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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2018

Open Access 01-12-2018 | Research

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

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

Published in: Orphanet Journal of Rare Diseases | Issue 1/2018

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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.
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Literature
1.
Coleman JA, Kwok MC, Molday RS. Localization, purification, and functional reconstitution of the P4-ATPase Atp8a2, a phosphatidylserine flippase in photoreceptor disc membranes. J Biol Chemi. 2009;284(47):32670–9.CrossRef
2.
3.
Holthius JC, Levine TP. Lipid traffic: floppy drives and a superhighway. Nat Rev Mol Cell Biol. 2005;6:209–20.CrossRef
4.
Andersen JP, Vestergaard AL, Mikkelsen SA, et al. P4-ATPases as phospholipid flippases – structure, function and enigmas. Frontiers Physiol. 2016;7:275.CrossRef
5.
Bull LN, Van Eijk MJ, Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet. 1998;18:219–24.CrossRefPubMed
6.
Cacciagli P, Haddad MR, Mignon-Ravix C, et al. Disruption of the ATP8A2 gene in a patient with a t(10;13) de novo balanced translocation and a severe neurological phenotype. Eur J Hum Genet. 2010;18:1360–3.CrossRefPubMedPubMedCentral
7.
Zhu X, Libby RT, de Vries WN, et al. Mutations in a P-type ATPase gene cause axonal degeneration. PLoS Genet. 2012;8(8)
8.
Onat OE, Gulsuner S, Bilguvar K, et al. Missense mutation in the ATPase, amino phospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion. Eur J Hum Genet. 2013;21:281–5.CrossRefPubMed
9.
Martin-Hernandez E, Rodriguez-Garcia ME, Camacho A, et al. New ATP8A2 gene mutations associated with a novel syndrome: encephalopathy, intellectual disability, severe hypotonia, chorea and optic atrophy. Neurogenetics. 2016;17:259–63.CrossRefPubMed
10.
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:e45–66.CrossRef
11.
12.
DePristoMA BE, Poplin R, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M, McKenna A, Fennell TJ, Kernytsky AM, Sivachenko AY, Cibulskis K, Gabriel SB, Altshuler D, Daly MJ. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491–8.CrossRef
13.
Retterer K, Scuffins J, Schmidt D, Lewis R, Pineda-Alvarez D, Stafford A, Schmidt L, Warren S, Gibellini F, Kondakova A, Blair A, Bale S, Matyakhina L, Meck J, Aradhya S, Haverfield E. Assessing copy number from exome sequencing and exome array CGH based on CNV spectrum in a large clinical cohort. Genet Med. 2015;17(8):623–9.CrossRefPubMed
14.
15.
16.
OMIM Online Mendelian Inheritance in Man. In: McKusick-Nathans Institute of Genetic Medicine JHM, National Human Genome Research Institute, editor. An online catalog of human genes and genetic disorders. Baltimore, MD.
17.
Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014;42(Database issue):D980–5.CrossRefPubMed
18.
Schultz TC, Young HY, Agulnick AD, et al. A scalable system for production of functional pancreatic progenitors from human embryonic stem cells. PLoS One. 2012;7(5):e37004.CrossRef
19.
Rezania A, Bruin JE, Arora P, et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol. 2014;32(11):1121–33.CrossRefPubMed
20.
Krentz NA, Nian C, Lynn FC. TALEN/CRISPER-mediated eGFP knock-in add-on at the OCT4 locus does not impact differentiation of human embryonic stem cells towards endoderm. PLoS One. 2014;9(12):e114275.CrossRefPubMedPubMedCentral
21.
Coleman JA, Zhu X, Djajadi HR, et al. Phospholipid flippase ATP8A2 is required for normal visual and auditory function and photoreceptor and spiral ganglion cell survival. J Cell Sci. 2014;127:1138–49.CrossRefPubMedPubMedCentral
22.
Vestergaard AL, Coleman JA, Lemmin T, et al. Critical roles of isoleucine-364 and adjacent residues in a hydrophobic gate control of phospholipid transport by the mammalian P4-ATPase ATP8A2. Proc Natl Acad Sci U S A. 2014;111(14):1334–43.CrossRef
Metadata
Title
Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy
Authors
Hugh J. McMillan
Aida Telegrafi
Amanda Singleton
Megan T. Cho
Daniel Lelli
Francis C. Lynn
Julie Griffin
Alexander Asamoah
Tuula Rinne
Corrie E. Erasmus
David A. Koolen
Charlotte A. Haaxma
Boris Keren
Diane Doummar
Cyril Mignot
Islay Thompson
Lea Velsher
Mohammadreza Dehghani
Mohammad Yahya Vahidi Mehrjardi
Reza Maroofian
Michel Tchan
Cas Simons
John Christodoulou
Elena Martín-Hernández
Maria J. Guillen Sacoto
Lindsay B. Henderson
Heather McLaughlin
Laurie L. Molday
Robert S. Molday
Grace Yoon
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2018
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-018-0825-3

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