Abstract Details

Title Atypical phenotypes caused by the ATP1A3 variant p.P775L

Topic Child Neurology and Developmental Neurology

Presentation(s) P13 - Poster Session 13 (5:30 PM-6:30 PM)

Poster/Presentation
Number 5-010

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 ��ձ�1��3-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.

Authors/Disclosures
Daniel Calame, MD, PhD (Baylor College of Medicine, Child Neurology) PRESENTER	Dr. Calame has nothing to disclose.
	No disclosure on file
	No disclosure on file
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	No disclosure on file
Timothy E. Lotze, MD, F�鶹��ýӳ�� (Texas Children's Hospital)	Dr. Lotze has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Department of Justice VICP. The institution of Dr. Lotze has received research support from NIH. The institution of Dr. Lotze has received research support from National MS Society. The institution of Dr. Lotze has received research support from Sarepta Therapeutics. The institution of Dr. Lotze has received research support from PTC THERAPEUTICS. The institution of Dr. Lotze has received research support from Avexis. Dr. Lotze has received publishing royalties from a publication relating to health care. Dr. Lotze has received publishing royalties from a publication relating to health care.
Sho T. Yano, MD, PhD (University of Chicago)	Dr. Yano has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Wiley for the journal "Molecular Genetics and Genomic Medicine".
	No disclosure on file

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