Developmental Delay And Seizures With Or Without Movement Abnormalities

A number sign (#) is used with this entry because of evidence that developmental delay and seizures with or without movement abnormalities (DEDSM) is caused by heterozygous mutation in the DHDDS gene (608172) on chromosome 1p36.

Description

DEDSM is a neurodevelopmental disorder characterized by global developmental delay, variable intellectual disability, and early-onset seizures with a myoclonic component. Most patients have delayed motor development and show abnormal movements, including ataxia, dystonia, and tremor (summary by Hamdan et al., 2017).

Clinical Features

Hamdan et al. (2017) reported 5 unrelated patients with global developmental delay and seizures. Four of the patients were between 5 and 7 years of age, and 1 was 35. All had global developmental delay, with moderate to severe intellectual disability. Four patients had mildly delayed walking and all had delayed speech; 1 girl was nonverbal at age 4. One patient showed normal early development with only hypotonia until about 2 years of age when global delay became apparent. The patients had onset of variable myoclonic seizures in the first decade of life (between 1 and 7 years). Seizure types included absence, eyelid myoclonus, isolated cortical myoclonus, and others. The seizures were difficult to control in most patients, and EEG, when performed, usually showed generalized spike-wave discharges. Two unrelated patients showed seizure sensitivity to light and fever. Additional more variable features included hypotonia, ataxia, tremor, dystonia, and short stature. The 35-year-old man had abnormal movements, including myokymia, bradykinesia, hypomimia, rigidity, freezing, and impaired postural reactions. Brain imaging was normal, except in 1 patient who had a Chiari I malformation. Two patients specifically studied had normal glycosylation assays.

Molecular Genetics

In 5 unrelated patients with DEDSM, Hamdan et al. (2017) identified 2 different de novo heterozygous missense mutations in the DHDDS gene (R37H, 608172.0002 and R211Q, 608172.0003). The mutations were found by whole-exome or whole-genome sequencing of several cohorts of patients with developmental delay and epilepsy. Studies of patient cells and functional studies of the variants were not performed, but Hamdan et al. (2017) postulated a gain-of-function or dominant-negative effect.