Familial Episodic Encephalopathy, Dysarthria, and Paralysis Is Associated with a Dominantly Inherited Mutation in ATP1A3 (P4.335)

OBJECTIVE: To describe a distinct clinical phenotype in a family with childhood onset atypical alternating hemiplegia (AHC) caused by a mutation in ATP1A3 gene. BACKGROUND: AHC is a rare sporadic disease and the most typical presentation includes recurrent hemiparesis, dystonia and delayed development. ATP1A3, a subunit of the sodium/potassium-ATPase, has been found to be mutated de novo in more than 75 percent of AHC cases. Allelic mutations in the same gene cause rapid-onset-dystonia-parkinsonism (RDP or DYT12). DESIGN/METHODS: We studied a three-generation family of four patients presenting with recurrent episodes of encephalopathy and slow recovery with residual ataxia and speech impairment. Genetic analysis of the ATP1a3 gene was performed by Sanger sequencing. RESULTS: The female siblings were 2-3 years old at the initial illness described as possible focal febrile seizure followed by quadriparesis or hemiparesis, mutism, and dysphagia. These symptoms have improved slowly with residual ataxia and speech impairment. Serum and CSF studies were negative for infections and metabolic parameters. The brain MRI/MRS studies showed no pathology. However, sequencing of ATP1A3 gene in the sisters and their mother revealed a hemizygous mutation previously reported in RDP syndrome. CONCLUSIONS: We present a three-generation family with an atypical alternating hemiplegia phenotype (weakness, dysarthria, encephalopathy and ataxia) caused by a missense mutation in the ATP1A3 gene. The same sporadic mutation was associated with a sporadic case of RDP. The neurological condition appears to stabilize in adulthood. This unique presentation further expands the phenotypic spectrum associated with mutations in ATP1A3. Disclosure: Dr. Acsadi has received personal compensation for activities with Athena Diagnostics. Dr. Acsadi has received research support from the National Institutes of Health, Muscular Dystrophy Association, and FSMA as an investigator. Dr. Young has nothing to disclose. Dr. Newcomb has nothing to disclose. Dr. Nelson has nothing to disclose. Dr. Viollet has nothing to disclose. Dr. Swoboda has received research support from BioMarin Pharmaceuticals, and Orphamed.