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Narayanaswami P.,Beth Israel Deaconess Medical Center | Weiss M.,University of Washington | Selcen D.,Mayo Medical School | David W.,Harvard University | And 9 more authors.
Neurology | Year: 2014

Objective: To review the current evidence and make practice recommendations regarding the diagnosis and treatment of limb-girdle muscular dystrophies (LGMDs). Methods: Systematic review and practice recommendation development using the American Academy of Neurology guideline development process. Results: Most LGMDs are rare, with estimated prevalences ranging from 0.07 per 100,000 to 0.43 per 100,000. The frequency of some muscular dystrophies varies based on the ethnic background of the population studied. Some LGMD subtypes have distinguishing features, including pattern of muscle involvement, cardiac abnormalities, extramuscular involvement, and muscle biopsy findings. The few published therapeutic trials were not designed to establish clinical efficacy of any treatment. Principal recommendations: For patients with suspected muscular dystrophy, clinicians should use a clinical approach to guide genetic diagnosis based on clinical phenotype, inheritance pattern, and associated manifestations (Level B). Clinicians should refer newly diagnosed patients with an LGMD subtype and high risk of cardiac complications for cardiology evaluation even if they are asymptomatic from a cardiac standpoint (Level B). In patients with LGMD with a known high risk of respiratory failure, clinicians should obtain periodic pulmonary function testing (Level B). Clinicians should refer patients with muscular dystrophy to a clinic that has access to multiple specialties designed specifically to care for patients with neuromuscular disorders (Level B). Clinicians should not offer patients with LGMD gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone outside of a research study designed to determine efficacy and safety of the treatment (Level R). Detailed results and recommendations are available on the Neurology® Web site at Neurology.org.

Hilton-Jones D.,West Wing | Bowler M.,Myotonic Dystrophy Support Group | Lochmueller H.,Institute of Genetic Medicine | Longman C.,Ferguson Smith Center for Clinical Genetics | And 5 more authors.
Neuromuscular Disorders | Year: 2012

Excessive daytime sleepiness (EDS), of very similar pattern to that seen in narcolepsy syndrome, is extremely common in myotonic dystrophy type 1 (DM1). In a significant minority it has a profound disabling effect on employment, social functioning and activities of daily living. Limited published studies have shown inconsistent results from use of the psychostimulant drug modafinil. A recent European Medicines Agency (EMA) review concluded that on current evidence regarding safety and efficacy, modafinil's use should be restricted to the treatment of narcolepsy. In other conditions (although DM1 was not specifically considered) it was concluded that there was insufficient evidence of benefit to outweigh potentially serious side-effects, including severe skin reactions and cardiac arrhythmia. Clinicians with extensive experience in the management of DM1 have found modafinil to be extremely effective in appropriately selected patients with a very low incidence of serious side-effects. Given the recent EMA review, patients have expressed concern about the potential restriction of the use of modafinil in DM1. This brief review is an audit of the experience of a large group of patients and their clinicians concerning EDS and DM1 and concludes that despite the limited literature there is strong evidence to support the use of modafinil in carefully selected patients. © 2012 Elsevier B.V.

Angelini C.,Neuromuscular Center | Savarese M.,nd University of Naples | Savarese M.,Telethon Institute of Genetics and Medicine | Fanin M.,University of Padua | And 2 more authors.
Muscle and Nerve | Year: 2016

Introduction: We report a patient in whom the diagnosis of a treatable disease was delayed for 30 years. Methods: Recent discoveries of next generation sequencing (NGS) have allowed us to reconsider the diagnosis of limb girdle muscular dystrophy (LGMD) cases of unknown etiology. Results: A 36-year-old man appeared to have LGMD with onset in shoulder girdle muscles, but all sarcolemmal and cytoskeletal proteins tested by immunoblotting and immunohistochemistry gave normal results. He developed respiratory insufficiency and became dependent on overnight ventilation at age 44. By NGS technology, 2 mutations in the GAA gene (intervening sequence 1 and a missense mutation in exon 11) allowed us to make a definite diagnosis of glycogenosis type II (Pompe disease) and start enzyme replacement therapy at age 71. Conclusions: Mild nondystrophic features on muscle biopsy and respiratory muscle involvement should suggest late-onset Pompe disease in patients with an unclassified LGMD phenotype. NGS may help make the diagnosis. © 2016 Wiley Periodicals, Inc.

Querin G.,Neuromuscular Center | D'Ascenzo C.,Neuromuscular Center | Peterle E.,Neuromuscular Center | Ermani M.,Neuromuscular Center | And 11 more authors.
Neurology | Year: 2013

Objective: To test the efficacy and tolerability of clenbuterol in patients with spinal and bulbar muscular atrophy (SBMA). Methods: Twenty patients with a diagnosis of SBMA were given oral clenbuterol (0.04 mg/d) for 12months. The primary efficacy end point was the change from baseline of the walking distance covered in 6 minutes at 12 months. Secondary end points included the change over time in muscle strength assessed with theMedical Research Council scale, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and forced vital capacity values. Safety was assessed by a series of laboratory and instrumental tests, as well as reporting of adverse events. Results: Sixteen patients completed the study. There was a significant and sustained increase in walking distance covered in 6 minutes and forced vital capacity between the baseline and the 12-month assessments (p < 0.001). No differences were recorded in Medical Research Council or ALSFRS-R scores between baseline and follow-up assessments. Serious side effects, including those on heart function, were absent. A significant increase in serum creatine kinase levels was observed. Conclusions: Our findings suggest a positive effect of clenbuterol on SBMA disease progression. Classification of evidence: This study provides Class IV evidence that clenbuterol is effective in improving motor function in SBMA. © 2013 American Academy of Neurology.

Pegoraro E.,Neuromuscular Center | Hoffman E.P.,University of California at Davis | Piva L.,Neuromuscular Center | Gavassini B.F.,Neuromuscular Center | And 18 more authors.
Neurology | Year: 2011

Objective: Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient-patient variability in disease onset and progression and response to glucocorticoids is seen, suggesting genetic or environmental modifiers. Methods: Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied. Results: Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%-19% less grip strength (CINRG cohort p = 0.0003). Conclusions: Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects. Copyright © 2011 by AAN Enterprises, Inc. All rights reserved.

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