Abstract
Amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP) are motor neuron diseases sharing clinical, pathological, and genetic similarities. While biallelic SPG7 mutations are known to cause recessively inherited HSP, heterozygous SPG7 mutations have repeatedly been identified in HSP and recently also in ALS cases. However, the frequency and clinical impact of rare SPG7 variants have not been studied in a larger ALS cohort. Here, whole-exome (WES) or targeted SPG7 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 heterozygous SPG7 variants, all of which were previously reported in patients with HSP or ALS. All detected SPG7 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 with SPG7 mutations more frequently presented with cerebellar symptoms, flail arm or leg syndrome compared to those without SPG7 mutations, and showed a partial clinical overlap with HSP. Brain MRI findings in SPG7 mutation carriers included cerebellar atrophy and patterns suggestive of frontotemporal dementia. Collectively, our findings suggest that SPG7 acts as a genetic risk factor for ALS. ALS patients carrying SPG7 mutations present with distinct features overlapping with HSP, particularly regarding cerebellar findings.
Highlights
Amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP) belong to the etiologically heterogeneous group of motor neuron diseases (MNDs) characterized by progressive degeneration and functional decline of motor neurons [1]
To detect rare ALS-associated variants, whole-exome sequencing (WES) was performed on DNA from whole blood of 23 unrelated ALS cases, and variants with a Minor allele frequencies (MAF) of < 1% in genes associated with ALS according to ALSoD (n = 126) that were classified as pathogenic or likely pathogenic using American College of Medical Genetics (ACMG) guidelines were retrieved from the datasets
We provide evidence that rare deleterious variants in the SPG7 gene encoding paraplegin contribute to the pathogenesis of ALS
Summary
Amyotrophic lateral sclerosis (ALS) and hereditary spastic paraplegia (HSP) belong to the etiologically heterogeneous group of motor neuron diseases (MNDs) characterized by progressive degeneration and functional decline of motor neurons [1]. In addition to signs of motor neuron involvement, both ALS and HSP patients may exhibit extra-motor symptoms. In “complicated” or “complex” HSP, patients may develop cerebellar dysfunction (ataxia, nystagmus, tremor), peripheral neuropathy, cognitive impairment, extrapyramidal features, and ophthalmological abnormalities [3]. Despite remarkable progress in understanding the molecular mechanisms of both ALS and HSP, no effective treatment currently exists [1]. Mutations in several genes such as VCP, SPG11, and KIF5A were reported to cause ALS and HSP [4,5,6], highlighting shared genetic mechanisms of clinically distinct MNDs
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