Objective: To investigate underlying pathomechanisms of DYT/PARK-ATP1A3 in Japanese patient with rapid-onset dystonia-parkinsonism (RDP).

Background: Mutations in ATP1A3 would lead to development of various neurological and psychological disorders, including RDP, alternating hemiplegia of childhood (AHC), cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), and schizophrenia. Further elucidation of genotype-phenotype correlations would contribute to better understanding of pathomechanisms of ATP1A3 related disorders. AHC is sporadically reported in Japan, however RPD has not been reported thus fur. We analyzed genes in a novel Japanese boy with RPD, who presented neonatal seizures and attention deficit hyperkinetic disorder (ADHD) in childhood, in order to investigate the genotype-phenotype correlation in Japanese patients of ATP1A3 gene related neurological disorder.

Methods: A 17-year-old Japanese boy with RDP was investigated clinically and genetically. Target resequencing of dystonia genes based on phenomenological assessments was conducted. Biological effects by nucleotide variation were predicted using bioinformatic tools and confirmed by reverse transcription polymerase chain reaction experiment. He was also subjected to neuroimaging and electrophysiological analyses.

Results: A novel 3-bp in-frame deletion mutation, c.886-888del (p.Phe296del), was identified in ATP1A3 [figure1]. Neurological features, including distribution and extension of dystonia, were consistent with those previously reported. Abnormal slow waves with small sharp in the bilateral frontal and central areas were observed in electroencephalogram [figure2]. Intelligence disabilities, especially in verbal comprehension, was detected in Wechsler Intelligence Scale for Children -Ⅳ. Mild hypoperfusion in the left putamen and cerebellum was demonstrated in eZIS analysis of 99mTc=ECD SPECT study. Frequency was decreased in memory guided saccade, reflecting the possible disability in dopaminergic function in basal ganglia. The clinical features suggested pervasive encephalopathy with DYT12, and additionally the history of neonatal seizures and ADHD supported the presence of broad cortical involvement.

Conclusions: Broad cerebral regions can be impaired in DYT/PARK-ATP1A3.

References: 1) Sweney MT, Newcomb TM, Swoboda KJ. The expanding spectrum of neurological phenotypes in children with ATP1A3 mutations, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia-Parkinsonism, CAPOS and beyond. Pediatr Neurol. 52(1):56-64,2015. 2) Termsarasab P, Yang AC, Frucht SJ.Intermediate Phenotypes of ATP1A3 Mutations: Phenotype–Genotype Correlations. Tremor Other Hyperkinet Mov (N Y). 5: 336, 2015.

« Back to 2018 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/encephalopathy-in-a-japanese-patient-with-rapid-onset-dystonia-parkinsonism-carrying-a-novel-atp1a3-mutation/