背景:脱氢二磷酸多醇合成酶(DHDDS)和核十一烯焦磷酸合酶1(NUS1)的变体引起神经发育障碍,典型的癫痫。最近的报道表明,一种复杂的运动障碍,并且由于它们在多力醇合成中的共同作用,已经假定了重叠的表型。
方法:我们描述了3例DHDDS杂合变异的患者和5例影响NUS1的变异。它们具有由多灶性肌阵挛症主导的运动障碍的非常相似的表型。诊断线索包括因动作和面部受累而加剧的肌阵挛症,缓慢渐进或稳定,步态共济失调,串联步态受损。神经生理学证实了肌阵鸣,包括面部肌肉的肌电图。
方法:关于DHDDS杂合变异的九十八份报告,NUS1和跨越NUS1的6q22.1染色体结构改变,证实了出生时张力减退的趋同表型,发育迟缓,多灶性肌阵鸣,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。其他特征包括定期恶化,刻板印象,焦虑,和畸形。尽管它们的基因产物有助于多立康醇的生物合成,N-糖基化的关键步骤,转铁蛋白同工型谱通常是正常的。成像是正常的或非特异性的。
结论:通过染色体微阵列和通过将DHDDS/NUS1纳入运动障碍基因组来识别它们的共有表型可以加速诊断。
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.
METHODS: 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.
METHODS: 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.