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Newcastle upon Tyne, United Kingdom

Pfeffer G.,Northumbria University | Pfeffer G.,Royal Infirmary | Barresi R.,Muscle Immunoanalysis Unit | Wilson I.J.,Northumbria University | And 22 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2014

Objective Titin gene (TTN) mutations have been described in eight families with hereditary myopathy with early respiratory failure (HMERF). Some of the original patients had features resembling myofibrillar myopathy (MFM), arguing that TTN mutations could be a much more common cause of inherited muscle disease, especially in presence of early respiratory involvement. Methods We studied 127 undiagnosed patients with clinical presentation compatible with MFM. Sanger sequencing for the two previously described TTN mutations in HMERF (p.C30071R in the 119th fibronectin-3 (FN3) domain, and p.R32450W in the kinase domain) was performed in all patients. Patients with mutations had detailed review of their clinical records, muscle MRI findings and muscle pathology. Results We identified five new families with the p.C30071R mutation who were clinically similar to previously reported cases, and muscle pathology demonstrated diagnostic features of MFM. Two further families had novel variants in the 119th FN3 domain (p.P30091L and p.N30145K). No patients were identified with mutations at position p.32450. Conclusions Mutations in TTN are a cause of MFM, and titinopathy is more common than previously thought. The finding of the p.C30071R mutation in 3.9% of our study population is likely due to a British founder effect. The occurrence of novel FN3 domain variants, although still of uncertain pathogenicity, suggests that other mutations in this domain may cause MFM, and that the disease is likely to be globally distributed. We suggest that HMERF due to mutations in the TTN gene be nosologically classified as MFM-titinopathy.

Hicks D.,Northumbria University | Sarkozy A.,Northumbria University | Muelas N.,Hospital Universitario La Paz | Koehler K.,TU Dresden | And 17 more authors.
Brain | Year: 2011

The limb-girdle muscular dystrophies are a group of disorders with wide genetic and clinical heterogeneity. Recently, mutations in the ANO5 gene, which encodes a putative calcium-activated chloride channel belonging to the Anoctamin family of proteins, were identified in five families with one of two previously identified disorders, limb-girdle muscular dystrophy 2L and non-dysferlin Miyoshi muscular dystrophy. We screened a candidate group of 64 patients from 59 British and German kindreds and found the truncating mutation, c.191dupA in exon 5 of ANO5 in 20 patients, homozygously in 15 and in compound heterozygosity with other ANO5 variants in the rest. An intragenic single nucleotide polymorphism and an extragenic microsatellite marker are in linkage disequilibrium with the mutation, suggesting a founder effect in the Northern European population. We have further defined the clinical phenotype of ANO5-associated muscular dystrophy. Patients show adult onset proximal lower limb weakness with highly raised serum creatine kinase values (average 4500 IU/l) and frequent muscle atrophy and asymmetry of muscle involvement. Onset varies from the early 20 s to 50 s and the weakness is generally slowly progressive, with most patients remaining ambulant for several decades. Distal presentation is much less common but a milder degree of distal lower limb weakness is often observed. Upper limb strength is only mildly affected and cardiac and respiratory function is normal. Females appear less frequently affected. In the North of England population we have identified eight patients with ANO5 mutations, suggesting a minimum prevalence of 0.27/100 000, twice as common as dysferlinopathy. We suggest that mutations in ANO5 represent a relatively common cause of adult onset muscular dystrophy with high serum creatine kinase and that mutation screening, particularly of the common mutation c.191dupA, should be an early step in the diagnostic algorithm of adult limb-girdle muscular dystrophy patients. © The Author (2010).

Harris E.,Northumbria University | Laval S.,Northumbria University | Hudson J.,Northumbria University | Barresi R.,Muscle Immunoanalysis Unit | And 6 more authors.
PLoS Currents | Year: 2013

Advances in the molecular characterisation of genetic muscle disease has been rapid, as demonstrated by a recent analysis of these conditions in the north of England by Norwood et al (2009), in which a genetic diagnosis was achieved for 75.7% of patients. However, there remain many patients with suspected genetic muscle disease in who a diagnosis is not obtained, often despite considerable diagnostic effort, and these patients are now being considered for the application of new technologies such as next generation sequencing. This study aimed to provide an in-depth phenotype analysis of undiagnosed patients referred to the Northern region muscle clinic with suspected genetic muscle disease, with the intention of gaining insight into these conditions, identifing cases with a shared phenotype who may be amenable to collective diagnostic testing or research, and evaluating the strengths and limitations of our current diagnostic strategy. We used two approaches: a review of clinical findings in patients with undiagnosed muscle disease, and a hierarchical cluster analysis to provide an unbiased interpretation of the phenotype data. These joint approaches identified a correlation of phenotypic features according to the age of disease onset and also delineated several interesting groups of patients, as well as highlighting areas of frequent diagnostic difficulty that could benefit from the use of new high-throughput diagnostic techniques. Correspondence to: anna.sarkozy@ncl.ac.uk.

Walsh R.,Trinity College Dublin | Hill F.,Trinity College Dublin | Breslin N.,Trinity College Dublin | Connolly S.,Trinity College Dublin | And 5 more authors.
Muscle and Nerve | Year: 2011

Dysphagia has not been reported in genetically confirmed limb-girdle muscular dystrophy type 2B (LGMD2B). A 40-year-old woman reported exercise-induced calf pain at age 34, followed by progressive lower and upper limb weakness. At age 38, progressive dysphagia for solids, and subsequently liquids, ensued. Endoscopic and videofluoroscopic-radiological findings indicated a myopathic swallowing disorder. Molecular genetic analysis confirmed two dysferlin gene mutations consistent with a compound heterozygote state. Progressive dysphagia should be considered as part of the expanding dysferlinopathy phenotype. © 2011 Wiley Periodicals, Inc.

Dick E.,University of Nottingham | Kalra S.,University of Nottingham | Anderson D.,University of Nottingham | George V.,University of Nottingham | And 6 more authors.
Stem Cells and Development | Year: 2013

With an incidence of ∼1:3,500 to 5,000 in male children, Duchenne muscular dystrophy (DMD) is an X-linked disorder in which progressive muscle degeneration occurs and affected boys usually die in their twenties or thirties. Cardiac involvement occurs in 90% of patients and heart failure accounts for up to 40% of deaths. To enable new therapeutics such as gene therapy and exon skipping to be tested in human cardiomyocytes, we produced human induced pluripotent stem cells (hiPSC) from seven patients harboring mutations across the DMD gene. Mutations were retained during differentiation and analysis indicated the cardiomyocytes showed a dystrophic gene expression profile. Antisense oligonucleotide-mediated skipping of exon 51 restored dystrophin expression to ∼30% of normal levels in hiPSC-cardiomyocytes carrying exon 47-50 or 48-50 deletions. Alternatively, delivery of a dystrophin minigene to cardiomyocytes with a deletion in exon 35 or a point mutation in exon 70 allowed expression levels similar to those seen in healthy cells. This demonstrates that DMD hiPSC-cardiomyocytes provide a novel tool to evaluate whether new therapeutics can restore dystrophin expression in the heart. © Mary Ann Liebert, Inc.

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