Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME): three new cases and review of the mutational spectrum

Abstract Background Spinal muscular atrophy (SMA) could be classified as 5q and non-5q, based on the chromosomal location of causative genes. A rare form of non-5q SMA is an autosomal-recessive condition called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), phenotypically characterized by myoclonic and generalized seizures with progressive neurological deterioration. SMA-PME is a clinically heterogeneous disorder that arises from biallelic pathogenic variants in ASAH1 gene. Methods Following clinical and primary laboratory assessments, whole-exome sequencing was performed to detect the disease-causing variants in three cases of SMA-PME from different families. Also, Multiplex ligation-dependent probe amplification (MLPA) was employed for determining the copy numbers of SMN1 and SMN2 genes to rule out 5q SMA. Results Exome sequencing revealed two different homozygous missense mutations (c.109 C > A [p.Pro37Thr] or c.125 C > T [p.Thr42Met]) in exon 2 of the ASAH1 gene in the affected members of the families. Sanger sequencing of the other family members showed the expected heterozygous carriers. In addition, no clinically relevant variant was identified in patients by MLPA. Conclusion This study describes two different ASAH1 mutations and the clinical picture of 3 SMA-PME patients. In addition, previously reported mutations have been reviewed. This study could help to fortify the database of this rare disease with more clinical and genomic data.