Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy: Report of New Cases and Review of the Literature

Abstract

Spinal muscular atrophy (SMA) is a clinically and genetically heterogeneous disease characterised by loss of motor function and muscle atrophy due to anterior horn cell degeneration. The most common variant is chromosome 5-linked proximal SMA, ranging in severity from congenital onset and infantile death to onset in adult life. Genetically separate variants with different distribution of weakness and/or additional features such as central nervous system involvement have been described. A rare variant with associated myoclonic epilepsy and lower motor neuron disease had been previously described in three families before the SMN gene, responsible for the common form of SMA, was isolated. We report four patients from two additional families affected by a syndrome characterised by severe and progressive myoclonic epilepsy and proximal weakness, tremor and lower motor neuron disease proven by electrophysiologic and muscle biopsy findings. Extensive metabolic investigations were normal and genetic analysis excluded the SMN gene. This study confirms that the association of myoclonic epilepsy and motor neuron disease represents a separate clinical and genetic entity from chromosome 5-linked SMA, the primary defect of which remains unknown.

ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a clinical, biochemical and molecular study

“…[5][6][7]15 Phenotype is considered clinically homogenous: patients develop progressive walking difficulties and frequent falls around age 5 and PME with slow and sharp bilateral waves of 3 to 4 cycles/s on EEG around age 7 (refs. 6,16) .…”

“…5,6 SMA-PME is an autosomal recessive condition characterized by muscle weakness and wasting and a combination of drug-resistant seizures and uncontrollable muscle jerks starting in childhood. [5][6][7] Variants causing SMA-PME result in reduced acid ceramidase activity (one-third of normal) and ceramide accumulation damaging cells less extensively than FL. 5,6 However, the disorder is progressive and patients die in the teenage years.…”

Spinal muscular atrophy associated with progressive myoclonic epilepsy: A rare condition caused by mutations in ASAH1

“…SMA‐PME is a rare condition that has been demonstrated recently to be linked to mutations in the ASAH1 gene . An overview of all patients reported in the literature, including those described before the discovery of the genetic cause, identifies as distinctive features: onset usually with proximal muscular weakness, later appearance of a generalized epilepsy with absences and myoclonic seizures, cognitive impairment of variable degree, and a progressive course. Epilepsy as first symptom, with early drug refractoriness and rapidly disabling, followed some years later by subtle muscular compromise was observed only in one patient .…”

“…A peculiar clinical picture characterized by the association of spinal muscular atrophy (SMA) and progressive myoclonic epilepsy (PME) was reported for the first time by Jankovic and Rivera, who described three subjects showing slight mental retardation, adult‐onset myoclonic epilepsy, and predominantly distal signs of SMA. Only a few individuals with a similar condition, inherited as an autosomal recessive trait, were published afterward . In most of these cases, SMN1 mutations were ruled out, suggesting that the association between SMA and PME (SMA‐PME) represented a separate clinical and genetic entity.…”

Uniparental disomy as a cause of spinal muscular atrophy and progressive myoclonic epilepsy: Phenotypic homogeneity due to the homozygous c.125C>T mutation in ASAH1

“…Early clinical reports depicted a heterogeneous syndrome with respect to age at onset, presenting symptoms, distribution of muscular atrophy and weakness, and prognosis. Additional associated neurological symptoms such as cognitive decline, sensorineural hearing loss, and bulbar or cerebellar involvement have been reported in some, but not all the patients [1][2][3][4][5]. While most of these patients lack a specific etiology, mutations in ASAH1, the gene encoding acid ceramidase, have been recently identified in 7 patients diagnosed as SMAPME [6,7].…”