Objective: To describe novel clinical features and treatment response in a patient with neurodevelopmental disorder due to variants in dehydrodolichol diphosphate synthetase (DHDDS).

Background: DHDDS variants cause a neurodevelopmental disorder characterized by developmental delay, complex movement disorders, and epilepsy. Effective treatments for movement symptoms (e.g., myoclonus) are typically limited in this syndrome. We describe symptomatic benefit from primidone in a patient with DHDDS-related disease, confirmed by neurophysiological study.

Method: A 49-year-old man with history of generalized epilepsy and intellectual disability presented for worsening tremors. Family history was notable for the patient’s daughter having similar neurodevelopmental delays and epilepsy. The patient’s seizures were well-controlled on carbamazepine currently, but had previously been on ethosuximide and topiramate. Patient was diagnosed with essential tremor (ET) locally and initiated on primidone. While patient reported subjective benefit of primidone (250 mg/day), tremors were increasingly disabling. Movement exam noted a jerky myoclonus across upper and lower limbs accentuated by action, as well as superimposed mild ataxia and wide based gait, without parkinsonism.

Results: Genetic testing showed a heterozygous pathogenic variant of the DHDDS gene, c.632G>A (p.Arg211Gln), consistent with an autosomal dominant DHDDS-related neurodevelopmental disorder. Patient increased primidone up to 300 mg/day with improvements. By neurophysiologic study, we 1) confirmed that patient’s abnormal movements are not characteristic of ET but instead diagnostic of cortical origin myoclonus, and 2) objectively demonstrated improvement of myoclonic discharges when patient was on [figure1] vs. off [figure2] primidone.

Conclusion: We describe a patient with DHDDS heterozygous pathogenic variant and movement phenotype consistent with prior case series reported in the literature.^[1][2][3][4] To our knowledge, this is the first report to demonstrate clinical benefit of DHDDS-associated cortical myoclonus with primidone. We suggest that primidone may improve cortical myoclonus through modulation of GABA-related circuitries, as shown in other forms of cortical myoclonus.^[5][6][7] Given limited therapies for myoclonus in this patient population, we propose consideration of primidone for symptomatic benefit, though larger studies are needed to validate our case report.

[figure1]

[figure2]

References: [1] Galosi, Serena, et al. “De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus.” Brain 145.1 (2022): 208-223.
[2] Piccolo, Gianluca, et al. “Complex neurological phenotype associated with a de novo DHDDS mutation in a boy with intellectual disability, refractory epilepsy, and movement disorder.” Journal of Pediatric Genetics 10.03 (2021): 236-238.
[3] Muffels, I. J. J., et al. “Assessing age of onset and clinical symptoms over time in patients with heterozygous pathogenic DHDDS variants.” Journal of inherited metabolic disease 47.5 (2024): 935-944.
[4] Mehta, Sahil, and Vivek Lal. “DHDDS Mutation: A Rare Cause of Refractory Epilepsy and Hyperkinetic Movement Disorder.” Journal of Movement Disorders 16.1 (2023): 107.
[5] Žakelj, Katarina Vogelnik, et al. “Mechanisms of tremor-modulating effects of primidone and propranolol in essential tremor.” Parkinsonism & Related Disorders 128 (2024): 107151.
[6] Caviness, John N. “Treatment of myoclonus.” Neurotherapeutics 11.1 (2014): 188-200.
[7] Obeso, J. A., et al. “The treatment of severe action myoclonus.” Brain 112.3 (1989): 765-777.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/autosomal-dominant-dhdds-related-movement-disorder-treated-with-primidone/