DHDDS and NUS1: A Converging Pathway and Common Phenotype

doi:10.1002/mdc3.13920

Review

. 2024 Jan;11(1):76-85.

doi: 10.1002/mdc3.13920. Epub 2023 Nov 28.

DHDDS and NUS1: A Converging Pathway and Common Phenotype

Laura J Williams¹, Sophie Waller¹, Jessica Qiu¹, Emily Innes^{2

3}, Noha Elserafy⁴, Peter Procopis^{2

5}, Hugo Sampaio^{6

7}, Neil Mahant¹, Michel C Tchan^{4

8}, Shekeeb S Mohammad^{2

9

10}, Hugo Morales-Briceño¹, Victor S C Fung^{1

10}

Affiliations

¹ Movement Disorder Unit, Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia.
² TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
³ School of Medicine Sydney, The University of Notre Dame, Sydney, New South Wales, Australia.
⁴ Department of Genomic Medicine, Westmead Hospital, Westmead, New South Wales, Australia.
⁵ The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
⁶ Department of Neurology, Sydney Children's Hospital, Randwick, New South Wales, Australia.
⁷ School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.
⁸ Specialty of Genomic Medicine, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
⁹ Kids Neuroscience Centre, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁰ Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.

PMID: 38291835
PMCID: PMC10828623 (available on 2024-11-28)
DOI: 10.1002/mdc3.13920

Review

DHDDS and NUS1: A Converging Pathway and Common Phenotype

Laura J Williams et al. Mov Disord Clin Pract. 2024 Jan.

. 2024 Jan;11(1):76-85.

doi: 10.1002/mdc3.13920. Epub 2023 Nov 28.

Authors

Affiliations

¹ Movement Disorder Unit, Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia.
² TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
³ School of Medicine Sydney, The University of Notre Dame, Sydney, New South Wales, Australia.
⁴ Department of Genomic Medicine, Westmead Hospital, Westmead, New South Wales, Australia.
⁵ The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
⁶ Department of Neurology, Sydney Children's Hospital, Randwick, New South Wales, Australia.
⁷ School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.
⁸ Specialty of Genomic Medicine, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
⁹ Kids Neuroscience Centre, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
¹⁰ Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.

PMID: 38291835
PMCID: PMC10828623 (available on 2024-11-28)
DOI: 10.1002/mdc3.13920

Abstract

Background: Variants in dehydrodolichol diphosphate synthetase (DHDDS) and nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) cause a neurodevelopmental disorder, classically with prominent epilepsy. Recent reports suggest a complex movement disorder and an overlapping phenotype has been postulated due to their combined role in dolichol synthesis.

Cases: We describe three patients with heterozygous variants in DHDDS and five with variants affecting NUS1. They bear a remarkably similar phenotype of a movement disorder dominated by multifocal myoclonus. Diagnostic clues include myoclonus exacerbated by action and facial involvement, and slowly progressive or stable, gait ataxia with disproportionately impaired tandem gait. Myoclonus is confirmed with neurophysiology, including EMG of facial muscles.

Literature review: Ninety-eight reports of heterozygous variants in DHDDS, NUS1 and chromosome 6q22.1 structural alterations spanning NUS1, confirm the convergent phenotype of hypotonia at birth, developmental delay, multifocal myoclonus, ataxia, dystonia and later parkinsonism with or without generalized epilepsy. Other features include periodic exacerbations, stereotypies, anxiety, and dysmorphisms. Although their gene products contribute to dolichol biosynthesis, a key step in N-glycosylation, transferrin isoform profiles are typically normal. Imaging is normal or non-specific.

Conclusions: Recognition of their shared phenotype may expedite diagnosis through chromosomal microarray and by including DHDDS/NUS1 in movement disorder gene panels.

Keywords: DHDDS; NUS1; Nogo B receptor; dehydrodolichol diphosphate synthetase; dolichol biosynthesis.

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References

1. Galosi S, Edani B, Martinelli S, et al. De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus. Brain 2021;139:16–17. - PMC - PubMed
1. Hamdan FF, Myers CT, Cossette P, et al. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am J Hum Genet 2017;101:664–685. - PMC - PubMed
1. Courage C, Oliver KL, Park EJ, et al. Progressive myoclonus epilepsies—residual unsolved cases have marked genetic heterogeneity including dolichol‐dependent protein glycosylation pathway genes. Am J Hum Genet 2021;108:722–738. - PMC - PubMed
1. Bastian AJ, Mink JW, Kaufman BA, et al. Posterior vermal split syndrome. Ann Neurol 1998;44:601–610. - PubMed
1. Kim J, Kim I, Koh S‐B. A novel variant of dehydrodolichol diphosphate synthase (DHDDS) mutation with adult‐onset progressive myoclonus ataxia. Parkinsonism Relat Disord 2021;87:135–136. - PubMed

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[1] Galosi S, Edani B, Martinelli S, et al. De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus. Brain 2021;139:16–17. - PMC - PubMed

[2] Galosi S, Edani B, Martinelli S, et al. De novo DHDDS variants cause a neurodevelopmental and neurodegenerative disorder with myoclonus. Brain 2021;139:16–17. - PMC - PubMed

[3] Hamdan FF, Myers CT, Cossette P, et al. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am J Hum Genet 2017;101:664–685. - PMC - PubMed

[4] Hamdan FF, Myers CT, Cossette P, et al. High rate of recurrent de novo mutations in developmental and epileptic encephalopathies. Am J Hum Genet 2017;101:664–685. - PMC - PubMed

[5] Courage C, Oliver KL, Park EJ, et al. Progressive myoclonus epilepsies—residual unsolved cases have marked genetic heterogeneity including dolichol‐dependent protein glycosylation pathway genes. Am J Hum Genet 2021;108:722–738. - PMC - PubMed

[6] Courage C, Oliver KL, Park EJ, et al. Progressive myoclonus epilepsies—residual unsolved cases have marked genetic heterogeneity including dolichol‐dependent protein glycosylation pathway genes. Am J Hum Genet 2021;108:722–738. - PMC - PubMed

[7] Bastian AJ, Mink JW, Kaufman BA, et al. Posterior vermal split syndrome. Ann Neurol 1998;44:601–610. - PubMed

[8] Bastian AJ, Mink JW, Kaufman BA, et al. Posterior vermal split syndrome. Ann Neurol 1998;44:601–610. - PubMed

[9] Kim J, Kim I, Koh S‐B. A novel variant of dehydrodolichol diphosphate synthase (DHDDS) mutation with adult‐onset progressive myoclonus ataxia. Parkinsonism Relat Disord 2021;87:135–136. - PubMed

[10] Kim J, Kim I, Koh S‐B. A novel variant of dehydrodolichol diphosphate synthase (DHDDS) mutation with adult‐onset progressive myoclonus ataxia. Parkinsonism Relat Disord 2021;87:135–136. - PubMed

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DHDDS and NUS1: A Converging Pathway and Common Phenotype

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DHDDS and NUS1: A Converging Pathway and Common Phenotype

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