Refractory myoclonic epilepsy and progressive movement disorder arising from recurrent DHDDS variants in Japanese...

Heterozygous DHDDS variants have been associated with intellectual disability and seizures, with or without movement disorders. We aimed to expand the known phenotypic spectrum of DHDDS-related disorders by elucidating the clinical characteristics of Japanese patients with recurrent DHDDS variants.

Patients with pathogenic DHDDS variants were recruited from individuals diagnosed with developmental and epileptic encephalopathy or progressive myoclonus epilepsies who were treated at the Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital, or the Department of Pediatrics, Osaka Metropolitan University Graduate School of Medicine. DHDDS pathogenic variants were identified using exome sequencing. Medical records and neurophysiological data were retrospectively reviewed.

Three de novo recurrent pathogenic DHDDS variants were identified in four patients: c.632G>A, p.(Arg211Gln) in two; c.614G>A, p.(Arg205Gln) in one; and c.110G>A, p.(Arg37His) in one. Three patients with p.(Arg211Gln) or p.(Arg37His) presented with severe intellectual disability and intractable generalized epilepsy, characterized by myoclonic, myoclonic-atonic, and atonic seizures. Eyelid myoclonia was the initial manifestation in infancy. One patient with p.(Arg205Gln) had a relatively mild course, with focal epilepsy and less severe intellectual disability. Myoclonus and tremor were present from infancy in two patients with p.(Arg211Gln) or p.(Arg37His), and from childhood in the patient with p.(Arg205Gln). One patient with p.(Arg211Gln) exhibited polymicrogyria in the right frontal lobe. Among the three patients with generalized epilepsy, fenfluramine effectively reduced myoclonic seizures in one, while total corpus callosotomy markedly reduced myoclonic-atonic or atonic seizures with falls in another.

DHDDS-related disorders should be considered in patients with intellectual disability, epilepsy with early-onset eyelid myoclonia and myoclonic or myoclonic-atonic seizures, and movement disorders, including myoclonus and tremor, with slow progression. We identified polymicrogyria as a novel finding in DHDDS patients. For drug-resistant epilepsy in these patients, corpus callosotomy and fenfluramine may represent promising treatment options, with this report providing specific insights into their efficacy.