Abstract-Text (inkl. Referenzen)

Introduction: Spinal muscular atrophy without deletions/mutations in SMN1 (non-5q-SMA) is a heterogeneous group of disorders and hard to distinguish from 5q-SMA.The new treatment options for 5q-SMA have necessitated extensive genetic testing of SMA, which in turn revealed a large group of patients without 5q-SMA. Methods: We used NGS methods to uncover the genetic defects in patients with non-5q-SMA.Since 2012, 195 families with SMA-related phenotype have been tested via gene panels, exome sequencing (ES) or genome sequencing (GS). Results: The neuromuscular disease gene panel enabled a genetic diagnosis in 43% of tested probands. In only 1/3 of cases, a causal mutation was found in genes associated with SMA/lower motor neuron disease. Furthermore, ES/GS in panel-negative patients yielded an extra diagnosis in 42% of the cases. Both findings highlight a large genetic heterogeneity of patients with non-5q-SMA. Despite diverse causes of non-5q-SMA, we observed a strong overlap of altered cellular processes. Thus,defects in mitochondrial bioenergetics, endocytosis, axonal RNA transport and local translation were the leading compromised cellular functions, as predicted by the identified pathogenic mutation. Discussion: The causes of non-5q-SMAs are diverse, which poses a challenge for classification. However, the strong coherence of the cellular defects in both 5q- and non-5q-SMA groups might suggest new therapy indicators and underlines combinatorial treatment approaches in SMA.