SPG7 mutations in amyotrophic lateral sclerosis: a genetic link to hereditary spastic paraplegia

AbstractAmyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP) are motor neuron diseases sharing clinical, pathological, and genetic similarities. While biallelicSPG7 mutations are known to cause recessively inherited HSP, heterozygousSPG7 mutations have repeatedly been identified in HSP and recently also in ALS cases. However, the frequency and clinical impact of rareSPG7 variants have not been studied in a larger ALS cohort. Here, whole-exome (WES) or targetedSPG7 sequencing was done in a cohort of 214 European ALS patients. The consequences of a splice site variant were analyzed on the mRNA level. The resulting protein alterations were visualized in a crystal structure model. All patients were subjected to clinical, electrophysiological, and neuroradiological characterization. In 9 of 214 (4.2%) ALS cases, we identified five different rare heterozygousSPG7 variants, all of which were previously reported in patients with HSP or ALS. All detectedSPG7 variants affect the AAA+  domain of the encoded mitochondrial metalloprotease paraplegin and impair its stability or function according to predictions from mRNA analysis or crystal structure modeling. ALS patients withSPG7 mutations more frequently presented with cerebellar symptoms, flail arm or leg syndrome compared to those withoutSPG7 mutations, and showed a partial clinical overlap with HSP. Brain MRI findings inSPG7 mutation carriers included cerebellar atrophy and patterns suggestive of frontotempor...

Source: Journal of Neurology - May 22, 2020 Category: Neurology Source Type: research