FXN – Friedreich Ataxia

Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, dysarthria, areflexia, and frequent hypertrophic cardiomyopathy. It is caused by deficient expression of the mitochondrial protein frataxin, encoded by the FXN gene. Most patients are homozygous for an expanded GAA trinucleotide repeat in intron 1 of FXN, which leads to transcriptional silencing and mitochondrial iron overload. The tight correlation between GAA repeat size, decreased frataxin levels, and age of onset underlies the clinical predictability of the disorder (PMID:9989622).

Approximately 4% of patients are compound heterozygotes, carrying a GAA expansion on one allele and a point mutation on the other. A novel initiation codon mutation, c.3G>A (p.Met1Ile), was identified in a 6-year-old patient with ~1,000 GAA repeats on the other allele, highlighting the necessity of sequencing when atypical presentations arise (PMID:10913738). Missense mutations such as c.389G>T (p.Gly130Val) are associated with a milder phenotype, including retained reflexes and slow progression, demonstrating genotype–phenotype correlations (PMID:11843702).

Segregation analyses in multiple consanguineous and pseudodominant families confirm autosomal recessive inheritance. In one cohort of 221 probands (196 expansion homozygotes and 25 compound heterozygotes), frataxin variants segregated with disease in multiplex families, with complete penetrance in homozygous individuals (PMID:9989622).

Frataxin functions as an allosteric activator of the mitochondrial iron–sulfur (Fe-S) cluster assembly complex. In vitro, frataxin binds the mitochondrial processing peptidase (MPP), and missense variants such as p.Gly130Val and p.Ile154Phe impair frataxin maturation, slowing conversion to the mature form (PMID:9700204). Yeast complementation studies demonstrate that human frataxin restores mitochondrial iron homeostasis in yfh1Δ strains, confirming functional conservation (PMID:11030757).

In mouse models, transduction of a TAT-frataxin fusion protein into cardiomyocytes and neurons increases lifespan, improves cardiac output, and rescues enzyme activities, illustrating therapeutic potential of protein replacement (PMID:22113996). Furthermore, inducible frataxin knockdown mice develop reversible motor deficits and cardiomyopathy, indicating that early intervention can reverse pathology (PMID:29257745).

Clinical diagnosis relies on detection of GAA expansions by PCR and sequencing of FXN coding exons to identify point mutations in atypical cases. Frataxin methylation assays can confirm heterozygous expansions when PCR is inconclusive (PMID:36635061). Comprehensive genetic testing informs prognosis, guides cascade testing, and supports emerging therapies. Key take-home: FXN genetic testing combined with functional assays enables precise diagnosis of Friedreich ataxia and underpins development of targeted treatments.

References

• Journal of the Neurological Sciences • 1999 • Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes PMID:9989622
• Pediatric Neurology • 2000 • Mutation detection in an equivocal case of Friedreich's ataxia PMID:10913738
• Archives of Neurology • 2002 • Intrafamilial phenotypic variability in Friedreich ataxia associated with a G130V mutation in the FRDA gene PMID:11843702
• Human Molecular Genetics • 1998 • Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase PMID:9700204
• Human Molecular Genetics • 2000 • Human frataxin maintains mitochondrial iron homeostasis in Saccharomyces cerevisiae PMID:11030757
• Human Molecular Genetics • 2012 • A TAT-frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich's ataxia mouse model PMID:22113996
• eLife • 2017 • Inducible and reversible phenotypes in a novel mouse model of Friedreich's Ataxia PMID:29257745
• Journal of Medical Genetics • 2023 • FXN gene methylation determines carrier status in Friedreich ataxia PMID:36635061

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