DHDDS variants in epilepsy and movement disorders: Two novel mutations and an updated literature review

Recent evidence suggests that dehydrodolichol diphosphate synthase (DHDDS, MIM*608,172) gene variation can cause neurological diseases. However, the complete clinical and genetic spectrum of DHDDS-related disorders has not been fully elucidated. This study aims to systematically describe the clinical and genetic features of five patients with molecularly confirmed DHDDS variants and to provide an updated review of previously reported cases.

We retrospectively enrolled patients with DHDDS gene variants in the Epilepsy Center of Beijing Tiantan Hospital, Capital Medical University from 2021 to 2023. Clinical, neuroimaging, electrophysiological and genetic data were collected. Whole‑exome sequencing and Sanger validation were performed for variant identification and ACMG‑based classification. PubMed was searched using the term "DHDDS" to identify previously reported cases. The clinical and genetic characteristics of the eligible cases were summarized descriptively.

Five patients in our hospital with two novel DHDDS variants (c.623G>A, p.G208E and c.697C>A, p.P233T) were reported. A total of 74 patients (3 from our center and 71 from the literature) carrying pathogenic or likely pathogenic variants were collected for the final analysis. The most prevalent variants were c.632G>A (p.R211Q, n = 26, 35.14%), c.110G>A (p.R37H, n = 16, 21.62%), c.109C>T (p.R37C, n = 9, 12.16%), and c.614G>A (p.R205Q, n = 9). The most common clinical manifestations included epilepsy (n = 64, 86.49%), intellectual disability (n = 62, 83.78%), ataxia (n = 50, 67.57%), global developmental delay (n = 50, 67.57%), tremor (n = 48, 64.86%), and myoclonus (n = 44, 59.46%). No significant phenotypic differences were observed among patients carrying different variants.

This study expanded the phenotypic spectrum of diseases related to DHDDS and reported two new variations. For cases of developmental epileptic encephalopathy of unknown cause, progressive myoclonus or complex movement disorders, DHDDS gene screening should be considered.