{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:16:48Z","timestamp":1790691408758,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T00:00:00Z","timestamp":1667433600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>The objectives of this study were to define the clinical and biochemical spectrum of spinal muscular atrophy with progressive myoclonic epilepsy (SMA\u2010PME) and to determine if aberrant cellular ceramide accumulation could be normalized by enzyme replacement.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Clinical features of 6 patients with SMA\u2010PME 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\u2010based 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\u00a0vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The six new patients showed the hallmark features of SMA\u2010PME, with variable initial symptom and age of onset. Five of six patients carried at least one of the recurrent SMA\u2010PME variants observed in two specific codons of <jats:italic>ASAH1<\/jats:italic>. A review of 30 total cases revealed that patients who were homozygous for the most common c.125C\u2009&gt;\u2009T variant presented in the first decade of life with limb\u2010girdle weakness as the initial symptom. Sensorineural hearing loss was associated with the c.456A\u2009&gt;\u2009C variant. Leukocyte acid ceramidase activity varied from 4.1%\u201313.1% of controls. Ceramide species in fibroblasts were detected and total cellular ceramide content was elevated by 2 to 9\u2010fold compared to controls. Treatment with rhAC normalized ceramide profiles in cultured fibroblasts to control levels within 48\u00a0h.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>This study details the genotype\u2013phenotype correlations observed in SMA\u2010PME and shows the impact of rhAC to correct the abnormal cellular ceramide profile in cells.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51687","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T07:47:25Z","timestamp":1667461645000},"page":"1941-1952","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The clinical spectrum of <scp>SMA\u2010PME<\/scp> and in\u00a0vitro normalization of its cellular ceramide profile"],"prefix":"10.1002","volume":"9","author":[{"given":"Michelle M.","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Neurology Washington University School of Medicine  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme S. 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