Objective: Spinal muscular atrophies (SMAs) are hereditary disorders characterized by weakness from degeneration of spinal motor neurons. Although most SMA cases with proximal weakness are recessively inherited, rare families with dominant inheritance have been reported. We aimed to clinically, pathologically, and genetically characterize a large North American family with an autosomal dominant proximal SMA.Methods: Affected family members underwent clinical and electrophysiologic evaluation. Twenty family members were genotyped on high-density genome-wide SNP arrays and linkage analysis was performed.Results: Ten affected individuals (ages 7-58 years) showed prominent quadriceps atrophy, moderate to severe weakness of quadriceps and hip abductors, and milder degrees of weakness in other leg muscles. Upper extremity strength and sensation was normal. Leg weakness was evident from early childhood and was static or very slowly progressive. Electrophysiology and muscle biopsies were consistent with chronic denervation. SNP-based linkage analysis showed a maximum 2-point lod score of 5.10 ( ϭ 0.00) at rs17679127 on 14q32. A disease-associated haplotype spanning from 114 cM to the 14q telomere was identified. A single recombination narrowed the minimal genomic interval to Chr14: 100,220,368,585. No segregating copy number variations were found within the disease interval. Conclusions:We describe a family with an early onset, autosomal dominant, proximal SMA with a distinctive phenotype: symptoms are limited to the legs and there is notable selectivity for the quadriceps. We demonstrate linkage to a 6.1-Mb interval on 14q32 and propose calling this disorder spinal muscular atrophy-lower extremity, dominant. Neurology Spinal muscular atrophies (SMAs) are hereditary disorders characterized by degeneration of spinal cord motor neurons. The majority of SMA cases show autosomal recessive inheritance and are caused by homozygous deletion or mutation of the SMN1 gene on 5q (OMIM 253300, 253550, 253400, and 271150). Non-5q SMAs are rare, clinically diverse, and genetically heterogeneous.1,2 They are commonly classified by inheritance pattern and whether weakness involves predominantly distal or proximal musculature.The non-5q SMAs with distal-predominant weakness show phenotypic overlap with the distal hereditary motor neuropathies. Recessive disorders in this category are caused by mutations in IGHMBP2, 3 PLEKHG5, 4 or show linkage to 9p21.1-p12 5 or 11q.13. 6 Dominant

No abstract

No abstract