Novel mutations in ATP1A3 associated with catastrophic early life epilepsy, episodic prolonged apnea, and postnatal microcephaly

Abstract

Objective Mutations of ATP1A3 have been associated with Rapid Onset Dystonia-Parkinsonism and more recently with Alternating Hemiplegia of Childhood. Here we report one child with catastrophic early life epilepsy and shortened survival, and another with epilepsy, episodic prolonged apnea, postnatal microcephaly, and severe developmental disability. Novel heterozygous mutations (p.Gly358Val and p.Ile363Asn) were identified in ATP1A3 in these children. Methods Subjects underwent next-generation sequencing under a research protocol. Clinical data were collected retrospectively. The biochemical effects of the mutations on ATP1A3 protein function were investigated. Post-mortem neuropathologic specimens from control and affected subjects were studied. Results The mutations localized to the P domain of the Na,K-ATPase α3 protein, and resulted in significant reduction of Na,K-ATPase activity in vitro. We demonstrate in both control human brain tissue and that from the subject with the p.Gly358Val mutation that ATP1A3 immunofluorescence is prominently associated with interneurons in the cortex, which may provide some insight into the pathogenesis of the disease. Significance The findings indicate these mutations cause severe phenotypes of ATP1A3-related disorder spectrum that include catastrophic early life epilepsy, episodic apnea, and postnatal microcephaly.

Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes

“…ATP1A2 , together with ATP1A3 , belongs to a family of genes coding for catalytic subunits of Na/K‐ATPase. The relevance of these genes in genetic epilepsies is also supported by the report of a child with catastrophic early life epilepsy and shortened survival carrying a mutation in ATP1A3 [Paciorkowski et al., ].…”

Progressive Brain Atrophy in Alternating Hemiplegia of Childhood

“…After assessing the conventional brain MRI findings and genotypes of our patients, we have shown for the first time that similar abnormal findings exist in patients with severe deterioration. Progressive brain atrophy and cerebellar atrophy/ataxia have been reported in a spectrum of ATP1A3 ‐related disorders other than AHC …”

Novel pregnancy‐triggered episodes of CAPOS syndrome

“…Recently, sudden unexpected death in epilepsy, cardiac structural abnormalities, episodic prolonged apnea, and postnatal microcephaly have been reported in patients with ATP1A3 -related disorders (Dard et al, 2015; Paciorkowski et al, 2015; Rosewich et al, 2012; Rosewich, Weise, Ohlenbusch, Gärtner, and Brockmann, 2014). Atypical and overlapping features of AHC, RDP, and CAPOS syndrome with intermediate phenotypes have been reported in patients with novel variants p.Arg756His and p.Arg756Cys in ATP1A3 (Jaffer et al, 2017; Kanemasa et al, 2016).…”

“…Pathogenic variants in ATP1A3 have been implicated in a phenotypic spectrum of autosomal dominant disorders including Alternating Hemiplegia of Childhood (AHC, OMIM 614820), Rapid-onset Dystonia-Parkinsonism (RDP, OMIM 128235) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss syndrome (CAPOS syndrome, OMIM 601338) (de Carvalho Aguiar et al, 2004; Demos et al, 2014; Heinzen et al, 2014; Paciorkowski et al, 2015; Rosewich et al, 2012; Sweney, Newcomb, & Swoboda, 2015). Marked genetic heterogeneity exists for AHC and RDP, including possible genotype-phenotype correlation (Yang et al, 2014) and mosaicism (Hully et al, 2017).…”