PRDX3 – Spinocerebellar Ataxia, Autosomal Recessive 32

Peroxiredoxin 3 (PRDX3) encodes a mitochondrial thioredoxin-dependent hydroperoxidase essential for reactive oxygen species (ROS) detoxification in neurons. Biallelic PRDX3 variants have been linked to autosomal recessive spinocerebellar ataxia type 32 (SCAR32), a childhood-onset, slowly progressive cerebellar ataxia often accompanied by cerebellar atrophy and variable brainstem involvement ([PMID:37553803]).

Six unrelated probands across four families have been reported ([PMID:35766882]; [PMID:37553803]; [PMID:38837640]). These include an infantile-onset case homozygous for c.489C>G (p.Asp163Glu) ([PMID:35766882]), three simplex cases homozygous for c.604G>A (p.Asp202Asn) ([PMID:37553803]), and two adolescent males compound heterozygous for c.525_535del (p.Leu176TrpfsTer11) and c.425C>G (p.Ala142Gly) ([PMID:38837640]).

All variants segregate in an autosomal recessive pattern with carrier parents and no affected relatives beyond the index cases. The variant spectrum comprises missense substitutions impairing active‐site or stability (p.Asp163Glu, p.Asp202Asn, p.Ala142Gly) and a frameshift truncation (p.Leu176TrpfsTer11).

Clinically, affected individuals present with early gait instability and limb ataxia progressing over years, with magnetic resonance imaging consistently showing cerebellar atrophy ([PMID:37553803]). Peripheral neuropathy may occur in infantile‐onset cases ([PMID:35766882]).

Functional studies demonstrate that p.Asp163Glu leads to PRDX3 misfolding, aggregation, reduced mitochondrial ROS defense, and unfolded protein stress in patient fibroblasts and primary neurons ([PMID:35766882]). A prdx3 “crispant” zebrafish model recapitulates motor impairment, heightened apoptosis in response to ROS, and reduced oxygen consumption rate, supporting a loss-of-function mechanism ([PMID:38837640]).

No conflicting reports have been published to date. Together, genetic and experimental data support a moderate clinical validity for the PRDX3–SCAR32 association. PRDX3 sequencing should be considered in children and adolescents with unexplained cerebellar ataxia and cerebellar atrophy.

References

• Annals of clinical and translational neurology • 2023 • Pure cerebellar ataxia due to bi-allelic PRDX3 variants including recurring p.Asp202Asn. PMID:37553803
• Human molecular genetics • 2022 • Protein misfolding and clearance in the pathogenesis of a new infantile onset ataxia caused by mutations in PRDX3. PMID:35766882
• Annals of clinical and translational neurology • 2024 • SCAR32: Functional characterization and expansion of the clinical-genetic spectrum. PMID:38837640

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