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.
Mov Disord Clin Pract. 2024 Jan;11(1):76-85. doi: 10.1002/mdc3.13920. Epub 2023 Nov 28.
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.
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.
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.
Recognition of their shared phenotype may expedite diagnosis through chromosomal microarray and by including DHDDS/NUS1 in movement disorder gene panels.
脱氢二氢羊毛固醇磷酸合成酶（DHDDS）和核十一碳烯焦磷酸合酶 1（NUS1）的变异可导致神经发育障碍，经典表现为明显的癫痫。最近的报告表明存在复杂的运动障碍，由于它们在羊毛固醇合成中的共同作用，推测存在重叠表型。
我们描述了 3 名 DHDDS 杂合变异患者和 5 名 NUS1 变异患者。他们具有非常相似的运动障碍表型，以多灶性肌阵挛为主。诊断线索包括动作和面部受累时肌阵挛加重，以及进行性或稳定的步态共济失调，伴不成比例的 tandem gait 障碍。肌阵挛通过神经生理学（包括面部肌肉 EMG）得到证实。
DHDDS、NUS1 和 6q22.1 染色体结构改变（跨越 NUS1）的杂合变异的 98 例报告证实了出生时存在肌张力低下、发育迟缓、多灶性肌阵挛、共济失调、肌张力障碍和后期帕金森病伴或不伴全身性癫痫的收敛表型。其他特征包括周期性恶化、刻板动作、焦虑和畸形。尽管它们的基因产物有助于羊毛固醇生物合成，这是 N-糖基化的关键步骤，但转铁蛋白同工型谱通常正常。影像学正常或非特异性。
通过染色体微阵列识别其共同表型，并将 DHDDS/NUS1 纳入运动障碍基因谱，可能会加速诊断。
