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

• DOI: 10.1186/s13023-018-0825-3
• Publication Date: 2018-05-31T12:43:06Z
• 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 Dehg...; Mohammad Yahya Va...; Reza Maroofian; Michel Tchan; Cas Simons; John Christodoulou; Elena Martín-Hern...; Maria J. Guillen ...; Lindsay B. Henderson; Heather McLaughlin; Laurie L. Molday; Robert S. Molday; Grace Yoon
• Keywords: Lethargy; Movement Disorders; Global developmental delay

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 mutations.An observational conducted at multiple diagnostic centres. Clinical data is presented from 9 unreported 2 previously reported mutations. We compare their features 3 additional that medical literature.Eleven biallelic were identified, a mean age 9.4 years (range 2.5-28 years). All (100%) demonstrated developmental delay, severe movement disorders, specifically chorea or choreoathetosis (100%), dystonia (27%) facial dyskinesia (18%). Optic atrophy observed 78% for whom funduscopic examination performed. Symptom onset all noted before 6 months age, 70% having symptoms birth. Feeding difficulties common (91%) although most able tolerate pureed thickened feeds, required gastrostomy tube insertion. MRI brain normal 50% patients. A smaller proportion mild cortical (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Functional studies performed on differentiated induced pluripotent cells one child, which confirmed decrease expression compared control cells.ATP8A2 gene emerged as cause novel neurological characterized by global delays, hyperkinetic latter being an important distinguishing feature. may only become apparent first few life, necessitating repeat ophthalmologic evaluation older children. Early recognition cardinal this condition will facilitate diagnosis complex neurologic disorder.