ATP8A2 was first reported in relation to autosomal recessive cerebellar ataxia, intellectual disability, and disequilibrium syndrome (CAMRQ) in 2018 (Alsahli S, et al., PMID: 29531481). Phenotypic features reported in affected individuals include ataxia, hypotonia, and intellectual impairment. Other features include absent deep tendon reflexes, hyperreflexia, speech and language delays, dysarthria, inability to walk, ataxic gait, and dyskinetic quadriplegia, with some individuals presenting with quadrupedal locomotion. Atrophy of the cerebral, cerebellar, and corpus callosum is also observed. Hearing loss is noted in some individuals, while eye-related issues include nystagmus, optic atrophy, retinal degeneration, blepharoptosis, and ptosis.
Nine variants (missense, nonsense and frameshift) reported in eight probands in six publications (PMIDs: 38109455, 35321980, 33079427, 29531481, 39066872, 30012219) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function, with the phenotypic severity depending on the protein's localization and protein misfolding (PMID: 38436085).
This gene-disease relationship is also supported by experimental evidence such as a mouse model. In Zhu et al, ATP8A2 was identified to be the causative gene in Wabbler-lethal mutant mice presenting with axonal degeneration (PMID: 22912588). RT-PCR analysis revealed ATP8A2 is widely expressed in the cerebrum, cerebellum, spinal cord and retina. The study also demonstrated that ATP8A2 is a phospholipid translocase, and the mutant protein failed to retain its function (PMID: 22912588).
In summary, there is definitive evidence to support the relationship between ATP8A2 and autosomal recessive cerebellar ataxia, intellectual disability, and dysequilibrium (CAMRQ). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on April 3, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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