BCAP31 Mutation Causing Congenital Dystonia and Central Hypomyelination Discovered Using Exome Sequencing (P2.232)

Abstract

Objective To present two cases of congenital dystonia and central hypomyelination discovered by exome sequencing. Background A mutation in BCAP31 was recently described in 3 families with strabismus, optic atrophy, deafness, congenital dystonia, and central hypomyelination. Lack of BCAP31 protein function disrupts endoplasmic reticulum (ER) metabolism, and causes disorganization of Golgi. It impacts ER-to-Golgi crosstalk and results in impaired protein trafficking. Design/Methods Two male siblings (18 and 21 yo) presented with poor head control and hypotonia at 2 months of age, strabismus and optic pallor at 4 months of age, and choreoathetotic/dyskinetic movements at 6-12 months of age that progressed to dystonia. Both had severe motor and language delay, sensorineural hearing loss, facial dysmorphism and neither could walk. The mother had similar facial features, but no neurological or cognitive problems. Both patients had minimal response to levodopa, pimozide, trihexyphenidyl, clonidine, baclofen, clonazepam, and tetrabenazine. Work up including inborn error screen, urine, blood, CSF studies and electrophysiologic studies were unremarkable. MRI brain revealed delayed myelination, decreased gray/white matter in posterior occipital lobes, hypoplasia of the superior cerebellar vermis and thinning of the corpus callosum. Genetic work up including subtelomeric FISH, screening for MERRF, MELAS, NARP, and Leigh’s mutations was negative. Non-random X- inactivation in studies of maternal DNA suggested X linked transmission. Results Exome sequencing was performed on the entire family.Both patients were found to have a 6 base-pair deletion in BCAP31 at Xq28, and the mother and patient’s sister were carriers. Conclusion This reports 2 patients in the same family affected by a recently diagnosed X linked disorder characterized by dystonia, deafness and central hypomyelination. This 6 base pair deletion in the BACP31 gene is expected to alter function of the protein. It highlights the clinical features of mutation in BCAP31 and the utility of exome sequencing to obtain diagnosis.

Disclosure: Dr. Vittal has nothing to disclose. Dr. Hall has nothing to disclose. Dr. Berry-Kravis has received personal compensation for activities with Seaside Therapeutics, Novartis, Roche, Neuren Pharmaceuticals, and Alcobra Pharma as a consultant.