Acid Ceramidase Deficiency: Bridging Gaps between Clinical Presentation, Mouse Models, and Future Therapeutic Interventions

Abstract

Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare, autosomal-recessive, acid ceramidase (ACDase) deficiency disorders caused by ASAH1 gene mutations. Currently, 73 different mutations in the ASAH1 gene have been described in humans. These mutations lead to reduced ACDase activity and ceramide (Cer) accumulation in many tissues. Presenting as divergent clinical phenotypes, the symptoms of FD vary depending on central nervous system (CNS) involvement and severity. Classic signs of FD include, but are not limited to, a hoarse voice, distended joints, and lipogranulomas found subcutaneously and in other tissues. Patients with SMA-PME lack the most prominent clinical signs seen in FD. Instead, they demonstrate muscle weakness, tremors, and myoclonic epilepsy. Several ACDase-deficient mouse models have been developed to help elucidate the complex consequences of Cer accumulation. In this review, we compare clinical reports on FD patients and experimental descriptions of ACDase-deficient mouse models. We also discuss clinical presentations, potential therapeutic strategies, and future directions for the study of FD and SMA-PME.

Acid ceramidase expression reduces IFNγ secretion by mouse CD4+ T cells and is crucial for maintaining B-cell numbers in mice

“…A possible explanation could be that, unlike T cells, B cells do not express caveolin, which means that they depend more heavily on lysosomal activity than T cells to maintain the integrity of the cell membrane ( 44 ). Whether the lysosomal dysfunction observed in Ac-deficient cells ( 45 ) extends to an ineptitude to properly repair cell membrane damage is, however, unknown. Our own observation that liposomes preferentially enhance B- versus T-cell survival in vitro ( 46 ) might support the notion that B cells are in higher demand for lipids than T cells generated either by the cells themselves or acquired from their environment.…”

Progressive Myoclonus Epilepsy: A Scoping Review of Diagnostic, Phenotypic and Therapeutic Advances

“…This therapeutic attempt and details on the patient's demise are to be published at a future date [95]. Successful gene therapy has been developed and obtained FDA approval for SMA type 1 (i.e., onasemnogene abeparvovec), which may build a case for use in SMA-PME, but there are no existing case reports of its use for these patients [96]. ERT with recombinant human acid ceramidase (rhACDase) is being developed [89,96,97].…”

“…Successful gene therapy has been developed and obtained FDA approval for SMA type 1 (i.e., onasemnogene abeparvovec), which may build a case for use in SMA-PME, but there are no existing case reports of its use for these patients [96]. ERT with recombinant human acid ceramidase (rhACDase) is being developed [89,96,97]. Given the success of ERT for CLN2 Batten disease, there is hope that similar therapies for the AC deficiencies will also be successful [97].…”