Atypical phenotypes caused by the ATP1A3 variant p.P775L (1946)

Objective: To describe atypical phenotypes associated with the p.P775L variant of ATP1A3, the gene encoding the alpha subunit of the Na/K-ATPase.

Background: ATP1A3 variants cause three distinct phenotypes, namely alternating hemiplegia of childhood (AHC), rapid onset dystonia-parkinsonism (RDP) and cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS). The spectrum of ATP1A3-related disease has recently expanded to include fever-induced paroxysmal weakness and encephalopathy (FIPWE) and catastrophic early life epilepsy. While spastic diplegia has been described in AHC and RDP, it has not been reported as isolated ATP1A3-related phenotype.

Design/Methods: One patient was identified at Texas Children’s Hospital by exome sequencing through Baylor Genetics Laboratories. Three additional patients were identified by querying GeneDx’s database for patients with the variant. Variants were confirmed by Sanger sequencing. Clinical data was collected from clinicians.

Results: Two patients had only developmental delay, mild intellectual disability and spastic diplegia. One also had sickle cell disease and had progressive gait deterioration triggered by pain crises. A third patient exhibited developmental delay, mild intellectual disability, spastic diplegia, hypotonia, epilepsy, and failure to thrive. Neither dystonia nor parkinsonism were observed in these patients. A fourth patient was developmentally normal until sixteen months of age when he had a febrile illness and prolonged episode of apnea and abnormal movements. He subsequently had severe static encephalopathy, microcephaly, spastic quadriplegia, epilepsy and dystonia. Two patients had de novo ATP1A3 variants. The other two patients’ fathers were not available for testing, but their mothers did not have the variant. The affected residue is highly conserved, and the variant is predicted to be deleterious with a CADD score of 34.

Conclusions: The p.P775L ATP1A3 variant causes developmental delay, spastic diplegia, epilepsy, and episodic neurological deterioration. Thus, ATP1A3 should be considered in the differential for diplegic cerebral palsy. These phenotypes are distinct from AHC and RDP.

Disclosure: Dr. Calame has nothing to disclose. Dr. Shinawi has nothing to disclose. Dr. Cohen has nothing to disclose. Dr. Person has nothing to disclose. Dr. Telegrafi has nothing to disclose. Dr. Lotze has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with He has served as a consultant/speaker for Biogen.. Dr. Lotze has received research support from PTC Therapeutics, Serepta Therapeutics and Catalyst Therapeutics. Dr. Yano has nothing to disclose. Dr. Regier has nothing to disclose.