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

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.

Fig. 1

a Severe bilateral optic atrophy on direct funduscopic examination. b Optical coherence tomography (OCT) reveals relatively thinning of the inner retinal layers suggestive of optic atrophy of those neuronal elements. Outer retinal layers (OPL, ONL) are less affected. RPE = retinal pigmented epithelium; ONL = outer nuclear layer; OPL = outer plexiform layer, RNFL = retinal nerve fiber layer; GCL = ganglion cell layer; IPL inner plexiform layer

Fig. 2

ATP8A2 expression in gut endoderm cells differentiated from patient and control fibroblasts. a ATP8A2 RNA expression levels were determined by Taqman qPCR; data were normalized to TBP and are expressed as an average +/− SEM for n = 4. b Representative western blots of foregut endodermal cell lysates, differentiated from control or patient induced pluripotent stem cells, and labeled for ATP8A2 and actin (loading control). c Quantification of ATP8A2 protein expression from western blots expressed as an average +/-SEM for n = 4. P values ** are ≤0.01