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Bosisio Parini, Italy

Tondo M.,Hospital Sant Joan de Deu | Gamez J.,Hospital Universitari Vall dHebron | Gutierrez-Rivas E.,NeuroMuscular Unit | Medel-Jimenez R.,Hospital Universitari Vall d Hebron | Martorell L.,Hospital Sant Joan de Deu
Journal of Neurology | Year: 2012

Oculopharyngeal muscular dystrophy is an autosomal dominant adult-onset disease with several clinical features. The genetic cause is an expanded (GCN)n mutation coding for polyalanine. Severity and the age of onset are variable and may depend on the size of the unstable triplet. Our objectives were to correlate the genotypic and phenotypic features in 34 affected patients, and to complete the molecular analysis for a control Spanish population in order to confirm the (GCN)n polymorphism frequency observed in other populations. We found a correlation between impaired CPK levels and sex. No statistical differences were found when comparing the length in triplet expansion and other variables. The (GCN)n polymorphism's frequency observed in other countries could not be proven in ours. Moreover, no correlation was observed amongst the size of the mutation, the age of onset, and the phenotype. This fact suggests that other conditions apart from the already known genotype could influence the age of onset and the severity of the symptoms. © Springer-Verlag 2012.

Al-Haggar M.,Mansoura University | Madej-Pilarczyk A.,NeuroMuscular Unit | Kozlowski L.,International Institute of Molecular and Cell Biology | Bujnicki J.M.,International Institute of Molecular and Cell Biology | And 7 more authors.
European Journal of Human Genetics | Year: 2012

Mandibuloacral dysplasia (MAD) is a rare disease resulting from a mutation of LMNA gene encoding lamins A and C. The most common mutation associated with this disease is a homozygous arginine 527 replacement by histidine. Three female patients originating from two unrelated families from Northeast Egypt were examined. Their growth was retarded; they had microcephaly, widened cranial sutures, prominent eyes and cheeks, micrognathia, dental crowding, hypoplastic mandible, acro-osteolysis of distal phalanges, and joint contractures. In addition, they presented some progeroid features, such as pinched nose, premature loss of teeth, loss of hair, scleroderma-like skin atrophy, spine rigidity, and waddling gait. The clinical presentation of the disease varied between the patient originating from Family 1 and patients from Family 2, suggesting that unknown, possibly epigenetic factors, modify the course of the disease. The first symptoms of the disease appeared at the age of 2.5 (a girl from Family 1), 5, and 3 years (girls from Family 2). All patients had the same, novel homozygous c.1580G>T LMNA mutation, resulting in the replacement of arginine 527 by leucine. Computational predictions of such substitution effects suggested that it might alter protein stability and increase the tendency for protein aggregation, and as a result, might influence its interaction with other proteins. In addition, restriction fragment-length polymorphism analysis performed in 178 unrelated individuals showed that up to 1.12% of inhabitants of Northeast Egypt might be heterozygous carriers of this mutation, suggesting the presence of a founder effect in this area. © 2012 Macmillan Publishers Limited. All rights reserved.

Tomik B.,Jagiellonian University | Guiloff R.J.,NeuroMuscular Unit
Amyotrophic Lateral Sclerosis | Year: 2010

Dysarthria is a motor disorder of speech characterized by abnormalities of the articulation and intelligibility of speech. Phonation and the rate of facial movements may also be affected. Understanding the nature and course of dysarthria in amyotrophic lateral sclerosis (ALS) is important because loss of communication prevents patients from participating in many activities, may lead to social isolation, and reduces the quality of life. The goal of management of dysarthria in ALS patients is to optimize communication effectiveness for as long as possible. The information about dysarthria in ALS is dispersed in physiological, pathological, speech therapy, otorhinolaringological and neurological publications. This review summarizes the current state of knowledge on the clinical features, differential diagnosis, pathophysiology, investigations and management of dysarthria in ALS patients. There is a need to compare the different methods used to assess dysarthria and for controlled clinical trials to assess therapeutic strategies.

Kim J.,University College London | Jimenez-Mallebrera C.,University College London | Jimenez-Mallebrera C.,NeuroMuscular Unit | Foley A.R.,University College London | And 7 more authors.
Neuromuscular Disorders | Year: 2012

Mutations in COL6A1, COL6A2 and COL6A3 genes result in collagen VI myopathies: Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) and intermediate phenotypes. At present, none of the existing diagnostic techniques for evaluating collagen VI expression is quantitative, and the detection of subtle changes in collagen VI expression remains challenging.We investigated flow cytometry analysis as a means of quantitatively measuring collagen VI in primary fibroblasts and compared this method with the standard method of fibroblast collagen VI immunohistochemical analysis. Eight UCMD and five BM molecularly confirmed patients were studied and compared to five controls.Flow cytometry analysis consistently detected a reduction of collagen VI of at least 60% in all UCMD cases. In BM cases the levels of collagen VI were variable but on average 20% less than controls.Flow cytometry analysis provides an alternative method for screening for collagen VI deficiency at the protein level in a quantitative, time and cost-effective manner. © 2011 Elsevier B.V.

Cassandrini D.,IRCCS Fondazione Stella Maris | Cilio M.R.,Bambino Gesu Childrens Research Hospital | Cilio M.R.,University of California at San Francisco | Bianchi M.,Bambino Gesu Childrens Research Hospital | And 19 more authors.
Journal of Inherited Metabolic Disease | Year: 2013

Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been associated with early onset encephalopathy with signs of oxidative phosphorylation defects classified as pontocerebellar hypoplasia 6. We describe clinical, neuroimaging and molecular features on five patients from three unrelated families who displayed mutations in RARS2. All patients rapidly developed a neonatal or early-infantile epileptic encephalopathy with intractable seizures. The long-term follow-up revealed a virtual absence of psychomotor development, progressive microcephaly, and feeding difficulties. Mitochondrial respiratory chain enzymes in muscle and fibroblasts were normal in two. Blood and CSF lactate was abnormally elevated in all five patients at early stages while appearing only occasionally abnormal with the progression of the disease. Cerebellar vermis hypoplasia with normal aspect of the cerebral and cerebellar hemispheres appeared within the first months of life at brain MRI. In three patients follow-up neuroimaging revealed a progressive pontocerebellar and cerebral cortical atrophy. Molecular investigations of RARS2 disclosed the c.25A>G/p.I9V and the c.1586+3A>T in family A, the c.734G>A/p.R245Q and the c.1406G>A/p.R469H in family B, and the c.721T>A/p.W241R and c.35A>G/p.Q12R in family C. Functional complementation studies in Saccharomyces cerevisiae showed that mutation MSR1-R531H (equivalent to human p.R469H) abolished respiration whereas the MSR1-R306Q strain (corresponding to p.R245Q) displayed a reduced growth on non-fermentable YPG medium. Although mutations functionally disrupted yeast we found a relatively well preserved arginine aminoacylation of mitochondrial tRNA. Clinical and neuroimaging findings are important clues to raise suspicion and to reach diagnostic accuracy for RARS2 mutations considering that biochemical abnormalities may be absent in muscle biopsy. © 2012 SSIEM and Springer.

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