ASAH1 Mutation in a Boy with Non-5q SMA and Progressive Myoclonic Epilepsy

Introduction: Spinal muscular atrophies (SMA) represent a clinically and genetically heterogeneous group of lower motor neuron diseases, most frequently caused by mutations in the SMN1 gene (5q SMA). Recently, mutations in ASAH1 were found to be responsible for a rare and distinct phenotype of SMA associated with progressive myoclonic epilepsy (PME). Here, we report on the case of a 14-year-old boy with non 5q-SMA who later suffered from severe and drug-resistant myoclonic epilepsy.

Case Report: Born to consanguineous, Turkish parents after an uneventful pregnancy, the boy showed normal early developmental milestones and was able to walk at the age of 12 months. First physical examination at the age of 3 years revealed proximal weakness and muscular atrophy, reduced deep tendon reflexes, and fasciculations of the tongue. CK was normal and SMN gene deletion study was negative. EMG and a muscle biopsy showed a denervation process, spinal and brain MRI were normal. By the age of 9 years, the patient developed respiratory insufficiency and noninvasive ventilation was started. At the age of 12 years, he began to have myoclonic and generalized seizures and the EEG demonstrated intensive epileptiform activity with bilateral spike and slow waves. To date, the epilepsy is progressive and resistant to therapy and mental functions deteriorate. Neurometabolic work-up revealed no abnormalities. Finally, molecular genetic analysis disclosed a homozygous mutation in ASAH1 (c.125C > T).

Conclusion: SMA associated with PME in childhood (SMA–PME) represents a rare clinical and genetic entity caused by ASAH1 mutations. Therefore, the occurrence of myoclonic seizures in a patient with SMA-like phenotype and negative SMN gene deletion test should result in molecular genetic analysis of the ASAH1 gene.

Keywords: ASAH1 mutation, spinal muscular atrophy, progressive myoclonic epilepsy.