DHDDS – Developmental Delay and Seizures with or without Movement Abnormalities

DHDDS encodes dehydrodolichyl diphosphate synthase, a key enzyme in dolichol synthesis and N-linked glycosylation. A single case links a heterozygous c.614G>A (p.Arg205Gln) variant in DHDDS to developmental delay and seizures with movement abnormalities (DEDSM) in a 45-year-old patient presenting with refractory epilepsy, ataxia (HP:0001251), dystonia (HP:0001332), parkinsonism (HP:0001300), and global developmental delay (HP:0001263) ([PMID:39576357]). No family segregation data were reported, and no additional unrelated cases have been described. While the enzymatic function of DHDDS is well established ([PMID:31661879]; [PMID:32245241]), variant-specific functional studies in the context of DEDSM are lacking, leaving the pathogenic mechanism for this phenotype unconfirmed.

Clinical Validity: Limited – single proband with de novo c.614G>A (p.Arg205Gln); no segregation; supportive mechanistic plausibility only.

Genetic Evidence: Limited – one reported case, no familial segregation, single variant.

Functional Evidence: Limited – demonstrated role of DHDDS in glycosylation, but no variant-specific assays for DEDSM.

Further case reports and mechanistic studies are required to confirm this association and inform diagnostic testing. Key Take-home: Consider DHDDS sequencing in patients with unexplained developmental delay, epilepsy, and movement disorders to enable early diagnosis and tailored management.

References

• Neurogenetics • 2024 • DHDDS-related epilepsy with hippocampal atrophy: a case report. PMID:39576357
• Biomolecules • 2019 • Structural Characterization of Full-Length Human Dehydrodolichyl Diphosphate Synthase Using an Integrative Computational and Experimental Approach. PMID:31661879
• Cells • 2020 • Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration. PMID:32245241

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