A novel de novo mutation inATP1A3and childhood-onset schizophrenia

Abstract

We describe a child with onset of command auditory hallucinations and behavioral regression at 6 yr of age in the context of longer standing selective mutism, aggression, and mild motor delays. His genetic evaluation included chromosomal microarray analysis and whole-exome sequencing. Sequencing revealed a previously unreported heterozygous de novo mutation c.385G>A in ATP1A3, predicted to result in a p.V129M amino acid change. This gene codes for a neuron-specific isoform of the catalytic α-subunit of the ATP-dependent transmembrane sodium–potassium pump. Heterozygous mutations in this gene have been reported as causing both sporadic and inherited forms of alternating hemiplegia of childhood and rapid-onset dystonia parkinsonism. We discuss the literature on phenotypes associated with known variants in ATP1A3, examine past functional studies of the role of ATP1A3 in neuronal function, and describe a novel clinical presentation associated with mutation of this gene.

The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease

“…Although the three syndromes were originally identified as phenotypically distinct, it has become clear that many patients do not strictly fall into one category or the other, but may have symptoms that fall on a continuous spectrum as well as unique symptoms for individual mutations (Rosewich et al, 2014; Paciorkowski et al, 2015; Sweney et al, 2015; Kanemasa et al, 2016; Liu et al, 2016; Smedemark-Margulies et al, 2016; Sweadner et al, 2016). …”

Childhood-Onset Schizophrenia: A Systematic Overview of Its Genetic Heterogeneity From Classical Studies to the Genomic Era

“…In total, 32 candidate genes have been described on 12 autosomes (1, 2, 3, 6, 7, 8, 11, 13, 15, 17, 19, and 22) and 1 sex chromosome (X) (Tables 1 and 2) through the following studies (Addington et al, 2004;Sekizawa et al, 2004;Gornick et al, 2005;Addington et al, 2005;Addington et al, 2007;Pakhomova et al, 2010;Addington et al, 2011;Raznahan et al, 2011;Smedemark-Margulies et al, 2016;Chaumette et al, 2018;Ambalavanan et al, 2019):…”

“…Finally, five studies by DNA sequencing (candidate genes or whole exome sequencing) have allowed identifying the following 18 mutations in 11 genes (Addington et al, 2011;Ambalavanan et al, 2016;Smedemark-Margulies et al, 2016;Chaumette et al, 2018;Ambalavanan et al, 2019). i.…”

Nosology and Phenomenology of Psychosis in Movement Disorders

“…In this condition, both hallucinations and paranoid delusions have been reported, usually associated with other psychiatric conditions, such as depression, panic disorder, social phobia, obsessive‐compulsive disorder, and alcohol dependence or abuse, but not with cognitive decline . In rapid‐onset dystonia‐parkinsonism caused by mutations in the ATP1A3 gene (DYT/PARK‐ATP1A3), psychotic symptoms may present before or concurrently with motor symptom onset or even in the absence of dystonia or parkinsonism . In other conditions, like secondary dystonia, dystonic features may be comorbid with the exacerbation or onset of psychotic symptoms …”

“…[138][139][140][141] In rapid-onset dystonia-parkinsonism caused by mutations in the ATP1A3 gene (DYT/ PARK-ATP1A3), psychotic symptoms may present before or concurrently with motor symptom onset 142 or even in the absence of dystonia or parkinsonism. 143 In other conditions, like secondary dystonia, dystonic features may be comorbid with the exacerbation or onset of psychotic symptoms. 144…”