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Myology research highlights

Discover our weekly selection of scientific and medical publications in the field of myology and of neuromuscular diseases :  summary of each publication aimed at the general reader, highlighting the main points of the article and the authors’ conclusions
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24/02/2015 - A novel approach to accelerate the molecular diagnosis of neuromuscular diseases

Neuromuscular diseases (NMDs) are a group of over 200 highly genetically as well as clinically heterogeneous inherited genetic disorders that affect the peripheral nervous and muscular systems, resulting in gross motor disability. The clinical and genetic heterogeneities of NMDs make disease diagnosis complicated and expensive, often involving multiple tests. To expedite the molecular diagnosis of NMDs, the authors designed and validated several next-generation sequencing (NGS)-based comprehensive gene panel tests that include complementary deletion and duplication testing through comparative genomic hybridization arrays (aCGH). Their validation established the targeted gene panel test to have 100% sensitivity and specificity for single nucleotide variant detection. To compare the clinical diagnostic yields of single gene (NMD associated) tests with the various NMD NGS panel tests, they analyzed data from all clinical tests performed at the Emory Genetics Laboratory (EGL) from October 2009 through May 2014. They further compared the clinical utility of the targeted NGS panel test with that of exome sequencing (ES). They find that NMD comprehensive panel testing has a 3-fold greater diagnostic yield (46%) than single gene testing (15-19%). Sanger fill-in of low-coverage exons, copy number variation (CNV) analysis, and thorough in-house validation of the assay all complement panel testing and allow the detection of all types of causative pathogenic variants, some of which (about 18%) may be missed by ES. These results strongly indicate that for molecular diagnosis of heterogeneous disorders like NMD, targeted panel testing has the highest clinical yield and should therefore be the preferred first-tier approach.

24/02/2015 - Mutant SNAP25B causes myasthenia, cortical hyperexcitability, ataxia, and intellectual disability

This study aimed to identify and characterize the molecular basis of a syndrome associated with myasthenia, cortical hyperexcitability, cerebellar ataxia, and intellectual disability. The authors performed in vitro microelectrode studies of neuromuscular transmission, exome and Sanger sequencing, and analyzed functional consequences of the identified mutation in expression studies. Neuromuscular transmission at patient endplates was compromised by reduced evoked quantal release. Exome sequencing identified a dominant de novo variant, p.Ile67Asn, in SNAP25B, a SNARE protein essential for exocytosis of synaptic vesicles from nerve terminals and of dense-core vesicles from endocrine cells. Ca2+-triggered exocytosis is initiated when synaptobrevin attached to synaptic vesicles (v-SNARE) assembles with SNAP25B and syntaxin anchored in the presynaptic membrane (t-SNAREs) into an α-helical coiled-coil held together by hydrophobic interactions. Pathogenicity of the Ile67Asn mutation was confirmed by 2 measures. First, the Ca2+ triggered fusion of liposomes incorporating v-SNARE with liposomes containing t-SNAREs was hindered when t-SNAREs harbored the mutant SNAP25B moiety. Second, depolarization of bovine chromaffin cells transfected with mutant SNAP25B or with mutant plus wild-type SNAP25B markedly reduced depolarization-evoked exocytosis compared with wild-type transfected cells. Ile67Asn variant in SNAP25B is pathogenic because it inhibits synaptic vesicle exocytosis. This has been attributed to the deleterious effects of the mutation to disruption of the hydrophobic α-helical coiled-coil structure of the SNARE complex by replacement of a highly hydrophobic isoleucine by a strongly hydrophilic asparagine.

24/02/2015 - Natural history of skeletal muscle involvement in myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy in adult. The aim of this study was to investigate the natural history of skeletal muscle weakness in adults, in a cross-sectional, retrospective study. In a cohort of 204 adult DM1 patients, the authors quantified muscle impairment, handgrip force and physical disability. Muscle strength was similarly affected in the legs and in the arms, the right and left side, and distally more than proximally in patients. The earliest and the most affected skeletal muscles were the digit flexors, foot dorsiflexors and neck flexors; whereas the elbow and knee extensors and flexors were the least affected muscle groups. The rate of decline of the muscle strength was -0.111 units/year. The handgrip values were lower in DM1 patients than the normative values and the rate of decline in handgrip force per year was -0.24 kg. Limitation in mobility or walking is observed in 84 % of DM1 patients but requirement of wheelchair is infrequent (3 %). The decrease in muscle strength, handgrip force and the increase in physical disability were highly correlated with duration of the disease and the number of CTG repeats in the blood. Significant association was found between decline in muscle strength and the age at onset, physical disability and the age of patients at evaluation, handgrip force and gender. Decline in muscle weakness is very slow and although limitation when walking is a common manifestation of DM1 in patients, the requirement of wheelchair is infrequent.

24/02/2015 - Investigating intestinal administration of antisense oligonucleotides

Antisense oligonucleotides (AONs) used to reframe dystrophin mRNA transcripts for Duchenne muscular dystrophy (DMD) patients are tested in clinical trials. Here, AONs are administered subcutaneously and intravenously, while the less invasive oral route would be preferred. Oral delivery of encapsulated AONs supplemented with a permeation enhancer, sodium caprate, has been successfully used to target tumor necrosis factor (TNF)-α expression in liver. To test the feasibility of orally delivered AONs for DMD, the authors applied 2'-O-methyl phosphorothioate AONs (with or without sodium caprate supplementation) directly to the intestine of mdx mice and compared pharmacokinetics and -dynamics with intravenous, intraperitoneal, and subcutaneous delivery. Intestinally infused AONs were taken up, but resulted in lower plasma levels compared to other delivery routes, although bioavailability could be largely improved by supplementation of sodium caprate. After intestinal infusion, AON levels in all tissues were lower than for other administration routes, as were the ratios of target versus nontarget organ levels, except for diaphragm and heart where comparable levels and ratios were observed. For each administration route, low levels of exon skipping in triceps was observed 3 hours post-AON administration. These data suggest that oral administration of naked 2'-O-methyl phosphorothioate AONs may be feasible, but only when high AON concentrations are used in combination with sodium caprate.

24/02/2015 - Determining the distribution of CMT subtypes and disease burden

The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. In this cross-sectional analysis, the authors analysed clinical and genetic data from 1652 patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. These findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT.

24/02/2015 - Insights into the clinical phenotype and natural history of BICD2 disease

Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein-dynactin complex and one of its cargo adaptors, BICD2. The authors have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. Overall, the features of BICD2 spinal muscular atrophy, lower extremity predominant are consistent with a pathological process that preferentially affects lumbar lower motor neurons, with or without additional upper motor neuron involvement. Defining the phenotypic features in this, the largest BICD2 disease cohort reported to date, will facilitate focused genetic testing and filtering of next generation sequencing-derived variants in cases with similar features.

24/02/2015 - The TREAT-NMD DMD Global database

Analysing the type and frequency of patient specific mutations that give rise to Duchenne Muscular Dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning and improved clinical care. Locus specific databases (LSDBs) allow for the collection, organization, storage and analysis of genetic variants of disease. This article describes the development and analysis of the TREAT-NMD DMD Global database ( Genetic data for 7149 DMD mutations held within the database were analysed. 5682 large mutations were observed (80% of total mutations), of which 4894 (86%) were deletions (1 exon or larger), and 784 (14%) were duplications (1 exon or larger). There were 1445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).

The TREAT-NMD DMD Global database: Analysis of More Than 7000 Duchenne Muscular Dystrophy Mutations. Bladen CL, Salgado D, Monges S, et al. Hum Mutat. 2015 Jan 21. doi: 10.1002/humu.22758. [Epub ahead of print]

24/02/2015 - DYNC1H1-associated spinal muscular atrophy: an increasing clinical spectrum

This articles aimed to expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1. The authors report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. This report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, the authors report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions.

14/02/2015 - Sarepta Therapeutics commences dosing in Duchenne Muscular Dystrophy study

Sarepta Therapeutics Inc. has initiated dosing of SRP-4053 in its first human trial, a Phase I/II study in Duchenne muscular dystrophy (DMD). This multiple-dose study will assess the safety, tolerability, efficacy, and pharmacokinetics of SRP-4053 in DMD patients with genotypes amenable to exon-53 skipping. The study will be conducted at four sites in Europe, (Rome, London, Newcastle Upon-Tyne and Paris at the Institute of Myology) under a consortium agreement between Sarepta and various European hospitals, institutions, and scientists established to conduct the study.