# ASAH2 deficiency affects sphingolipid homeostasis and neuromotor control, causing a progressive neurological disorder

## TL;DR

This study identifies ASAH2 gene variants as a cause of a neurological disorder involving cognitive and motor impairments due to disrupted lipid metabolism.

## Contribution

The study links ASAH2 deficiency to a novel neurodevelopmental disorder with progressive neurological features.

## Key findings

- ASAH2 variants were found in a patient with cognitive impairment, neuropathy, and cerebellar atrophy.
- Lipidomic profiling showed glucosylceramide accumulation in the patient's cells.
- Drosophila studies confirmed ASAH2 variants caused unstable protein and neuromotor defects.

## Abstract

Sphingolipids are integral components of cell membranes and modulate cell survival, proliferation, and apoptosis. ASAH2 is a brain- and gut-enriched gene encoding the neutral N-acylsphingosine amidohydrolase 2, a poorly characterized member of the human ceramidase family. This enzyme plays a pivotal role in maintaining the sphingolipid homeostasis, which is crucial for neurogenesis and synaptic function in the central and peripheral nervous systems. In fact, a dysregulated sphingolipid metabolism is associated with progressive neurological conditions, including Alzheimer disease and Parkinson disease. Here, we report the identification of biallelic ASAH2 variants in an individual with a neurodevelopmental condition featuring cognitive impairment, neuropathy, ophthalmoplegia, and progressive cerebellar and extraocular muscles atrophy. Through exome sequencing, we identified very rare missense ASAH2 variants, predicted to be deleterious by in silico analyses. Muscle biopsy histopathologic evaluation revealed features suggestive of neuropathic damage. Lipidomic profiling revealed a hyper-accumulation of glucosylceramide in the subject’s cells. Then, the functional investigation of the ASAH2 variants in Drosophila showed the production of an unstable protein and consistent loss-of-function neuromotor phenotypes. Our findings support ASAH2 as a candidate gene for a previously uncharacterized neurodevelopmental disorder with neuropathic features and progressive cerebellar atrophy, underscoring the important role of this ceramidase in human nervous systems.

We report rare variants in the gene ASAH2, encoding a ceramidase involved in lipid metabolism, in a subject with neurodevelopmental disorder, neuropathy, and cerebellar atrophy. Functional studies revealed disrupted sphingolipid metabolism in human cells and neuromotor disorders in fruit flies. Our work links ASAH2 dysfunction to human nervous system disease.