The clinical spectrum of SMA-PME and in vitro normalization of its cellular ceramide profile
No Preview Available
Citations
Altmetric:
Altmetric::
Download
Associated Records
File Licence
Editors
Date
2022-12-01
Source Title
Annals of Clinical and Translational Neurology
Journal Title
Journal ISSN
Volume Title
Publisher
WILEY
Melbourne Authors
Affiliation
Minerva Elements
Document Type
Journal Article
Subject Code
Citation
Lee, M. M., McDowell, G. S. V., De Vivo, D. C., Friedman, D., Berkovic, S. F., Spanou, M., Dinopoulos, A., Grand, K., Sanchez-Lara, P. A., Allen-Sharpley, M., Warman-Chardon, J., Solyom, A., Levade, T., Schuchman, E. H., Bennett, S. A. L., Dyment, D. A. & Pearson, T. S. (2022). The clinical spectrum of SMA-PME and in vitro normalization of its cellular ceramide profile. Annals of Clinical and Translational Neurology, 9 (12), pp.1941-1952. https://doi.org/10.1002/acn3.51687.
Access Status
Open Access
Access URL
Open Access URL
Open Access at PMC
Linked Resource URL
NHMRC Grant Code
ARC Grant Code
Description
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.