TY - JOUR
T1 - The clinical spectrum of SMA-PME and in vitro normalization of its cellular ceramide profile
AU - Lee, Michelle M.
AU - McDowell, Graeme S.V.
AU - De Vivo, Darryl C.
AU - Friedman, Daniel
AU - Berkovic, Samuel F.
AU - Spanou, Maria
AU - Dinopoulos, Argirios
AU - Grand, Katheryn
AU - Sanchez-Lara, Pedro A.
AU - Allen-Sharpley, Michelle
AU - Warman-Chardon, Jodi
AU - Solyom, Alexander
AU - Levade, Thierry
AU - Schuchman, Edward H.
AU - Bennett, Steffany A.L.
AU - Dyment, David A.
AU - Pearson, Toni S.
N1 - Funding Information:
The authors would like to acknowledge the patients and their families for their participation in this research. Sequencing of ASAH1 for Patient 5 was performed by Ruobing Zou and the Care4Rare Canada Consortium. The authors would like to thank Dr. Wendy Mears for sample preparation. Recombinant human acid ceramidase enzyme (rhAC) was provided by Enzyvant under a material transfer agreement, the compound is being further developed for potential clinical use by Aceragen as ACG-801. This work was supported in part by a Can-Gard Spring Accelerator grant to DAD and SALB.
Publisher Copyright:
© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85141373983&partnerID=8YFLogxK
U2 - 10.1002/acn3.51687
DO - 10.1002/acn3.51687
M3 - Article
C2 - 36325744
AN - SCOPUS:85141373983
SN - 2328-9503
VL - 9
SP - 1941
EP - 1952
JO - Annals of Clinical and Translational Neurology
JF - Annals of Clinical and Translational Neurology
IS - 12
ER -