APTX – Ataxia with Oculomotor Apraxia Type 1

Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive neurodegenerative disorder characterized by early-onset cerebellar ataxia, oculomotor apraxia, hypoalbuminemia, hypercholesterolemia and peripheral neuropathy. The disease is caused by biallelic pathogenic variants in the aprataxin gene (APTX). AOA1 corresponds to MONDO:0008842 (Ataxia with oculomotor apraxia type 1).

Genetic evidence supports a definitive gene–disease relationship: more than 40 unrelated probands from at least 20 distinct families have been reported with autosomal recessive inheritance and segregation of APTX variants (PMID:11170899; PMID:15596775). The variant spectrum includes nonsense (e.g., c.559C>T (p.Gln187Ter)), frameshift and missense alleles distributed across the coding sequence. Consanguineous pedigrees and compound heterozygotes further confirm recessive segregation in approximately 10 additional affected relatives (PMID:23183622; PMID:32750061).

Clinically, patients present in childhood with progressive cerebellar ataxia (HP:0001251), oculomotor apraxia (HP:0000657), areflexia, peripheral axonal neuropathy (HP:0009830) and biochemical findings of hypoalbuminemia (HP:0003073) and hypercholesterolemia. Cognitive impairment and variable onset ages reflect allelic heterogeneity (PMID:36382100; PMID:36119692).

Functional assays demonstrate that aprataxin possesses AMP-lysine and GMP-lysine hydrolase activity essential for DNA single-strand break repair. Disease-associated mutations abrogate this enzymatic function, destabilize the protein, and delay repair kinetics in patient cells without altering ionizing radiation sensitivity (PMID:15790557).

Further studies reveal that aprataxin deficiency impairs mitochondrial biogenesis by downregulating the APE1/NRF1/NRF2 pathway, resulting in coenzyme Q10 deficiency and bioenergetic defects that are reversible by NRF2 upregulation (PMID:25976310).

Integration of genetic and functional data establishes a definitive association between APTX loss-of-function and AOA1 pathogenesis. APTX testing is essential for accurate diagnosis, genetic counseling and potential targeted therapies (e.g., CoQ10 supplementation).

References

• American Journal of Human Genetics • 2001 • Homozygosity mapping of Portuguese and Japanese forms of ataxia-oculomotor apraxia to 9p13, and evidence for genetic heterogeneity. PMID:11170899
• Neurology • 2004 • Ataxia with oculomotor apraxia type 1 in Southern Italy: late onset and variable phenotype. PMID:15596775
• Iranian Biomedical Journal • 2012 • A novel mutation in the aprataxin (APTX) gene in an Iranian individual suffering early-onset ataxia with oculomotor apraxia type 1(AOA1) disease. PMID:23183622
• PLoS One • 2020 • Identification of APTX disease-causing mutation in two unrelated Jordanian families with cerebellar ataxia and sensitivity to DNA damaging agents. PMID:32750061
• Experimental and Therapeutic Medicine • 2022 • Ataxia with oculomotor apraxia type 1 associated with mutation in the APTX gene: A case study and literature review PMID:36382100
• Frontiers in Neurology • 2022 • Case report: A novel APTX p.Ser168GlufsTer19 mutation in a Chinese family with ataxia with oculomotor apraxia type 1. PMID:36119692
• The Journal of Biological Chemistry • 2005 • Disease-associated mutations inactivate AMP-lysine hydrolase activity of Aprataxin. PMID:15790557
• Human Molecular Genetics • 2015 • Lack of aprataxin impairs mitochondrial functions via downregulation of the APE1/NRF1/NRF2 pathway. PMID:25976310

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