Dominant spinal muscular atrophy with lower extremity predominance
Linkage to 14q32
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Abstract
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 (θ = 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: 100,220,765–106,368,585. 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.
Footnotes
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Supplemental data at www.neurology.org
Study funding: Supported by National Institutes of Health grant NS055980 (to R.H.B.), the Neuroscience Blueprint Core Grant NS057105 (to Washington University), the Hope Center for Neurological Disorders, the Muscular Dystrophy Association, and the Children's Discovery Institute. R.H.B. holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant P30 CA91842.
Disclosure: Author disclosures are provided at the end of the article.
Received January 19, 2010. Accepted in final form April 26, 2010.
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