PI4K2A deficiency in an intellectual disability, epilepsy, myoclonus, akathisia syndrome

Abstract

We report a family of Saudi Arabian ancestry with two children presenting with global developmental delay, dystonia, disturbed sleep, and heat intolerance. By genome sequencing, we identified a nonsense variant in the first exon of PI4K2A that was homozygous in both affected individuals and was absent from, or heterozygous in, seven unaffected siblings. PI4K2A is highly expressed in the brain and a mouse model displays a neurological phenotype, implicating PI4K2A as a new disease gene for a neurological disorder.

Novel defect in phosphatidylinositol 4‐kinase type 2‐alpha (PI4K2A) at the membrane‐enzyme interface is associated with metabolic cutis laxa

“…Based on the presentation in our patient, the patients described by Alkhater et al 17 and the previously characterised mice model we define a novel metabolic defect in the phosphatidylinositol pathway, presenting with a severe neurologic phenotype and expanding the existing phenotype with cutis laxa. Further work is needed to investigate how this might be relevant to the patient's clinical presentation.…”

“…The male siblings described by Alkhater et al 17 presented with subtle facial dysmorphism at birth, but showed a normal development till the age of 5 to 6 months. From that age global developmental delay, dystonia, visual inattentiveness and loss of acquired skills were noted.…”

“…16 Recently two siblings, with complete loss of function of PI4K2A, leading to intellectual disability, epilepsy, myoclonus and akathisia, have been described. 17…”

“…In terms of human disease, changes in PI4K2A expression, possibly due to gene copy number variations, have been reported in breast cancer 14,15 and advanced glioblastoma 16 . Recently two siblings, with complete loss of function of PI4K2A, leading to intellectual disability, epilepsy, myoclonus and akathisia, have been described 17 …”

Recent genetic advances in early-onset dystonia

“…They shared a homozygous nonsense variant in P14K2A, a gene involved in membrane trafficking and neuronal survival. 23 Although the pathogenicity of this variant is plausible, it cannot be considered proven in the absence of either a second affected family or extensive functional analysis.…”