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

Abstract

Objective The objectives of this study were to define the clinical and biochemical spectrum of spinal muscular atrophy with progressive myoclonic epilepsy (SMA‐PME) and to determine if aberrant cellular ceramide accumulation could be normalized by enzyme replacement. Methods Clinical features of 6 patients with SMA‐PME were assessed by retrospective chart review, and a literature review of 24 previously published cases was performed. Leukocyte enzyme activity of acid ceramidase was assessed with a fluorescence‐based assay. Skin fibroblast ceramide content and was assessed by high performance liquid chromatography, electrospray ionization tandem mass spectroscopy. Enzyme replacement was assessed using recombinant human acid ceramidase (rhAC) in vitro. Results The six new patients showed the hallmark features of SMA‐PME, with variable initial symptom and age of onset. Five of six patients carried at least one of the recurrent SMA‐PME variants observed in two specific codons of ASAH1. A review of 30 total cases revealed that patients who were homozygous for the most common c.125C > T variant presented in the first decade of life with limb‐girdle weakness as the initial symptom. Sensorineural hearing loss was associated with the c.456A > C variant. Leukocyte acid ceramidase activity varied from 4.1%–13.1% of controls. Ceramide species in fibroblasts were detected and total cellular ceramide content was elevated by 2 to 9‐fold compared to controls. Treatment with rhAC normalized ceramide profiles in cultured fibroblasts to control levels within 48 h. Interpretation This study details the genotype–phenotype correlations observed in SMA‐PME and shows the impact of rhAC to correct the abnormal cellular ceramide profile in cells.

Inhibiting de novo ceramide synthesis restores mitochondrial and protein homeostasis in muscle aging

“…Hence, the preservation of the function of these pathways may have contributed to the improved health span in aged mice and increased life span in worms treated with myriocin. This is consistent with previous reports showing that ceramides are key signaling contributors to the pathogenesis of various proteotoxic neuromuscular diseases such as Parkinson's disease, progressive cerebello-cerebral atrophy type 2, Huntington’s disease, spinal muscular atrophy, and valosin-containing protein (VCP)–associated inclusion body myopathy ( 43 , 48 – 50 ). Given the known effects of ceramides on human pathophysiology, such as in insulin resistance, dyslipidemia, and cardiovascular diseases ( 19 – 22 ), it will be of interest to study whether ceramide dysregulation also causes proteotoxicity in these obesity-fueled disorders.…”

Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME): three new cases and review of the mutational spectrum

“…Zielonka et al showed that a higher residual activity of aCDase is associated with later onset and longer survival of Farber patients [ 27 ]. A similar pattern seems to be true also for SMA-PME which is an ultrarare (Prevalence: < 1/1 000 000 ) [ 28 – 30 ] childhood neurological condition leading to muscle weakness and atrophy. It also manifests seizures and uncontrollable myoclonic epilepsy [ 8 ].…”

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

“…In a study of three Iranian patients, exome sequencing in combination with testing to evaluate survival motor neuron 1 (SMN1) and 2 (SMN2) copy numbers to rule out SMA revealed new causative variants in ASAH1 [90]. In a study of six new patients with the hallmark features of SMA-PME-namely lower motor neuron disease, tremor, and ataxia without the triad of FD-five of the six patients carried at least one of the known SMA-PME variants in ASAH1 [92]. In the same study, a review of 30 cases showed that patients homozygous for the common c.125C>T variant presented in the first decade of life with limb-girdle weakness, while patients with the c.456A>C variant experienced sensorineural hearing loss.…”