Submission Details

ATL1 has first been described in the context of autosomal dominant hereditary spastic paraplegia (HSP; PMIDs: 11685207, 12112092, 12499504, 12939451, 15596607, etc.). Encoding a homo-oligomeric GTPase, it is known to be responsible for shaping the tubular structure of the endoplasmic reticulum (PMID: 27339937). In three families presenting with severe sensory neuropathy and foot ulcerations in an autosomal dominant pedigree, Guelly et al. described co-segregating variants in ATL1, one of which recurrently described in another publication, but in the same population (PMID: 22340599). Both genetic (LOD scores 2.94 and 3.31) and functional evidence (disturbed GTPase function and ER structure) on the variant level, support the assumption that these variants are responsible for the patients’ phenotype. Clinically, the authors describe a notable overlap with the HSP phenotype, which is supported by the fact that both phenotypes, neuropathy and HSP, are associated with these variants in the ClinVar database. In HSP cases, on the other hand, neuropathy seems to be a common feature as well, pointing towards an inseparable overlap between those two phenotypes. Functional evidence on ATL1, including studies on protein expression, biochemical function, and model organisms (drosophila and zebrafish) support the gene-disease relationship, which is, however, not specific for the neuropathy phenotype. The expert panel concludes that HSAN1D is part of an axonopathy spectrum definitively associated with ATL1 that mainly manifests with HSP as the leading phenotype. As neuropathy can still be an early or even leading symptom in rare constellations, we recommend that ATL1 should be implemented on both HSP and neuropathy panels.