Five patients with spinal muscular atrophy-progressive myoclonic epilepsy (SMA-PME): a novel pathogenic variant, treatment and review of the literature

Published:August 06, 2022DOI:


      • SMA-PME is rare inherited disease with bi-allelic mutations in the ASAH1 gene.
      • SMA-PME characterized by progressive myoclonic epilepsy, proximal weakness.
      • A novel variant c.109C>T(p. Pro37Thr) was reported for SMA-PME in this study.


      Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a rare inherited autosomal recessive disease due to bi-allelic mutations in the ASAH1 gene. SMA-PME is characterized by progressive muscle weakness from three to seven years of age, accompanied by epilepsy, intractable seizures, and sometimes sensorineural hearing loss. To the best of our knowledge, 47 cases have been reported. The present study reports five patients from four different families affected by SMA-PME characterized by progressive myoclonic epilepsy, proximal weakness, and lower motor neuron disease, as proven by electrodiagnostic studies. Genetic analysis identified two different mutations in the ASAH1 (NM_177924.4) gene, a previously reported pathogenic variant, c.125C>T (p.Thr42Met), and a novel likely pathogenic variant c.109C>A (p.Pro37Thr). In addition to reporting a novel pathogenic variant in the ASAH1 gene causing SMA-PME disease, this study compares the signs, phenotypic, and genetic findings of the case series with previous reports and discusses some symptomatic treatments.


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        • Prior T.W.
        • Leach M.E.
        • Finanger E.
        Spinal muscular atrophy summary GeneReview scope.
        GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2022., 2020: 1-30
        • Menkes J.H.
        • Sarnat H.B.
        Diseases of the motor unit.
        (Menkes, JH SH, editors)Child neurology. 6th ed. Philadelphia: Lippincott Williams and Wilkins, 2000: 1027-1092
        • Verhaart I.E.C.
        • Robertson A.
        • Wilson I.J.
        • Aartsma-Rus A.
        • Cameron S.
        • Jones C.C.
        • et al.
        Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review.
        Orphanet J Rare Dis. 2017; 12: 124
        • Topaloglu H.
        • Melki J.
        Spinal muscular atrophy associated with progressive myoclonus epilepsy.
        Epileptic Disord. 2016; 18: 128-134
        • Yu F.P.S.
        • Amintas S.
        • Levade T.
        • Medin J.A.
        Acid ceramidase deficiency: farber disease and SMA-PME.
        Orphanet J Rare Dis. 2018; 13: 121
        • Koch J.
        • Gärtner S.
        • Li C.M.
        • Quintern L.E.
        • Bernardo K.
        • Levran O.
        • et al.
        Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase. Identification Of the first molecular lesion causing Farber disease.
        J Biol Chem. 1996; 271: 33110-33115
        • Rubboli G.
        • Veggiotti P.
        • Pini A.
        • Berardinelli A.
        • Cantalupo G.
        • Bertini E.
        • et al.
        Spinal muscular atrophy associated with progressive myoclonic epilepsy: a rare condition caused by mutations in ASAH1.
        Epilepsia. 2015; 56: 692-698
        • Zhou J.
        • Tawk M.
        • Tiziano F.D.
        • Veillet J.
        • Bayes M.
        • Nolent F.
        • et al.
        Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1.
        Am J Hum Genet. 2012; 91: 5-14
        • Fattahi Z.
        • Beheshtian M.
        • Mohseni M.
        • Poustchi H.
        • Sellars E.
        • Nezhadi S.H.
        • et al.
        Iranome: a catalog of genomic variations in the Iranian population.
        Hum Mutat. 2019; 40: 1968-1984
        • Shervin Badv R.
        • Nilipour Y.
        • Rahimi-Dehgolan S.
        • Rashidi-Nezhad A.
        • Ghahvechi Akbari M.
        A novel case report of spinal muscular atrophy with progressive myoclonic epilepsy from Iran.
        Int Med Case Rep J. 2019; Volume 12: 155-159
        • Teoh H.L.
        • Solyom A.
        • Schuchman E.H.
        • Mowat D.
        • Roscioli T.
        • Farrar M.
        • et al.
        Polyarticular arthritis and spinal muscular atrophy in acid ceramidase deficiency.
        Pediatrics. 2016; 138
        • Lee B.H.
        • Mongiovi P.
        • Levade T.
        • Marston B.
        • Mountain J.
        • Ciafaloni E.
        Spinal muscular atrophy and Farber disease due to ASAH1 variants: a case report.
        Am J Med Genet Part A. 2020; 182: 2369-2371
        • Yildiz E.P.
        • Yesil G.
        • Bektas G.
        • Caliskan M.
        • Tatlı B.
        • Aydinli N.
        • et al.
        Spinal muscular atrophy with progressive myoclonic epilepsy linked to mutations in ASAH1.
        Clin Neurol Neurosurg. 2018; 164: 47-49
        • Axente M.
        • Shelby E.S.
        • Mirea A.
        • Sporea C.
        • Badina M.
        • Padure L.
        • et al.
        Clinical features and genetics in non-5q spinal muscular atrophy caused by acid ceramidase deficiency.
        J Med Life. 2021; 14: 424-428
        • Radhakrishnan D.M.
        • Shree R.
        • Madhaw G.
        • Manchanda R.
        • Mahadevan A.
        • Kumar N.
        Spinal muscular atrophy and progressive myoclonic epilepsy: a rare association.
        J Neurosci Rural Pract. 2021; 12: 210-212
        • Dyment D.A.
        • Bennett S.A.L.
        • Medin J.A.
        • Levade T.
        ASAH1-related disorders.
        GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022., 2018 (Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, et al., editors., Seattle (WA))
        • Filosto M.
        • Aureli M.
        • Castellotti B.
        • Rinaldi F.
        • Schiumarini D.
        • Valsecchi M.
        • et al.
        ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a clinical, biochemical and molecular study.
        Eur J Hum Genet. 2016; 24: 1578-1583
        • Walia J.S.
        • Neschadim A.
        • Lopez-Perez O.
        • Alayoubi A.
        • Fan X.
        • Carpentier S.
        • et al.
        Autologous transplantation of lentivector/acid ceramidase-transduced hematopoietic cells in nonhuman primates.
        Hum Gene Ther. 2011; 22: 679-687
        • Yeager A.M.
        • Uhas K.A.
        • Coles C.D.
        • Davis P.C.
        • Krause W.L.
        • Moser H.W.
        Bone marrow transplantation for infantile ceramidase deficiency (Farber disease).
        Bone Marrow Transpl. 2000; 26: 357-363
        • Pattali R.
        • Mou Y.
        • Li X.J.
        AAV9 vector: a novel modality in gene therapy for spinal muscular atrophy.
        Gene Ther. 2019; 26: 287-295
        • Chaytow H.
        • Faller K.M.E.
        • Huang Y.T.
        • Gillingwater T.H.
        Spinal muscular atrophy: from approved therapies to future therapeutic targets for personalized medicine.
        Cell Rep Med. 2021; 2100346