Proximal Predominant Weakness Research Articles

Management of immune-mediated necrotizing myopathy.

The immune-mediated necrotizing myopathies (IMNM) are autoimmune myositides clinically characterized by proximal predominant weakness and elevated creatine kinase (CK). They may be associated with autoantibodies (anti-HMGCR, anti-SRP), triggered by statin use (e.g., anti-HMGCR myopathy), associated with cancer, or may be idiopathic. Immunotherapy is required to improve strength and decrease the CK level, but no therapies are currently approved by the U.S. Food and Drug Administration for the treatment of IMNM. The optimal treatment strategy for IMNM is currently unknown and wide practice variation exists in the management of this condition. However, observational studies and expert opinion suggest that certain therapies may be more effective for the different serological subtypes of IMNM. HMGCR IMNM often responds favorably to intravenous immunoglobulin (IVIG) even as monotherapy. Signal recognition peptide and seronegative IMNM typically require combination immunotherapy, most often consisting of an oral immunosuppressant, corticosteroids, and IVIG or rituximab. Patients often remain on immunotherapy for years and relapse is common during tapering of immunotherapy. Further studies are needed to guide the optimal management of these patients.

Novel ACTA1 Mutation in a Family with Congenital Myopathy and Variably-penetrant Cardiomyopathy (P6-8.008)

<h3>Objective:</h3> To describe characteristics of a family with congenital myopathy, variably-penetrant dilated cardiomyopathy, and a novel, likely pathogenic variant in <i>ACTA1</i>, c.81C&gt;A (p.Asp27Glu). <h3>Background:</h3> <i>ACTA1</i> encodes skeletal muscle alpha-actin, the primary actin isoform in human skeletal muscle, also expressed to a lesser degree in cardiac muscle. Mutations in <i>ACTA1</i> are common in patients with congenital myopathies; however, associated cardiomyopathy is rare. <h3>Design/Methods:</h3> Retrospective chart review of the proband and 3 family members. <h3>Results:</h3> The proband was a 47-year-old Caucasian male of Ukrainian heritage. His mother (73), sister (40), and nephew (18) were similarly affected. All were hypotonic at birth, had delayed motor milestones, and presented with high-arched palate, elongated facies, and mild-moderate axial and proximal-predominant weakness. The proband had dilated cardiomyopathy with congestive heart failure and intraventricular conduction delay, his sister had dilated cardiomyopathy with left anterior fascicular block, his nephew had left ventricular dilatation with preserved function and normal conduction, and his mother had atrial fibrillation without structural heart disease. Biceps brachii biopsy in the proband demonstrated congenital fiber-type disproportion (CFTD), in addition to rare nemaline rods on electron microscopy. Next-generation sequencing identified a novel, likely pathogenic variant in <i>ACTA1</i>, c.81C&gt;A (p.Asp27Glu), segregating in affected family members. This missense variant is not present in population databases and affects a highly conserved amino acid. In silico models predicted a deleterious effect on protein structure and function (PolyPhen-2: probably damaging; SIFT: 0.0; MutationTaster: disease-causing). <h3>Conclusions:</h3> This family expands the genotypic and phenotypic spectrum of <i>ACTA1-</i>related myopathies. The novel missense variant c.81C&gt;A (p.Asp27Glu) associates with autosomal dominant congenital myopathy, CFTD, and variable, non-age-dependent penetrance of cardiac structural abnormalities along the spectrum of left ventricular dilatation and systolic dysfunction. Dilated cardiomyopathy and CFTD are rare in both isolation and combination in <i>ACTA1</i>-related myopathies. We emphasize that early cardiac surveillance is important in patients with <i>ACTA1-</i>related myopathies. <b>Disclosure:</b> Dr. Putko has nothing to disclose. Dr. Schmitt has nothing to disclose. Dr. Oudit has nothing to disclose. Dr. Phan has nothing to disclose. Dr. Beecher has nothing to disclose.

Hereditary Motor and Sensory Neuropathy With Proximal Predominance (HMSN-P)

Hereditary motor and sensory neuropathy with proximal predominance (HMSN-P) is a rare disorder inherited in an autosomal dominant fashion. Patients present with slowly progressive proximal-predominant weakness, painful muscle cramps, fasciculations, large-fiber sensory loss, and areflexia. Electrodiagnostic (EDX) studies typically reveal abnormalities consistent with a sensorimotor neuronopathy. A patient with HMSN-P underwent EDX studies, revealing ongoing and chronic neurogenic denervation, motor unit instability, and neuromyotonic discharges, further defining the spectrum of EDX findings in HMSN-P. The clinical, pathological, and genetic features are also reviewed. The appearance of HMSN-P in the United States and elsewhere calls for clinicians in nonendemic regions to be familiar with this rare disorder, which has typically been geographically confined.

Oculopharyngodistal myopathy is a distinct entity

Oculopharyngodistal myopathy (OPDM) has been reported as a rare, adult-onset hereditary muscle disease with putative autosomal dominant and autosomal recessive inheritance. Patients with OPDM present with progressive ocular, pharyngeal, and distal limb muscle involvement. The genetic defect causing OPDM has not been elucidated. Clinical and genetic findings of 47 patients from 9 unrelated Turkish families diagnosed with OPDM at the Department of Neurology, Istanbul Faculty of Medicine, between 1982 and 2009 were evaluated. The mean age at onset was around 22 years. Both autosomal dominant and autosomal recessive traits were observed, without any clear difference in clinical phenotype or severity. The most common initial symptom was ptosis, followed by oropharyngeal symptoms and distal weakness, which started after the fifth disease year. Intrafamilial variability of disease phenotype and severity was notable in the largest autosomal dominant family. Atypical presentations, such as absence of limb weakness in long-term follow-up in 9, proximal predominant weakness in 4, and asymmetric ptosis in 3 patients, were observed. Swallowing difficulty was due to oropharyngeal dysphagia with myopathic origin. Serum creatine kinase levels were slightly increased and EMG revealed myopathic pattern with occasional myotonic discharges. Myopathologic findings included rimmed and autophagic vacuoles and chronic myopathic changes. Importantly, a considerable proportion of patients developed respiratory muscle weakness while still ambulant. Linkage to the genetic loci for all known muscular dystrophies, and for distal and myofibrillar myopathies, was excluded in the largest autosomal dominant and autosomal recessive OPDM families. We suggest that OPDM is a clinically and genetically distinct myopathy.