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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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For your information, there are at present more than 1250 news items on myology online.
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12/01/2015 - Development of the EuroBioBank Network over the past decade

The EuroBioBank (EBB) network ( is the first operating network of biobanks in Europe to provide human DNA, cell and tissue samples as a service to the scientific community conducting research on rare diseases (RDs). The EBB was established in 2001 to facilitate access to RD biospecimens and associated data; it obtained funding from the European Commission in 2002 (5th framework programme) and started operation in 2003. The set-up phase, during the EC funding period 2003-2006, established the basis for running the network; the following consolidation phase has seen the growth of the network through the joining of new partners, better network cohesion, improved coordination of activities, and the development of a quality-control system. During this phase the network participated in the EC-funded TREAT-NMD programme and was involved in planning of the European Biobanking and Biomolecular Resources Research Infrastructure. Recently, EBB became a partner of RD-Connect, an FP7 EU programme aimed at linking RD biobanks, registries, and bioinformatics data. Within RD-Connect, EBB contributes expertise, promotes high professional standards, and best practices in RD biobanking, is implementing integration with RD patient registries and 'omics' data, thus challenging the fragmentation of international cooperation on the field.

12/01/2015 - COL6 mutations predict severe clinical evolution in Bethlem myopathy

Mutations in one of the 3 genes encoding collagen VI (COLVI) are responsible for a group of heterogeneous phenotypes of which Bethlem myopathy (BM) represents the milder end of the spectrum. Genotype-phenotype correlations and long-term follow-up description in BM remain scarce. Here, the authors retrospectively evaluated the long-term clinical evolution, and genotype-phenotype correlations in 35 genetically identified BM patients (23 index cases). Nineteen patients showed a typical clinical picture with contractures, proximal weakness and slow disease progression while 11 presented a more severe evolution. Five patients showed an atypical presentation, namely a limb girdle muscle weakness in 2 and a congenital myopathy pattern with either no contractures, or only limited to ankles, in 3 of them. Pathogenic COL6A1-3 mutations were mostly missense or in frame exon-skipping resulting in substitutions or deletions. Twenty-one different mutations were identified including 12 novel ones. The mode of inheritance was autosomal dominant in 83% of the index patients (including 17% (N=4) with a de novo mutation), recessive in 13%, and undetermined in one patient. Skipping of exon 14 of COL6A1 was found in 35% of index cases and was mostly associated with a severe clinical evolution. Missense mutations were detected in 39% of index cases and associated with milder forms of the disease. Long-term follow-up identified important phenotypic variability in this cohort of 35 BM patients. However, worsening of the functional disability appeared typically after the age of 40 in 47% of our patients, and was frequently associated with COL6A1 exon 14 skipping.

12/01/2015 - Systemic PTEN depletion can modestly improve survival in a severe SMA mouse model

Spinal muscular atrophy (SMA) is the second most common genetic cause of death in childhood. However, no effective treatment is available to halt disease progression. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene. The authors have previously reported that PTEN depletion leads to an increase in survival of SMN-deficient motor neurons. Here, they aimed to establish the impact of PTEN modulation in an SMA mouse model in vivo. Initial experiments using intramuscular delivery of adeno-associated vector serotype 6 (AAV6) expressing shRNA against PTEN in an established mouse model of severe SMA (SMNΔ7) demonstrated the ability to ameliorate the severity of neuromuscular junction pathology. Subsequently, they developed self-complementary AAV9 expressing siPTEN (scAAV9-siPTEN) to allow evaluation of the effect of systemic suppression of PTEN on the disease course of SMA in vivo. Treatment with a single injection of scAAV9-siPTEN at post-natal day 1 resulted in a modest 3-fold extension of the life span of SMNΔ7 mice, increasing mean survival to 30 days, compared to 10 days in untreated mice. These data revealed that systemic PTEN depletion is an important disease-modifier in SMNΔ7 mice, and therapies aimed at lowering PTEN expression may therefore offer a potential therapeutic strategy for SMA.

12/01/2015 - Human adipose-derived mesenchymal stem cells as a new model of spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is an X-linked CAG/polyglutamine expansion motoneuron disease, in which an elongated polyglutamine tract (polyQ) in the N-terminal androgen receptor (ARpolyQ) confers toxicity to this protein. Typical markers of SBMA disease are ARpolyQ intranuclear inclusions. These are generated after the ARpolyQ binds to its endogenous ligands, which promotes AR release from chaperones, activation and nuclear translocation, but also cell toxicity. The SBMA mouse models developed so far, and used in preclinical studies, all contain an expanded CAG repeat significantly longer than that of SBMA patients. Here, the authors propose the use of SBMA patients adipose-derived mesenchymal stem cells (MSCs) as a new human in vitro model to study ARpolyQ toxicity. These cells have the advantage of expressing only ARpolyQ, and not the wild type AR allele. Therefore, adipose-derived MSCs were isolated and characterized from three SBMA patients (ADSC from Kennedy's patients, ADSCK) and three control volunteers (ADSCs). Both ADSCs and ADSCKs were found to express mesenchymal antigens, even if only ADSCs can differentiate into the three typical cell lineages (adipocytes, chondrocytes and osteocytes), whereas ADSCKs, from SBMA patients, showed a lower growth potential and differentiated only into adipocyte. Moreover, analysing AR expression on mesenchymal cultures revealed lower levels in all ADSCKs than ADSCs, possibly related to negative pressures exerted by toxic ARpolyQ in ADSCKs. In addition, with proteasome inhibition the ARpolyQ levels increased specifically in ADSCKs, inducing the formation of HSP70 and ubiquitin positive nuclear ARpolyQ inclusions. Considering all of this evidence, SBMA patients adipose-derived MSCs cultures should be considered an innovative in vitro human model to understand the molecular mechanisms of ARpolyQ toxicity and to test novel therapeutic approaches in SBMA.

12/01/2015 - Preliminary results from the Missouri lysosomal storage disorder pilot study

This ongoing study evaluated the performance of a statewide full-population pilot study in Missouri on newborn blood spots for screening of lysosomal storage disorders (LSDs) using digital microfluidics. Multiplexed fluorometric enzymatic assay was used to detect Pompe disease, Fabry disease, Gaucher disease, and mucopolysaccharidosis type I (MPS I) in the Missouri newborn population. Provisional cutoff values were determined during a prepilot study. All newborn dried blood spots received at the Missouri State Public Health Laboratory for routine newborn screening were screened for the 4 LSDs during the pilot study. Newborns determined to be screen-positive were referred for confirmatory testing. The study commenced on January 11, 2013; during the first 6 months, 43 701 specimens were screened, and 27 newborns with a confirmed diagnosis of an LSD genotype (8 with Pompe disease, 1 with Gaucher disease, 15 with Fabry disease, and 3 with MPS I) were identified. These numbers correspond to detection rates of 1:5463 for Pompe disease, 1:43 701 for Gaucher disease, 1:2913 for Fabry disease, and 1:14 567 for MPS I. The positive predictive values were 47% for Pompe disease with 1 lost to follow-up, 10% for Gaucher disease, 58% for Fabry disease with 2 lost to follow-up, and 11% for MPS I with 4 pending. The first 6 months of the Missouri LSD pilot study provided the opportunity to validate the effectiveness of the digital microfluidic screening method, refine the cutoffs for detection of these LSDs, and test the entire system of infant referral, follow-up, confirmation, treatment, and screening program communication.

Lysosomal storage disorder screening implementation: findings from the first six months of full population pilot testing in missouri. Hopkins PV, Campbell C, Klug T, et al. J Pediatr. 2015 Jan;166(1):172-7.

12/01/2015 - A novel of case of nemaline myopathy outside of the Old Order Amish

Nemaline myopathy (NM) is a congenital neuromuscular disorder often characterized by hypotonia, facial weakness, skeletal muscle weakness, and the presence of rods on muscle biopsy. A rare form of nemaline myopathy known as Amish Nemaline Myopathy has only been seen in a genetically isolated cohort of Old Order Amish patients who may additionally present with tremors in the first 2-3 months of life. The authors describe a Hispanic male diagnosed with nemaline myopathy histopathologically and subsequently confirmed by next generation gene sequencing. : Direct sequencing revealed that the individual is homozygous for a pathogenic nonsense variant c.323C>G (p.S108X) in exon 9 of the TNNT1 gene. This report describes a novel pathogenic variant in the TNNT1 gene and represents a nemaline myopathy-causing variant in the TNNT1 gene outside of the Old Order Amish and Dutch ancestry.

12/01/2015 - Oral delivery of antisense oligonucleotides is feasible when supplemented with sodium caprate

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, we 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.

12/01/2015 - Ventricular assist devices as a new therapeutic option in DMD

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, characterized by progressive skeletal muscle weakness, loss of ambulation, and death secondary to cardiac or respiratory failure. End-stage dilated cardiomyopathy (DCM) is a frequent finding in DMD patients, they are rarely candidates for cardiac transplantation. Recently, the use of ventricular assist devices as a destination therapy (DT) as an alternative to cardiac transplantation in DMD patients has been described. Preoperative planning and patient selection play a significant role in the successful postoperative course of these patients. Here, the authors describe the preoperative, intraoperative and postoperative management of Jarvik 2000 implantation in 4 DMD pediatric (age range 12-17 years) patients. They also describe the complications that may occur. The most frequent were bleeding and difficulty in weaning from mechanical ventilation. Their standard protocol includes: 1) preoperative multidisciplinary evaluation and selection, 2) preoperative and postoperative non-invasive ventilation and cough machine cycles, 3) intraoperative use of near infrared spectroscopy (NIRS) and transesophageal echocardiography, 4) attention on surgical blood loss, use of tranexamic acid and prothrombin complexes, 5) early extubation and 6) avoiding the use of nasogastric feeding tubes and nasal temperature probes. The authors describe the use of Jarvik 2000 as a destination therapy in young patients emphasizing the use of ventricular assist devices as a new therapeutic option in DMD.

12/01/2015 - Clinical severity of a variety of CMT subtypes

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. Herein, the authors analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. Data were analysed from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). A total of 997 of the 1652 patients (60.4%) received a genetic diagnosis. 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.