ASAH1 – spinal muscular atrophy with progressive myoclonic epilepsy syndrome

Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is an ultrarare, autosomal recessive neurodegenerative disorder characterized by childhood-onset lower motor neuron degeneration followed by intractable myoclonic seizures and premature death from respiratory failure. Causative variants in the ASAH1 gene underlie this condition, establishing a direct genotype–phenotype correlation in SMA-PME (PMID:24164096).

Genetic studies across multiple unrelated families have identified at least 30 distinct pathogenic ASAH1 variants in over 47 probands, all presenting with biallelic mutations consistent with autosomal recessive inheritance. Key variants include c.850G>T (p.Gly284Ter) and c.456A>C (p.Lys152Asn) leading to premature truncation and amino acid substitution, respectively (PMID:24164096).

Segregation analysis in three independent families demonstrated co-segregation of homozygous or compound heterozygous ASAH1 variants with SMA-PME in six additional affected relatives, confirming familial linkage and high penetrance of these alleles (PMID:22703880).

Functional assays in patient-derived fibroblasts revealed markedly reduced acid ceramidase activity and a 2-fold increase in cellular ceramide content, directly implicating loss of enzyme function in disease pathogenesis (PMID:24164096). Morpholino-mediated knockdown of asah1 in zebrafish recapitulated motor neuron axonal defects and increased neuronal apoptosis, thus modeling the human SMA-PME phenotype in vivo (PMID:22703880).

Clinically, patients manifest progressive proximal muscle weakness (HP:0003323), myoclonus (HP:0001336), tremor (HP:0001337), sensorineural hearing impairment (HP:0000407), and generalized seizures (HP:0001250), with cognitive impairment variably observed (PMID:26526000; PMID:29169047).

A comprehensive review of 30 cases including six newly described patients confirms genotype–phenotype correlations, notably the recurrent c.125C>T (p.Thr42Met) variant associated with early-onset limb-girdle weakness and epilepsy, and highlights the therapeutic potential of recombinant acid ceramidase to normalize cellular ceramide profiles (PMID:36325744).

Integration of robust genetic, segregation, and functional data across diverse cohorts meets criteria for a Definitive gene–disease relationship. ASAH1 variant analysis should be prioritized in patients with unexplained motor neuron disease accompanied by myoclonic epilepsy. Key take-home: early genetic diagnosis enables targeted metabolic evaluation and paves the way for enzyme replacement or gene therapy approaches.

References

• Clinical genetics • 2014 • Evidence for clinical, genetic and biochemical variability in spinal muscular atrophy with progressive myoclonic epilepsy. PMID:24164096
• American journal of human genetics • 2012 • Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1. PMID:22703880
• Neuromuscular disorders · 2015 · Acid ceramidase deficiency associated with spinal muscular atrophy with progressive myoclonic epilepsy. PMID:26526000
• Clinical neurology and neurosurgery · 2018 · Spinal muscular atrophy with progressive myoclonic epilepsy linked to mutations in ASAH1. PMID:29169047
• Annals of clinical and translational neurology · 2022 · The clinical spectrum of SMA-PME and in vitro normalization of its cellular ceramide profile. PMID:36325744

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