Dominant spinal muscular atrophy with lower extremity predominance: linkage to 14q32

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 (theta = 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.

Figure 1 Spinal muscular atrophy–lower extremity, dominant pedigree and haplotype analysis Gender and birth order have been deidentified to protect family privacy. Filled diamonds denote affected individuals while open diamonds represent unaffected individuals. A slash indicates deceased individuals. Generations are labeled with roman numerals while individuals are identified by numeral. The disease-associated haplotype is shaded in gray. The proband is marked with a large arrow. The small arrow and arrowhead mark recombination events that narrow the overall locus. Inferred haplotypes are indicated in italics. Eleven descendants of IV-1 are affected by family reports but were not available for study.

Figure 2 Spinal muscular atrophy–lower extremity, dominant phenotype and muscle pathology (A) Leg atrophy in the proband (IV-13) was most pronounced in quadriceps, but also present in muscles of the lower leg. (B) Neurogenic giant motor unit potentials on EMG of the quadriceps in the proband (IV-13). (C) Hematoxylin-eosin–stained frozen section of the vastus medialis muscle (patient IV-8). Changes include internal nuclei, fiber splitting, muscle fiber hypertrophy, and atrophy. Small muscle fibers are angular (black arrow). (D) In another region, cellular infiltrate surrounds a perimysial vessel (white arrowhead). Bar = 30 μm.

Figure 3 Linkage analysis of the spinal muscular atrophy–lower extremity, dominant pedigree (A) Two-point linkage analysis of single-nucleotide polymorphism (SNP) markers spaced every 0.05 cM was performed, showing SNPs with logarithm of the odds (lod) scores >3.00 on chromosomes 3, 9, and 14. (B) Two-point linkage analysis with all Affymetrix GenomeWide 5.0 SNPs on distal 14q showed additional SNPs with significant lod scores. (C) Multipoint linkage analysis using SNPs spaced at 1-cM intervals (and increased around potential recombination sites) across distal 14q.