ARX-associated infantile epileptic-dyskinetic encephalopathy with responsiveness to valproate for controlling seizures and reduced activity of muscle mitochondrial complex IV

Abstract

Background: ARX genetic defect is associated with a spectrum of neurodevelopmental disorders that exhibit a high degree of phenotypic heterogeneity. Methods: We studied a family with a 13-year old Chinese boy and his two elder brothers presented with infantile epileptic-dyskinetic encephalopathy and clarified the unknown genetic etiology of the youngest brother by whole exome sequencing. Results: The youngest brother of this family presented with developmental regression, dystonia, epilepsy, microcephaly, visual impairment and oromotor dysfunction. Hyperlactataemia, raised alanine and muscle complex IV deficiency indicated that he had mitochondrial dysfunction. Likely pathogenic hemizygous missense ARX variants (c.989G>A; p.Arg330His) located in conserved nuclear localization sequence was identified. The variant was carried by his asymptomatic mother and not found in his asymptomatic third elder brother. The intractable seizures showed complete but transient responsiveness to pyridoxal phosphate and finally controlled by valproate treatment. Conclusion: This is the first case of ARX-associated encephalopathy showing mitochondrial dysfunction and transient responsiveness to pyridoxal phosphate treatment.