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Budapest, Hungary
Budapest, Hungary
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Ivanov I.S.,Medical university-Plovdiv | Azmanov D.N.,University of Western Australia | Ivanova M.B.,Medical University-Sofia | Chamova T.,Medical University-Sofia | And 28 more authors.
Molecular Genetics and Metabolism | Year: 2014

Investigation of 31 of Roma patients with congenital lactic acidosis (CLA) from Bulgaria identified homozygosity for the R446* mutation in the PDHX gene as the most common cause of the disorder in this ethnic group. It accounted for around 60% of patients in the study and over 25% of all CLA cases referred to the National Genetic Laboratory in Bulgaria. The detection of a homozygous patient from Hungary and carriers among population controls from Romania and Slovakia suggests a wide spread of the mutation in the European Roma population.The clinical phenotype of the twenty R446* homozygotes was relatively homogeneous, with lactic acidosis crisis in the first days or months of life as the most common initial presentation (15/20 patients) and delayed psychomotor development and/or seizures in infancy as the leading manifestations in a smaller group (5/20 patients). The subsequent clinical picture was dominated by impaired physical growth and a very consistent pattern of static cerebral palsy-like encephalopathy with spasticity and severe to profound mental retardation seen in over 80% of cases. Most patients had a positive family history.We propose testing for the R446* mutation in PDHX as a rapid first screening in Roma infants with metabolic acidosis. It will facilitate and accelerate diagnosis in a large proportion of cases, allow early rehabilitation to alleviate the chronic clinical course, and prevent further affected births in high-risk families. © 2014.


Bladen C.L.,Northumbria University | Bladen C.L.,South Health Campus | Salgado D.,Aix - Marseille University | Salgado D.,South Health Campus | And 59 more authors.
Human Mutation | Year: 2015

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations). © 2015 The Authors.


Bladen C.L.,Institute of Genetic Medicine | Rafferty K.,Institute of Genetic Medicine | Straub V.,Institute of Genetic Medicine | Monges S.,Hospital Pediatria J P Garrahan | And 59 more authors.
Human Mutation | Year: 2013

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease, caused by the absence of the dystrophin protein. Although many novel therapies are under development for DMD, there is currently no cure and affected individuals are often confined to a wheelchair by their teens and die in their twenties/thirties. DMD is a rare disease (prevalence <5/10,000). Even the largest countries do not have enough affected patients to rigorously assess novel therapies, unravel genetic complexities, and determine patient outcomes. TREAT-NMD is a worldwide network for neuromuscular diseases that provides an infrastructure to support the delivery of promising new therapies for patients. The harmonized implementation of national and ultimately global patient registries has been central to the success of TREAT-NMD. For the DMD registries within TREAT-NMD, individual countries have chosen to collect patient information in the form of standardized patient registries to increase the overall patient population on which clinical outcomes and new technologies can be assessed. The registries comprise more than 13,500 patients from 31 different countries. Here, we describe how the TREAT-NMD national patient registries for DMD were established. We look at their continued growth and assess how successful they have been at fostering collaboration between academia, patient organizations, and industry. © 2013 WILEY PERIODICALS, INC.


PubMed | NIEH, Royal Infirmary, Northumbria University and Semmelweis University
Type: Journal Article | Journal: Journal of neuromuscular diseases | Year: 2016

Behrs syndrome is a classical phenotypic description of childhood-onset optic atrophy combined with various neurological symptoms, including ophthalmoparesis, nystagmus, spastic paraparesis, ataxia, peripheral neuropathy and learning difficulties.Here we describe 4 patients with the classical Behrs syndrome phenotype from 3 unrelated families who carry homozygous nonsense mutations in the C12orf65 gene encoding a protein involved in mitochondrial translation.Whole exome sequencing was performed in genomic DNA and oxygen consumption was measured in patient cell lines.We detected 2 different homozygous C12orf65 nonsense mutations in 4 patients with a homogeneous clinical presentation matching the historical description of Behrs syndrome. The first symptom in all patients was childhood-onset optic atrophy, followed by spastic paraparesis, distal weakness, motor neuropathy and ophthalmoparesis.We think that C12orf65 mutations are more frequent than previously suggested and screening of this gene should be considered not only in patients with mitochondrial respiratory chain deficiencies, but also in inherited peripheral neuropathies, spastic paraplegias and ataxias, especially with pre-existing optic atrophy.


PubMed | NIEH, Royal Infirmary, Northumbria University and Semmelweis University
Type: Journal Article | Journal: Journal of neuromuscular diseases | Year: 2016

Behrs syndrome is a classical phenotypic description of childhood-onset optic atrophy combined with various neurological symptoms, including ophthalmoparesis, nystagmus, spastic paraparesis, ataxia, peripheral neuropathy and learning difficulties.Here we describe 4 patients with the classical Behrs syndrome phenotype from 3 unrelated families who carry homozygous nonsense mutations in the Whole exome sequencing was performed in genomic DNA and oxygen consumption was measured in patient cell lines.We detected 2 different homozygous We think that


PubMed | Hebrew University of Jerusalem, Josa Andras Hospital, NIEH, Charité - Medical University of Berlin and 6 more.
Type: | Journal: Nature communications | Year: 2014

The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here we show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease.


Lehtokari V.-L.,University of Helsinki | Pelin K.,University of Helsinki | Herczegfalvi A.,Heim Pal Hospital | Karcagi V.,NIEH | And 9 more authors.
Neuromuscular Disorders | Year: 2011

Mutations in the nebulin gene are the main cause of autosomal recessive nemaline myopathy, with clinical presentations ranging from mild to severe disease. We have previously reported a nonspecific distal myopathy caused by homozygous missense mutations in the nebulin gene in six Finnish patients from four different families. Here we describe three non-Finnish patients in two unrelated families with distal nemaline myopathy caused by four different compound heterozygous nebulin mutations, only one of which is a missense mutation. One of the mutations has previously been identified in one family with the severe form of nemaline myopathy. We conclude that nemaline myopathy and distal myopathy caused by nebulin mutations form a clinical and histological continuum. Nemaline myopathy should be considered as a differential diagnosis in patients presenting with an early-onset predominantly distal myopathy. © 2011 Elsevier B.V.


Boczonadi V.,Northumbria University | Muller J.S.,Northumbria University | Pyle A.,Northumbria University | Munkley J.,Northumbria University | And 24 more authors.
Nature Communications | Year: 2014

The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here we show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease. © 2014 Macmillan Publishers Limited.


Annesi-Maesano I.,University Pierre and Marie Curie | Annesi-Maesano I.,French Institute of Health and Medical Research | Baiz N.,University Pierre and Marie Curie | Baiz N.,French Institute of Health and Medical Research | And 5 more authors.
Journal of Toxicology and Environmental Health - Part B: Critical Reviews | Year: 2013

Good indoor air quality in schools is important to provide a safe, healthy, productive, and comfortable environment for students, teachers, and other school staff. However, existing studies demonstrated that various air pollutants are found in classrooms, sometimes at elevated concentrations. Data also indicated that poor air quality may impact children's health, in particular respiratory health, attendance, and academic performance. Nevertheless, it should be noted that there are other adverse health effects that are less documented. Few data exist for teachers and other adults that work in schools. Allergic individuals seem to be at a higher risk for adverse respiratory health consequences. Air quality improvement represents an important measure for prevention of adverse health consequences in children and adults in schools. Copyright © 2013 Taylor and Francis Group, LLC.


Durmus H.,Istanbul University | Laval S.H.,Northumbria University | Deymeer F.,Istanbul University | Parman Y.,Istanbul University | And 10 more authors.
Neurology | Year: 2011

Background: Oculopharyngodistal myopathy (OPDM) has been reported as a rare, adult-onset hereditary muscle disease with putative autosomal dominant and autosomal recessive inheritance. Patients with OPDM present with progressive ocular, pharyngeal, and distal limb muscle involvement. The genetic defect causing OPDM has not been elucidated. Methods: Clinical and genetic findings of 47 patients from 9 unrelated Turkish families diagnosed with OPDM at the Department of Neurology, Istanbul Faculty of Medicine, between 1982 and 2009 were evaluated. Results: The mean age at onset was around 22 years. Both autosomal dominant and autosomal recessive traits were observed, without any clear difference in clinical phenotype or severity. The most common initial symptom was ptosis, followed by oropharyngeal symptoms and distal weakness, which started after the fifth disease year. Intrafamilial variability of disease phenotype and severity was notable in the largest autosomal dominant family. Atypical presentations, such as absence of limb weakness in long-term follow-up in 9, proximal predominant weakness in 4, and asymmetric ptosis in 3 patients, were observed. Swallowing difficulty was due to oropharyngeal dysphagia with myopathic origin. Serum creatine kinase levels were slightly increased and EMG revealed myopathic pattern with occasional myotonic discharges. Myopathologic findings included rimmed and autophagic vacuoles and chronic myopathic changes. Importantly, a considerable proportion of patients developed respiratory muscle weakness while still ambulant. Linkage to the genetic loci for all known muscular dystrophies, and for distal and myofibrillar myopathies, was excluded in the largest autosomal dominant and autosomal recessive OPDM families. Conclusions: We suggest that OPDM is a clinically and genetically distinct myopathy. Copyright © 2011 by AAN Enterprises, Inc. All rights reserved.

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