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Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy
Copyright policy )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.
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
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
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
- University of Ottawa (Université dOttawa) Canada
- University of Melbourne Australia
- Westmead Hospital Australia
- University of Sydney Australia
- University of Louisville United States
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Martin-Hernandez, E, Rodriguez-Garcia, ME, Camacho, A. New ATP8A2 gene mutations associated with a novel syndrome: encephalopathy, intellectual disability, severe hypotonia, chorea and optic atrophy. Neurogenetics. 2016; 17: 259-263 [OpenAIRE] [PubMed] [DOI]
Quintas, S, Moldovan, O, Proenca dos Santos, T, Levy, A. New syndrome associated with ATP8A2 gene mutations: encephalopathy, intellectual disability, severe hypotonia, chorea and optic atrophy; whole exome sequencing role in the diagnosis of new diseases. Eur J Paediatr Neurol. 2017; 21: e45-e66 [OpenAIRE] [DOI]
- Canadian Institutes of Health Research (CIHR)
- Netherlands Organisation for Scientific Research (NWO) (NWO)
- 2300153186
- National Institutes of Health (NIH)
- 5R01EY002422-23
- NATIONAL EYE INSTITUTE
- University of Ottawa (Université dOttawa) Canada
- University of Melbourne Australia
- Westmead Hospital Australia
- University of Sydney Australia
- University of Louisville United States
- Shahid Sadoughi University of Medical Sciences Iran (Islamic Republic of)
- University of Queensland Australia
- University of Toronto Canada
- Universtity of Sydney Australia
- North York General Hospital Canada
- North York General Hospital Canada
- St George's, University of London United Kingdom
- University of Ottawa Canada
- Assistance Publique -Hopitaux De Paris France
- Shahid Sadoughi University of Medical Science Iran (Islamic Republic of)
- University of Queensland Australia
- Hôpital Armand Trousseau France
- University of British Columbia Canada
- Child and Family Research Institute Canada
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.