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Publication . Article . 2018

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

Hugh J. McMillan; Aida Telegrafi; Amanda Singleton; Megan T. Cho; Daniel A Lelli; Francis C. Lynn; Julie Griffin; +23 Authors
Open Access
Published: 01 May 2018 Journal: Orphanet Journal of Rare Diseases, volume 13 (eissn: 1750-1172, Copyright policy )
Publisher: BioMed Central
Country: Netherlands

Background 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. Methods An 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. Results Eleven 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. Conclusions 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. 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. Electronic supplementary material The online version of this article (10.1186/s13023-018-0825-3) contains supplementary material, which is available to authorized users.

Subjects by Vocabulary

Microsoft Academic Graph classification: Chorea medicine.symptom medicine Pediatrics medicine.medical_specialty Exome sequencing Movement disorders Choreoathetosis Gene mutation Dystonia medicine.disease business.industry business Atrophy Hypotonia

Library of Congress Subject Headings: lcsh:Medicine lcsh:R


Research, ATP8A2, Phospholipid transfer protein, Optic atrophy, Chorea, Choreoathetosis, Dystonia, Developmental disabilities, Whole exome sequencing, Adenosine Triphosphatases, Brain, Cognitive Dysfunction, Humans, Magnetic Resonance Imaging, Muscle Hypotonia, Mutation, Phospholipid Transfer Proteins, Exome Sequencing, Pharmacology (medical), Genetics (clinical), General Medicine

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Funded by
  • Funder: Canadian Institutes of Health Research (CIHR)
NWO| XCiDE: Crossing the Combustion modes in Diesel Engines
  • Funder: Netherlands Organisation for Scientific Research (NWO) (NWO)
  • Project Code: 2300153186
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01EY002422-23
  • Funding stream: NATIONAL EYE INSTITUTE
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