Stanley Iyadurai

Autophagic vacuolar pathology in desminopathies

Autophagic vacuolar myopathies are an emerging group of muscle diseases with common pathologic features. These include autophagic vacuoles containing both lysosomal and autophagosomal proteins sometimes lined with sarcolemmal proteins such as dystrophin. These features have been most clearly described in patients with Danons disease due to LAMP2 deficiency and X-linked myopathy with excessive autophagy (XMEA) due to mutations in VMA21. Disruptions of these proteins lead to lysosomal dysfunction and subsequent autophagic vacuolar pathology. We performed whole exome sequencing on two families with autosomal dominantly inherited myopathies with autophagic vacuolar pathology and surprisingly identified a p.R454W tail domain mutation and a novel p.S6W head domain mutation in desmin, DES. In addition, re-evaluation of muscle tissue from another family with a novel p.I402N missense DES mutation also identified autophagic vacuoles. We suggest that autophagic vacuoles may be an underappreciated pathology present in desminopathy patient muscle. Moreover, autophagic vacuolar pathology can be due to genetic etiologies unrelated to primary defects in the lysosomes or autophagic machinery. Specifically, cytoskeletal derangement and the accumulation of aggregated proteins such as desmin may activate the autophagic system leading to the pathologic features of an autophagic vacuolar myopathy.

The Limb-Girdle Muscular Dystrophies and the Dystrophinopathies.

ABSTRACTPurpose of Review: The classic approach to identifying and accurately diagnosing limb-girdle muscular dystrophies (LGMDs) relied heavily on phenotypic characterization and ancillary studies including muscle biopsy. Because of rapid advances in genetic sequencing methodologies, several additional LGMDs have been molecularly characterized, and the diagnostic approach to these disorders has been simplified. This article summarizes the epidemiology, clinical features, and genetic defects underlying the LGMDs.Recent Findings: In recent years, the advent of next-generation sequencing has heralded an era of molecular diagnosis in conjunction with physical characterization. Inadvertently, this process has also led to the “next-generation aftermath,” whereby variants of unknown significance are identified in most patients. Similar to the published diagnostic and treatment guidelines for Duchenne muscular dystrophy, diagnostic and treatment guidelines have recently been published for LGMDs. In addition, the first medication (based on the exon-skipping strategy) for treatment of patients with a subset of Duchenne muscular dystrophy has been recently approved by the US Food and Drug Administration (FDA).Summary: The LGMDs are a heterogeneous group of hereditary, progressive, and degenerative neuromuscular disorders that present with primary symptoms of shoulder girdle and pelvic girdle weakness. Although a combination of clinical and molecular genetic evaluations may be sufficient for accurate diagnosis of LGMDs in many cases, the contribution of imaging and histopathologic correlations still remains a critical, if not a necessary, component of evaluation in some cases.

Dynamin-2-associated myopathy with electrical but not clinical myotonia

plex and more evident cryoglobulinemia after rituximab, despite WM improvement. In contrast to rituximab, which only targets CD20 Bcells, cyclophosphamide also targets the antibodyproducing plasma cells. As seen in a similar case, there was clinical stabilization of mononeuritis multiplex as well as disappearance of cryoglobulins after cyclophosphamide. The patient may have deteriorated again several weeks after stopping cyclophosphamide due to reappearance of abnormal plasma cells and resumed immunecomplex deposition, as demonstrated in the retina. In conclusion, mild axonal sensory neuropathy progressed to severe mononeuritis multiplex after rituximab in a patient with anti–MAG-negative IgM-j-MGUS, elevated RF, and immune-complex deposition. Accelerated cryoprecipitation of RF-rituximab complexes and worsening of underlying cryoglobulinemic vasculitis might be potential mechanisms.

Decrement with high frequency repetitive nerve stimulation in a RAPSN congenital myasthenic syndrome

Congenital myasthenic syndromes (CMS) are a heterogenous group of inherited disorders that underlie mutations in the structural components of the neuromuscular junction complex. Mutations in RAPSN, whose encoded protein acts to concentrate and anchor acetylcholine receptors in the postsynaptic membrane, account for about 14% of cases. The clinical presentation can be quite variable, and the signs and symptoms may be subtle. Most commonly, patients present at birth or in early childhood with fatigable muscle weakness, ptosis, dysconjugate gaze, diplopia, dysphagia, and/or respiratory difficulties (including episodes of apnea). The electrodiagnostic characteristics in CMS are also multifarious. Repetitive nerve stimulation (RNS) may show decrement only at low frequency stimulation (225 HZ), rate-dependent decrement, or postexercise facilitation, depending on the mutation. Patients with RAPSN mutations typically have decrements at low frequency stimulation; however, decrements at high frequencies have not been studied extensively. Here, we report a patient with a Rapsyn (N88K/N88K) mutation whose RNS revealed a decrement and immediate postexercise repair at low and high frequencies.

Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial

BACKGROUND Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy. METHODS In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). Eligible patients were 18 years or older with a confirmed genetic diagnosis of spinal and bulbar muscular atrophy, were ambulatory, had symptomatic weakness, and had serum IGF-1 concentrations of 170 ng/mL or lower. Patients were randomly assigned (2:1) to study drug or placebo by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. After a safety and tolerability assessment with eight patients, BVS857 was administered once a week (0·06 mg/kg intravenously) for 12 weeks. Primary outcome measures were safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) measured by MRI. The ratio of TMV at day 85 to baseline was analysed with ANCOVA per protocol. Secondary outcomes of muscle strength and function were measured with the Adult Myopathy Assessment Tool, lean body mass through dual energy x-ray absorptiometry, and BVS857 pharmacokinetics. This trial was registered with ClinicalTrials.gov, NCT02024932. FINDINGS 31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. Immunogenicity was detected in 13 (72%) of 18 patients in the BVS857 group, including crossreacting antibodies with neutralising capacity to endogenous IGF-1 in five patients. TMV decreased from baseline to day 85 in the placebo group (-3·4% [-110 cm3]) but not in the BVS857 group (0% [2 cm3]). A significant difference in change in TMV was observed in the BVS857 group versus the placebo group (geometric-mean ratio 1·04 [90% CI 1·01-1·07]; p=0·02). There were no differences between groups in measures of muscle strength and function. INTERPRETATION TMV remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease. FUNDING Novartis Pharmaceuticals and the US National Institutes of Health.

Bringing smiles to faces: Evidence-based guidelines for facioscapulohumeral dystrophy: Editorial

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disorder and the third most common muscular dystrophy after Duchenne dystrophy and myotonic dystrophy. It has a prevalence of approximately 1:15–20,000 individuals. The clinical features of the disorder are quite unique and were first described approximately 130 years ago by Landouzy and Dejerine. As the name implies, they described involvement of the facial (including the inability to smile properly), scapular, humeral, and peroneal/fibular muscles in “classical” cases. However, the presence of atypical (with differential involvement of muscles noted above) and de novo cases (approximately 20%) have added heterogeneity to the clinical presentation, making it challenging to make a clinical diagnosis in some patients. Despite the distinctive presentation and relatively high prevalence of the condition, the exact molecular pathogenesis of this unique disorder has remained elusive. Even 20 years after the first descriptions of linkage of FSHD to a size reduction in a polymorphic EcoRI fragment at the 4q35 locus, an elegant series of experiments demonstrating the DUX4c de-repression, and the elucidation of the epigenetic nature of the disease, there is much we do not know. Current understanding suggests that shortening of the D4Z4 repeats (to 1–10 repeats), de-repression of DUX4c, and a permissive allele (allele A) in cis (allowing polyadenylation of DUX4c transcript), are required for disease manifestation, but the gamut of downstream targets of the transcriptional regulator, DUX4c, remain to be identified. In addition, 2 distinct loci have been associated with the FSHD phenotype: FSHD1 (95%; locus 4q35) and FSHD2 (5%; locus 18p11). Although definitive molecular diagnosis of FSHD1 rests on complex molecular genetic analysis, reliable testing is now available from several commercial laboratories. A growing body of evidence suggests that FSHD1, once thought to be a purely skeletal muscle disorder, may in some cases have extramuscular manifestations. Since its description more than a century ago, manifestations of symptoms in other systems have been noted, including cardiac, orthopedic, respiratory, hearing, visual, and sensory (pain). Previous FSHD practice guidelines (2010, 2011) have been based on expert opinion and addressed areas related to genetic diagnoses and management aspects. Since 2010, a total of 293 research studies have been written on FSHD (compared with 721 studies from 1966 to 2010); these allow clinicians to take an evidence-based approach (and systematic review) to come up with new guidelines, including extramuscular evaluations. Given the importance and complexity of the muscular dystrophies to neuromuscular clinicians of all types, the American Academy of Neurology and the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM), through a cooperative agreement award with the Centers for Disease Control and Prevention, are preparing evidence-based guidelines on the management of several types of muscular dystrophies. The first guidelines addressed the limb-girdle dystrophies and the second, congenital muscular dystrophies. The third report in this series, which addresses the diagnosis, evaluation, and management of FSHD, is being published in Neurology in July and appears on the AANEM website. The details are available at the respective websites (www.aanem.org and www. neurology.org). This guideline primarily addresses FSHD1, as the majority of the literature evaluated covers this most common form of FSHD. The preparation and publication of any disease guideline is a heavily labor-intensive and timeconsuming affair. Starting with 977 abstracts spanning the years 1948–2012, the authors critically reviewed 176 full-text articles (2 panel members for each article, independent of each other), with strict guidelines for evidence rating. Although some of the conclusions may seem obvious, it is crucial to bear in mind that these recommendations are based not simply on clinical experience Correspondence to: Dr. John Kissel; e-mail: John.Kissel@osumc.edu