ATP8A2 – Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome type 4

ATP8A2 encodes a P4-ATPase critical for phospholipid translocation in neurons. Biallelic ATP8A2 variants cause cerebellar ataxia, intellectual disability, and dysequilibrium syndrome type 4 (CAMRQ4), characterized by early-onset hypotonia, movement disorders, and cerebellar atrophy. The gene–disease link is supported by human case series, segregation in multiple families, and concordant functional and animal model data.

Inheritance is autosomal recessive. Over 32 unrelated patients from at least 10 families harbor biallelic missense, in-frame deletion, and splice-site variants in ATP8A2, all presenting with global developmental delay and cerebellar dysfunction (>32 probands) ([PMID:30012219]). Segregation studies in consanguineous and non-consanguineous pedigrees confirm recessive inheritance patterns, with at least 18 additional affected relatives showing homozygosity or compound heterozygosity for ATP8A2 variants.

The recurrent in-frame deletion c.1286_1288del (p.Lys429del) was identified homozygous in an Iranian family and tracked over a 7-year period, segregating perfectly with disease status and correlating with stable cerebellar atrophy on imaging ([PMID:39931767]). This variant expands the allelic series, which includes missense changes such as c.1128C>G (p.Ile376Met) that abolish ATPase activity despite normal expression levels ([PMID:30012219]).

Functional assays demonstrate that many CAMRQ4-associated variants misfold or degrade rapidly, resulting in loss of phosphatidylserine-activated ATPase function. For example, p.Ile376Met and p.Lys429Met localize to Golgi-endosomes but lack enzymatic activity ([PMID:31397519]), while mouse wabbler-lethal Atp8a2 knockouts recapitulate progressive ataxia and neurodegeneration due to loss of flippase function ([PMID:22912588]). In silico stability predictions correlate with misfolding and loss-of-function phenotypes for catalytic-domain variants ([PMID:38436085]).

No studies dispute a pathogenic role; common variants with preserved ATPase function (e.g., p.Glu459Gln) are considered benign. Taken together, the genetic and experimental data fulfill ClinGen criteria for a definitive gene–disease relationship.

Key Take-home: ATP8A2 testing is clinically actionable for early diagnosis of CAMRQ4, guiding prognostic counseling and potential future proteostasis-based therapies.

References

• Molecular genetics & genomic medicine • 2025 • Reevaluation of the Impact of the Novel Likely Pathogenic Variant c.1286_1288delAGA in the ATP8A2 Gene [PMID:39931767]
• Orphanet journal of rare diseases • 2018 • Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy [PMID:30012219]
• PLoS genetics • 2012 • Mutations in a P-type ATPase gene cause axonal degeneration [PMID:22912588]
• 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]

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