Clinical and molecular assessment of a spastic ataxia 4 (SPAX4) patient with a novel variant in the MTPAP gene, and a systematic review

Abstract

Spastic ataxia (SPAX) is a heterogeneous neurodegenerative disorder characterized by the simultaneous occurrence of spastic paraplegia and cerebellar ataxia, making the diagnosis and classification challenging. Genetically, SPAX is categorized into subtypes SPAX1-10. Mutations in the MTPAP gene lead to SPAX4 and some other neurological diseases. This gene encodes an enzyme with a key role in polyadenylation of mitochondrial mRNAs. Here, during whole-exome sequencing of an Iranian HSP cohort, we identified the first Iranian SPAX4 case, and fifth globally with a novel MTPAP variant. We also performed a systematic review based on the PRISMA 2020 guidelines to catalog all known MTPAP variants and assess the clinical and genetic profiles of all identified cases. A novel variant, c.1072C > T in the MTPAP gene was identified and confirmed within the family using Sanger sequencing. The systematic review in four major databases for articles on MTPAP variants identified 12 MTPAP variants linked to various phenotypes. By comparing the obtained results, clinical and genetic heterogeneity was evident in the MTPAP-related disorders. Our findings significantly broaden the clinical and molecular landscape of MTPAP-related variants, extending beyond the confines of SPAX4. Due to the rarity of these diseases, considerable knowledge gaps persist regarding their underlying mechanisms and the implicated gene. Consequently, our research endeavors may facilitate the elucidation of pertinent biological pathways and the development of potential therapies.