Episodic weakness, cerebellar ataxia, deafness and optic atrophy - a new phenotype of a novel ATP1A3 mutation

Introduction: Todelineate the molecular basis for a novel genetic syndrome in a mother and hertwo children. The syndrome is characterized by infantile acute onset severe muscleweakness episodes, ataxia , remitting gradually but recur and became permanentin adulthood associated with acquired permanent areflexia, progressive sensorineuralhearing loss and optic atrophy. Methods:Sequencingthe mitochondrial DNA and sequencing and MLPA of the OPA1 gene were applied toexclude mitochondrial disease in general and OPA1 plus related diseasespecifically which were suggestive by inheritance pattern and the involvedsystems. Whole exome sequencing was performed on all patients and Sangersequencing was subsequently used to verify the mutation in the patients andasses segregation within the family.Results:Wholeexome sequencing revealed a previously unreported E818K mutation in the ATP1A3gene in all three patients. Sanger sequencing confirmed mutation presence inthe patients and its absence in all nine unaffected family members that werechecked. Conclusion:ATP1A3gene was implicated in the last decade as the causative gene of two distinctdiseases - rapid onset dystonia parkinsonism (RDP) and alternating hemiplegiaof childhood (AHC). The clinicalpresentation in the family described in here differs significantly from thesetwo diseases by the predominance of ataxia rather than extrapyramidal movementdisorder that prevail in DRP and AHC and by the peripheral neural systeminvolvement (e.g weakness, areflexia, hearing loss and optic nerve pallor ).We conclude that ATP1A3 mutation is the cause of a novel distinct ADgenetic syndrome.