Neuromuscular disorders : NMD
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Neuromuscul. Disord. · Nov 2014
Randomized Controlled TrialSelected items from the Charcot-Marie-Tooth (CMT) Neuropathy Score and secondary clinical outcome measures serve as sensitive clinical markers of disease severity in CMT1A patients.
This study evaluates primary and secondary clinical outcome measures in Charcot-Marie-Tooth disease type 1A (CMT1A) with regard to their contribution towards discrimination of disease severity. The nine components of the composite Charcot-Marie-Tooth disease Neuropathy Score and six additional secondary clinical outcome measures were assessed in 479 adult patients with genetically proven CMT1A and 126 healthy controls. Using hierarchical clustering, we identified four significant clusters of patients according to clinical severity. ⋯ From these findings, we identified three different composite measures as score hypotheses and compared their discriminant power with that of the CMTNS. A composite of eight components CMAP, Motor symptoms legs, Motor symptoms arms, Strength of Legs, Sensory symptoms), displayed the strongest power to discriminate between the clusters. As a conclusion, five items from the CMTNS and three secondary clinical outcome measures improve the clinical assessment of patients with CMT1A significantly and are beneficial for upcoming clinical and therapeutic trials.
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Neuromuscul. Disord. · May 2014
Hereditary myopathy with early respiratory failure is associated with misfolding of the titin fibronectin III 119 subdomain.
Hereditary myopathy with early respiratory failure is a rare disease with muscle weakness and respiratory failure as early symptoms. Muscle pathology is characterized by the presence of multiple cytoplasmic bodies and other protein aggregates in muscle fibers. The disease is associated with mutations in the titin gene (TTN). ⋯ S30125F) did not have this effect. In silico analyses further support the notion that disease-causing mutations impair proper folding of the FN3 119 domain. The results suggest that hereditary myopathy with early respiratory failure is caused by defective protein folding.
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Neuromuscul. Disord. · May 2014
Deletion of atrophy enhancing genes fails to ameliorate the phenotype in a mouse model of spinal muscular atrophy.
Spinal muscular atrophy (SMA) is an autosomal recessive disease causing degeneration of lower motor neurons and muscle atrophy. One therapeutic avenue for SMA is targeting signaling pathways in muscle to ameliorate atrophy. Muscle Atrophy F-box, MAFbx, and Muscle RING Finger 1, MuRF1, are muscle-specific ubiquitin ligases upregulated in skeletal and cardiac muscle during atrophy. ⋯ In skeletal and cardiac tissue MAFbx and MuRF1 transcripts were upregulated whereas MuRF2 and MuRF3 levels were unchanged in Δ7 SMA mice. We conclude that deletion of the muscle ubiquitin ligases does not improve the phenotype of a Δ7 SMA mouse. Furthermore, it seems unlikely that the beneficial effect of HDAC inhibitors is mediated through inhibition of MAFbx and MuRF1.
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Neuromuscul. Disord. · Mar 2014
A new disease allele for the p.C30071R mutation in titin causing hereditary myopathy with early respiratory failure.
Hereditary myopathy with early respiratory failure is an autosomal dominant myopathy caused by mutations in the 119th fibronectin-3 domain of titin. To date all reported patients with the most common mutation in this domain (p. C30071R) appear to share ancestral disease alleles. ⋯ Cloning of the 119th fibronectin-3 domain in this patient demonstrated polymorphisms rs191484894 and novel noncoding variant c.90225C>T on the same allele as the mutation, which is distinct from previously reported British families. This proves that the p. C30071R mutation itself (rather than the haplotype containing this mutation) causes hereditary myopathy with early respiratory failure and suggests its independent origin in different ethnic groups.
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Neuromuscul. Disord. · Jan 2014
Case ReportsClinical, electrophysiological and magnetic resonance findings in a family with hereditary neuropathy with liability to pressure palsies caused by a novel PMP22 mutation.
Hereditary neuropathy with liability to pressure palsies (HNPP) is a disorder mainly caused by a 1.5-Mb deletion at 17p11.2-12 (and in some rare cases by point mutations) and clinically associated with recurrent painless palsies. Here, we performed electrophysiological (motor, sensory and terminal latency index), MRI and genetic studies in a family referred for ulnar neuropathy with pain. Surprisingly, we found typical neurophysiological features of HNPP (prolongation of distal motor latencies and diffuse SNCV slowing with significant slowing of motor nerve conduction velocities). ⋯ Molecular studies identified a novel frameshift mutation in PMP22 confirming the diagnosis of HNPP. Our data suggest that neurophysiological studies are essential to characterize underdiagnosed HNPP patients referred for peripheral neuropathy. Our experience shows that MRI could be a complementary tool for the diagnosis of these patients.