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

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.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0825-3) contains supplementary material, which is available to authorized users.

Expression and functional characterization of missense mutations in ATP8A2 linked to severe neurological disorders

“…Although these two categories of mutations display significant differences in levels of protein expression, they both can be considered as loss‐in‐function mutations since neither category displayed phospholipid activated ATPase activity. This is in agreement with clinical studies in which patients with these different missense mutations all show similar severe neurological phenotypes as found in patients homozygous for premature stop codons and frameshift mutations in the ATP8A2 gene (Alsahli et al, ; Martín‐Hernández et al, ; McMillan et al, ; Onat et al, ).…”

“…To date, seven missense mutations in ATP8A2 have been reported to cause severe neurological disorders in humans (Alsahli et al, ; Martín‐Hernández et al, ; McMillan et al, ). These include p.K429M, p.K429N, and p.W702R mutations in the phosphorylation domain (P domain), p.A544P and p.R625W mutations in the nucleotide‐binding domain (N domain), and the p.I376M and p.N917D mutations in the membrane domain of ATP8A2 (Figure a).…”

“…Although severe neurological phenotypes including hypotonia, cognitive impairment, and hyperkinetic movement disorders have been observed in all reported patients with mutations in ATP8A2 , some phenotypic traits such as progressive optic atrophy, hearing loss, dystonia, and cerebral and cerebellar atrophy were only observed in some patients (McMillan et al, ). Variations in these clinical features do not appear to be associated with differences in the activity of the ATP8A2 variants since all mutations result in a loss‐in‐function protein.…”

“…Genetic analysis of four members of a consanguineous Turkish family led to the discovery that a p.Ile376Met (p.I376M) mutation in ATP8A2 caused cerebellar ataxia, mental retardation, and disequilibrium (CAMRQ) syndrome (Onat et al, ). More recently, missense, nonsense, and splice‐site mutations have been found in individuals with intellectual disability, severe hypotonia, chorea, hyperkinetic movement disorders, and optic atrophy with or without cerebellar atrophy (Alsahli, Alrifai, Al Tala, Mutairi, & Alfadhel, ; Cacciagli et al, ; Martín‐Hernández et al, ; McMillan et al, ).…”

Identification and functional analyses of disease-associated P4-ATPase phospholipid flippase variants in red blood cells

“…A third class of ATP-independent phospholipid transporters, scramblases, when active, serve to dissipate phospholipid asymmetry, a process important in such cellular processes as blood coagulation, apoptosis, and phagocytosis (9,10). The importance of phospholipid transporters in generating, maintaining, and dissipating lipid asymmetry is evident in the finding that loss-in-function mutations in these transporters have been linked to severe human and rodent disorders, including anemia, blood clotting dysfunction, cholestasis, neurodegenerative diseases, sensory disorders, and ataxia among others (11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”