Intrafamiliäre Variabilität des Phänotyps der 5q-assoziierten spinalen Muskelatrophie am Beispiel von 2 Geschwistern

5q-associated spinal muscular atrophy (5q-SMA) is an autosomal recessive disorder caused by biallelic defects in the SMN1 (survival of motor neuron 1) gene on chromosome 5q. The ongoing loss of motor neurons in the spinal cord leads to progressive atrophic paresis. Age of manifestation and disease severity may vary widely. The SMN2 gene copy number is the key modifier, while influences from other factors are suspected. Using the example of two brothers with 5q-associated SMA, we show that despite the same SMN2 gene copy number, both age of manifestation and clinical phenotype may show significant divergence. This observation has implications for the genetic counseling of clinically normal siblings of 5q-SMA patients, as it demonstrates that older siblings of affected individuals are at risk to develop the disease as well. Genetic testing of siblings therefore does not only reveal the carrier status but provides a predictive value as well. This is of relevance with respect to the effective treatment options for 5q-SMA which have been available for several years and whose efficacy is particularly high when therapy is started early in life.