Adult-onset KMT2B-related dystonia
Edoardo Monfrini, Andrea Ciolfi, Francesco Cavallieri, Marco Ferilli, Paola Soliveri, Lucia Pedace, Roberto Erro, Francesca Del Sorbo, Franco Valzania, Valentina Fioravanti, Giovanni Cossu, Maria Pellegrini, Leonardo Salviati, Federica Invernizzi, Valentina Oppo, Daniela Murgia, Bruno Giometto, Marina Picillo, Barbara Garavaglia, Francesca Morgante, Marco Tartaglia, Miryam Carecchio, Alessio Di Fonzo
Abstract
Abstract KMT2B-related dystonia (DYT-KMT2B, also known as DYT28) is an autosomal dominant neurological disorder characterized by varying combinations of generalized dystonia, psychomotor developmental delay, mild-to-moderate intellectual disability and short stature. Disease onset occurs typically before 10 years of age. We report the clinical and genetic findings of a series of subjects affected by adult-onset dystonia, hearing loss or intellectual disability carrying rare heterozygous KMT2B variants. Twelve cases from five unrelated families carrying four rare KMT2B missense variants predicted to impact protein function are described. Seven affected subjects presented with adult-onset focal or segmental dystonia, three developed isolated progressive hearing loss, and one displayed intellectual disability and short stature. Genome-wide DNA methylation profiling allowed to discriminate these adult-onset dystonia cases from controls and early-onset DYT-KMT2B patients. These findings document the relevance of KMT2B variants as a potential genetic determinant of adult-onset dystonia and prompt to further characterize KMT2B carriers investigating non-dystonic features.