Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy

David A. Koolen,Alexander Asamoah,Aida Telegrafi,Lindsay B. Henderson,Francis C. Lynn,Charlotte A. Haaxma,Robert S. Molday,John Christodoulou,Cyril Mignot,Boris Keren,Reza Maroofian,Corrie E. Erasmus,Michel Tchan,Cas Simons,Grace Yoon,María J. Guillen Sacoto ,Diane Doummar,Tuula Rinne,Elena Martín‐Hernández ,Mohammadreza Dehghani,Islay Thompson,Lea Velsher,Laurie L. Molday,Hugh J. McMillan,Julie Griffin,Mohammad Yahya Vahidi Mehrjardi,Amanda Singleton,Heather McLaughlin,Megan T. Cho,Daniel Lelli

doi:10.1186/s13023-018-0825-3

Abstract

BackgroundATP8A2 mutations have recently been described in several patients with severe, early-onset hypotonia and cognitive impairment. The aim of our study was to characterize the clinical phenotype of patients with ATP8A2 mutations.MethodsAn observational study was conducted at multiple diagnostic centres. Clinical data is presented from 9 unreported and 2 previously reported patients with ATP8A2 mutations. We compare their features with 3 additional patients that have been previously reported in the medical literature.ResultsEleven patients with biallelic ATP8A2 mutations were identified, with a mean age of 9.4 years (range 2.5–28 years). All patients with ATP8A2 mutations (100%) demonstrated developmental delay, severe hypotonia and movement disorders, specifically chorea or choreoathetosis (100%), dystonia (27%) and facial dyskinesia (18%). Optic atrophy was observed in 78% of patients for whom funduscopic examination was performed. Symptom onset in all (100%) was noted before 6 months of age, with 70% having symptoms noted at birth. Feeding difficulties were common (91%) although most patients were able to tolerate pureed or thickened feeds, and 3 patients required gastrostomy tube insertion. MRI of the brain was normal in 50% of the patients. A smaller proportion was noted to have mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Functional studies were performed on differentiated induced pluripotent cells from one child, which confirmed a decrease in ATP8A2 expression compared to control cells.ConclusionsATP8A2 gene mutations have emerged as the cause of a novel neurological phenotype characterized by global developmental delays, severe hypotonia and hyperkinetic movement disorders, the latter being an important distinguishing feature. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation in older children. Early recognition of the cardinal features of this condition will facilitate diagnosis of this complex neurologic disorder.

Highlights

ATP8A2 mutations have recently been described in several patients with severe, early-onset hypotonia and cognitive impairment
ATP8A2 gene mutations have emerged as the cause of a novel neurological phenotype characterized by global developmental delays, severe hypotonia and hyperkinetic movement disorders, the latter being an important distinguishing feature
ATP8A2 has been linked to a phenotype of intellectual disability, severe hypotonia, chorea and optic atrophy without obvious radiographic evidence of cerebellar atrophy [6, 9, 10]

Summary

Introduction

ATP8A2 mutations have recently been described in several patients with severe, early-onset hypotonia and cognitive impairment. The aim of our study was to characterize the clinical phenotype of patients with ATP8A2 mutations. 14 P4-ATPases (flippases) have been identified, only two genes (ATP8A2 and ATP8B1) have been associated with human disease [1, 5]. Mutations in ATP8A2 were initially identified in a family with a clinical phenotype of cerebellar ataxia, mental retardation and disequilibrium (CAMRQ syndrome) [8]. ATP8A2 has been linked to a phenotype of intellectual disability, severe hypotonia, chorea and optic atrophy without obvious radiographic evidence of cerebellar atrophy [6, 9, 10]

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