Phenotype of heterozygous variants of dehydrodolichol diphosphate synthase

Abstract

Aim To further identify and broaden the phenotypic characteristics and genotype spectrum of the dehydrodolichol diphosphate synthase (DHDDS) gene. Method Pathogenic variants of DHDDS were identified by whole‐exome sequencing; clinical data of 10 patients (six males, four females; age range 2–14y; mean age 5y 9mo, SD 3y 3mo) were collected and analysed. Results All patients had seizures, and myoclonic seizures could be seen in eight patients, with myoclonic status epilepticus in three. The interictal electroencephalogram (EEG) in four patients at seizure onset showed generalized slow waves, slow wave mixed spikes, and spike and waves. Tremor, ataxia, and hypertonia was observed in six, five, and three patients respectively. The results of short‐latency somatosensory evoked potential in two patients were normal, and the symptom of tremor was captured on EEG without time‐locked discharges in one patient, suggesting that the tremor in both patients was a motor impairment rather than myoclonic seizures. Global developmental delay occurred in all patients, among whom nine showed severe intellectual disability and one moderate. Five DHDDS variants were identified, three of which have not been reported previously. Interpretation Myoclonic seizure is the most common seizure type in heterozygous DHDDS variants, while myoclonic status epilepticus can also occur. The pattern of interictal EEG discharges is characterized by slow waves rather than spike and waves, and generalized discharges was prominent.

Vertebrate Animal Models of RP59: Current Status and Future Prospects

“…The recent report of a microdeletion that specifically removed codon 42 leading to brain neurologic disease, but not retinal disease, emphasizes the importance of the protein structure in the net effect of a DHDDS mutation. DHDDS mutations that cause seizures and other neurological brain deficits [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ] have been reported as dominant gain-of-effect mutations. We hypothesize that these mutations are also due to true gain-of-function, involving unidentified brain protein (s) that abnormally interact with the mutant DHDDS protein.…”

“…Hence, it seems unwarranted (or at least premature) to classify RP59 as a CDG. Additionally, several recent reports have described DHDDS variants with a limited range of non-ocular pathological features, including progressive myoclonic epileptic seizures, tremor, hypertonia, myoclonic status epilepticus, and congenital malformations [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. One of these reports identified a patient with a specific deletion of amino acid K42 without ocular abnormalities [ 35 ].…”

DHDDS and NUS1: A Converging Pathway and Common Phenotype

“…Reports of interstitial 6q deletions were included if they spanned the NUS1 locus (GRCh38/hg38:chr6:117,675,469–117,710,727; GRCh37/hg19:chr6:117,996,617–118,031,886) and where genotype–phenotype correlation was possible. We identified 49 cases from 10 publications with heterozygous DHDDS variants 1–3,5–12 and 21 with heterozygous mutations in NUS1 from 11 publications (Table S1). 2,3,13–19 Twenty patients with structural variants affecting chromosome 6q spanning NUS1 were included.…”

Vertebrate Animal Models of RP59: Current Status and Future Prospects

“…Hence, it seems unwarranted (or at least premature) to classify RP59 as a CDG. Also, several recent reports have described DHDDS variants with a limited range of non-ocular pathological features, including progressive myoclonic epileptic seizures, tremor, hypertonia, myoclonic status epilepticus, and congenital malformations [32][33][34][35][36][37][38][39][40][41]. One of these reports identified a patient with a specific deletion of amino acid K42 without ocular abnormalities [35].…”