The phenotype of Becker muscular dystrophy (BMD) varies from Duchenne-like severity (loss of ambulation in second decade) to much milder disease with ambulation retained into adulthood. We performed a prospective, natural history study (BNHS) of males with in-frame dystrophin deletions causing BMD to better characterize the clinical course. Analysis of the longitudinal dataset offers the opportunity to develop robust outcomes crucial to clinical treatment trials. The BNHS followed 83 ambulatory and non-ambulatory males with BMD aged 5.5 to 75.5 years at enrolment for up to three years with annual assessments. Baseline characteristics of these participants have been published. In this post-baseline analysis, we studied binned repeated cross-sectional clinical outcome data, shift-based analyses of NSAA, longitudinal mixed-effect modeling of clinical outcomes, and survival analysis of time to stand. Analyses were stratified by age (<18 or ≥18 years old). In this dataset, we found that the most common deletion mutations were deletion of dystrophin exons 45-47 or exons 45-48. In those <18 years, the NSAA showed a ceiling effect not observed with other outcomes. In longitudinal modeling of percentage predicted FVC, 3 timed function tests, 6-minute walk distance, and NSAA, age was found to be significantly associated with outcome performance in adulthood but not in those <18 years. Mutation status (del 45-47, 45-48, vs. others) was significantly associated with some outcomes. The median age at which it took 10 seconds or longer to stand was estimated as 51 years (95% CI: 45 years, infinity) by time to event analysis. In conclusion, while the sample size was small, our data demonstrated variable progression of different outcomes based on age groups, and mutation groups, and found that disease progression seems to largely manifest in adulthood for BMD. Our study has clinical trial design implications for enrolment criteria, efficacy determination, and sample size calculations. The phenotype of Becker muscular dystrophy (BMD) varies from Duchenne-like severity (loss of ambulation in second decade) to much milder disease with ambulation retained into adulthood. We performed a prospective, natural history study (BNHS) of males with in-frame dystrophin deletions causing BMD to better characterize the clinical course. Analysis of the longitudinal dataset offers the opportunity to develop robust outcomes crucial to clinical treatment trials. The BNHS followed 83 ambulatory and non-ambulatory males with BMD aged 5.5 to 75.5 years at enrolment for up to three years with annual assessments. Baseline characteristics of these participants have been published. In this post-baseline analysis, we studied binned repeated cross-sectional clinical outcome data, shift-based analyses of NSAA, longitudinal mixed-effect modeling of clinical outcomes, and survival analysis of time to stand. Analyses were stratified by age (<18 or ≥18 years old). In this dataset, we found that the most common deletion mutations were deletion of dystrophin exons 45-47 or exons 45-48. In those <18 years, the NSAA showed a ceiling effect not observed with other outcomes. In longitudinal modeling of percentage predicted FVC, 3 timed function tests, 6-minute walk distance, and NSAA, age was found to be significantly associated with outcome performance in adulthood but not in those <18 years. Mutation status (del 45-47, 45-48, vs. others) was significantly associated with some outcomes. The median age at which it took 10 seconds or longer to stand was estimated as 51 years (95% CI: 45 years, infinity) by time to event analysis. In conclusion, while the sample size was small, our data demonstrated variable progression of different outcomes based on age groups, and mutation groups, and found that disease progression seems to largely manifest in adulthood for BMD. Our study has clinical trial design implications for enrolment criteria, efficacy determination, and sample size calculations.

Las miopatías inflamatorias idiopáticas (MII) son un grupo de enfermedades autoinmunes crónicas que afectan principalmente a los músculos proximales. Los tipos más comunes son dermatomiositis (DM), polimiositis (PM), miopatía autoinmune necrotizante y miositis por cuerpos de inclusión. Se identifican de forma única por su presentación clínica que consiste en manifestaciones musculares y extramusculares, sus alteraciones miopáticas en el electromiograma y la elevación de las enzimas musculares. Sin embargo, la biopsia muscular sigue siendo el gold estándar para el diagnóstico. Estos trastornos son potencialmente tratables con un diagnóstico adecuado. Los objetivos del tratamiento son eliminar la inflamación, restaurar el rendimiento muscular, reducir la morbilidad y mejorar la calidad de vida. Esta revisión tiene como objetivo proporcionar un enfoque de diagnóstico básico a los pacientes con sospecha de MMI a través de sus principales hallazgos clínicos, de laboratorio e histopatológicos.

A case of triple-negative myasthenia gravis Lambert-Eaton overlap syndrome with negative Agrin and LRP-4 antibodies. Myasthenia gravis (MG) is an autoimmune disorder that shares similar features with Lambert-Eaton myasthenic syndrome. The combined clinical and electrophysiological findings of MG and Lambert-Eaton myasthenic syndrome have been reported, these cases represent the so-called "myasthenia gravis Lambert-Eaton overlap syndrome" (MLOS). A total of 55 MLOS cases have been identified, 13 cases were reported before the acetylcholine receptor (AChR) antibody (ab) testing era, 14 during the AChR-ab era, 26 during the voltage-gated calcium channel (VGCC)-ab era, and 2 cases have been reported during the muscle-specific kinase (MuSK)-ab era, of these; only 1 patient tested negative for all 3 antibodies. New immunological markers have been identified in the study of MG [Agrin and the low-density lipopro-tein receptor-related protein 4 (LRP-4)]. We present a patient with MLOS who tested negative for all 5 (AChR, MuSK, VGCC, Agrin, and LRP-4) serologic markers.

Introduction:The objective of this study was to review the literature and analyze the clinical presentation and response to therapy of late onset myasthenia gravis (LOMG) in our center.Methods: Previous reports of LOMG and the records of 24 cases of LOMG seen in our neuromuscular clinic were reviewed, and the demographic data, clinical presentations, and responses to therapy were studied.The definition of LOMG's age of onset varies, but we have defined the cases in our center as LOMG when symptoms first appear at 65 years of age or older. Results:In our center, the age range was 65-82 years--the male sex predominated in 16 patients (67%) while 8 patients (33%) were women; the presenting symptom was ocular in 12 patients (50%), generalized (not confined to a specific muscle group) in 7 (29%), and bulbar in 5 (21%); this is similar to statistics reported previously.The most common comorbidities were diabetes, essential hypertension, and thyroid disease.The treatment consisted of acetylcholinesterase inhibitors (monotherapy) in two patients; prednisone plus acetylcholinesterase inhibitors were administered in 20 patients (83%); 17 subjects (71%) needed immunosuppression with azathioprine / mycophenolate mofetil (due to lack of response or for steroid sparing).Ten patients (42%) in our center required plasma exchange or intravenous immunoglobulin infusions; thymectomy was performed in three cases, and one of these had a thymoma; otherwise, no patients experienced thymic hyperplasia. Conclusions:As in the literature, we found LOMG to have a clear male predominance; ocular presentation was the most common manifestation.Clinically, antibody positivity and response to therapy in LOMG were similar to younger myasthenia patients (non-LOMG patients) as evidenced by previous studies.Thymoma was rare.

Phenotypic variation in Becker muscular dystrophy (BMD) presents a challenge to clinical trial design for drug development. Age of onset, speed of progression and affected tissues in patients with BMD exhibit wide variability. Therefore, it is essential to gather data on the natural history of patients with BMD. Sixteen study sites in the Cooperative International Neuromuscular Research Group (CINRG) across the US, Canada, the UK and Italy enrolled a total of 84 participants in a CINRG BMD Natural History Study (BNHS) for baseline and follow up visits. Patients with BMD who were age 4 years or older with a deletion in the dystrophin gene that is predicted to be in-frame were eligible to participate. Goals of the study include characterization of the BMD phenotype that corresponds to deletions that would be generated by skipping of exons 45, 51 or 53 in patients with out-of-frame dystrophin deletions causing Duchenne muscular dystrophy (mutation group (MG)-45, MG-51 and MG-53). Collection of clinical data across multiple body systems with correlation to high-resolution deletion break-point mapping. Phenotype – genotype correlations in BMD. Baseline age of participants ranged from 5.6 to 75.4 years. Age at symptom onset ranged from first year of life to 57 years. Age at diagnosis ranged from first year of life to 75 years. Sixty-five percent of participants are in MG-45, corresponding to a DMD deletion with an exon 45 skip. We have characterized the correlation between time since onset of symptoms and multiple motor function, strength and pulmonary function criteria in MG-45, MG-51 and MG-53. Analysis of this cohort offers the potential to assess time-to-event characteristics of the natural history of BMD that will inform clinical care and the design of interventional trials of potential treatments for patients with BMD.

BACKGROUND:Molecular diagnostics in the genetic myopathies often requires testing of the largest and most complex transcript units in the human genome (DMD, TTN, NEB). Iteratively targeting single genes for sequencing has traditionally entailed high costs and long turnaround times. Exome sequencing has begun to supplant single targeted genes, but there are concerns regarding coverage and needed depth of the very large and complex genes that frequently cause myopathies.OBJECTIVE:To evaluate efficiency of next-generation sequencing technologies to provide molecular diagnostics for patients with previously undiagnosed myopathies.METHODS:We tested a targeted re-sequencing approach, using a 45 gene emulsion PCR myopathy panel, with subsequent sequencing on the Illumina platform in 94 undiagnosed patients. We compared the targeted re-sequencing approach to exome sequencing for 10 of these patients studied.RESULTS:We detected likely pathogenic mutations in 33 out of 94 patients with a molecular diagnostic rate of approximately 35%. The remaining patients showed variants of unknown significance (35/94 patients) or no mutations detected in the 45 genes tested (26/94 patients). Mutation detection rates for targeted re-sequencing vs. whole exome were similar in both methods; however exome sequencing showed better distribution of reads and fewer exon dropouts.CONCLUSIONS:Given that costs of highly parallel re-sequencing and whole exome sequencing are similar, and that exome sequencing now takes considerably less laboratory processing time than targeted re-sequencing, we recommend exome sequencing as the standard approach for molecular diagnostics of myopathies.

We describe a case of hemi-atrophy in a young adult male, with a positive family history of three maternal uncles with Duchenne muscular dystrophy (DMD). The patient showed progressive weakness localized to the left side, an abnormal electromyography, and creatine kinase levels >3000 IU/l. Muscle biopsy showed both dystrophin-positive and -negative myofibers. An out-of-frame duplication variant in DMD, that is, c.(93+1_94-1)_(649+1_650-1)dup(p.?) resulting in duplication of exons 3–7 was inherited, but the muscle biopsy showed dystrophin mRNA with and without the duplication. Dystrophin quantification using mass spectrometry showed 25% normal dystrophin protein levels in the muscle biopsy from the stronger right side. Sex chromosome aneuploidy was ruled out. We conclude that the patient inherited the duplication variant, but early in development an inner cell mass underwent a somatic recombination event removing the duplication and restoring dystrophin expression. To our knowledge, this is the first report of a reversion leading to somatic mosaicism in DMD.

Objectives: We conducted a retrospective study analyzing the clinical features, laboratory findings, demographics, and long-term prognoses of patients with juvenile inflammatory myopathies to determine possible predictors indicating the use of aggressive immunotherapy and the response to and complications of treatment. Methods: The medical records of 41 patients with juvenile inflammatory myopathies seen at University of Tennessee–affiliated hospitals in Memphis from 1969 to 2008 were evaluated. Patients' clinical characteristics, laboratory studies, muscle biopsies, and electromyography were reviewed. All patients were treated with prednisone initially; additionally, 14 patients received varying combinations of other immunosuppressant therapies. Results: Seventy-three percent of the patients experienced remission. Patients in the group that did not go into remission had specific characteristics at onset: they were comparatively older and had more severe rashes, contractures, arthritis, and systemic involvement. Also, patients with positive autoantibodies (antinuclear antibody, rheumatoid arthritis factor) had better outcomes. Conclusions: Juvenile inflammatory myopathies have relatively good prognoses. Initial presentation at advanced age or with severe rash, systemic vasculopathies, anemia, or arthritis portends refractory disease; in these patients, second- and third-line therapies improve outcome.

Needle electromyography is an important tool in the diagnosis of neuromuscular diseases and has also been applied successfully in the evaluation of the vocal cord paralysis. Laryngeal electromyography, initially described by Weddell, is used to determine the cause of vocal cord paralysis and to differentiate organic from nonorganic causes of speech disorders. This test allows the diagnosis of lower motor neuron and nerve paralysis as well as myopathies. Laryngeal electromyography also helps to determine the prognosis of paralysis caused by traumatic injury of the laryngeal nerves and is used for guidance during botulinum toxin injection in spasmodic dysphonias. Single fiber electromyography is used to diagnose abnormalities of neuromuscular transmission and is applied in the study the architecture of the motor unit in muscles. This article reviews the techniques of laryngeal muscles single fiber electromyography, provides limited informative data, and discusses its potential value in the evaluation of patients with dysphonia.

Disorders of the adrenal glands frequently have secondary neurological manifestations, while some diseases that involve the central nervous system are accompanied by adrenal gland dysfunction. Excessive corticosteroid secretions in primary or secondary Cushing's syndrome causes muscle weakness and behavioral disturbances, such as emotional lability and sometimes depression, while adrenal insufficiency may cause fatigue, weakness, and depression. Adrenoleukodystrophy and adrenoneuromyelopathy are X-linked recessive disorders of the metabolism of very long chain fatty acids that manifest with white matter abnormalities of the brain, myelopathy and/or neuropathy, as well as adrenal insufficiency. Other disorders of the adrenal glands include hyperaldosteroidism, which may cause weakness from hypokalemia. Dysfunction of the adrenal medulla causes excessive or deficient secretion of catecholamines, primarily causing cardiovascular symptoms. This chapter reviews the clinical manifestations and diagnostic aspects and treatment of the various disorders of the adrenal glands. Some of the congenital adrenal diseases are also discussed.

This is a case of an adult male with history of motor difficulties, speech, and behavioral problems since early childhood found to have progressive spastic paraparesis, impaired vibration and proprioception, and gait instability. His medical history included bilateral cataracts status post surgical removal at the age of 30, cholelithiasis status post cholecystectomy at age 45, and high cholesterol levels.

Muscle disease shows extensive genetic and allelic heterogeneity, with many genes causing related phenotypes. Some of the gene loci causing muscular dystrophy are the largest in the human genome (e.g. titin, dystrophin) making molecular diagnostics particularly challenging and expensive. Next generation sequencing promises single-test approach to diagnostics. A commonly utilized nextgen approach is whole exome sequence (WES), where hybrid capture of exons enables parallel sequencing of most exons in a single sequencing run. However, WES has an exonic drop-out rate of about 10% – 1 in 10 dystrophin, nebulin, titin or other gene exons would remain ‘non-sequenced’ with the WES approach. Thus, a negative result on WES does not necessarily rule out common genetic causes of muscle disease. An alternative approach is targeted sequencing panels. Here, each exon of specific candidate myopathy genes is individually amplified by microbubble PCR (RainDance), and this highly enriched DNA is then subjected to nextgen sequencing. Here, we develop and test a targeted muscle disease gene panel for 45 of the most common myopathy genes (1851 amplimers). We report our experience with this panel in 89 myopathy patients. We found greater consistency in depth of coverage (average 1000-fold coverage), less drop-out (2% instead of 10% in exomes), and genotype/phenotype concordance with clinician-determined differential diagnosis. Overall, targeted re-sequencing panels allow for more definitive testing of known muscular dystrophy genes. We give some specific case examples, with mutation in titin (TTN), ryanodine receptor (RYR1), and nebulin (NEB) genes. Both WES and targeted sequencing panels permit more centralized testing at greatly reduced cost and more rapid turn-around compared to single gene testing. The routine implementation of nextgen sequencing approaches should streamline molecular diagnostics, genetic counseling, and patient navigation for clinical trials.

To study the safety of 3-4 diaminopyridine (DAP) in patients with motor neuron diseases and to examine its efficacy in reducing muscle fatigue and weakness and in improving objective parameters of muscle function.Assessments of safety included a questionnaire of symptoms, clinical examination, blood testing, and electrocardiography at each visit; efficacy was assessed by subjective scores of fatigue and weakness; an Amyotrophic Lateral Sclerosis Functional Rating Scale and functional ability scores, including timed verbal scores; manual muscle testing; grip dynamometry; pulmonary function tests; timed functional tests; and electrophysiological studies.Thirteen subjects with amyotrophic lateral sclerosis and seven subjects with only a lower motor neuron syndrome.Assess tolerability of DAP and determine if there was symptomatic improvement of muscle fatigue. SECONDARY OUTCOME: To determine the effects of DAP on objective parameters of muscle function.The drug was well tolerated with only four subjects reporting tingling of lips and fingers during the active drug period. The subjective scores for fatigue and weakness showed a mild improvement after 4 weeks on DAP compared with placebo. A significant benefit of DAP was also demonstrated in the timed verbal scores.3-4 DAP appeared to be safe and produced subjective benefit in motor neuron diseases. The drug could be added for symptomatic treatment in these diseases. Larger studies are necessary to demonstrate efficacy.

Hereditary inclusion‐body myopathy (HIBM) or distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive disorder characterized by preferential involvement of distal muscles in the lower extremities, especially the anterior compartment of the legs, with relative preservation of the quadriceps.This is referred to as quadriceps‐sparing myopathy. Previous reports have revealed exclusive involvement in skeletal muscles. Herein we describe two siblings with typical HIBM/DMRV. The patients developed exertional dyspnea 20–26 years after disease onset. Echocardiogram revealed a cardiomyopathy in both patients. This is the first report of the association between HIBM/DMRV and cardiomyopathy. Muscle Nerve, 2011