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Phenotypic heterogeneity of spinal muscular atrophy mapping to chromosome 5q11.2-13.3 (SMA 5q)

Neuromuscular Research Unit, Department of Neurology, Tufts-New England Medical Center (Dr. Munsat and L. Skerry), Boston, MA; Children's Hospital Medical Center (Drs. Korf and Pober), Boston, MA; Hadassah Hospital (Dr. Schapira), Jerusalem, Israel; King Faisal Specialist Hospital and Research Center (Dr. Gascon), Riyadh, Saudi Arabia; King Faisal University Hospital (Dr. Al-Rajeh), Dammam, Saudi Arabia; Hammersmith Hospital (Dr. Dubowitz), London, UK; John Radcliffe Hospital (Dr. Davies), Oxford, UK; and Columbia University (Dr. Brzustowicz, G.K. Penchaszadeh, and Dr. Gilliam), New York, NY.

We made phenotypic analysis of 14 families with spinal muscular atrophy (SMA) linking to chromosome 5q11.2-13.3 (SMA 5q), and 2 that may not map to this locus, to assess clinical symptoms among SMA families known to result from mutation at the identical gene/locus. Although the current number of families is still small, the correlation of clinical phenotype and molecular genotype supports 2 observations. First, SMA mutations at the 5q locus present with a broad continuum of clinical abnormalities, and 2nd, the single clearly unlinked family presents with an unusual phenotype characterized by relatively late onset and early death. Thus, there are as yet no unambiguous cases of typical SMA families that are clearly unlinked to the locus at 5q–ie, no clear cases of nonallelic heterogeneity. Analysis of SMA 5q families supports the view that, with certain exceptions, there is little phenotypic intrafamilial variability. When families were ranked by severity of disease there was a strong correlation with age of onset. Onset within the 1st few months was associated with early death, but not in all cases. With rare exception, onset after 1 year of age was associated with less severe disease and greater longevity.

Address correspondence and reprint requests to Dr. Theodore L. Munsat, Neuromuscular Research Unit, New England Medical Center, 750 Washington Street, Boston, MA 02111.

Supported by grants from the Muscular Dystrophy Association and the W.M. Keck Foundation.

Received July 31, 1990. Accepted for publication in-final form August 15, 1990.

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