Adult‐onset rapidly worsening progressive myoclonic epilepsy caused by a novel variant in DHDDS

Kim, Seondeuk; Kim, Man Jin; Son, Hyoshin; Hwang, Sungeun; Kang, Mi-Kyoung; Chu, Kon; Lee, Sang Kun; Moon, Jangsup

doi:10.1002/acn3.51483

Cited by 10 publications

(11 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To these groups we now suggest adding a fourth one, having a more specific epileptic phenotype, overlapping with the classical PME or with a PME/progressive myoclonic ataxia continuum. 17 In patients with myoclonic seizures we found 11 different IRF2BPL mutations. All but one were truncating variants located in the "variable region" of the IRF2BPL protein, whereas only one patient had a variant located in the terminal C3HC4 Ring Domain (Figure 2).…”

Section: Discussionmentioning

confidence: 77%

IRF2BPL: A new genotype for progressive myoclonus epilepsies

et al. 2023

View full text Add to dashboard Cite

The progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders, typically presenting in late childhood. An etiologic diagnosis is achieved in about 80% of patients with PME, and genome‐wide molecular studies on remaining, well‐selected, undiagnosed cases can further dissect the underlying genetic heterogeneity. Through whole‐exome sequencing (WES), we identified pathogenic truncating variants in the IRF2BPL gene in two, unrelated patients presenting with PME. IRF2BPL belongs to the transcriptional regulators family and it is expressed in multiple human tissues, including the brain. Recently missense and nonsense mutations in IRF2BPL were found in patients presenting with developmental delay and epileptic encephalopathy, ataxia, and movement disorders, but none with clear PME. We identified 13 other patients in the literature with myoclonic seizures and IRF2BPL variants. There was no clear genotype–phenotype correlation. With the description of these cases, the IRF2BPL gene should be considered in the list of genes to be tested in the presence of PME, in addition to patients with neurodevelopmental or movement disorders.

show abstract

Section: Discussionmentioning

confidence: 77%

IRF2BPL: A new genotype for progressive myoclonus epilepsies

et al. 2023

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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 ].…”

Section: Introductionmentioning

confidence: 99%

Vertebrate Animal Models of RP59: Current Status and Future Prospects

Fliesler

Rao

Nguyen

et al. 2022

IJMS

View full text Add to dashboard Cite

Retinitis pigmentosa-59 (RP59) is a rare, recessive form of RP, caused by mutations in the gene encoding DHDDS (dehydrodolichyl diphosphate synthase). DHDDS forms a heterotetrameric complex with Nogo-B receptor (NgBR; gene NUS1) to form a cis-prenyltransferase (CPT) enzyme complex, which is required for the synthesis of dolichol, which in turn is required for protein N-glycosylation as well as other glycosylation reactions in eukaryotic cells. Herein, we review the published phenotypic characteristics of RP59 models extant, with an emphasis on their ocular phenotypes, based primarily upon knock-in of known RP59-associated DHDDS mutations as well as cell type- and tissue-specific knockout of DHDDS alleles in mice. We also briefly review findings in RP59 patients with retinal disease and other patients with DHDDS mutations causing epilepsy and other neurologic disease. We discuss these findings in the context of addressing “knowledge gaps” in our current understanding of the underlying pathobiology mechanism of RP59, as well as their potential utility for developing therapeutic interventions to block the onset or to dampen the severity or progression of RP59.

show abstract

“…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].…”

Section: Introductionmentioning

confidence: 99%

Vertebrate Animal Models of RP59: Current Status and Future Prospects

Fliesler¹,

Rao²,

Nguyen³

et al. 2022

Preprint

View full text Add to dashboard Cite

Retinitis pigmentosa-59 (RP59) is a rare, recessive form of RP, caused by mutations in the gene encoding DHDDS (dehydrodolichyl diphosphate synthase). DHDDS forms a heterotetrameric complex with Nogo-B Receptor (NgBR; gene NUS1) to form a cis-prenyltransferase (CPT) enzyme complex, which is required for synthesis of dolichol, which in turn is required for protein N-glycosylation as well as other glycosylation reactions in eukaryotic cells. Herein, we review the published phenotypic characteristics of RP59 models extant, with an emphasis on their ocular phenotypes, based primarily upon knock-in of known RP59-associated DHDDS mutations as well as cell type- and tissue-specific knockout of DHDDS alleles in mice. We also briefly review findings in RP59 patients with retinal disease and other patients with DHDDS mutations causing epilepsy and other neurologic disease. We discuss these findings in the context of addressing “knowledge gaps” in our current understanding of the underlying pathobiology mechanism of RP59, as well as their potential utility for developing therapeutic interventions to block the onset, or to dampen the severity or progression, of RP59.

show abstract

Adult‐onset rapidly worsening progressive myoclonic epilepsy caused by a novel variant in DHDDS

Cited by 10 publications

References 18 publications

IRF2BPL: A new genotype for progressive myoclonus epilepsies

IRF2BPL: A new genotype for progressive myoclonus epilepsies

Vertebrate Animal Models of RP59: Current Status and Future Prospects

Vertebrate Animal Models of RP59: Current Status and Future Prospects

Contact Info

Product

Resources

About