Novel ASAH1 Variant in an Indian Boy with Biochemical Evidence of Reduced Alpha Ceramidase Activity

Abstract Bi-allelic pathogenic ASAH1 variants are associated with two genetic disorders – Infantile-onset Farber lipogranulomatosis and juvenile/late onset spinal muscular atrophy (SMA), with or without epilepsy (SMA progressive myoclonic epilepsy/SMA). Globally, there are sparse reports of ASAH1- associated SMA. Its clinical features overlap with those of the frequently occurring 5q SMA. Herein, we report a 12-year-old Indian male child who was referred with clinical suspicion of SMA, but was subsequently diagnosed with ASAH1- related SMA, resulting from a novel variant in the gene. We also provide biochemical evidence for the pathogenicity of the identified variant via an acid ceramidase assay. Pathogenic ASAH1 mutations are an extremely rare cause of non-5q SMA, and the phenotype of this disorder is still evolving. The acid ceramidase assay provides functional evidence of variant pathogenicity in patients with novel variants in the ASAH1 gene.