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IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody–positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8 114 394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0 × 10−8 was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P = 3.98 × 10−8; odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P = 1.08 × 10−8; odds ratio, 2.31; 95% CI, 2.02 - 2.60), and TNFRSF11A (rs4263037; P = 1.60 × 10−9; odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P = 1.32 × 10−12; odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P = 7.02 × 10−18; odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P = 2.52 × 10−11; odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.

To identify patients with GFPT1-related limb-girdle myasthenia and analyze phenotypic consequences of the mutations.

Myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) are neuromuscular disorders that may share certain symptoms but have vastly different pathophysiologies, treatments, and outcomes. ALS is a fatal neurodegenerative disease that causes death of motor neurons in the brain, brainstem, and spinal cord, leading to weakness of voluntary muscles including bulbar, respiratory, facial, trunk, and limb muscles. MG is an autoimmune disease of the neuromuscular junction that leads to a similar distribution of weakness with the additional involvement of the extraocular muscles. The hallmark of MG is fatigable muscle weakness, but patients with ALS may also have fatigue, particularly early in the disease course. Despite these similarities, MG and ALS have distinct clinical characteristics that, when recognized, aid the clinician in making the correct diagnosis.

Mycophenolate mofetil (MM) is an immunosuppressive agent developed and originally used to prevent acute rejection of solid-organ transplantation. There have been preliminary reports of its successful use in the treatment of autoimmune myasthenia gravis (MG). We conducted a double-blind, placebo-controlled pilot trial of MM in the treatment of suboptimally controlled, stable MG. Results of this pilot study are promising and suggestive of greater improvement in the patients who received MM compared to placebo.

A-waves are generally considered a nonspecific finding of unclear electrodiagnostic and clinical significance. We systematically identified A-waves during routine F-wave studies and defined them as supramaximally elicited reproducible intermediate to late responses that are clearly separate from the M-responses. In patients with A-waves, we noted electrophysiologic diagnoses, the nerve in which the A-wave was identified, the presence of A-waves in multiple nerves, and A-wave morphology. In 54 of 1,258 studies performed, A-waves were present in one or more nerves. Electrophysiologic diagnoses in patients with A-waves included diffuse axonal neuropathy (11.5%), demyelinating neuropathy (66.7%), motor neuron disease (6.5%), radiculopathy (3.6%), mononeuropathy (3.9%), and normal (tibial nerve only) 0.7%. A-waves were abnormal when found in any nerve except the tibial nerve. They were particularly prevalent and present in multiple nerves in acquired and hereditary demyelinating neuropathies, and they more often had a complex morphology. We postulate that demyelination is the crucial underlying pathophysiologic correlate of the supramaximally stimulated A-wave. © 2000 John Wiley & Sons, Inc. Muscle Nerve 23: 1117–1120, 2000

We report a patient with adult‐onset spinal muscular atrophy (SMA) of the scapulohumeral type with neurogenic muscle hypertrophy (NMH) in markedly weakened biceps muscles in association with continuous complex repetitive discharges (CRDs). This is an apparently unique case due to the bilaterality of the NMH associated with CRDs as well as the well‐circumscribed symmetric upper extremity distribution of the hypertrophy. The possible mechanisms of NMH in association with spontaneous motor activity are discussed. © 1999 John Wiley & Sons, Inc. Muscle Nerve 22: 1603–1606, 1999

X-linked bulbospinal neuronopathy (XLBSN) or Kennedys disease is a rare inherited neuromuscular disease characterized by adult-onset muscle weakness, usually in a limb-girdle distribution. It is frequently misdiagnosed despite a distinctive clinical presentation, usually due to the absence of a clear family history, and perhaps also due to failure of recognition. Accurate diagnosis is crucial for genetic counseling purposes and because alternative diagnoses usually carry a poorer prognosis. We evaluated 4 patients with XLBSN and one symptomatic female heterozygote patient. Based on our clinical observations in these patients and a systematic review of previously reported cases, the following clinical and electrophysiologic features when present in the setting of adult-onset muscle weakness, are strongly suggestive of the disorder: 1) facial weakness, 2) facial twitching or fasciculations, 3) tongue weakness and atrophy, 4) postural hand tremor, 5) hypo- or areflexia, and 6) absent or low-amplitude sensory nerve action potentials despite clinically normal sensation. We also hypothesize regarding the possibility of partial expression of the abnormal XLBSN gene in a symptomatic heterozygote female patient. © 1999 John Wiley & Sons, Inc. Muscle Nerve 22: 1693–1697, 1999

The inability to manage oral and bronchial secretions is a major problem affecting patients with cerebral palsy and other chronic neurologic disorders. There is no medical consensus on a proper approach to diagnosis and treatment of deglutition disorders of this kind. The physiology of drooling disorders in cerebral palsy is discussed, with special focus on an algorithm for management.

We describe a patient with Kennedy's disease (X-linked bulbospinal neuronopathy) who experienced leg muscle fatigue with long-distance running. The patient also reported muscle twitching involving the face and extremities and long-standing muscle cramps. Aside from mild facial and tongue weakness (and fasciculations), his examination was normal, including completely preserved muscle strength in the extremities. Electrodiagnostic evaluation revealed evidence for a chronic motor axonopathy/neuronopathy and abnormal sensory nerve action potentials. In addition, repetitive nerve stimulation studies were normal, but neuromuscular jitter tested in the same muscle was markedly abnormal. The normal clinical strength and repetitive nerve stimulation studies in a muscle showing markedly increased neuromuscular jitter suggested a mechanism for this patient's symptoms of muscle fatigue, related to failure of neuromuscular transmission at a critical number of endplates during extremes of physical activity. Muscle Nerve 27: 249–251, 2003

We report a patient with myasthenia gravis (MG) who had marked clinical benefit in response to treatment with mycophenolate mofetil as documented by serial quantitative measures of strength and muscle fatigue. Our patient had experienced either adverse side effects or a suboptimal response to the usual immunosuppressive agents used in MG. Mycophenolate mofetil was used in combination with cyclosporine and prednisone and allowed for significant reductions in dosage of these immunosuppressants. We conclude that mycophenolate mofetil deserves further study as a therapeutic agent in MG. In particular, its role as a steroid‐sparing agent and as a drug to be used in combination immunotherapy in more severe or refractory cases of MG should be investigated. © 2000 John Wiley & Sons, Inc. Muscle Nerve 23: 1287–1289, 2000.

Treatment with interferon‐α (IFN‐α) has been associated with the occurrence of a number of autoimmune disorders. We report a case of chronic inflammatory demyelinating polyneuropathy (CIDP) occurring in a patient with a chronic viral hepatitis C infection who received a novel, long‐acting form of IFN‐α. After withdrawal of the interferon treatment, this patient responded to a single extended course of plasma exchange that resulted in a complete clinical remission of symptoms without relapse. © 2000 John Wiley & Sons, Inc. Muscle Nerve 23: 433–435, 2000