Dominant spinal muscular atrophy with lower extremity predominance

Linkage to 14q32

M. B. Harms, P. Allred, R. Gardner, Jose Americo M Fernandes Filho, J. Florence, A. Pestronk, M. Al-Lozi, R. H. Baloh

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)539-546
Number of pages8
JournalNeurology
Volume75
Issue number6
DOIs
StatePublished - Aug 10 2010

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Spinal Muscular Atrophy
Lower Extremity
Leg
Single Nucleotide Polymorphism
Lod Score
Muscles
Electrophysiology
Telomere
Motor Neurons
Denervation
Upper Extremity
Haplotypes
Genetic Recombination
Atrophy
Hip
Genome
Phenotype
Biopsy

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Harms, M. B., Allred, P., Gardner, R., Fernandes Filho, J. A. M., Florence, J., Pestronk, A., ... Baloh, R. H. (2010). Dominant spinal muscular atrophy with lower extremity predominance: Linkage to 14q32. Neurology, 75(6), 539-546. https://doi.org/10.1212/WNL.0b013e3181ec800c

Dominant spinal muscular atrophy with lower extremity predominance : Linkage to 14q32. / Harms, M. B.; Allred, P.; Gardner, R.; Fernandes Filho, Jose Americo M; Florence, J.; Pestronk, A.; Al-Lozi, M.; Baloh, R. H.

In: Neurology, Vol. 75, No. 6, 10.08.2010, p. 539-546.

Research output: Contribution to journalArticle

Harms, MB, Allred, P, Gardner, R, Fernandes Filho, JAM, Florence, J, Pestronk, A, Al-Lozi, M & Baloh, RH 2010, 'Dominant spinal muscular atrophy with lower extremity predominance: Linkage to 14q32', Neurology, vol. 75, no. 6, pp. 539-546. https://doi.org/10.1212/WNL.0b013e3181ec800c
Harms, M. B. ; Allred, P. ; Gardner, R. ; Fernandes Filho, Jose Americo M ; Florence, J. ; Pestronk, A. ; Al-Lozi, M. ; Baloh, R. H. / Dominant spinal muscular atrophy with lower extremity predominance : Linkage to 14q32. In: Neurology. 2010 ; Vol. 75, No. 6. pp. 539-546.
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AU - Florence, J.

AU - Pestronk, A.

AU - Al-Lozi, M.

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