MTPAP – Spastic Ataxia

MTPAP has been robustly implicated in spastic ataxia, a neurodegenerative disorder manifesting as cerebellar ataxia coupled with spastic paraplegia. The association is supported by detailed case reports and multi‐patient systematic reviews that highlight both a diverse mutational spectrum and familial segregation. In the index study, a novel variant was identified in an Iranian SPAX4 patient, representing the fifth reported case globally (PMID:40174712). This clinical observation was further reinforced by a systematic review that catalogued 12 unique MTPAP variants across various affected individuals. Such convergent genetic findings, together with confirmatory segregation analysis using Sanger sequencing, underscore the reliability of these observations. Overall, these data provide strong grounds for considering MTPAP mutations as causative in spastic ataxia.

The genetic evidence is exemplified by the autosomal recessive inheritance pattern observed in SPAX4. Affected individuals in the reported family have been confirmed to carry the pathogenic variant, supporting familial segregation. Although explicit counts of additional affected relatives are limited, the replication of these findings across unrelated probands further solidifies the genetic link. The observed variant spectrum, which includes the c.1072C>T (p.Arg358Trp) mutation, reinforces the loss‐of‐function impact on the encoded mitochondrial poly(A) polymerase. Additionally, the systematic review across diverse cohorts highlights the recurring genetic theme in these patients. Such uniformity in genetic findings is pivotal in diagnostic decision‑making.

The novel variant c.1072C>T (p.Arg358Trp) has emerged as a critical marker in the genetic analysis of SPAX4 patients. Identified through robust whole-exome sequencing and confirmed by familial Sanger sequencing, this variant provides a clear link between the genotype and the clinical phenotype (PMID:40174712). Multiple case reports have corroborated the pathogenicity of this specific alteration, contributing significantly to the overall genetic evidence. In addition to missense variants, the cumulative evidence from 12 MTPAP variants reinforces the concept of allelic heterogeneity in spastic ataxia. The aggregation of these data points yields a compelling genetic rationale that informs both clinical testing and subsequent family counseling. This clarity in the genetic architecture aids in defining the diagnostic boundaries for the disorder.

Functional evidence substantially augments the genetic findings. Investigations using fibroblast cell lines from affected individuals have demonstrated that the mutant mtPAP protein exhibits markedly reduced polyadenylation activity (PMID:25008111). These studies revealed that the mutated enzyme is unable to generate adequate oligo(A) tails on mitochondrial transcripts, leading to compromised transcript stability and mitochondrial dysfunction. Rescue experiments involving overexpression of wild‑type mtPAP effectively restored normal polyadenylation activity, thereby validating the loss‑of‑function mechanism. This experimental corroboration is well aligned with the clinical manifestations seen in spastic ataxia patients. Together, the in vitro assays provide a moderate yet convincing layer of functional evidence supporting the pathogenic role of MTPAP mutations.

Integrating the genetic and functional data, the overall gene-disease association for MTPAP in spastic ataxia is best classified as Strong. The combination of multiple, independent case reports, systematic identification of 12 distinct variants, and rigorous functional assays consolidates the diagnostic relevance of MTPAP mutations. While some gaps remain owing to the rarity of SPAX4, the current body of evidence exceeds typical ClinGen scoring thresholds in several aspects. This multi‑faceted validation is essential not only for clinical diagnostic precision but also for enabling commercial test development and advancing future therapeutic research. The coherent narrative provided by both genetic and experimental studies lays a solid foundation for the continued exploration of mitochondrial dysfunction in neurodegenerative disorders.

Key take‑home: MTPAP mutations represent a pivotal diagnostic marker for spastic ataxia, facilitating early detection and guiding targeted future therapies.

References

• Gene • 2025 • Clinical and molecular assessment of a spastic ataxia 4 (SPAX4) patient with a novel variant in the MTPAP gene, and a systematic review PMID:40174712
• Human Molecular Genetics • 2014 • A human mitochondrial poly(A) polymerase mutation reveals the complexities of post‑transcriptional mitochondrial gene expression PMID:25008111

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