A novel missense variant in the ATPase domain of ATP8A2 and review of phenotypic variability of ATP8A2 -related disorders caused by missense changes.

ATPase, class 1, type 8A, member 2 (ATP8A2) is a P4-ATPase with a critical role in phospholipid translocation across the plasma membrane. Pathogenic variants in ATP8A2 are known to cause cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) which is often associated with encephalopathy, global developmental delay, and severe motor deficits. Here, we present a family with two siblings presenting with global developmental delay, intellectual disability, spasticity, ataxia, nystagmus, and thin corpus callosum. Whole exome sequencing revealed a homozygous missense variant in the nucleotide binding domain of ATP8A2 (p.Leu538Pro) that results in near complete loss of protein expression. This is in line with other missense variants in the same domain leading to protein misfolding and loss of ATPase function. In addition, by performing diffusion-weighted imaging, we identified bilateral hyperintensities in the posterior limbs of the internal capsule suggesting possible microstructural changes in axon tracts that had not been appreciated before and could contribute to the sensorimotor deficits in these individuals.