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Journal: Neuromuscular disorders : NMD

34

In Duchenne muscular dystrophy (DMD), progressive loss of respiratory function leads to restrictive pulmonary disease and places patients at significant risk for severe respiratory complications. Of particular concern are ineffective cough, secretion retention and recurrent respiratory tract infections. In a Phase 3 randomized controlled study (DMD Long-term Idebenone Study, DELOS) in DMD patients 10-18 years of age and not taking concomitant glucocorticoid steroids, idebenone (900 mg/day) reduced significantly the loss of respiratory function over a 1-year study period. In a post-hoc analysis of DELOS we found that more patients in the placebo group compared to the idebenone group experienced bronchopulmonary adverse events (BAEs): placebo: 17 of 33 patients, 28 events; idebenone: 6 of 31 patients, 7 events. The hazard ratios (HR) calculated “by patient” (HR 0.33, p = 0.0187) and for “all BAEs” (HR 0.28, p = 0.0026) indicated a clear idebenone treatment effect. The overall duration of BAEs was 222 days (placebo) vs. 82 days (idebenone). In addition, there was also a difference in the use of systemic antibiotics utilized for the treatment of BAEs. In the placebo group, 13 patients (39.4%) reported 17 episodes of antibiotic use compared to 7 patients (22.6%) reporting 8 episodes of antibiotic use in the idebenone group. Furthermore, patients in the placebo group used systemic antibiotics for longer (105 days) compared to patients in the idebenone group (65 days). This post-hoc analysis of DELOS indicates that the protective effect of idebenone on respiratory function is associated with a reduced risk of bronchopulmonary complications and a reduced need for systemic antibiotics.

Concepts: Medicine, Clinical trial, Bacteria, Respiratory system, Clinical research, Antibiotic, Muscular dystrophy, Duchenne muscular dystrophy

28

Inclusion body myopathy associated with Paget’s disease of the bone and frontotemporal dementia is a rare but highly penetrant autosomal dominant progressive disorder linked to mutations in valosin containing protein (VCP). Here, we characterize a novel mutation in the linker 1 domain of VCP leading to inclusion body myopathy and/or frontotemporal dementia in 3 generations of a Swiss family. A detailed history of several years of clinical follow-up and electrophysiological, radiological and pathological findings are presented. Five out of 6 individuals suffered from progressive myopathy and 2 out of 6 from frontotemporal dementia, respectively. A radiologically suspected Paget’s disease of the bone could not been confirmed at autopsy. This case study illustrates that only a subset of individuals shows the full triad of the disease complex and that clinicopathological findings are - when interpreted apart from familial history - hard to distinguish from sporadic inclusion body myositis.

Concepts: Cancer, Diseases and disorders, Death, Prion, Frontotemporal lobar degeneration, Inclusion body myositis, Myopathy, Hereditary inclusion body myopathy

28

The clinical presentation, disease course, response to treatment, and long-term outcome of thirty childhood chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients are presented representing the largest cohort reported to date. Most children (60%) presented with chronic (>8-weeks) symptom-onset while a smaller proportion showed sub-acute (4-8 weeks) or acute (“GBS-like”; <4 weeks) onset of disease. No gender predilection was observed. The majority of patients had a relapsing (70%) versus a monophasic (30%) temporal profile. Most received initial IVIG monotherapy; 80% showing a good response. Long-term follow-up (mean=3.8 years) was available for 23 patients; 45% were off all immunomodulatory medications, demonstrating no detectable (55%) or minimal (43%) clinical deficits. Our data were compared with 11 previously published childhood CIDP series providing a comprehensive review of 143 childhood CIDP cases. The combined initial or first-line treatment response across all studies was favourable for IVIG (79% patients) and corticosteroids (84% patients). Response to first-line plasma exchange was poor (only 14% patients improved) although it may offer some transient or partial benefit as an adjuvant or temporary therapy for selected patients. The combined long-term outcome of our cohort and the literature reveals a favourable prognosis for most patients. The combined modified Rankin scale decreased from 3.7 (at presentation) to 0.7 (at last follow-up). This review provides important data pertaining to clinical course, treatment response and long-term outcome of this relatively uncommon paediatric autoimmune disease.

Concepts: Medicine, Modified Rankin Scale, Myelin, Autoimmune diseases, Neurological disorders, Chronic inflammatory demyelinating polyneuropathy, Plasmapheresis, Progressive inflammatory neuropathy

27

The congenital myopathies are a group of inherited neuromuscular disorders mainly defined on the basis of characteristic histopathological features. We analysed 66 patients assessed at a single centre over a 5year period. Of the 54 patients where muscle biopsy was available, 29 (54%) had a core myopathy (Central Core Disease, Multi-minicore Disease), 9 (17%) had Nemaline Myopathy, 7 (13%) had Myotubular/Centronuclear Myopathy, 2 (4%) had Congenital Fibre Type Disproportion, 6 (11%) had isolated type 1 predominance and 1 (2%) had a mixed Core-Rod Myopathy. Of the 44 patients with a genetic diagnosis, RYR1 was mutated in 26 (59%), ACTA1 in 7 (16%), SEPN1 in 7 (16%), MTM1 in 2 (5%), NEB in 1 (2%) and TPM3 in 1 (2%). Clinically, 77% of patients older than 18months could walk independently. 35% of all patients required ventilatory support and/or enteral feeding. Clinical course was stable or improved in 57/66 (86%) patients, whilst 4 (6%) got worse and 5 (8%) died. These findings indicate that core myopathies are the most common form of congenital myopathies and that more than half can be attributed to RYR1 mutations. The underlying genetic defect remains to be identified in 1/3 of congenital myopathies cases.

Concepts: Genetics, Cancer, Genetic disorder, Mutation, United Kingdom, Genetic disorders, Neuromuscular disease, Muscular disorders

25

Charcot-Marie-Tooth disease is a group of genetically heterogeneous disorders characterized by a sensorimotor polyneuropathy with subsequent muscle atrophy, areflexia, and sensory loss. More than 60 genes have been linked to Charcot-Marie-Tooth phenotypes, including IGHMBP2. Until recently, mutations in IGHMBP2 were exclusively associated with spinal muscular atrophy with respiratory distress (SMARD1). We present a sibling pair with a novel homozygous truncating mutation in IGHMBP2. The patients presented with childhood-onset distal weakness, wasting in the upper and lower limbs, areflexia and decreased sensation, but no respiratory involvement. Exome sequencing was performed and a homozygous variant was identified (c.2601_2604del; p.Lys868Profs*109). Sanger sequencing confirmed the presence of this variant in a homozygous state in the two affected siblings, while both parents were heterozygous. Further analyses showed decreased mRNA and IGHMBP2 protein in a lymphoblast cell line derived from one of the siblings. We demonstrate the utility of next-generation sequencing in reaching a molecular diagnosis for a heterogeneous condition such as Charcot-Marie-Tooth. Taken together, our data and that from the literature suggest that the spectrum of clinical presentations associated with mutations in IGHMBP2 may be secondary, at least in part, to the amount of residual protein.

Concepts: DNA, Gene, Genetics, Molecular biology, Muscle, Muscle atrophy, Zygosity, Atrophy

15

High variability in patients' changes in 6 minute walk distance (6MWD) over time has complicated clinical trials of treatment efficacy in Duchenne muscular dystrophy (DMD). We assessed whether boys with DMD could be grouped into classes that shared similar ambulatory function trajectories as measured by 6MWD. Ambulatory boys aged 5 years or older with genetically confirmed DMD who were enrolled in a natural history study at 11 care centers throughout Italy were included. For each boy, standardized assessments of 6MWD were available at annual intervals spanning 3 years. Trajectories of 6MWD vs. age and trajectories of 6MWD vs. time from enrollment were examined using latent class analysis. A total of 96 boys were included. At enrollment, the mean age was 8.3 years (mean 6MWD: 374 meters). After accounting for age, baseline 6MWD, and steroid use, four latent trajectory classes were identified as explaining 3-year 6MWD outcomes significantly better than a single average trajectory. Patient trajectories of 6MWD change from enrollment were categorized as having fast decline (n = 25), moderate decline (n = 19), stable function (n = 37), and improving function (n = 15) during the 3-year follow-up. After accounting for trajectory classes, the standard deviation of variation in 6MWD was reduced by approximately 40%. The natural history of ambulatory function in DMD may be composed of distinct trajectory classes. The extent to which trajectories are associated with novel and established prognostic factors warrants further study. Reducing unexplained variation in patient outcomes could help to further improve DMD clinical trial design and analysis.

Concepts: Clinical trial, Patient, Arithmetic mean, Standard deviation, Muscular dystrophy, Duchenne muscular dystrophy, Muscular Dystrophy Association, Natural history

4

Perceived fatigue is a prominent symptom in patients with mitochondrial disease but to date its prevalence, impact and aetiology are poorly understood. Our aim was to determine the prevalence and assess for comorbidities associated with clinically relevant fatigue in patients with mitochondrial disease. A cross-sectional postal survey of patients with mitochondrial disease was undertaken using a validated self-completion, patient-reported outcome measures (response rate: 60%; n = 132). The prevalence and perceived functional impact of experienced fatigue were assessed using the Fatigue Impact Scale. Other putative biological mechanisms were evaluated using the Hospital Anxiety Depression scale and Epworth sleepiness scale. Data were compared with those for healthy control subjects and patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome matched for age and gender. Sixty-two per cent of patients with mitochondrial disease reported excessive symptomatic fatigue (Fatigue Impact Scale ≥ 40); whilst 32% reported severe, functionally limiting fatigue symptoms (Fatigue Impact Scale ≥ 80) comparable to perceived fatigue in patients with Myalgic Encephalopathy/Chronic Fatigue Syndrome. Fatigue is common and often severe in patients with mitochondrial disease irrespective of age, gender or genotype. Future evaluation of causal factors in mitochondrial disease-associated fatigue is warranted with the potential to guide future treatment modalities.

Concepts: Epidemiology, Disease, Symptoms, Symptom, Assessment, Fatigue, Prevalence, Epworth Sleepiness Scale

2

An eight week old Labrador Retriever puppy presented with stiff-legged robotic gait. Abnormal gait was most evident after rest and improved with prolonged activity. On occasions, initiation of sudden movements would result in collapse with rigidity of the trunk and stiff extended limbs for several seconds. Other clinical signs were excitement-induced upper airway stridor and oropharyngeal dysphagia. Myotonia congenita was diagnosed based on clinical signs, abundant myotonic discharges on electromyography and exclusion of structural myopathies on histology. Whole exome sequencing revealed a case-specific homozygous variant in CLCN1, c.2275A > T resulting in a premature stop codon, p.R759X. The CLCN1 variant was absent from the genomes of 127 Labrador Retriever controls and 474 control dogs from other breeds. This study expands the spectrum of identified canine CLCN1 mutations and the list of affected breeds in myotonia congenita and highlights the potential value of dogs as translational large animal models of human genetic diseases.

2

Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene leading to dystrophin deficiency, muscle fiber degeneration and progressive fibrotic replacement of muscles. Givinostat, a histone deacetylase (HDAC) inhibitor, significantly reduced fibrosis and promoted compensatory muscle regeneration in mdx mice. This study was conducted to evaluate whether the beneficial histological effects of Givinostat could be extended to DMD boys. Twenty ambulant DMD boys aged 7 to <11 years on stable corticosteroid treatment were enrolled in the study and treated for ≥12 months with Givinostat. A muscle biopsy was collected at the beginning and at the end of treatment to evaluate the amount of muscle and fibrotic tissue. Histological effects were the primary objectives of the study. Treatment with Givinostat significantly increased the fraction of muscle tissue in the biopsies and reduced the amount of fibrotic tissue. It also substantially reduced tissue necrosis and fatty replacement. Overall the drug was safe and tolerated. Improvement in functional tests was not observed in this study, but the sample size of the study was not sufficient to draw definitive conclusions. This study showed that treatment with Givinostat for more than 1 year significantly counteracted histological disease progression in ambulant DMD boys aged 7 to 10 years.

Concepts: Histone deacetylase, Muscle, Cardiac muscle, Electromyography, Muscular system, Muscular dystrophy, Duchenne muscular dystrophy, Muscle biopsy

2

Myofibrillar myopathies (MFM) are characterised by focal myofibrillar destruction and accumulation of myofibrillar elements as protein aggregates. They are caused by mutations in the DES, MYOT, CRYAB, FLNC, BAG3, DNAJB6 and ZASP genes as well as other as yet unidentified genes. Previous studies have reported changes in mitochondrial morphology and cellular positioning, as well as clonally-expanded, large-scale mitochondrial DNA (mtDNA) deletions and focal respiratory chain deficiency in muscle of MFM patients. Here we examine skeletal muscle from patients with desmin (n = 6), ZASP (n = 1) and myotilin (n = 2) mutations and MFM protein aggregates, to understand how mitochondrial dysfunction may contribute to the underlying mechanisms causing disease pathology. We have used a validated quantitative immunofluorescent assay to study respiratory chain protein levels, together with oxidative enzyme histochemistry and single cell mitochondrial DNA analysis, to examine mitochondrial changes. Results demonstrate a small number of clonally-expanded mitochondrial DNA deletions, which we conclude are due to both ageing and disease pathology. Further to this we report higher levels of respiratory chain complex I and IV deficiency compared to age matched controls, although overall levels of respiratory deficient muscle fibres in patient biopsies are low. More strikingly, a significantly higher percentage of myofibrillar myopathy patient muscle fibres have a low mitochondrial mass compared to controls. We concluded this is mechanistically unrelated to desmin and myotilin protein aggregates; however, correlation between mitochondrial mass and muscle fibre area is found. We suggest this may be due to reduced mitochondrial biogenesis in combination with muscle fibre hypertrophy.

Concepts: DNA, Cell, Cancer, Mitochondrion, Mitochondrial DNA, Glycogen, Myosin, Smooth muscle