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We explored the effects of standardized calf massage in ambulant boys with Duchenne muscular dystrophy (DMD) using a prospective study design. Twenty boys completed two study visits, 1 week apart. At both visits, each leg received a 10-min calf massage (intervention) and a 10-min control rest period (placebo) in randomized order. Muscle length of calf and hamstrings and gastrocnemius stiffness were measured by a blinded assessor before and after intervention and placebo. Measures of gait function (timed 10-m walk/run and spatio-temporal gait parameters); gastrocnemius muscle ultrasound findings; participant perception of leg pain, stiffness and effort of walking and general psychological well-being were also collected. Consistent significant small increases in muscle length of soleus, gastrocnemius and hamstrings were recorded post-massage, and gastrocnemius stiffness decreased. Small changes in gastrocnemius and soleus length only were also recorded following the control rest period. Gait function and general well-being remained stable throughout. Measurement across both study visits suggested that gains in muscle length may be cumulative with repeated massage. Calf massage is safe and associated with benefits to muscle length and stiffness for ambulant boys with DMD.Implications for RehabilitationIn a small sample of boys with Duchenne muscular dystrophy, calf massage was found to be safe, well-tolerated and associated with increased muscle length and decreased stiffness.The use of massage may assist in managing muscle length in boys with Duchenne muscular dystrophy. In a small sample of boys with Duchenne muscular dystrophy, calf massage was found to be safe, well-tolerated and associated with increased muscle length and decreased stiffness. The use of massage may assist in managing muscle length in boys with Duchenne muscular dystrophy.

Contains fulltext : 196367.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Vici syndrome is a progressive neurodevelopmental multisystem disorder caused by mutations in the autophagy gene EPG5. Byrne et al. characterise the phenotype of 50 affected children, revealing callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, immune dysfunction, developmental delay and microcephaly. Downregulation of epg5 in Drosophila results in autophagic abnormalities and progressive neurodegeneration., Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0–49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.