ATP1A3 variants and slowly progressive cerebellar ataxia without paroxysmal or episodic symptoms in children

Abstract

Alternating hemiplegia of childhood CAPOS syndrome Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensory motor hearing loss A heterogeneous spectrum of clinical manifestations caused by mutations in ATP1A3 have been previously described. Here we report two cases of infantile-onset cerebellar ataxia, due to two different ATP1A3 variants. Both patients showed slowly progressive cerebellar ataxia without paroxysmal or episodic symptoms. Brain magnetic resonance imaging revealed mild cerebellar cortical atrophy in both patients. Whole exome sequencing revealed a de novo heterozygous variant in ATP1A3 in both patients. One patient had the c.460A>G (p.Met154Val) variant, while the other carried the c.1050C>A (p.Asp350Lys) variant. This phenotype was characterized by a slowly progressive cerebellar ataxia since the infantile period, which has not been previously described in association with ATP1A3 variants or in ATP1A3-related clinical conditions. Our report contributes to extend the phenotypic spectrum of ATP1A3 mutations, showing paediatric slowly progressive cerebellar ataxia with mild cerebellar atrophy alone as an additional clinical presentation of ATP1A3-related neurological disorders.

Chinese patients with p.Arg756 mutations of ATP1A3: Clinical manifestations, treatment, and follow‐up

“…Its dysfunction may lead to multiple impairments in the nervous system. 5 , 6 Mutations in ATPA13 result in diverse phenotypes (Figure S1 ), both classical (e.g., AHC, RDP, and CAPOS) and non‐classical (e.g., early infantile epileptic encephalopathy, 7 RECA, 2 FIPWE, 3 rapid‐onset cerebellar ataxia, 8 progressive cerebellar ataxia without paroxysmal or episodic symptoms, 9 and childhood‐onset schizophrenia/autistic spectrum disorder 10 ). RECA and FIPWE have been identified as distinct phenotypes associated with Arg756 mutations in ATP1A3 .…”

Pump-Opathies: Mutations in Na+–K+-ATPase Genes Produce Severe Developmental Epileptic Encephalopathies

“…4 Furthermore, it is now apparent that chronic and progressive disorders can also arise from ATP1A mutations. 5 The present article describes a previously underappreciated spectrum of severe developmental epileptic encephalopathies associated with ATP1A mutations and expands the underlying spectrum of neurological mechanisms in this range of disorders. 6 The authors report genotype-phenotype correlations in 22 patients with de novo or inherited heterozygous ATP1A2/3 mutations.…”

“… 4 Furthermore, it is now apparent that chronic and progressive disorders can also arise from ATP1A mutations. 5 …”

ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum

“…None of these patients presented with paroxysmal or episodic symptoms. One patient had the ATP1A3 p.Met154Val variant, while the other carried the p.Asp350Lys variant ( 59 ).…”