Submission Details

The relationship between ASAH1 and ASAH1-related sphingolipidosis, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of October, 2023. ASAH1 encodes a member of the acid ceramidase family of proteins. A preproprotein is encoded that undergoes proteolytic processing generating alpha and beta subunits that heterodimerize to form the mature lysosomal enzyme, acid ceramidase, which catalyzes the degradation of ceramide into sphingosine and free fatty acid.

OMIM disease entities: Farber lipogranulomatosis (MIM: 228000) and Spinal muscular atrophy with progressive myoclonic epilepsy (MIM: 159950). The term "ASAH1-related sphingolipidosis", also referred to as acid ceramidase deficiency in the literature, has been introduced to lump the two disease assertions related to ASAH1. Both Farber lipogranulomatosis and Spinal muscular atrophy form a continuum (PMID: 32449975, 30029679), with progressive myoclonic epilepsy have moderate phenotypic overlap, including a patient with features of both diseases (PMID: 27650050), are inherited in the autosomal recessive manner, and result from biallelic variants in ASAH1 that result in loss of function.

ASAH1 was first reported in relation to autosomal recessive ASAH1-related sphingolipidosis in 1996 (Koch et al, PMID: 8955159). At least 100 missense variants have been reported in human patients. Evidence supporting this gene-disease relationship includes case-level data and experimental data.

Summary of Case Level Data (12 points):

Variants in this gene have been reported in at least 11 probands in 6 publications (PMID: 22703880, 28251733, 8955159, 27650050, 24355074, 11241842) showing classic Farber lipogranulomatosis of varying severity, spinal muscular atrophy with progressive myoclonic epilepsy or a blended phenotype of both disorders. Much more evidence is available in the literature, but the maximum score for genetic evidence was reached.

The mechanism for disease is expected to be biallelic loss of function.

Summary of experimental data (6 points):

This gene-disease relationship is supported by in vitro functional studies, model organisms and rescue evidence. Reduction in acid ceramidase activity leads to the accumulation of ceramides in the lysosomes (PMID: 27155573). Zebrafish and mouse models that partially recapitulate the human phenotype have been reported (PMID: 11829492, 23681708, 22703880). Rescue of phenotype by the wild-type gene product has been reported in a knock-in mouse model (PMID: 23681708).

In summary, ASAH1 is definitively associated with autosomal recessive ASAH1-related sphingolipidosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Lysosomal Diseases GCEP on October 4, 2023 (SOP v9).

Additional information on prenatal phenotype (added May 1, 2024): Prenatal phenotypes described in the literature in association with ASAH1 include non-immune hydrops fetalis, abnormal cardiac structure, arrhythmia, and bradycardia. Two cases are reported with bi-allelic splicing variants and an exonic deletion (PMID: 8650144, 9128814, 23707712, 37962265). Given the limited reports in the literature the association of ASAH1 with prenatal phenotypes is currently limited.