MOLECULAR SCREENING AND DELETION ANALYSIS IN SPINAL MUSCULAR-ATROPHY TYPES I-III

Autosomal recessive spinal muscular atrophy (SMA) is, after cystic fib rosis, the second most common fatal monogenic disorder. The disease is characterized by degeneration of anterior horn cells leading to progr essive paralysis with muscular atrophy. Depending on the clinical type (Werdnig-Hoffmann = type I, intermediate form = type II, Kugelberg-We lander = type III), SMA causes early death or increasing disability in childhood. The SMA-critical region on the long arm of chromosome 5q13 .1 contains many duplicated genes and polymorphisms. Recently, two pre sumptive SMA genes (survival motoneuron gene = SMN, and neuronal apopt osis inhibitory protein = NAIP) have been identified. Deletions involv ing critical regions of these genes are very often associated with SMA , and the extent of the deletions seems to correlate in part with dise ase severity. We have evaluated the diagnostic and prognostic value of molecular analysis in a large number of SMA patients. 57 patients and 78 healthy relatives were molecularly screened for deletions in the S MA critical region. We demonstrated homozygous deletions removing the SMN genes in over 90% of patients, whereas nearly 45% of patients exhi bited NAIP gene deletions. Large deletions involving both genes on eac h chromosome are generally found in patients with severe SMA (Werdnig- Hoffman cases), while mildly affected Kugelberg-Welander cases frequen tly show only deleted SMN genes. Molecular classification based on com bined deletion sizes, however, seems not to be exact, especially for t he group with chronic SMA (type II and III). Direct DNA testing of pat ients in whom SMA is suspected is a highly reliable, fast, and noninva sive method. The ability to detect homozygous gene deletions in a high percentage of typical SMA patients will much improve genetic counsell ing and prenatal diagnosis in affected families.