ASAH1 pathogenic variants associated with acid ceramidase deficiency: Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy

Abstract

Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are a spectrum of rare lysosomal storage disorders characterized by acid ceramidase deficiency (ACD), resulting from pathogenic variants in N‐acylsphingosine amidohydrolase 1 (ASAH1). Other than simple listings provided in literature reviews, a curated, comprehensive list of ASAH1 mutations associated with ACD clinical phenotypes has not yet been published. This publication includes mutations in ASAH1 collected through the Observational and Cross‐Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NHS), http://ClinicalTrials.gov identifier NCT03233841, in combination with an up‐to‐date curated list of published mutations. The NHS is the first to collect retrospective and prospective data on living and deceased patients with ACD presenting as Farber disease, who had or had not undergone hematopoietic stem cell transplantation. Forty‐five patients representing the known clinical spectrum of Farber disease (living patients aged 1–28 years) were enrolled. The curation of known ASAH1 pathogenic variants using a single reference transcript includes 10 previously unpublished from the NHS and 63 that were previously reported. The publication of ASAH1 variants will be greatly beneficial to patients undergoing genetic testing in the future by providing a significantly expanded reference list of disease‐causing variants.

The clinical spectrum of SMA‐PME and in vitro normalization of its cellular ceramide profile

“…Cognitive decline became apparent during the course of the disease for patients 1–4. Cervical and foot dystonia, not previously reported as manifestations of SMA‐PME, 19 were uniquely observed in patient 1.…”

“…We excluded reports of cases that lacked clinical data 26 and historical reports of SMA‐PME that lacked molecular confirmation. Because several transcripts have been used in the literature when describing variants in ASAH1 , we have converted variants to nomenclature corresponding to the NM_177924.5 transcript 19 …”

“…Because several transcripts have been used in the literature when describing variants in ASAH1 , we have converted variants to nomenclature corresponding to the NM_177924.5 transcript. 19 …”

“…This gene encodes the enzyme acid ceramidase (AC), which catalyzes the breakdown of ceramides into sphingosine and free fatty acids in the lysosome 4 . SMA‐PME is a rare condition and, to date, a total of 24 patients from 19 families have been reported in detail in the literature with confirmed pathogenic variation in ASAH1 3,5–19 . Reported patients commonly present with proximal weakness in mid‐childhood, followed by progressive seizures and myoclonus 20 .…”

“… 4 SMA‐PME is a rare condition and, to date, a total of 24 patients from 19 families have been reported in detail in the literature with confirmed pathogenic variation in ASAH1 . 3 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 Reported patients commonly present with proximal weakness in mid‐childhood, followed by progressive seizures and myoclonus. 20 Mortality may result from respiratory insufficiency in early adulthood or from complications of refractory seizures.…”