DHDDS and NUS1: A Converging Pathway and Common Phenotype.

Laura J Williams, Sophie Waller, Jessica Qiu, Emily Innes, Noha Elserafy, Peter Procopis, Hugo Sampaio, Neil Mahant, Michel C Tchan, Shekeeb S Mohammad, Hugo Morales-Briceño, Victor S C Fung

Journal: Movement disorders clinical practice 2024;11(1):76-85

PMID: 38291835

Free Full Text on PubMed Central View on PubMed

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.

Address: Movement Disorder Unit, Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia.; TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.; School of Medicine Sydney, The University of Notre Dame, Sydney, New South Wales, Australia.; Department of Genomic Medicine, Westmead Hospital, Westmead, New South Wales, Australia.; The Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.; Department of Neurology, Sydney Children's Hospital, Randwick, New South Wales, Australia.; School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.; Specialty of Genomic Medicine, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.; Kids Neuroscience Centre, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.; Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.

DOI: 10.1002/mdc3.13920

Link outs

Free resources

Full Text Sources:

Medical:

https://medlineplus.gov/movementdisorders.html

MeSH Terms: Infant, Newborn, Humans, Diphosphates, Myoclonus, Movement Disorders, Phenotype, Ataxia, Dolichols, Receptors, Cell Surface