein in patient cells. We generated a CRISPR-Cas9-mediated non-homologous end joining (NHEJ) approach to excise a major contributor to Leber congenital amaurosis, the IVS26 cryptic-splice mutation in CEP290, and demonstrated correction of the transcript and protein in patient iPSCs. Lastly, we designed allele-specific CRISPR guides that selectively target the mutant Pro23His rhodopsin (RHO) allele, which, following delivery to both patient iPSCs in vitro and pig retina in vivo, created a frameshift and premature stop that would prevent transcription of the disease-causing variant. The strategies developed in this study will prove useful for correcting a wide range of genetic variants in genes that cause inherited retinal degeneration. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

American Journal of Ophthalmology Contributions to Ophthalmic Genetics.

PubMed

MacDonald, Ian M; Sieving, Pamela C

2018-06-01

To review the contributions to ophthalmic genetics through the American Journal of Ophthalmology (AJO). Perspective. A literature search to retrieve original articles, letters, editorials, and published lectures from 1966 to 2017, providing a 50-year review. Titles were excluded that gave no reference to genetics or that presented findings related to a nongenetic ocular condition. From a search of the Scopus database, 719 articles were ascertained. Of these, 115 were excluded because the title did not reference a genetic condition or have a focus on genetic factors; 4 were excluded because they described animal phenotypes (1966-1967); and 4 were excluded owing to having received no citations up to and including 2015. The highest number of citations was 283 times for a single article on familial aggregation in age-related macular degeneration. The Web of Science database yielded 771 articles; of these, 118 were excluded owing to not reporting human genetic studies; 55 received no citations. The highest number of citations was 307 for a single article, a 1991 paper on Leber hereditary optic neuropathy. The Journal's contributions to our understanding of the heritability of human ocular traits have been broad and deep, with international reach. The development of new techniques fostered new concepts and new approaches to rapidly expand the number of known single gene disorders with a defined molecular genetic cause. Reports on Mendelian and complex traits in the AJO abound, along with 6 Edward Jackson Memorial Lectures on retinal dystrophies, Leber congenital amaurosis, age-related macular degeneration, and glaucoma. Copyright © 2018 Elsevier Inc. All rights reserved.

The gene therapy revolution in ophthalmology.

PubMed

Al-Saikhan, Fahad I

2013-04-01

The advances in gene therapy hold significant promise for the treatment of ophthalmic conditions. Several studies using animal models have been published. Animal models on retinitis pigmentosa, Leber's Congenital Amaurosis (LCA), and Stargardt disease have involved the use of adeno-associated virus (AAV) to deliver functional genes into mice and canines. Mice models have been used to show that a mutation in cGMP phosphodiesterase that results in retinitis pigmentosa can be corrected using rAAV vectors. Additionally, rAAV vectors have been successfully used to deliver ribozyme into mice with a subsequent improvement in autosomal dominant retinitis pigmentosa. By using dog models, researchers have made progress in studying X-linked retinitis pigmentosa which results from a RPGR gene mutation. Mouse and canine models have also been used in the study of LCA. The widely studied form of LCA is LCA2, resulting from a mutation in the gene RPE65. Mice and canines that were injected with normal copies of RPE65 gene showed signs such as improved retinal pigment epithelium transduction, visual acuity, and functional recovery. Studies on Stargardt disease have shown that mutations in the ABCA4 gene can be corrected with AAV vectors, or nanoparticles. Gene therapy for the treatment of red-green color blindness was successful in squirrel monkeys. Plans are at an advanced stage to begin clinical trials. Researchers have also proved that CD59 can be used with AMD. Gene therapy is also able to treat primary open angle glaucoma (POAG) in animal models, and studies show it is economically viable.

Preimplantation genetic diagnosis as a strategy to prevent having a child born with an heritable eye disease.

PubMed

Yahalom, Claudia; Macarov, Michal; Lazer-Derbeko, Galit; Altarescu, Gheona; Imbar, Tal; Hyman, Jordana H; Eldar-Geva, Talia; Blumenfeld, Anat

2018-05-21

In developed countries, genetically inherited eye diseases are responsible for a high percentage of childhood visual impairment. We aim to report our experience using preimplantation genetic diagnostics (PGD) in order to avoid transmitting a genetic form of eye disease associated with childhood visual impairment and ocular cancer. Retrospective case series of women who underwent in vitro fertilization (IVF) and PGD due to a familial history of inherited eye disease and/or ocular cancer, in order to avoid having a child affected with the known familial disease. Each family underwent genetic testing in order to identify the underlying disease-causing mutation. IVF and PGD treatment were performed; unaffected embryos were implanted in their respective mothers. Thirty-five unrelated mothers underwent PGD, and the following hereditary conditions were identified in their families: albinism (10 families); retinitis pigmentosa (7 families); retinoblastoma (4 families); blue cone monochromatism, achromatopsia, and aniridia (2 families each); and Hermansky-Pudlak syndrome, Leber congenital amaurosis, Norrie disease, papillorenal syndrome, primary congenital cataract, congenital glaucoma, Usher syndrome type 1F, and microphthalmia with coloboma (1 family each). Following a total of 88 PGD cycles, 18 healthy (i.e., unaffected) children were born. Our findings underscore the importance an ophthalmologist plays in informing patients regarding the options now available for using prenatal and preimplantation genetic diagnosis to avoid having a child with a potentially devastating genetic form of eye disease or ocular cancer. This strategy is highly relevant, particularly given the limited options currently available for treating these conditions.

Progress and challenges in viral vector manufacturing

PubMed Central

van der Loo, Johannes C.M.; Wright, J. Fraser

2016-01-01

Promising results in several clinical studies have emphasized the potential of gene therapy to address important medical needs and initiated a surge of investments in drug development and commercialization. This enthusiasm is driven by positive data in clinical trials including gene replacement for Hemophilia B, X-linked Severe Combined Immunodeficiency, Leber's Congenital Amaurosis Type 2 and in cancer immunotherapy trials for hematological malignancies using chimeric antigen receptor T cells. These results build on the recent licensure of the European gene therapy product Glybera for the treatment of lipoprotein lipase deficiency. The progress from clinical development towards product licensure of several programs presents challenges to gene therapy product manufacturing. These include challenges in viral vector-manufacturing capacity, where an estimated 1–2 orders of magnitude increase will likely be needed to support eventual commercial supply requirements for many of the promising disease indications. In addition, the expanding potential commercial product pipeline and the continuously advancing development of recombinant viral vectors for gene therapy require that products are well characterized and consistently manufactured to rigorous tolerances of purity, potency and safety. Finally, there is an increase in regulatory scrutiny that affects manufacturers of investigational drugs for early-phase clinical trials engaged in industry partnerships. Along with the recent increase in biopharmaceutical funding in gene therapy, industry partners are requiring their academic counterparts to meet higher levels of GMP compliance at earlier stages of clinical development. This chapter provides a brief overview of current progress in the field and discusses challenges in vector manufacturing. PMID:26519140

The gene therapy revolution in ophthalmology

PubMed Central

Al-Saikhan, Fahad I.

2013-01-01

The advances in gene therapy hold significant promise for the treatment of ophthalmic conditions. Several studies using animal models have been published. Animal models on retinitis pigmentosa, Leber’s Congenital Amaurosis (LCA), and Stargardt disease have involved the use of adeno-associated virus (AAV) to deliver functional genes into mice and canines. Mice models have been used to show that a mutation in cGMP phosphodiesterase that results in retinitis pigmentosa can be corrected using rAAV vectors. Additionally, rAAV vectors have been successfully used to deliver ribozyme into mice with a subsequent improvement in autosomal dominant retinitis pigmentosa. By using dog models, researchers have made progress in studying X-linked retinitis pigmentosa which results from a RPGR gene mutation. Mouse and canine models have also been used in the study of LCA. The widely studied form of LCA is LCA2, resulting from a mutation in the gene RPE65. Mice and canines that were injected with normal copies of RPE65 gene showed signs such as improved retinal pigment epithelium transduction, visual acuity, and functional recovery. Studies on Stargardt disease have shown that mutations in the ABCA4 gene can be corrected with AAV vectors, or nanoparticles. Gene therapy for the treatment of red–green color blindness was successful in squirrel monkeys. Plans are at an advanced stage to begin clinical trials. Researchers have also proved that CD59 can be used with AMD. Gene therapy is also able to treat primary open angle glaucoma (POAG) in animal models, and studies show it is economically viable. PMID:24227970

The Pathway From Genes to Gene Therapy in Glaucoma: A Review of Possibilities for Using Genes as Glaucoma Drugs

PubMed Central

Borrás, Teresa

2018-01-01

Treatment of diseases with gene therapy is advancing rapidly. The use of gene therapy has expanded from the original concept of replacing the mutated gene causing the disease to the use of genes to control nonphysiological levels of expression or to modify pathways known to affect the disease. Genes offer numerous advantages over conventional drugs. They have longer duration of action and are more specific. Genes can be delivered to the target site by naked DNA, cells, nonviral, and viral vectors. The enormous progress of the past decade in molecular biology and delivery systems has provided ways for targeting genes to the intended cell/tissue and safe, long-term vectors. The eye is an ideal organ for gene therapy. It is easily accessible and it is an immune-privileged site. Currently, there are clinical trials for diseases affecting practically every tissue of the eye, including those to restore vision in patients with Leber congenital amaurosis. However, the number of eye trials compared with those for systemic diseases is quite low (1.8%). Nevertheless, judging by the vast amount of ongoing preclinical studies, it is expected that such number will increase considerably in the near future. One area of great need for eye gene therapy is glaucoma, where a long-term gene drug would eliminate daily applications and compliance issues. Here, we review the current state of gene therapy for glaucoma and the possibilities for treating the trabecular meshwork to lower intraocular pressure and the retinal ganglion cells to protect them from neurodegeneration. PMID:28161916

Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration

PubMed Central

Ma, Hongwei; Thapa, Arjun; Morris, Lynsie; Redmond, T. Michael; Baehr, Wolfgang; Ding, Xi-Qin

2014-01-01

Cone phototransduction and survival of cones in the human macula is essential for color vision and for visual acuity. Progressive cone degeneration in age-related macular degeneration, Stargardt disease, and recessive cone dystrophies is a major cause of blindness. Thyroid hormone (TH) signaling, which regulates cell proliferation, differentiation, and apoptosis, plays a central role in cone opsin expression and patterning in the retina. Here, we investigated whether TH signaling affects cone viability in inherited retinal degeneration mouse models. Retinol isomerase RPE65-deficient mice [a model of Leber congenital amaurosis (LCA) with rapid cone loss] and cone photoreceptor function loss type 1 mice (severe recessive achromatopsia) were used to determine whether suppressing TH signaling with antithyroid treatment reduces cone death. Further, cone cyclic nucleotide-gated channel B subunit-deficient mice (moderate achromatopsia) and guanylate cyclase 2e-deficient mice (LCA with slower cone loss) were used to determine whether triiodothyronine (T3) treatment (stimulating TH signaling) causes deterioration of cones. We found that cone density in retinol isomerase RPE65-deficient and cone photoreceptor function loss type 1 mice increased about sixfold following antithyroid treatment. Cone density in cone cyclic nucleotide-gated channel B subunit-deficient and guanylate cyclase 2e-deficient mice decreased about 40% following T3 treatment. The effect of TH signaling on cone viability appears to be independent of its regulation on cone opsin expression. This work demonstrates that suppressing TH signaling in retina dystrophy mouse models is protective of cones, providing insights into cone preservation and therapeutic interventions. PMID:24550448

[Long-term follow-up of patients with suprasellar germinomas].

PubMed

Bauditz, Juergen; Lochs, Herbert; Ventz, Manfred

2007-10-15

Suprasellar germinomas are rare intracranial neoplasms, which mainly occur in children and adolescents and manifest with endocrine symptoms and/or compression syndromes. The clinical, hormonal and morphological findings as well as treatment and complications were investigated in seven patients (six male, one female) with germinomas. Mean age at diagnosis was 19.7 years (range 15-32 years). First disease-related symptoms were diabetes insipidus (three patients), loss of libido (two patients), pseudopubertas praecox (one patient), and dwarfism (one patient). However, decisive symptoms leading to final diagnosis were visual disturbances (five patients), pubertas tarda (one patient), and hypogonadism (one patient). All patients were treated by transcranial radiation with a dose of 40-54 Gy. One patient received additional chemotherapy with cisplatin, etoposide, and ifosfamide (PEI). Patients were followed up for 14.6 years (range 7-27 years). Intracranial and pulmonary relapses were observed in two patients. Panhypopituitarism and diabetes insipidus were seen in all patients after treatment. Two patients suffered from loss of vision, two further patients from unilateral amaurosis. One patient developed epilepsy and persistent cognitive impairment. Long-term follow-up shows that two patients died from recurrent disease and decompensated liver cirrhosis, respectively. The other patients are long-term survivors. Full social integration with employment was possible in one case. Suprasellar germinomas cause endocrine symptoms during early tumor stages, however, diagnosis is generally established when ocular symptoms related to tumor compression are already present. Long-term survival is characterized by panhypopituitarism, diabetes insipidus and, partly, ocular or cerebral defects.

Dawn of ocular gene therapy: implications for molecular diagnosis in retinal disease

PubMed Central

Jacques, ZANEVELD; Feng, WANG; Xia, WANG; Rui, CHEN

2013-01-01

Personalized medicine aims to utilize genomic information about patients to tailor treatment. Gene replacement therapy for rare genetic disorders is perhaps the most extreme form of personalized medicine, in that the patients’ genome wholly determines their treatment regimen. Gene therapy for retinal disorders is poised to become a clinical reality. The eye is an optimal site for gene therapy due to the relative ease of precise vector delivery, immune system isolation, and availability for monitoring of any potential damage or side effects. Due to these advantages, clinical trials for gene therapy of retinal diseases are currently underway. A necessary precursor to such gene therapies is accurate molecular diagnosis of the mutation(s) underlying disease. In this review, we discuss the application of Next Generation Sequencing (NGS) to obtain such a diagnosis and identify disease causing genes, using retinal disorders as a case study. After reviewing ocular gene therapy, we discuss the application of NGS to the identification of novel Mendelian disease genes. We then compare current, array based mutation detection methods against next NGS-based methods in three retinal diseases: Leber’s Congenital Amaurosis, Retinitis Pigmentosa, and Stargardt’s disease. We conclude that next-generation sequencing based diagnosis offers several advantages over array based methods, including a higher rate of successful diagnosis and the ability to more deeply and efficiently assay a broad spectrum of mutations. However, the relative difficulty of interpreting sequence results and the development of standardized, reliable bioinformatic tools remain outstanding concerns. In this review, recent advances NGS based molecular diagnoses are discussed, as well as their implications for the development of personalized medicine. PMID:23393028

Dysfunction of outer segment guanylate cyclase caused by retinal disease related mutations

PubMed Central

Zägel, Patrick; Koch, Karl-Wilhelm

2014-01-01

Membrane bound guanylate cyclases are expressed in rod and cone cells of the vertebrate retina and mutations in several domains of rod outer segment guanylate cyclase 1 (ROS-GC1 encoded by the gene GUCY2D) correlate with different forms of retinal degenerations. In the present work we investigated the biochemical consequences of three point mutations, one is located in position P575L in the juxtamembrane domain close to the kinase homology domain and two are located in the cyclase catalytic domain at H1019P and P1069R. These mutations correlate with various retinal diseases like autosomal dominant progressive cone degeneration, e.g., Leber Congenital Amaurosis and a juvenile form of retinitis pigmentosa. Wildtype and mutant forms of ROS-GC1 were heterologously expressed in HEK cells, their cellular distribution was investigated and activity profiles in the presence and absence of guanylate cyclase-activating proteins were measured. The mutant P575L was active under all tested conditions, but it displayed a twofold shift in the Ca2+-sensitivity, whereas the mutant P1069R remained inactive despite normal expression levels. The mutation H1019P caused the cyclase to become more labile. The different biochemical consequences of these mutations seem to reflect the different clinical symptoms. The mutation P575L induces a dysregulation of the Ca2+-sensitive cyclase activation profile causing a slow progression of the disease by the distortion of the Ca2+-cGMP homeostasis. In contrast, a strong reduction in cGMP synthesis due to an inactive or structurally unstable ROS-GC1 would trigger more severe forms of retinal diseases. PMID:24616660

Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration.

PubMed

Yang, Fan; Ma, Hongwei; Belcher, Joshua; Butler, Michael R; Redmond, T Michael; Boye, Sanford L; Hauswirth, William W; Ding, Xi-Qin

2016-12-01

Recent studies have implicated thyroid hormone (TH) signaling in cone photoreceptor viability. Using mouse models of retinal degeneration, we found that antithyroid treatment preserves cones. This work investigates the significance of targeting intracellular TH components locally in the retina. The cellular TH level is mainly regulated by deiodinase iodothyronine (DIO)-2 and -3. DIO2 converts thyroxine (T4) to triiodothyronine (T3), which binds to the TH receptor, whereas DIO3 degrades T3 and T4. We examined cone survival after overexpression of DIO3 and inhibition of DIO2 and demonstrated the benefits of these manipulations. Subretinal delivery of AAV5-IRBP/GNAT2-DIO3, which directs expression of human DIO3 specifically in cones, increased cone density by 30-40% in a Rpe65 -/- mouse model of Lebers congenital amaurosis (LCA) and in a Cpfl1 mouse with Pde6c defect model of achromatopsia, compared with their respective untreated controls. Intravitreal and topical delivery of the DIO2 inhibitor iopanoic acid also significantly improved cone survival in the LCA model mice. Moreover, the expression levels of DIO2 and Slc16a2 were significantly higher in the diseased retinas, suggesting locally elevated TH signaling. We show that targeting DIOs protects cones, and intracellular inhibition of TH components locally in the retina may represent a novel strategy for retinal degeneration management.-Yang, F., Ma, H., Belcher, J., Butler, M. R., Redmond, T. M., Boye, S. L., Hauswirth, W. W., Ding, X.-Q. Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration. © FASEB.

Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1.

PubMed

Li, Sisi; Xi, Quansheng; Zhang, Xiaoyu; Yu, Dong; Li, Lin; Jiang, Zhenyang; Chen, Qiuyun; Wang, Qing K; Traboulsi, Elias I

2018-06-01

We investigated an Amish family in which three siblings presented with an early-onset childhood retinal dystrophy inherited in an autosomal recessive fashion. Genome-wide linkage analysis identified significant linkage to marker D2S2216 on 2q11 with a two-point LOD score of 1.95 and a multi-point LOD score of 3.76. Whole exome sequencing was then performed for the three affected individuals and identified a homozygous nonsense mutation (c.C1813T, p.R605X) in the cyclin and CBS domain divalent metal cation transport mediator 4 (CNNM4) gene located within the 2p14-2q14 Jalili syndrome locus. The initial assessment and collection of the family were performed before the clinical delineation of Jalili syndrome. Another assessment was made after the discovery of the responsible gene and the dental abnormalities characteristic of Jalili syndrome were retrospectively identified. The p.R605X mutation represents the first probable founder mutation of Jalili syndrome identified in the Amish community. The molecular mechanism underlying Jalili syndrome is unknown. Here we show that CNNM4 interacts with IQCB1, which causes Leber congenital amaurosis (LCA) when mutated. A truncated CNNM4 protein starting at R605 significantly increased the rate of apoptosis, and significantly increased the interaction between CNNM4 and IQCB1. Mutation p.R605X may cause Jalili syndrome by a nonsense-mediated decay mechanism, affecting the function of IQCB1 and apoptosis, or both. Our data, for the first time, functionally link Jalili syndrome gene CNNM4 to LCA gene IQCB1, providing important insights into the molecular pathogenic mechanism of retinal dystrophy in Jalili syndrome.

Evaluation of clinical measurements and development of new diagnostic criteria for Takayasu arteritis in a Chinese population.

PubMed

Kong, X; Ma, L; Wu, L; Chen, H; Ma, L; Sun, Y; Wu, W; Ji, Z; Zhang, Z; Yang, C; Ye, S; Chen, S; Dai, S; Xue, Y; Qin, G; Zou, Y; Yu, Q; Jiang, L

2015-01-01

Takayasu arteritis (TA) is a chronic granulomatous large-vessel vasculitis. When diagnosing TA, the criteria designed by the American College of Rheumatology (ACR) are used commonly but they were just classification criteria. There is an urgent need for a new set of diagnostic criteria. One hundred and thirty-one TA patients and 132 control patients with other types of vascular disease were enrolled and both groups were distributed into a "training set" and a "validation set". All general information as well as clinical, laboratory and imaging data were collected. After comparing all the medical records of two groups in the training set, logistic regression and clinical judgment were used to form the new criteria for TA. The new criteria were tested by the validation set. New TA diagnostic criteria within total score 26 include age (<40 years), female, chest pain/chest distress, amaurosis, vascular bruits, a decreased/absent pulse, involvement of the aortic arch or its major branches, and involvement of the abdominal aorta or its branches. Patients with a score ≥ 8 were diagnosed as TA. The sensitivity and specificity of our new criteria were 91.92% and 93.94%, respectively, higher than those of the ACR criteria (75.76%, 85.86%) and the Ishikawa criteria (56.57%, 94.95%). The areas under the ROC curves of the new criteria and ACR criteria were 0.981 and 0.868, respectively (p<0.001). Sensitivity and specificity tested in the validation set were 90.63% and 96.97%, respectively. The new diagnostic criteria exhibited high sensitivity and specificity and have demonstrated to be feasible in the diagnosis of TA.

Genetic testing for retinal dystrophies and dysfunctions: benefits, dilemmas and solutions.

PubMed

Koenekoop, Robert K; Lopez, Irma; den Hollander, Anneke I; Allikmets, Rando; Cremers, Frans P M

2007-07-01

Human retinal dystrophies have unparalleled genetic and clinical diversity and are currently linked to more than 185 genetic loci. Genotyping is a crucial exercise, as human gene-specific clinical trials to study photoreceptor rescue are on their way. Testing confirms the diagnosis at the molecular level and allows for a more precise prognosis of the possible future clinical evolution. As treatments are gene-specific and the 'window of opportunity' is time-sensitive; accurate, rapid and cost-effective genetic testing will play an ever-increasing crucial role. The gold standard is sequencing but is fraught with excessive costs, time, manpower issues and finding non-pathogenic variants. Therefore, no centre offers testing of all currently 132 known genes. Several new micro-array technologies have emerged recently, that offer rapid, cost-effective and accurate genotyping. The new disease chips from Asper Ophthalmics (for Stargardt dystrophy, Leber congenital amaurosis [LCA], Usher syndromes and retinitis pigmentosa) offer an excellent first pass opportunity. All known mutations are placed on the chip and in 4 h a patient's DNA is screened. Identification rates (identifying at least one disease-associated mutation) are currently approximately 70% (Stargardt), approximately 60-70% (LCA) and approximately 45% (Usher syndrome subtype 1). This may be combined with genotype-phenotype correlations that suggest the causal gene from the clinical appearance (e.g. preserved para-arteriolar retinal pigment epithelium suggests the involvement of the CRB1 gene in LCA). As approximately 50% of the retinal dystrophy genes still await discovery, these technologies will improve dramatically as additional novel mutations are added. Genetic testing will then become standard practice to complement the ophthalmic evaluation.

Correlation of ultra-widefield fundus autofluorescence patterns with the underlying genotype in retinal dystrophies and retinitis pigmentosa.

PubMed

Trichonas, George; Traboulsi, Elias I; Ehlers, Justis P

2017-01-01

Ultra-widefield fundus autofluorescence (UW-FAF) allows the characterization of the peripheral retinal features of vitreoretinal diseases. The purpose of this study was to examine possible genotypic/phenotypic correlations of UW-FAF patterns in patients with a variety of retinal dystrophies and retinitis pigmentosa (RP). An IRB-approved retrospective consecutive case series study was performed of genetically characterized retinal dystrophy or RP patients who underwent UW-FAF imaging. UW-FAF was performed with the Optos 200Tx system. Clinical variables, genotypic analysis, and phenotypic characteristics were reviewed. Seventeen patients were identified who had identified mutations in retinal dystrophy or RP genes and who also had undergone UW-FAF. Three patients had X-linked RP with RPGR mutations. Six patients had autosomal dominant RP (four with RHO mutations and one with a PRPF31 mutation, and one with RDS/PRPH2 mutation). Four patients had autosomal recessive RP (four with USH2A mutations). Three patients had Leber Congenital Amaurosis (LCA) with mutations including CRB1, CEP290, and RPGRIP1. Macular hyperautofluorescence was noted in all patients. A ring of hyperautofluorescence was clear in patients with RHO and USH2A mutations, and patients with USH2A mutations demonstrated a second ring of hyperautofluorescence. In the periphery, patients with RHO or RPGR mutations exhibited hyperautofluorescence with patchy areas of hypoautofluorescence. Patients with USH2A mutations had a distinctive pattern of diffuse and homogeneous peripheral hypoautofluorescence. UW-FAF may provide important information to facilitate diagnosis and further research is needed to better characterize this technology as an imaging biomarker for genotype association in retinal dystrophies and RP.

Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics

PubMed Central

Cideciyan, Artur V.; Aleman, Tomas S.; Boye, Sanford L.; Schwartz, Sharon B.; Kaushal, Shalesh; Roman, Alejandro J.; Pang, Ji-jing; Sumaroka, Alexander; Windsor, Elizabeth A. M.; Wilson, James M.; Flotte, Terence R.; Fishman, Gerald A.; Heon, Elise; Stone, Edwin M.; Byrne, Barry J.; Jacobson, Samuel G.; Hauswirth, William W.

2008-01-01

The RPE65 gene encodes the isomerase of the retinoid cycle, the enzymatic pathway that underlies mammalian vision. Mutations in RPE65 disrupt the retinoid cycle and cause a congenital human blindness known as Leber congenital amaurosis (LCA). We used adeno-associated virus-2-based RPE65 gene replacement therapy to treat three young adults with RPE65-LCA and measured their vision before and up to 90 days after the intervention. All three patients showed a statistically significant increase in visual sensitivity at 30 days after treatment localized to retinal areas that had received the vector. There were no changes in the effect between 30 and 90 days. Both cone- and rod-photoreceptor-based vision could be demonstrated in treated areas. For cones, there were increases of up to 1.7 log units (i.e., 50 fold); and for rods, there were gains of up to 4.8 log units (i.e., 63,000 fold). To assess what fraction of full vision potential was restored by gene therapy, we related the degree of light sensitivity to the level of remaining photoreceptors within the treatment area. We found that the intervention could overcome nearly all of the loss of light sensitivity resulting from the biochemical blockade. However, this reconstituted retinoid cycle was not completely normal. Resensitization kinetics of the newly treated rods were remarkably slow and required 8 h or more for the attainment of full sensitivity, compared with <1 h in normal eyes. Cone-sensitivity recovery time was rapid. These results demonstrate dramatic, albeit imperfect, recovery of rod- and cone-photoreceptor-based vision after RPE65 gene therapy. PMID:18809924

Unique structural features of the AIPL1–FKBP domain that support prenyl lipid binding and underlie protein malfunction in blindness

PubMed Central

Yadav, Ravi P.; Gakhar, Lokesh; Yu, Liping

2017-01-01

FKBP-domain proteins (FKBPs) are pivotal modulators of cellular signaling, protein folding, and gene transcription. Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is a distinctive member of the FKBP superfamily in terms of its biochemical properties, and it plays an important biological role as a chaperone of phosphodiesterase 6 (PDE6), an effector enzyme of the visual transduction cascade. Malfunction of mutant AIPL1 proteins triggers a severe form of Leber congenital amaurosis and leads to blindness. The mechanism underlying the chaperone activity of AIPL1 is largely unknown, but involves the binding of isoprenyl groups on PDE6 to the FKBP domain of AIPL1. We solved the crystal structures of the AIPL1–FKBP domain and its pathogenic mutant V71F, both in the apo form and in complex with isoprenyl moieties. These structures reveal a module for lipid binding that is unparalleled within the FKBP superfamily. The prenyl binding is enabled by a unique “loop-out” conformation of the β4-α1 loop and a conformational “flip-out” switch of the key W72 residue. A second major conformation of apo AIPL1–FKBP was identified by NMR studies. This conformation, wherein W72 flips into the ligand-binding pocket and renders the protein incapable of prenyl binding, is supported by molecular dynamics simulations and appears to underlie the pathogenicity of the V71F mutant. Our findings offer critical insights into the mechanisms that underlie AIPL1 function in health and disease, and highlight the structural and functional diversity of the FKBPs. PMID:28739921

The clinical evaluation of infantile nystagmus: What to do first and why

PubMed Central

Bertsch, Morgan; Floyd, Michael; Kehoe, Taylor; Pfeifer, Wanda; Drack, Arlene V.

2017-01-01

Introduction Infantile nystagmus has many causes, some life threatening. We determined the most common diagnoses in order to develop a testing algorithm. Methods Retrospective chart review. Exclusion criteria were no nystagmus, acquired after 6 months, or lack of examination. Data collected: pediatric eye examination findings, ancillary testing, order of testing, referral, and final diagnoses. Final diagnosis was defined as meeting published clinical criteria and/or confirmed by diagnostic testing. Patients with a diagnosis not meeting the definition were “unknown.” Patients with incomplete testing were “incomplete.” Patients with multiple plausible etiologies were “multifactorial.” Patients with negative complete workup were “motor.” Results 284 charts were identified; 202 met inclusion criteria. The 3 most common causes were Albinism(19%), Leber Congenital Amaurosis(LCA)(14%) and Non-LCA retinal dystrophy (13%). Anatomic retinal disorders comprised 10%, motor another 10%. The most common first test was MRI (74/202) with a diagnostic yield of 16%. For 28 MRI-first patients, nystagmus alone was the indication; for 46 MRI-first patients other neurologic signs were present. 0/28 nystagmus-only patients had a diagnostic MRI while 14/46 (30%) with neurologic signs did. Yield of ERG as first test was 56%, OCT 55%, and molecular genetic testing 47%. 90% of patients had an etiology identified. Conclusion The most common causes of infantile nystagmus were retinal disorders (56%), however the most common first test was brain MRI. For patients without other neurologic stigmata complete pediatric eye examination, ERG, OCT and molecular genetic testing had a higher yield than MRI scan. If MRI is not diagnostic, a complete ophthalmologic workup should be pursued. PMID:28177849

Molecular anthropology meets genetic medicine to treat blindness in the North African Jewish population: human gene therapy initiated in Israel.

PubMed

Banin, Eyal; Bandah-Rozenfeld, Dikla; Obolensky, Alexey; Cideciyan, Artur V; Aleman, Tomas S; Marks-Ohana, Devora; Sela, Malka; Boye, Sanford; Sumaroka, Alexander; Roman, Alejandro J; Schwartz, Sharon B; Hauswirth, William W; Jacobson, Samuel G; Hemo, Itzhak; Sharon, Dror

2010-12-01

The history of the North African Jewish community is ancient and complicated with a number of immigration waves and persecutions dramatically affecting its population size. A decade-long process in Israel of clinical-molecular screening of North African Jews with incurable autosomal recessive blindness led to the identification of a homozygous splicing mutation (c.95-2A > T; IVS2-2A > T) in RPE65, the gene encoding the isomerase that catalyzes a key step in the retinoid-visual cycle, in patients from 10 unrelated families. A total of 33 patients (four now deceased) had the severe childhood blindness known as Leber congenital amaurosis (LCA), making it the most common cause of retinal degeneration in this population. Haplotype analysis in seven of the patients revealed a shared homozygous region, indicating a population-specific founder mutation. The age of the RPE65 founder mutation was estimated to have emerged 100-230 (mean, 153) generations ago, suggesting it originated before the establishment of the Jewish community in North Africa. Individuals with this RPE65 mutation were characterized with retinal studies to determine if they were candidates for gene replacement, the recent and only therapy to date for this otherwise incurable blindness. The step from molecular anthropological studies to application of genetic medicine was then taken, and a representative of this patient subgroup was treated with subretinal rAAV2-RPE65 gene therapy. An increase in vision was present in the treated area as early as 15 days after the intervention. This process of genetically analyzing affected isolated populations as a screen for gene-based therapy suggests a new paradigm for disease diagnosis and treatment.

Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa.

PubMed

Booij, J C; Florijn, R J; ten Brink, J B; Loves, W; Meire, F; van Schooneveld, M J; de Jong, P T V M; Bergen, A A B

2005-11-01

To identify mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa. Mutation analysis was carried out in a group of 35 unrelated patients with juvenile autosomal recessive retinitis pigmentosa (ARRP), Leber's congenital amaurosis (LCA), or juvenile isolated retinitis pigmentosa (IRP), by denaturing high performance liquid chromatography followed by direct sequencing. All three groups of patients showed typical combinations of eye signs associated with retinitis pigmentosa: pale optic discs, narrow arterioles, pigmentary changes, and nystagmus. Mutations were found in 34% of in CRB1 (11%), GUCY2D (11%), RPE65 (6%), and RPGRIP1 (6%). Nine mutations are reported, including a new combination of two mutations in CRB1, and new mutations in GUCY2D and RPGRIP1. The new GUCY2D mutation (c.3283delC, p.Pro1069ArgfsX37) is the first pathological sequence change reported in the intracellular C-terminal domain of GUCY2D, and did not lead to the commonly associated LCA, but to a juvenile retinitis pigmentosa phenotype. The polymorphic nature of three previously described (pathological) sequence changes in AIPL1, CRB1, and RPGRIP1 was established. Seven new polymorphic changes, useful for further association studies, were found. New and previously described sequence changes were detected in retinitis pigmentosa in CRB1, GUCY2D, and RPGRIP1; and in LCA patients in CRB1, GUCY2D, and RPE65. These data, combined with previous reports, suggest that LCA and juvenile ARRP are closely related and belong to a continuous spectrum of juvenile retinitis pigmentosa.

Children with blindness - major causes, developmental outcomes and implications for habilitation and educational support: a two-decade, Swedish population-based study.

PubMed

de Verdier, Kim; Ulla, Ek; Löfgren, Stefan; Fernell, Elisabeth

2018-05-01

The aim was to describe the population of children with congenital or early infancy blindness in Sweden, with regard to causes of blindness and prevalence of neurodevelopmental impairments. Medical, psychological and pedagogical records of Swedish children with congenital or early infancy blindness (total blindness or light perception at the most) born in 1988-2008 were analysed regarding year of birth, gender, cause of blindness, gestational age, associated neurological disorders/syndromes, associated neurodevelopmental impairments, cognitive level and type of school placement. A total of 150 individuals, 80 girls and 70 boys, were identified, corresponding to a prevalence of 7/100 000. Five causes of blindness dominated, constituting 76% of all represented aetiologies: retinopathy of prematurity (ROP), optic nerve hypoplasia (ONH), Leber congenital amaurosis (LCA), optic nerve atrophy (ONA) and microphthalmia/anophthalmia. Nearly three of four children in the study population had at least one additional disability besides blindness; the most common being intellectual disability (ID) and autism spectrum disorder (ASD). More than half of the population had more than one additional disability. Autism spectrum disorder (ASD) was most common in children with ONH, ROP, LCA and microphthalmia/anophthalmia. In children born within the last decades, isolated blindness is uncommon and the rate of multidisabilities is high. Autism spectrum disorder (ASD) seems to be more strongly associated with specific aetiological subgroups. Further development of the support to families and schools should be based on knowledge about the considerable heterogeneity of the population of children with blindness, and the common occurrence of coexisting neurodevelopmental disorders, especially ID and ASD. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Basal exon skipping and nonsense-associated altered splicing allows bypassing complete CEP290 loss-of-function in individuals with unusually mild retinal disease.

PubMed

Barny, Iris; Perrault, Isabelle; Michel, Christel; Soussan, Mickael; Goudin, Nicolas; Rio, Marlène; Thomas, Sophie; Attié-Bitach, Tania; Hamel, Christian; Dollfus, Hélène; Kaplan, Josseline; Rozet, Jean-Michel; Gerard, Xavier

2018-05-16

CEP290 mutations cause a spectrum of ciliopathies from Leber congenital amaurosis type 10 (LCA10) to embryo-lethal Meckel syndrome (MKS). Using panel-based molecular diagnosis testing for inherited retinal diseases, we identified two individuals with some preserved vision despite biallelism for presumably truncating CEP290 mutations. The first one carried a homozygous 1 base-pair deletion in exon 17, introducing a premature termination codon (PTC) in exon 18 (c.1666del; p.Ile556Phefs*17). mRNA analysis revealed a basal exon skipping (BES) of exon 18, providing mutant cells with the ability to escape protein truncation, while disrupting the reading frame in controls. The second individual harbored compound heterozygous nonsense mutations in exon 8 (c.508A>T, p.Lys170*) and exon 32 (c.4090G>T, p.Glu1364*), respectively. Some CEP290 lacking exon 8 were detected in mutant fibroblasts but not in controls whereas some skipping of exon 32 occurred in both lines, but with higher amplitude in the mutant. Considering that the deletion of either exon maintains the reading frame in either line, skipping in mutant cells likely involves nonsense-associated altered splicing (NAS) alone (exon 8), or with BES (exon 32). Skipping of PTC-containing exons in mutant cells allowed production of CEP290 isoforms with preserved ability to assemble into a high molecular weight complex and to interact efficiently with proteins important for cilia formation and intraflagellar trafficking. In contrast, studying LCA10 and MKS fibroblasts we show moderate to severe cilia alterations, providing support for a correlation between disease severity and the ability of cells to express shortened, yet functional, CEP290 isoforms.

Atypical CLN2 with later onset and prolonged course: a neuropathologic study showing different sensitivity of neuronal subpopulations to TPP1 deficiency

PubMed Central

Dvořáková, Lenka; Stolnaja, Larisa; Vlášková, Hana; Hůlková, Helena; Druga, Rastislav; Poupětová, Helena; Košťálová, Eva; Mikuláštík, Josef

2008-01-01

This is the first neuropathology report of a male patient (born 1960–died 1975) with an extremely rare, atypical variant of CLN2 that has been diagnosed only in five families so far. The clinical history started during his preschool years with relatively mild motor and psychological difficulties, but with normal intellect and vision. Since age six there were progressive cerebellar and extrapyramidal symptomatology, amaurosis, and mental deterioration. Epileptic seizures were absent. The child died aged 15 years in extreme cachexy. Neuropathology revealed neurolysosomal storage of autofluorescent, curvilinear and subunit c of mitochondrial ATP synthase (SCMAS) rich material. The neuronal storage led to laminar neuronal depopulation in the cerebral cortex and to a practically total eradication of the cerebellar cortical neurons. The other areas of the central nervous system including hippocampus, which are usually heavily affected in classical forms of CLN2, displayed either a lesser degree or absence of neuronal storage, or storage without significant neuronal loss. Transformation of the stored material to the spheroid like perikaryal inclusions was rudimentary. The follow-up, after 30 years, showed heterozygous values of TPP1 (tripeptidylpeptidase 1) activity in the white blood cells of both parents and the sister. DNA analysis of CLN2 gene identified a paternal frequent null mutation c.622C > T (p.Arg208 X) in the 6th exon and a maternal novel mutation c.1439 T > G in exon 12 (p.Val480Gly). TPP1 immunohistochemistry using a specific antibody gave negative results in the brain and other organs. Our report supports the notion that the spectrum of CLN2 phenotypes may be surprisingly broad. The study revealed variable sensitivities in neuronal subpopulations to the metabolic defect which may be responsible for the variant’s serious course. PMID:18283468

Biochemical Properties of Purified Human Retinol Dehydrogenase 12 (RDH12): Catalytic Efficiency toward Retinoids and C9 Aldehydes and Effects of Cellular Retinol-Binding Protein Type I (CRBPI) and Cellular Retinaldehyde-Binding Protein (CRALBP) on the Oxidation and Reduction of Retinoids†

PubMed Central

Belyaeva, Olga V.; Korkina, Olga V.; Stetsenko, Anton V.; Kim, Tom; Nelson, Peter S.; Kedishvili, Natalia Y.

2008-01-01

Retinol dehydrogenase 12 (RDH12) is a novel member of the short-chain dehydrogenase/reductase superfamily of proteins that was recently linked to Leber’s congenital amaurosis 3 (LCA). We report the first biochemical characterization of purified human RDH12 and analysis of its expression in human tissues. RDH12 exhibits ~2000-fold lower Km values for NADP+ and NADPH than for NAD+ and NADH and recognizes both retinoids and lipid peroxidation products (C9 aldehydes) as substrates. The kcat values of RDH12 for retinaldehydes and C9 aldehydes are similar, but the Km values are, in general, lower for retinoids. The enzyme exhibits the highest catalytic efficiency for all-trans-retinal (kcat/Km ~900 min−1 μM−1), followed by 11-cis-retinal (450 min−1 mM−1) and 9-cis-retinal (100 min−1 mM−1). Analysis of RDH12 activity toward retinoids in the presence of cellular retinol-binding protein (CRBP) type I or cellular retinaldehyde-binding protein (CRALBP) suggests that RDH12 utilizes the unbound forms of all-trans- and 11-cis-retinoids. As a result, the widely expressed CRBPI, which binds all-trans-retinol with much higher affinity than all-trans-retinaldehyde, restricts the oxidation of all-trans-retinol by RDH12, but has little effect on the reduction of all-trans-retinaldehyde, and CRALBP inhibits the reduction of 11-cis-retinal stronger than the oxidation of 11-cis-retinol, in accord with its higher affinity for 11-cis-retinal. Together, the tissue distribution of RDH12 and its catalytic properties suggest that, in most tissues, RDH12 primarily contributes to the reduction of all-trans-retinaldehyde; however, at saturating concentrations of peroxidic aldehydes in the cells undergoing oxidative stress, for example, photoreceptors, RDH12 might also play a role in detoxification of lipid peroxidation products. PMID:15865448

The susceptibility of the retina to photochemical damage from visible light

PubMed Central

Hunter, Jennifer J; Morgan, Jessica I W; Merigan, William H; Sliney, David H; Sparrow, Janet R; Williams, David R

2011-01-01

The photoreceptor/RPE complex must maintain a delicate balance between maximizing the absorption of photons for vision and retinal image quality while simultaneously minimizing the risk of photodamage when exposed to bright light. We review the recent discovery of two new effects of light exposure on the photoreceptor/RPE complex in the context of current thinking about the causes of retinal phototoxicity. These effects are autofluorescence photobleaching in which exposure to bright light reduces lipofuscin autofluorescence and, at higher light levels, RPE disruption in which the pattern of autofluorescence is permanently altered following light exposure. Both effects occur following exposure to visible light at irradiances that were previously thought to be safe. Photopigment, retinoids involved in the visual cycle, and bisretinoids in lipofuscin have been implicated as possible photosensitizers for photochemical damage. The mechanism of RPE disruption may follow either of these paths. On the other hand, autofluorescence photobleaching is likely an indicator of photooxidation of lipofuscin. The permanent changes inherent in RPE disruption might require modification of the light safety standards. AF photobleaching recovers after several hours although the mechanisms by which this occurs are not yet clear. Understanding the mechanisms of phototoxicity is all the more important given the potential for increased susceptibility in the presence of ocular diseases that affect either the visual cycle and/or lipofuscin accumulation. In addition, knowledge of photochemical mechanisms can improve our understanding of some disease processes that may be influenced by light exposure, such as some forms of Leber’s congenital amaurosis, and aid in the development of new therapies. Such treatment prior to intentional light exposures, as in ophthalmic examinations or surgeries, could provide an effective preventative strategy. PMID:22085795

Lentiviral Expression of Retinal Guanylate Cyclase-1 (RetGC1) Restores Vision in an Avian Model of Childhood Blindness

PubMed Central

Haire, Shannon E; Aleman, Tomas S; Cideciyan, Artur V; Sokal, Izabel; Palczewski, Krzysztof; Jacobson, Samuel G; Semple-Rowland, Susan L

2006-01-01

Background Leber congenital amaurosis (LCA) is a genetically heterogeneous group of retinal diseases that cause congenital blindness in infants and children. Mutations in the GUCY2D gene that encodes retinal guanylate cyclase–1 (retGC1) were the first to be linked to this disease group (LCA type 1 [LCA1]) and account for 10%–20% of LCA cases. These mutations disrupt synthesis of cGMP in photoreceptor cells, a key second messenger required for function of these cells. The GUCY1*B chicken, which carries a null mutation in the retGC1 gene, is blind at hatching and serves as an animal model for the study of LCA1 pathology and potential treatments in humans. Methods and Findings A lentivirus-based gene transfer vector carrying the GUCY2D gene was developed and injected into early-stage GUCY1*B embryos to determine if photoreceptor function and sight could be restored to these animals. Like human LCA1, the avian disease shows early-onset blindness, but there is a window of opportunity for intervention. In both diseases there is a period of photoreceptor cell dysfunction that precedes retinal degeneration. Of seven treated animals, six exhibited sight as evidenced by robust optokinetic and volitional visual behaviors. Electroretinographic responses, absent in untreated animals, were partially restored in treated animals. Morphological analyses indicated there was slowing of the retinal degeneration. Conclusions Blindness associated with loss of function of retGC1 in the GUCY1*B avian model of LCA1 can be reversed using viral vector-mediated gene transfer. Furthermore, this reversal can be achieved by restoring function to a relatively low percentage of retinal photoreceptors. These results represent a first step toward development of gene therapies for one of the more common forms of childhood blindness. PMID:16700630

The Role of Gene Therapy in the Treatment of Retinal Diseases: A Review.

PubMed

Campa, C; Gallenga, C E; Bolletta, E; Perri, P

2017-01-01

Gene therapy represents the therapeutic delivery of nucleic acid polymers into patient cells with the aim of treating an underlying disease. Over the past 2 decades this new therapy has made substantial progress owing to better understanding of the pathobiologic basis of various diseases coupled with growth of gene transfer biotechnologies. The eye, in particular, represents a suitable target for such therapy due to the immune privilege provided by the blood-ocular barrier, the ability to directly visualize, access and locally treat the cells and the minimal amount of vector needed given the size of this organ. It is not surprising therefore that several clinical trials are now ongoing in this field. The purpose of this review was to provide an update on gene therapy for retinal diseases, discussing differences in treatment strategies, vector designs and surgical techniques. Research was performed on PubMed, ClinicalTrials.gov, and Home Genetic Reference. We additionally utilized the internet database for genetics of retinal diseases, the portal for rare diseases and orphan drugs and the NCBI database Online Mendelian Inheritance in Man. No restriction was applied on the language of publications. We present the available results of current active clinical trials for inherited retinal disease such as Leber's congenital amaurosis type 2, choroideremia, Stargardt disease, achromatopsia and juvenile X-linked retinoschisis. We also illustrate a new approach of this therapy for the treatment of much more common ocular diseases such as age-related macular degeneration and diabetic retinopathy. Gene therapy represents an emerging and promising therapeutic approach for the treatment not only of rare inherited retinal diseases but also much more common retinal pathologies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Retinal findings in a patient of French ancestry with CABP4-related retinal disease.

PubMed

Smirnov, Vasily Mikhaïlovitch; Zeitz, Christina; Soumittra, Nagasamy; Audo, Isabelle; Defoort-Dhellemmes, Sabine

2018-04-01

CABP4-related retinal dysfunction is a cone-rod synaptic transmission disorder with electronegative electroretinogram (ERG) waveform. It is a rare retinal dysfunction that can be classified into the incomplete form of congenital stationary night blindness. Absent foveal reflex and overall foveal thinning were previously reported, but in most cases the fundus appearance was described as nearly normal. We report here peculiar macular changes in a patient of French ancestry harbouring CABP4 mutations. Complete ocular examination and full-field ERG were performed at the initial presentation and follow-up. Multimodal fundus imagining, including spectral-domain optical coherence tomography, colour, infrared reflectance and short-wavelength autofluorescence photographs, was performed during follow-up visits. A 7-month-old infant was addressed to our department for visual unresponsiveness and nystagmus. ERG had an electronegative waveform, even for light-adapted stimuli, thus supporting the diagnosis of photoreceptor-bipolar cell transmission disorder. Genetic investigations discovered a compound heterozygous mutation in CABP4: c.646C > T, p.Arg216*/c.673C > T, p.Arg225*. Multimodal fundus imaging, performed at follow-up visits, showed fine radial folds at the vitreomacular interface and dark foveal dots in both eyes. Optic coherence tomography revealed a focal foveal ellipsoid zone gap. Initial presentation was misleading with Leber congenital amaurosis. The electronegative ERG waveform reoriented the genetic investigations and thus establishing a correct diagnosis. To the best of our knowledge, the peculiar fundus changes observed in our patient were never reported before. We hypothesized that a foveal ellipsoid zone interruption discovered in our patient could reflect mostly a cone dysfunction. It was unclear whether the fine radial folds in both maculae were linked with high hyperopia or were an intrinsic feature of the retinal disease. CABP4-related retinal

A clinical and molecular characterisation of CRB1-associated maculopathy.

PubMed

Khan, Kamron N; Robson, Anthony; Mahroo, Omar A R; Arno, Gavin; Inglehearn, Chris F; Armengol, Monica; Waseem, Naushin; Holder, Graham E; Carss, Keren J; Raymond, Lucy F; Webster, Andrew R; Moore, Anthony T; McKibbin, Martin; van Genderen, Maria M; Poulter, James A; Michaelides, Michel

2018-05-01

To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype-phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull's-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes-intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.

Exome capture sequencing identifies a novel mutation in BBS4

PubMed Central

Wang, Hui; Chen, Xianfeng; Dudinsky, Lynn; Patenia, Claire; Chen, Yiyun; Li, Yumei; Wei, Yue; Abboud, Emad B.; Al-Rajhi, Ali A.; Lewis, Richard Alan; Lupski, James R.; Mardon, Graeme; Gibbs, Richard A.; Perkins, Brian D.

2011-01-01

Purpose Leber congenital amaurosis (LCA) is one of the most severe eye dystrophies characterized by severe vision loss at an early stage and accounts for approximately 5% of all retinal dystrophies. The purpose of this study was to identify a novel LCA disease allele or gene and to develop an approach combining genetic mapping with whole exome sequencing. Methods Three patients from King Khaled Eye Specialist Hospital (KKESH205) underwent whole genome single nucleotide polymorphism genotyping, and a single candidate region was identified. Taking advantage of next-generation high-throughput DNA sequencing technologies, whole exome capture sequencing was performed on patient KKESH205#7. Sanger direct sequencing was used during the validation step. The zebrafish model was used to examine the function of the mutant allele. Results A novel missense mutation in Bardet-Biedl syndrome 4 protein (BBS4) was identified in a consanguineous family from Saudi Arabia. This missense mutation in the fifth exon (c.253G>C;p.E85Q) of BBS4 is likely a disease-causing mutation as it segregates with the disease. The mutation is not found in the single nucleotide polymorphism (SNP) database, the 1000 Genomes Project, or matching normal controls. Functional analysis of this mutation in zebrafish indicates that the G253C allele is pathogenic. Coinjection of the G253C allele cannot rescue the mislocalization of rhodopsin in the retina when BBS4 is knocked down by morpholino injection. Immunofluorescence analysis in cell culture shows that this missense mutation in BBS4 does not cause obvious defects in protein expression or pericentriolar localization. Conclusions This mutation likely mainly reduces or abolishes BBS4 function in the retina. Further studies of this allele will provide important insights concerning the pleiotropic nature of BBS4 function. PMID:22219648

Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies.

PubMed

Eisenberger, Tobias; Neuhaus, Christine; Khan, Arif O; Decker, Christian; Preising, Markus N; Friedburg, Christoph; Bieg, Anika; Gliem, Martin; Charbel Issa, Peter; Holz, Frank G; Baig, Shahid M; Hellenbroich, Yorck; Galvez, Alberto; Platzer, Konrad; Wollnik, Bernd; Laddach, Nadja; Ghaffari, Saeed Reza; Rafati, Maryam; Botzenhart, Elke; Tinschert, Sigrid; Börger, Doris; Bohring, Axel; Schreml, Julia; Körtge-Jung, Stefani; Schell-Apacik, Chayim; Bakur, Khadijah; Al-Aama, Jumana Y; Neuhann, Teresa; Herkenrath, Peter; Nürnberg, Gudrun; Nürnberg, Peter; Davis, John S; Gal, Andreas; Bergmann, Carsten; Lorenz, Birgit; Bolz, Hanno J

2013-01-01

Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are major causes of blindness. They result from mutations in many genes which has long hampered comprehensive genetic analysis. Recently, targeted next-generation sequencing (NGS) has proven useful to overcome this limitation. To uncover "hidden mutations" such as copy number variations (CNVs) and mutations in non-coding regions, we extended the use of NGS data by quantitative readout for the exons of 55 RP and LCA genes in 126 patients, and by including non-coding 5' exons. We detected several causative CNVs which were key to the diagnosis in hitherto unsolved constellations, e.g. hemizygous point mutations in consanguineous families, and CNVs complemented apparently monoallelic recessive alleles. Mutations of non-coding exon 1 of EYS revealed its contribution to disease. In view of the high carrier frequency for retinal disease gene mutations in the general population, we considered the overall variant load in each patient to assess if a mutation was causative or reflected accidental carriership in patients with mutations in several genes or with single recessive alleles. For example, truncating mutations in RP1, a gene implicated in both recessive and dominant RP, were causative in biallelic constellations, unrelated to disease when heterozygous on a biallelic mutation background of another gene, or even non-pathogenic if close to the C-terminus. Patients with mutations in several loci were common, but without evidence for di- or oligogenic inheritance. Although the number of targeted genes was low compared to previous studies, the mutation detection rate was highest (70%) which likely results from completeness and depth of coverage, and quantitative data analysis. CNV analysis should routinely be applied in targeted NGS, and mutations in non-coding exons give reason to systematically include 5'-UTRs in disease gene or exome panels. Consideration of all variants is indispensable because even

Pseudo-Fovea Formation After Gene Therapy for RPE65-LCA

PubMed Central

Cideciyan, Artur V.; Aguirre, Geoffrey K.; Jacobson, Samuel G.; Butt, Omar H.; Schwartz, Sharon B.; Swider, Malgorzata; Roman, Alejandro J.; Sadigh, Sam; Hauswirth, William W.

2015-01-01

Purpose. The purpose of this study was to evaluate fixation location and oculomotor characteristics of 15 patients with Leber congenital amaurosis (LCA) caused by RPE65 mutations (RPE65-LCA) who underwent retinal gene therapy. Methods. Eye movements were quantified under infrared imaging of the retina while the subject fixated on a stationary target. In a subset of patients, letter recognition under retinal imaging was performed. Cortical responses to visual stimulation were measured using functional magnetic resonance imaging (fMRI) in two patients before and after therapy. Results. All patients were able to fixate on a 1° diameter visible target in the dark. The preferred retinal locus of fixation was either at the anatomical fovea or at an extrafoveal locus. There were a wide range of oculomotor abnormalities. Natural history showed little change in oculomotor abnormalities if target illuminance was increased to maintain target visibility as the disease progressed. Eleven of 15 study eyes treated with gene therapy showed no differences from baseline fixation locations or instability over an average of follow-up of 3.5 years. Four of 15 eyes developed new pseudo-foveas in the treated retinal regions 9 to 12 months after therapy that persisted for up to 6 years; patients used their pseudo-foveas for letter identification. fMRI studies demonstrated that preservation of light sensitivity was restricted to the cortical projection zone of the pseudo-foveas. Conclusions. The slow emergence of pseudo-foveas many months after the initial increases in light sensitivity points to a substantial plasticity of the adult visual system and a complex interaction between it and the progression of underlying retinal disease. The visual significance of pseudo-foveas suggests careful consideration of treatment zones for future gene therapy trials. (ClinicalTrials.gov number, NCT00481546.) PMID:25537204

[Preimplantation genetic diagnosis and monogenic inherited eye diseases].

PubMed

Hlavatá, L; Ďuďáková, Ľ; Trková, M; Soldátová, I; Skalická, P; Kousal, B; Lišková, P

Preimplantation genetic diagnosis (PGD) is an established application of genetic testing in the context of in vitro fertilization. PGD is an alternative method to prenatal diagnosis which aims to prevent the transmission of an inherited disorder to the progeny by implanting only embryos that do not carry genetic predisposition for a particular disease. The aim of this study is to provide an overview of eye disorders for which PGD has been carried out. The European literature search focused on best practices, ethical issues, risks and results of PGD for inherited eye disorders. PGD is performed for a number of ocular disorders; a prerequisite for its application is however, the knowledge of a disease-causing mutation(s). The main advantage of this method is that the couple is not exposed to a decision of whether or not to undergo an abortion. Qualified counselling must be provided prior to the PGD in order to completely understand the risk of disability in any child conceived, consequences of disease manifestation, and advantages as well as limitations of this method. In the group of non-syndromic eye diseases and diseases in which ocular findings dominate, PGD has been performed in European countries for aniridia, choroideremia, congenital fibrosis of extraocular muscles, Leber congenital amaurosis, ocular albinism, retinitis pigmentosa, X-linked retinoschisis, Stargardt disease, blepharophimosis-ptosis-inverse epicanthus syndrome and retinoblastoma. Sexing for X-linked or mitochondrial diseases has been carried out for blue cone monochromatism, choroideremia, familial exudative vitreoretinopathy, Leber hereditary optic neuropathy, macular dystrophy (not further specified), Norrie disease, X-linked congenital stationary night blindness, X-linked retinoschisis and nystagmus (not further specified). In recent years, there has been an increase in potential to use PGD. The spectrum of diseases for this method has widened to include severe inherited eye diseases

The Disease Protein Tulp1 Is Essential for Periactive Zone Endocytosis in Photoreceptor Ribbon Synapses

PubMed Central

Wahl, Silke; Magupalli, Venkat Giri; Dembla, Mayur; Katiyar, Rashmi; Schwarz, Karin; Köblitz, Louise; Alpadi, Kannan; Krause, Elmar; Rettig, Jens; Sung, Ching-Hwa; Goldberg, Andrew F. X.

2016-01-01

Mutations in the Tulp1 gene cause severe, early-onset retinitis pigmentosa (RP14) in humans. In the retina, Tulp1 is mainly expressed in photoreceptors that use ribbon synapses to communicate with the inner retina. In the present study, we demonstrate that Tulp1 is highly enriched in the periactive zone of photoreceptor presynaptic terminals where Tulp1 colocalizes with major endocytic proteins close to the synaptic ribbon. Analyses of Tulp1 knock-out mice demonstrate that Tulp1 is essential to keep endocytic proteins enriched at the periactive zone and to maintain high levels of endocytic activity close to the synaptic ribbon. Moreover, we have discovered a novel interaction between Tulp1 and the synaptic ribbon protein RIBEYE, which is important to maintain synaptic ribbon integrity. The current findings suggest a new model for Tulp1-mediated localization of the endocytic machinery at the periactive zone of ribbon synapses and offer a new rationale and mechanism for vision loss associated with genetic defects in Tulp1. SIGNIFICANCE STATEMENT Mutations in the Tulp1 gene cause severe, early-onset retinitis pigmentosa (RP14) and Leber congenital amaurosis (LCA15) in human patients. In this study, we discovered that the phosphoinositol-4,5-bisphosphate-binding protein Tulp1 is essential for the structural and functional organization of the periactive zone in photoreceptor synapses. Using Tulp1 knock-out mice, we found that Tulp1 is required to enrich major endocytic proteins at the periactive zone next to the synaptic ribbon. We demonstrate that Tulp1 is needed to promote endocytic vesicle retrieval at the periactive zone. Moreover, we discovered a novel interaction between Tulp1 and the synaptic ribbon protein RIBEYE. This newly discovered disease-sensitive interaction provides a molecular model for the control of endocytosis close to the synaptic ribbon. PMID:26911694

Linear headache: a recurrent unilateral head pain circumscribed in a line-shaped area.

PubMed

Wang, Yu; Tian, Miao-Miao; Wang, Xian-Hong; Zhu, Xiao-Qun; Liu, Ying; Lu, Ya-Nan; Pan, Qing-Qing

2014-06-26

A headache circumscribed in a line-shaped area but not confined to the territory of one particular nerve had ever been described in Epicrania Fugax (EF) of which the head pain is moving and ultrashort. In a 25-month period from Feb 2012 to Mar 2014, we encountered 12 patients with a paroxysmal motionless head pain restricted in a linear trajectory. The head pain trajectory was similar to that of EF, but its all other features obviously different from those of EF. We named this distinctive but undescribed type of headache linear headache (LH). A detailed clinical feature of the headache was obtained in all cases to differentiate with EF, trigeminal autonomic cephalalgias (TACs) and cranial neuralgia. Similarities and differences in clinical features were compared between LH and migraine. The twelve LH patients (mean age 43.9 ± 12.2) complained of a recurrent, moderate to severe, distending (n = 9), pressure-like (n = 3) or pulsating (n = 3) pain within a strictly unilateral line-shaped area. The painful line is distributed from occipital or occipitocervical region to the ipsilateral eye (n = 5), forehead (n = 6) or parietal region (n = 1). The pain line has a trajecory similar to that of EF but no characteristics of moving. The headache duration would be ranged from five minutes to three days, but usually from half day to one day in most cases (n = 8). Six patients had the accompaniment of nausea with or without vomiting, and two patients had the accompaniment of ipsilateral dizziness. The attacks could be either spontaneous (n = 10) or triggered by noise, depression and resting after physical activity (n = 1), or by stress and staying up late (n = 1). The frequency of attacks was variable. The patients had well response to flunarizine, sodium valproate and amitriptyline but not to carbamazepine or oxcarbazepine. LH is different from EF, trigeminal autonomic cephalalgias (TACs) and cranial neuralgia, but it had couple of features similar to that of migraine. The

Linear headache: a recurrent unilateral head pain circumscribed in a line-shaped area

PubMed Central

2014-01-01

Background A headache circumscribed in a line-shaped area but not confined to the territory of one particular nerve had ever been described in Epicrania Fugax (EF) of which the head pain is moving and ultrashort. In a 25-month period from Feb 2012 to Mar 2014, we encountered 12 patients with a paroxysmal motionless head pain restricted in a linear trajectory. The head pain trajectory was similar to that of EF, but its all other features obviously different from those of EF. We named this distinctive but undescribed type of headache linear headache (LH). Methods A detailed clinical feature of the headache was obtained in all cases to differentiate with EF, trigeminal autonomic cephalalgias (TACs) and cranial neuralgia. Similarities and differences in clinical features were compared between LH and migraine. Results The twelve LH patients (mean age 43.9 ± 12.2) complained of a recurrent, moderate to severe, distending (n = 9), pressure-like (n = 3) or pulsating (n = 3) pain within a strictly unilateral line-shaped area. The painful line is distributed from occipital or occipitocervical region to the ipsilateral eye (n = 5), forehead (n = 6) or parietal region (n = 1). The pain line has a trajecory similar to that of EF but no characteristics of moving. The headache duration would be ranged from five minutes to three days, but usually from half day to one day in most cases (n = 8). Six patients had the accompaniment of nausea with or without vomiting, and two patients had the accompaniment of ipsilateral dizziness. The attacks could be either spontaneous (n = 10) or triggered by noise, depression and resting after physical activity (n = 1), or by stress and staying up late (n = 1). The frequency of attacks was variable. The patients had well response to flunarizine, sodium valproate and amitriptyline but not to carbamazepine or oxcarbazepine. LH is different from EF, trigeminal autonomic cephalalgias (TACs) and cranial neuralgia, but it had couple of features similar

Inguinal hernia vs. arthritis of the hip in sporting adolescents--case report and review of the literature.

PubMed

Holzheimer, R G; Gresser, U

2007-07-26

Chronic pain in the hip, groin or thigh can be caused by a wide spectrum of diseases posing extended diagnostic problems. We describe the case of a 10-years old child with chronic pain in the groin with gait restriction for more than six months without successful classification and treatment. The girl suffered from heavy pain in the groin after a sporting contest which forced her to walk with walking sticks and to avoid climbing stairs. Within six months she was examined by pediatric, orthopedic, pediatric surgery, pediatric orthopedic, radiology, pediatric rheumatology specialists. Working diagnoses were transient synovitis (coxitis fugax), arthritis, streptococcal arthritis, Morbus Perthes, rheumatic fever, rheumatoid arthritis. She was treated with antibiotics and ibuprofen in high dosage. Repeated laboratory tests and imaging studies (ultrasound, x-rays, magnetic resonance imaging) of the hip and pelvis did not support any of these diagnoses. Six months after beginning of the complaints the girl was presented by her mother to our institution. The physical examination showed a sharp localized pain in the groin, just in the region of the inguinal ligament with otherwise free hip movement. There was no visible inguinal hernia. The family history for hernia was positive. After infiltration of the ilioinguinal nerve the girl had a complete long-lasting disappearance of pain and gait disturbance. This led to the diagnosis of inguinal hernia with nerve entrapment. After hernia repair and neurolysis/neurectomy there was a continuous state of disappearance of pain and gait disturbances. To avoid such a diagnostic dilemma one should always discuss all possible causes. Non-visible inguinal hernia may be more common in females than previously thought. Nerve entrapment as a cause of groin pain has been well described. The relationship of the start of complaints with sporting activity, a positive family history for inguinal hernia, a lack of signs of inflammation and bone

Variations of Leaf Cuticular Waxes Among C3 and C4 Gramineae Herbs.

PubMed

He, Yuji; Gao, Jianhua; Guo, Na; Guo, Yanjun

2016-11-01

Modern C4 plants are commonly distributed in hot and dry environments whereas C3 plants predominate in cool and shade areas. At the outmost of plant surface, the deposition and chemical composition of cuticular waxes vary under different environmental conditions. However, whether such variation of cuticular wax is related to the distribution of C3 and C4 under different environmental conditions is still not clear. In this study, leaves of six C3 Gramineae herbs distributed in spring, Roegneria kamoji, Polypogon fugax, Poa annua, Avena fatua, Alopecurus aequalis, and Oplismenus undulatifolius, and four C4 and one C3 Gramineae herbs distributed in summer, Digitaria sanguinalis, Eleusine indica, Setaria viridis, S. plicata, and O. undulatifolius, were sampled and analyzed for cuticular wax. Plates were the main epicuticular wax morphology in both C3 and C4 plants except S. plicata. The plates melted in C4 plants but not in C3 plants. The total cuticular wax amounts in C4 plants were significantly lower than those in C3 plants, except for O. undulatifolius. Primary alcohols were the most abundant compounds in C3 plants, whereas n-alkanes were relatively the most abundant compounds in C4 plants. C 29 was the most abundant n-alkane in C3 plants except for O. undulatifolius, whereas the most abundant n-alkane was C 31 or C 33 in C4 plants. The average chain length (ACL) of n-alkanes was higher in C4 than in C3 plants, whereas the ACL of n-alkanoic acids was higher in C3 than C4 plants. The cluster analysis based on the distribution of n-alkanes clearly distinguished C3 and C4 plants into two groups, except for O. undulatifolius which was grouped with C4 plants. These results suggest that the variations of cuticular waxes among C3 and C4 Gramineae herbs are related to the distribution of C3 and C4 plants under different environmental conditions. © 2016 Wiley-VHCA AG, Zurich, Switzerland.

Dog as a model in studies on human hereditary diseases and their gene therapy.

PubMed

Switonski, Marek

2014-03-01

During the last 15 years spectacular progress has been achieved in knowledge on the dog genome organization and the molecular background of hereditary diseases in this species. A majority of canine genetic diseases have their counterparts in humans and thus dogs are considered as a very important large animal model in human biomedicine. Among canine monogenic diseases with known causative gene mutations there are two large groups classified as retinal dystrophies and lysosomal storage diseases. Specific types of these diseases are usually diagnosed in a single or several breeds. A well known disorder, restricted to a single breed, is congenital stationary night blindness described in Briards. This disease is a counterpart of Leber amaurosis in children. On the other hand, one of the most common monogenic human diseases (Duchenne muscular dystrophy), has its canine counterparts in several breeds (e.g., the Golden retriever, Beagle and German short-haired pointer). For some of the canine diseases gene therapy strategy was successfully applied, e.g., for congenital stationary night blindness, rod-cone dystrophy and muccopolysaccharydoses type I, IIIB and VII. Since phenotypic variability between the breeds is exceptionally high, the dog is an interesting model to study the molecular background of congenital malformations (e.g., dwarfism and osteoporosis imperfecta). Also disorders of sexual development (DSD), especially testicular or ovotesticular DSD (78,XX; SRY-negative), which is widely distributed across dozens of breeds, are of particular interest. Studies on the genetic background of canine cancers, a major health problem in this species, are also quite advanced. On the other hand, genetic studies on canine counterparts of major human complex diseases (e.g., obesity, the metabolic syndrome and diabetes mellitus) are still in their infancy. Copyright © 2014 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish

Increasing the Yield in Targeted Next-Generation Sequencing by Implicating CNV Analysis, Non-Coding Exons and the Overall Variant Load: The Example of Retinal Dystrophies

PubMed Central

Eisenberger, Tobias; Neuhaus, Christine; Khan, Arif O.; Decker, Christian; Preising, Markus N.; Friedburg, Christoph; Bieg, Anika; Gliem, Martin; Issa, Peter Charbel; Holz, Frank G.; Baig, Shahid M.; Hellenbroich, Yorck; Galvez, Alberto; Platzer, Konrad; Wollnik, Bernd; Laddach, Nadja; Ghaffari, Saeed Reza; Rafati, Maryam; Botzenhart, Elke; Tinschert, Sigrid; Börger, Doris; Bohring, Axel; Schreml, Julia; Körtge-Jung, Stefani; Schell-Apacik, Chayim; Bakur, Khadijah; Al-Aama, Jumana Y.; Neuhann, Teresa; Herkenrath, Peter; Nürnberg, Gudrun; Nürnberg, Peter; Davis, John S.; Gal, Andreas; Bergmann, Carsten; Lorenz, Birgit; Bolz, Hanno J.

2013-01-01

Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are major causes of blindness. They result from mutations in many genes which has long hampered comprehensive genetic analysis. Recently, targeted next-generation sequencing (NGS) has proven useful to overcome this limitation. To uncover “hidden mutations” such as copy number variations (CNVs) and mutations in non-coding regions, we extended the use of NGS data by quantitative readout for the exons of 55 RP and LCA genes in 126 patients, and by including non-coding 5′ exons. We detected several causative CNVs which were key to the diagnosis in hitherto unsolved constellations, e.g. hemizygous point mutations in consanguineous families, and CNVs complemented apparently monoallelic recessive alleles. Mutations of non-coding exon 1 of EYS revealed its contribution to disease. In view of the high carrier frequency for retinal disease gene mutations in the general population, we considered the overall variant load in each patient to assess if a mutation was causative or reflected accidental carriership in patients with mutations in several genes or with single recessive alleles. For example, truncating mutations in RP1, a gene implicated in both recessive and dominant RP, were causative in biallelic constellations, unrelated to disease when heterozygous on a biallelic mutation background of another gene, or even non-pathogenic if close to the C-terminus. Patients with mutations in several loci were common, but without evidence for di- or oligogenic inheritance. Although the number of targeted genes was low compared to previous studies, the mutation detection rate was highest (70%) which likely results from completeness and depth of coverage, and quantitative data analysis. CNV analysis should routinely be applied in targeted NGS, and mutations in non-coding exons give reason to systematically include 5′-UTRs in disease gene or exome panels. Consideration of all variants is indispensable because even

Vitritis in Pediatric Genetic Retinal Disorders

PubMed Central

Stunkel, Maria; Bhattarai, Sajag; Kemerley, Andrew; Stone, Edwin M.; Wang, Kai; Mullins, Robert F.; Drack, Arlene V.

2014-01-01

Structured Abstract Purpose To determine which types of pediatric retinal degeneration are associated with inflammatory cells in the anterior vitreous (AV). Design Retrospective, observational study in humans. Methods Retrospective chart review was performed for pediatric patients with suspected retinal degeneration presenting to a single examiner from 2008–2013. Age, visual acuity (VA), slit lamp examination of AV (SLAV), clinical and molecular genetic diagnoses were documented. Anterior vitreous cells were graded clinically with SLAV from rare cells (1–4) to 1+ (5–9), 2+ (10–30), or 3+ (more than 30). Cells were also counted in magnified slit beam photographs masked to molecular diagnosis when obtainable. Main outcome measures Cell counts in SLAV, best corrected VA, molecular and clinical diagnoses. Results One hundred and five charts were evaluated, 68 of which (64.8%) included SLAV data. Numerous (1+ or greater) cells were present in 22/68 (32.4%) patients, whereas 4/68 (5.9%) had rare cells and 42/68 (61.8%) had no cells. The average age between patients with cells, no-cells, and rare cells did not differ significantly (p=0.25). VA averaged 20/124 in patients with cells, 20/143 in patients with no-cells, and 20/68 in patients with rare cells (p= 0.70). The most frequent diagnoses with cells included Bardet Biedl syndrome, Leber congenital amaurosis (LCA), and retinitis pigmentosa. The most frequent diagnoses without cells included congenital stationary night blindness, LCA, Stargardt disease, and blue cone monochromacy. Discussion A non-random subset of pediatric retinal degenerations exhibit vitritis. Cells were present in 5/5 BBS patients (a progressive degeneration) whereas cells were not detected in any of the 12 patients with CSNB (a stable dysfunction). Conclusion Studying vitritis in pediatric retinal degenerations may reveal whether inflammation accompanies progressive vision loss in certain sub-types. Potentially, inflammation could be treated

Vitritis in pediatric genetic retinal disorders.

PubMed

Stunkel, Maria; Bhattarai, Sajag; Kemerley, Andrew; Stone, Edwin M; Wang, Kai; Mullins, Robert F; Drack, Arlene V

2015-01-01

To determine which types of pediatric retinal degeneration are associated with inflammatory cells in the anterior vitreous. Retrospective, observational study in humans. Retrospective chart review was performed for pediatric patients with suspected retinal degeneration presenting to a single examiner from 2008 to 2013. Age, visual acuity (VA), slit-lamp examination of anterior vitreous (SLAV), and clinical and molecular genetic diagnoses were documented. Anterior vitreous cells were graded clinically with SLAV from rare cells (1-4) to 1+ (5-9), 2+ (10-30), or 3+ (>30). Cells were also counted in magnified slit beam photographs masked to molecular diagnosis when obtainable. Cell counts in SLAV, best-corrected VA, and molecular and clinical diagnoses. We evaluated 105 charts, 68 of which (64.8%) included SLAV data. Numerous (1+ or greater) cells were present in 22 of 68 patients (32.4%), whereas 4 of 68 (5.9%) had rare cells and 42 of 68 (61.8%) had no cells. The average age between patients with cells, no cells, and rare cells did not differ significantly (P = 0.25). The VA averaged 20/124 in patients with cells, 20/143 in patients with no cells, and 20/68 in patients with rare cells (P = 0.70). The most frequent diagnoses with cells included Bardet Biedl syndrome (BBS), Leber congenital amaurosis (LCA), and retinitis pigmentosa. The most frequent diagnoses without cells included congenital stationary night blindness (CSNB), LCA, Stargardt disease, and blue cone monochromacy. A nonrandom subset of pediatric retinal degenerations exhibit vitritis. Cells were present in 5 of 5 BBS patients (a progressive degeneration), whereas cells were not detected in any of the 12 patients with CSNB (a stable dysfunction). Studying vitritis in pediatric retinal degenerations may reveal whether inflammation accompanies progressive vision loss in certain subtypes. Potentially, inflammation could be treated. In addition, SLAV may aid in clinical diagnosis. Copyright © 2015 American

Application of a high-throughput genotyping method for loci exclusion in non-consanguineous Australian pedigrees with autosomal recessive retinitis pigmentosa.

PubMed

Paterson, Rachel L; De Roach, John N; McLaren, Terri L; Hewitt, Alex W; Hoffmann, Ling; Lamey, Tina M

2012-01-01

Retinitis pigmentosa (RP) is the most common form of inherited blindness, caused by progressive degeneration of photoreceptor cells in the retina, and affects approximately 1 in 3,000 people. Over the past decade, significant progress has been made in gene therapy for RP and related diseases, making genetic characterization increasingly important. Recently, high-throughput technologies have provided an option for reasonably fast, cost-effective genetic characterization of autosomal recessive RP (arRP). The current study used a single nucleotide polymorphism (SNP) genotyping method to exclude up to 28 possible disease-causing genes in 31 non-consanguineous Australian families affected by arRP. DNA samples were collected from 59 individuals affected with arRP and 74 unaffected family members from 31 Australian families. Five to six SNPs were genotyped for 28 genes known to cause arRP or the related disease Leber congenital amaurosis (LCA). Cosegregation analyses were used to exclude possible causative genes from each of the 31 families. Bidirectional sequencing was used to identify disease-causing mutations in prioritized genes that were not excluded with cosegregation analyses. Two families were excluded from analysis due to identification of false paternity. An average of 28.9% of genes were excluded per family when only one affected individual was available, in contrast to an average of 71.4% or 89.8% of genes when either two, or three or more affected individuals were analyzed, respectively. A statistically significant relationship between the proportion of genes excluded and the number of affected individuals analyzed was identified using a multivariate regression model (p<0.0001). Subsequent DNA sequencing resulted in identification of the likely disease-causing gene as CRB1 in one family (c.2548 G>A) and USH2A in two families (c.2276 G>T). This study has shown that SNP genotyping cosegregation analysis can be successfully used to refine and expedite the

Poly(β-Amino Ester)-Nanoparticle Mediated Transfection of Retinal Pigment Epithelial Cells In Vitro and In Vivo

PubMed Central

Bhutto, Imran; Handa, James T.; Green, Jordan J.

2012-01-01

A variety of genetic diseases in the retina, including retinitis pigmentosa and leber congenital amaurosis, might be excellent targets for gene delivery as treatment. A major challenge in non-viral gene delivery remains finding a safe and effective delivery system. Poly(beta-amino ester)s (PBAEs) have shown great potential as gene delivery reagents because they are easily synthesized and they transfect a wide variety of cell types with high efficacy in vitro. We synthesized a combinatorial library of PBAEs and evaluated them for transfection efficacy and toxicity in retinal pigment epithelial (ARPE-19) cells to identify lead polymer structures and transfection formulations. Our optimal polymer (B5-S5-E7 at 60 w/w polymer∶DNA ratio) transfected ARPE-19 cells with 44±5% transfection efficacy, significantly higher than with optimized formulations of leading commercially available reagents Lipofectamine 2000 (26±7%) and X-tremeGENE HP DNA (22±6%); (p<0.001 for both). Ten formulations exceeded 30% transfection efficacy. This high non-viral efficacy was achieved with comparable cytotoxicity (23±6%) to controls; optimized formulations of Lipofectamine 2000 and X-tremeGENE HP DNA showed 15±3% and 32±9% toxicity respectively (p>0.05 for both). Our optimal polymer was also significantly better than a gold standard polymeric transfection reagent, branched 25 kDa polyethyleneimine (PEI), which achieved only 8±1% transfection efficacy with 25±6% cytotoxicity. Subretinal injections using lyophilized GFP-PBAE nanoparticles resulted in 1.1±1×103-fold and 1.5±0.7×103-fold increased GFP expression in the retinal pigment epithelium (RPE)/choroid and neural retina respectively, compared to injection of DNA alone (p = 0.003 for RPE/choroid, p<0.001 for neural retina). The successful transfection of the RPE in vivo suggests that these nanoparticles could be used to study a number of genetic diseases in the laboratory with the potential to treat debilitating eye

Mechanistically Distinct Mouse Models for CRX-Associated Retinopathy

PubMed Central

Tran, Nicholas M.; Zhang, Alan; Zhang, Xiaodong; Huecker, Julie B.; Hennig, Anne K.; Chen, Shiming

2014-01-01

Cone-rod homeobox (CRX) protein is a “paired-like” homeodomain transcription factor that is essential for regulating rod and cone photoreceptor transcription. Mutations in human CRX are associated with the dominant retinopathies Retinitis Pigmentosa (RP), Cone-Rod Dystrophy (CoRD) and Leber Congenital Amaurosis (LCA), with variable severity. Heterozygous Crx Knock-Out (KO) mice (“+/−”) have normal vision as adults and fail to model the dominant human disease. To investigate how different mutant CRX proteins produce distinct disease pathologies, we generated two Crx Knock-IN (K-IN) mouse models: CrxE168d2 (“E168d2”) and CrxR90W (“R90W”). E168d2 mice carry a frameshift mutation in the CRX activation domain, Glu168del2, which is associated with severe dominant CoRD or LCA in humans. R90W mice carry a substitution mutation in the CRX homeodomain, Arg90Trp, which is associated with dominant mild late-onset CoRD and recessive LCA. As seen in human patients, heterozygous E168d2 (“E168d2/+”) but not R90W (“R90W/+”) mice show severely impaired retinal function, while mice homozygous for either mutation are blind and undergo rapid photoreceptor degeneration. E168d2/+ mice also display abnormal rod/cone morphology, greater impairment of CRX target gene expression than R90W/+ or +/− mice, and undergo progressive photoreceptor degeneration. Surprisingly, E168d2/+ mice express more mutant CRX protein than wild-type CRX. E168d2neo/+, a subline of E168d2 with reduced mutant allele expression, displays a much milder retinal phenotype, demonstrating the impact of Crx expression level on disease severity. Both CRX[E168d2] and CRX[R90W] proteins fail to activate transcription in vitro, but CRX[E168d2] interferes more strongly with the function of wild type (WT) CRX, supporting an antimorphic mechanism. E168d2 and R90W are mechanistically distinct mouse models for CRX-associated disease that will allow the elucidation of molecular mechanisms and testing of

Orbital complications in children: differential diagnosis of a challenging disease.

PubMed

Welkoborsky, Hans-J; Graß, Sylvia; Deichmüller, Cordula; Bertram, Oliver; Hinni, Michael L

2015-05-01

Orbital swelling in children presents diagnostic and therapeutic challenges. Most are associated with acute sinusitis with complicating factors possibly including: amaurosis, meningitis, intracranial abscess or even cavernous sinus thrombosis. However not all acute orbital swelling is associated with acute sinusitis. A careful evaluation is critical prior to initiating therapy. Clinical records of 49 children (27 girls, 22 boys, with an average age of 11.8 years) were retrospectively reviewed. Historical data evaluated included all available information from parents and previous treating physicians. All patients underwent intensive pediatric, ophthalmologic, and otorhinolaryngologic examinations. Computed tomography (CT scans) were additionally performed in 40 % of children. The results of any examinations were also evaluated. Eighteen of the 49 patients had an orbital complication due to acute sinusitis. All 18 had elevated body temperature, C-Reactive Protein (CRP) values and white blood cell counts. Endoscopy of the nose revealed pus in the middle meatus in each case. According to Chandlers' classification, ten children presented with a preseptal, and eight children had a postseptal orbital cellulitis. All patients were admitted to the hospital and treated with intravenous antibiotics. CT scans further demonstrated signs of subperiostal abscess in four children. Functional endoscopic sinus surgery (FESS) was required in six children, including all patients with subperiostal abscess. Twenty children experienced orbital swelling unrelated to acute sinusitis, i.e. atheroma, inflammed insect stings, dental related abscess, conjunctivitis, and Herpes simplex associated superinfection. In three children, acute orbital swelling was caused by an orbital tumor. Orbital complications of an acute sinusitis occur often in the pediatric patient group, and most of these patients can be treated conservative with intravenous antibiotics. Indications for FESS include failure to

Application of a high-throughput genotyping method for loci exclusion in non-consanguineous Australian pedigrees with autosomal recessive retinitis pigmentosa

PubMed Central

Paterson, Rachel L.; McLaren, Terri L.; Hewitt, Alex W.; Hoffmann, Ling; Lamey, Tina M.

2012-01-01

Purpose Retinitis pigmentosa (RP) is the most common form of inherited blindness, caused by progressive degeneration of photoreceptor cells in the retina, and affects approximately 1 in 3,000 people. Over the past decade, significant progress has been made in gene therapy for RP and related diseases, making genetic characterization increasingly important. Recently, high-throughput technologies have provided an option for reasonably fast, cost-effective genetic characterization of autosomal recessive RP (arRP). The current study used a single nucleotide polymorphism (SNP) genotyping method to exclude up to 28 possible disease-causing genes in 31 non-consanguineous Australian families affected by arRP. Methods DNA samples were collected from 59 individuals affected with arRP and 74 unaffected family members from 31 Australian families. Five to six SNPs were genotyped for 28 genes known to cause arRP or the related disease Leber congenital amaurosis (LCA). Cosegregation analyses were used to exclude possible causative genes from each of the 31 families. Bidirectional sequencing was used to identify disease-causing mutations in prioritized genes that were not excluded with cosegregation analyses. Results Two families were excluded from analysis due to identification of false paternity. An average of 28.9% of genes were excluded per family when only one affected individual was available, in contrast to an average of 71.4% or 89.8% of genes when either two, or three or more affected individuals were analyzed, respectively. A statistically significant relationship between the proportion of genes excluded and the number of affected individuals analyzed was identified using a multivariate regression model (p<0.0001). Subsequent DNA sequencing resulted in identification of the likely disease-causing gene as CRB1 in one family (c.2548 G>A) and USH2A in two families (c.2276 G>T). Conclusions This study has shown that SNP genotyping cosegregation analysis can be successfully

[Early therapeutic trials for retinitis pigmentosa].

PubMed

Dufier, Jean-Louis

2003-01-01

Non syndromic forms of Retinitis Pigmentosa (RP) constitute a collection of clinically and genetically heterogeneous inherited retinal degenerative diseases. They are characterized by a bilateral progressive visual loss susceptible to cause blindness. These diseases are transmitted through pedigrees according to all known modes of inheritance. They are bilateral and usually start during infancy. However, very early clinical presentations exist, such as those observed in children affected by Leber Congenital Amaurosis, as well as late onset autosomal dominant forms of retinitis pigmentosa. The characteristic clinical aspect of the rod-cone RP dystrophies is marked by alterations of the peripheral retina associated with a night blindness and a progressive narrowing of the visual field. The ophthalmoscopic examination of RP patients commonly reveals thin retinal arteries and scattered pigmentary accumulations. In contrast, there are cone rod retinal dystrophies whose onset is marked by a decreased visual acuity before the appearance of any visual field alteration. Some forms of RPs display an ocular fundus devoid of any pigmentary alteration. Syndromic forms of RPs are not uncommon. The association of deafness with RP is detected in nearly 30% of the patients. Other associations with RP can include mental deficiency, facial dysmorphy, microcephaly, obesity, kidney deficiency, immune deficiencies, metabolic disorders. The existence of such syndromic forms of RP localizes RPs at the crossroad of several medical specialties. A long lasting collaboration between our department of ophthalmology and the department of medical genetics of the Necker-Sick Children Hospital has allowed us to establish numerous genotype-phenotype correlations, especially in LCA and Stargardt's disease. ABCR gene mutations cause Stargardt disease. ABCR mutations may also cause some types of Ages Related Macular Degenerations (AMD). Nowadays, there is no known efficient therapy available for

[Anorexia with sinus bradycardia: a case report].

PubMed

Wang, Fang-fang; Xu, Ling; Chen, Bao-xia; Cui, Ming; Zhang, Yuan

2016-02-18

As anorexia patients always go to the psychiatric clinic, little is concerned about the occurrence of sinus bradycardia in these patients for cardiologists and psychiatrists. The aim of this paper is to discuss the relationship between anorexia and sinus bradycardia, and the feature analysis, differential diagnosis and therapeutic principles of this type of sinus bradycardia. We report a case of sinus bradycardia in an anorexia patient with the clinical manifestations, laboratory exams, auxiliary exams, therapeutic methods, and her prognosis, who was admitted to Peking University Third Hospital recently. The patient was a 19-year-old female, who had the manifestation of anorexia. She lost obvious weight in a short time (about 15 kg in 6 months), and her body mass index was 14.8 kg/m(2). The patient felt apparent palpitation, chest depression and short breath, without dizziness, amaurosis or unconsciousness. Vitals on presentation were notable for hypotension, and bradycardia. The initial exam was significant for emaciation, but without lethargy or lower extremity edema. The electrocardiogram showed sinus bradycardia with her heart rate being 32 beats per minute. The laboratory work -up revealed her normal blood routine, electrolytes and liver function. But in her thyroid function test, the free thyroid (FT) hormones 3 was 0.91 ng/L (2.3-4.2 ng/L),and FT4 was 8.2 ng/L (8.9-18.0 ng/L), which were all lower; yet the thyroid stimulating hormone (TSH) was normal 1.48 IU/mL (0.55-4.78 IU/mL). Ultrasound revealed her normal thyroid. Anorexia is an eating disorder characterized by extremely low body weight, fear of gaining weight or distorted perception of body image, and amenorrhea. Anorexia patients who lose weight apparently in short time enhance the excitability of the parasympathetic nerve, and inhibit the sympathetic nerve which lead to the appearance of sinus bradycardia, and functional abnormalities of multiple systems such as hypothyroidism. But this kind of sinus

True Brachial Artery Aneurysm in a Patient with Vascular Access for Haemodialysis and Kidney Graft.

PubMed

Correia, Mafalda; Marinho, André; Mendes, Carolina; Antunes, Luís; Gonçalves, Óscar

2017-01-01

True brachial artery aneurysms are rare and some of them have been described as a late complication in patients with vascular access for haemodialysis and kidney graft. The purpose of this paper is to present a clinical case of a patient with a true brachial artery aneurysm and its following treatment. This case concerns a caucasian male patient with 43 years old who had vesicoureteral reflux at 7 years old, and subsequent end-stage renal disease, and started on haemodialysis at the age of twelve. The patient had homolateral radial and brachiocephalic arteriovenous fistulas (AVF), two sequential kidney grafts and was under immunosuppressant therapy for several years. As part of the medical history he also had bilateral amaurosis, Hepatitis B and C and was submitted to total parathyroidectomy and a following auto-transplant. In the latest years the patient presented with several aneurysms related to the vascular access. After the finding of an anastomotic false aneurysm and venous aneurysms complicating the AVF, the patient had removal of the aneurysms and ligation of the AVF. Later, he was diagnosed, in different times, with two true brachial artery aneurysms. At the time of the diagnosis of the first true aneurysm, the patient presented with local pain and occasional paraesthesias relative to compression symptoms. At physical examination the patient had a brachial pulsatile mass and a palpable radial pulse. The Doppler ultrasound exam revealed a true brachial artery aneurysm with 4,5 cm diameter. After two years, the patient was once again diagnosed with a true brachial artery aneurysm with 3,1 cm diameter. At this time the patient was asymptomatic and had palpable brachial mass and radial pulse. At the time of the diagnosis of the first true brachial aneurysm the patient was submitted to partial aneurysmectomy and brachiobrachial graft with PTFE 8. The patency of the graft persisted until the diagnosis of the second aneurysm. After two years, the patient was

Impact of set-aside management on soil mesofauna

NASA Astrophysics Data System (ADS)

Landi, Silvia; d'Errico, Giada; Mazza, Giuseppe; Mocali, Stefano; Bazzoffi, Paolo; Roversi, Pio Federico

2014-05-01

(MI) resulted significantly higher in set-aside managements than in conventional crops in Fagna and Metaponto sites. In contrast, Caorle was characterized by a significant soil degradation (prevalence of extreme colonizers) and any increase of MI values in the set-aside have been not detected. About microarthropods, the taxa richness was significantly higher in set-aside managements than conventional crops in all the sites sampled. QBS index showed the same trend, but the differences were not significant. Caorle site was characterized by a lack of balance in the relative abundance among soil microarthropods taxa. In particular, set-aside managements showed a strong prevalence of an aggressive ants Solenopsis fugax (Hymenoptera: Formicidae). In conclusion, the best results were observed in Fagna and Metaponto sites, where MI and QBS values increased under set-aside management as compared to the conventional. Further analyses will be carried out over a long period to better understand the possible correlation between the enhancement of the organic matter observed in the soils less degraded and the biological quality improvement.

[Mechanical injuries of the eyeball: frequency, structure, and possibility of the prevention].

PubMed

Jovanović, Milos

2006-01-01

injuries were almost evenly distributed. Considering the period of a day, even 77.4% of the injuries occurred during daytime, from 10 a.m. to 10 p.m. The highest percentage - 43.5% - of the injuries occurred while working something out of working place, while 24.5% of injuries were inflicted at working places. On admission, the majority of patients - 32.9% had visual acuity L+P+, but this visual acuity ranged from amaurosis to 1.0. There were 746 (45.4%) contusion injuries and 870 (53.0%) penetrating injuries. The rest were the injuries of other ocular adnexa. The majority of primary wound managements were performed in the first 24 hours of the injury - 67.1%. It may be concluded that working population and students are most commonly injured, and that men are five times more frequently injured than women; then, a piece of wood, sharp objects and glass are the most often causes of injury; the number of contusion and penetrating injuries is equal, and that required primary surgical wound management is most often performed in the first 24 hours from the injury. Further analysis of these factors suggests that many of these injuries could have been prevented, and consequently long-term treatment and treatment costs could have been evaded. Most important is that permanent disability due to visual impairment or even blindness of the injured eye could have been avoided.