ATP8A2 – Cerebellar Ataxia, Intellectual Disability, and Dysequilibrium Syndrome 4

ATP8A2 encodes a P4-ATPase essential for phospholipid translocation at the plasma membrane. Biallelic pathogenic variants in ATP8A2 underlie cerebellar ataxia, intellectual disability, and dysequilibrium syndrome type 4 (CAMRQ4), an autosomal recessive neurodevelopmental disorder characterized by global developmental delay, severe hypotonia, ataxia, spasticity, nystagmus, and thin corpus callosum (MONDO:0014104).

Inheritance is autosomal recessive with segregation confirmed in multiple consanguineous families. A cohort of 17 affected individuals from three Saudi families demonstrated homozygous or compound heterozygous ATP8A2 variants with segregation in all available relatives (17 probands)[PMID:29531481]. Subsequent reports include 11 patients with nine novel loss-of-function alleles (11 probands)[PMID:30012219] and an expanded review of 32 patients across diverse populations (32 probands)[PMID:33079427].

The variant spectrum comprises missense changes clustering in the ATP-binding and actuator domains, canonical splice-site mutations, frameshifts, and nonsense alleles. Representative variants include c.1110C>G (p.Tyr370Ter) causing premature truncation ([PMID:29531481]) and the novel nucleotide-binding domain change c.1612T>C (p.Leu538Pro) associated with near-absent ATP8A2 expression ([PMID:38798571]). No recurrent founder variant has been established to date.

Functional assays in patient-derived cells and heterologous systems consistently show severe protein misfolding, endoplasmic reticulum retention, and loss of phosphatidylserine-activated ATPase activity for most missense variants. Proteasome inhibition rescues expression of several alleles (e.g., p.Ile376Met, p.Lys644Thr)[PMID:31397519], whereas in silico/biophysical studies validate misfolding of G447R and A772P but exclude E459Q from pathogenicity ([PMID:38436085]). A murine wabbler-lethal model confirms that Atp8a2 loss causes axon degeneration analogous to human CAMRQ4 ([PMID:22912588]).

No convincing conflicting reports have emerged; all described alleles in ATP8A2 share concordant genotype-phenotype correlations and pathogenic mechanisms. Experimental and clinical data span >10 years, with replication in multiple centers and diverse populations.

Integrating genetic and functional findings supports a definitive gene–disease relationship. ATP8A2 sequencing and copy-number analysis should be prioritized in patients with early‐onset ataxia, intellectual disability, and dysequilibrium. Key take-home: ATP8A2 loss-of-function underlies CAMRQ4 through a recessive mechanism, with consistent clinical features and robust functional validation.

References

• Journal of central nervous system disease • 2018 • Further Delineation of the Clinical Phenotype of Cerebellar Ataxia, Mental Retardation, and Disequilibrium Syndrome Type 4 PMID:29531481
• Orphanet Journal of Rare Diseases • 2018 • Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy PMID:30012219
• Journal of clinical laboratory analysis • 2020 • A novel homozygous variant in an Iranian pedigree with cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4 PMID:33079427
• Human Mutation • 2019 • Expression and functional characterization of missense mutations in ATP8A2 linked to severe neurological disorders PMID:31397519
• Disease Models & Mechanisms • 2024 • Functional and in silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases PMID:38436085
• medRxiv • 2024 • A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability of ATP8A2-related disorders caused by missense changes PMID:38798571
• PLoS Genetics • 2012 • Mutations in a P-type ATPase gene cause axonal degeneration PMID:22912588

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