Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number

• Published in: Human genetics Vol. 119; no. 4; pp. 422 - 428
• Main Authors: WIRTH, B, BRICHTA, L, SCHRANK, B, LOCHMÜLLER, H, BLICK, S, BAASNER, A, HELLER, R
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01-05-2006; Berlin Springer Nature B.V; New York, NY
• Subjects: Adult; Age; Age of Onset; Atrophy; Biological and medical sciences; Classical genetics, quantitative genetics, hybrids; Clinical trials; Cyclic AMP Response Element-Binding Protein - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diseases of striated muscles. Neuromuscular diseases; Female; Fundamental and applied biological sciences. Psychology; Gene Deletion; Gene Dosage; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Homozygote; Human; Humans; Male; Medical prognosis; Medical sciences; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - prevention & control; Mutation; Nerve Tissue Proteins - genetics; Neurology; Pedigree; Phenotype; Proteins; RNA-Binding Proteins - genetics; SMN Complex Proteins; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein; Human; Neuromuscular diseases; Nervous system diseases; Copy number; Spinal amyotrophy; Central nervous system disease; Genetics; Patient; Degenerative disease; Spinal cord disease
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-006-0156-7

Spinal muscular atrophy (SMA) is a recessive neuromuscular disorder caused by loss of the SMN1 gene. The clinical distinction between SMA type I to IV reflects different age of onset and disease severity. SMN2, a nearly identical copy gene of SMN1, produces only 10% of full-length SMN RNA/protein and is an excellent target for a potential therapy. Several clinical trials with drugs that increase the SMN2 expression such as valproic acid and phenylbutyrate are in progress. Solid natural history data for SMA are crucial to enable a correlation between genotype and phenotype as well as the outcome of therapy. We provide genotypic and phenotypic data from 115 SMA patients with type IIIa (age of onset <3 years), type IIIb (age of onset >3 years) and rare type IV (onset >30 years). While 62% of type IIIa patients carry two or three SMN2 copies, 65% of type IIIb patients carry four or five SMN2 copies. Three type IV SMA patients had four and one had six SMN2 copies. Our data support the disease-modifying role of SMN2 leading to later onset and a better prognosis. A statistically significant correlation for > or =4 SMN2 copies with SMA type IIIb or a milder phenotype suggests that SMN2 copy number can be used as a clinical prognostic indicator in SMA patients. The additional case of a foetus with homozygous SMN1 deletion and postnatal measurement of five SMN2 copies illustrates the role of genotypic information in making informed decisions on the management and therapy of such patients.