Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by loss or mutation of the survival motor neuron 1 (SMN1) gene and retention of SMN2. We performed targeted capture and sequencing of the SMN2, CFTR, and PLS3 genes in 217 SMA patients. We identified a 6.3 kilobase deletion that occurred in both SMN1 and SMN2 (SMN½) and removed exons 7 and 8. The deletion junction was flanked by a 21 base pair repeat that occurred 15 times in the SMN½ gene. We screened for its presence in 466 individuals with known SMN1 and SMN2 copy number. In individuals with 1 SMN1 and 0 SMN2 copies the deletion occurred in 63% of cases. We modeled the deletion junction frequency and determined that the deletion occurred in both SMN1 and SMN2. We have identified the first deletion junction where the deletion removes exons 7 and 8 of SMN½. As it occurred in SMN1 it is a pathogenic mutation. We called variants in the PLS3 and SMN2 genes and tested for association with mild or severe exception patients. The variants A-44G, A-549G and C-1897T in intron 6 of SMN2 were significantly associated with mild exception patients but no PLS3 variants correlated with severity. The variants occurred in 14 out of 58 of our mild exception patients indicating that mild exception patients with an intact SMN2 gene

Introduction Distal hereditary motor neuropathy (dHMN) causes distal-predominant weakness without prominent sensory loss. Myosin heavy chain disorders most commonly result in distal myopathy and cardiomyopathy with or without hearing loss, but a complex phenotype with dHMN, myopathy, hoarseness, and hearing loss was reported in a Korean family with a c.2822G>T mutation in MYH14. Objective To report phenotypic features in a North American family with the c.2822G>T in MYH14. Methods Clinical and molecular characterization was performed in a large, 6-generation, Caucasian family with MYH14 dHMN. Results A total of 11 affected and 7 unaffected individuals were evaluated and showed varying age of onset and severity of weakness. Genotypic concordance was confirmed with molecular analysis. Electrophysiological studies demonstrated distal motor axonal degeneration without myopathy in all affected subjects tested. Conclusions Mutation of MYH14 can result in a range of neuromuscular phenotypes that includes a dHMN and hearing loss phenotype with variable age of onset.

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S99 after treatment with Nusinersen. MDI scores did not differ significantly, but MCAI scores differed significantly at some measurement sites. On the other hand, though the CHOP-INTEND scores improved, neither MDI nor MCAI, as determined by BIA, showed improvement in type II patients. BIA is the method used to infer fat-free mass and lean body mass from impedance of muscle and fat. It was recently reported that there is a correlation of MDI with motor function in Duchenne muscular dystrophy, showing BIA to be a useful method. However, a correlation of MCAI and motor function in Fukuyama congenital muscular dystrophy was also reported. In this study, though BIA scores in type II cases did not improve after treatment with Nusinersen, type I cases experienced improvement based on higher CHOP-INTEND scores. Most SMA type I patients require tracheostomized positive pressure ventilation, such that they are at high risk for skeletal muscle changes on magnetic resonance imaging. BIA thus could be one tool for estimating motor function in SMA type I patients.