PMPCA – Autosomal Recessive Spinocerebellar Ataxia 2

Autosomal recessive spinocerebellar ataxia 2 (SCAR2) is a rare neurodegenerative disorder characterized by early‐onset progressive cerebellar ataxia, tremor, dysarthria and learning difficulties. It follows an autosomal recessive inheritance pattern with onset typically in childhood. SCAR2 has been linked to biallelic variants in the peptidase, mitochondrial processing subunit alpha gene PMPCA.

A single 12-year-old Saudi patient presented with progressive cerebellar ataxia, fine motor impairment, intentional tremor and slow slurred speech. Whole exome sequencing revealed a novel homozygous missense variant, c.802C>T (p.Arg268Trp), in PMPCA, confirmed by Sanger sequencing (PMID:39554679). The clinical phenotype closely matches previously described SCAR2 features.

No additional unrelated probands or familial segregation data have been reported for SCAR2, and only this single homozygous variant has been documented to date. The variant spectrum for SCAR2 remains limited to missense changes affecting the substrate binding and catalytic regions of MPPα.

Functional studies in patient-derived fibroblasts from a separate mitochondrial disease cohort demonstrated that pathogenic PMPCA variants reduce α‐MPP protein levels, impair mitochondrial precursor processing and frataxin maturation, and that these defects can be rescued by exogenous wild-type PMPCA cDNA (PMID:27148589). These data support a loss-of-function mechanism.

Integrating genetic and experimental findings, biallelic PMPCA variants cause SCAR2 through haploinsufficiency of the mitochondrial processing peptidase α‐subunit, leading to cerebellar neuron vulnerability. Further case collection and segregation studies are needed to strengthen the genetic evidence for this association.

Key Take-home: PMPCA c.802C>T (p.Arg268Trp) is a likely pathogenic variant for SCAR2; genetic testing and functional assays are critical for diagnosis.

References

• Pakistan Journal of Medical Sciences • 2024 • Clinical whole Exome Sequencing Reveals Novel Homozygous Missense Variant in the PMPCA Gene causing Autosomal Recessive Spinocerebellar Ataxia. PMID:39554679
• Cold Spring Harbor Molecular Case Studies • 2016 • Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease PMID:27148589

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