Early-Onset Hyperkinetic Movement Disorders Define the Most Severe Presentation of the ATP8A2-Related Phenotypic...

Variants in ATP8A2 gene have been traditionally associated with cerebellar ataxia, mental retardation and disequilibrium syndrome type 4 (CAMRQ4). However, this nomenclature fails to capture the predominantly extrapyramidal and encephalopathic nature of the most severe presentation of the ATP8A2-related phenotypic spectrum. We report two siblings with a novel homozygous ATP8A2 frameshift variant (p.Ser839Glyfs*21) presenting with a complex neurodevelopmental encephalopathy. Their phenotype was characterized by very early-onset hyperkinetic movement disorders, including chorea, dystonia and myoclonus, accompanied by optic atrophy and sensorineural hearing loss. A critical literature review suggests that the profound neuromotor impairment in these patients often precludes an accurate assessment of ataxia, while hyperkinetic movements predominate. The multisystem involvement (ophthalmoplegia, ptosis and sensory loss) frequently mimics mitochondrial disorders, further complicating the diagnostic path. We argue that the current OMIM classification is restrictive and clinically misleading. We therefore propose formally revising the clinical definition of ATP8A2-related disorders to emphasize early-onset complex encephalopathy with movement disorders, rather than ataxia, as the hallmark of severe cases. Integrating ATP8A2 into next-generation sequencing (NGS) panels for early-onset hyperkinesia is essential to ensure prompt diagnosis and resolve the diagnostic odyssey.