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Orphanet J Rare Dis. 2018 May 31;13(1):86. doi: 10.1186/s13023-018-0825-3.

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

Author information

1
Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
2
GeneDx, Gaithersburg, MD, USA.
3
Division of Neurology, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada.
4
Diabetes Research Program, Child and Family Research Institute, Vancouver, BC, Canada.
5
Department of Surgery and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
6
Weisskopf Child Evaluation Center, Department of Pediatrics, School of Medicine, University of Louisville, Louisville, KY, USA.
7
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
8
Department of Neurology, Donders Center of Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
9
Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
10
Assistance Publique Hôpitaux de Paris, Département de Génétique, Groupe Hospitalier, Pitié-Salpêtrière, Paris, France.
11
Service de Neuropédiatrie, Hôpital Armand-Trousseau, Paris, France.
12
Centre de Référence Déficiences Intellectuelles de Causes Rares, GH Pitié Salpêtrière, Paris, France.
13
Groupe de Recherche Clinique UPMC Déficience Intellectuelle de Causes Rares et Autisme GH Pitié-Salpêtrière, Paris, France.
14
Genetics Program, North York General Hospital, Toronto, ON, Canada.
15
Medical Genetics Research Centre, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
16
Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
17
Diabetes Research Centre, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
18
Human Genetics Research Centre, Molecular and Clinical Sciences Institute, St George's University of London, London, UK.
19
Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, Australia.
20
Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
21
Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia.
22
Neurodevelopmental Genomics Research Group, Murdoch Childrens Research Institute and Department of Paediatrics, Melbourne Medical School, University of Melbourne, Melbourne, VIC, Australia.
23
Unidad de Enfermedades Mitocondriales-Metabólicas Hereditarias, Servicio de Pediatría Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain.
24
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada.
25
Department of Ophthalmology and Visual Sciences, Centre for Macular Research, University of British Columbia, Vancouver, BC, Canada.
26
Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. grace.yoon@utoronto.ca.
27
Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada. grace.yoon@utoronto.ca.

Abstract

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.

KEYWORDS:

ATP8A2; Chorea; Choreoathetosis; Developmental disabilities; Dystonia; Optic atrophy; Phospholipid transfer protein; Whole exome sequencing

PMID:
30012219
PMCID:
PMC6048855
DOI:
10.1186/s13023-018-0825-3
[Indexed for MEDLINE]
Free PMC Article

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