Search for a command to run...
Childhood-onset parkinsonism is rare and usually suggests an underlying genetic or metabolic cause. Advances in next-generation sequencing have shown that several neurodevelopmental disorders may present with a broad spectrum of movement disorder phenotypes. NUS1 encodes the Nogo-B receptor (NgBR), a subunit of the cis-prenyltransferase complex required for dolichol biosynthesis and protein glycosylation; pathogenic variants disrupt these pathways, leading to impaired glycosylation and cellular dysfunction.1 NUS1-related disorders are typically inherited in an autosomal dominant manner, most often due to de novo variants.2 Initially associated with developmental epileptic encephalopathies and intellectual disability, NUS1 variants have more recently been linked to diverse movement disorders, including ataxia, tremor, myoclonus, and dystonia, with variable age at onset.2 Heterozygous variants have also been reported in adults with early-onset parkinsonism.3 Childhood-onset parkinsonism due to NUS1 mutations remains exceptionally rare, with only a limited number of cases reported to date.2, 4 We report a 15-year-old boy born at term after an uncomplicated pregnancy, with mild language delay. At age 5, he developed a mild upper-limb tremor that progressively worsened. By age 13, stiffness, hypomimia, bradykinesia, and occasional falls appeared. Family history was unremarkable. Neurological examination revealed hypomimia, mild symmetric bradykinesia, and rigidity. Postural and action tremor with superimposed irregular, jerky movements suggestive of a myoclonic component were observed. Gait showed mildly reduced arm swing and impaired postural reflexes (Video 1). Additional findings included lower-limb spasticity with brisk reflexes and subtle dysmetria. Routine laboratory studies, including serum copper and ceruloplasmin, were normal. Brain and spinal MRI showed no structural abnormalities, ophthalmologic examination revealed no Kayser–Fleischer rings. EEG demonstrated moderate interictal epileptiform activity with posterior dominant rhythm slowing, without clinical correlates. Surface EMG of the deltoid during jerky movements did not reveal a cortical correlate, and electromyography and nerve conduction studies were unremarkable. Dopamine transporter imaging (DaTscan) was normal. Neuropsychological evaluation showed mild intellectual disability. Clinical exome sequencing identified a likely pathogenic NUS1 variant (c.305 + G>A; p.Gly102Asp). Parental testing was not performed, and de novo status could not be confirmed. Levodopa treatment resulted in subjective improvement and partial objective benefit in bradykinesia. Propranolol was ineffective for tremor, whereas primidone achieved partial control. Levetiracetam was added for EEG abnormalities, with improvement on follow-up. The patient has never experienced clinical seizures. This case expands the phenotypic spectrum of NUS1-related disease by demonstrating that parkinsonism, although rarely reported, can manifest during childhood. The presence of a myoclonic tremor phenotype—previously described in NUS1-related disorders—clearly highlights the overlapping nature of motor manifestations. The same variant identified in our patient has also been reported in an adult with dystonia, myoclonus, and mild intellectual disability.2 In the largest case series reported to date, parkinsonism was observed in 6 of 41 patients (14%), exclusively in adults and typically in combination with other movement disorders (Table 1).2 c.128_141dupCCGCCTCTGCCGCG; p.Val48fs* NUS1 encodes the stabilizing subunit of the cis-prenyltransferase complex, with DHDDS acting as the catalytic subunit. Autosomal dominant variants in both genes are associated with a shared neurological spectrum5, supporting consideration of NUS1 in children presenting with early-onset parkinsonian or mixed movement disorder phenotypes. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. D.M.C.: 1A, 1B, 1C, 3A. M.T.: 1C, 3B. A.M.: 1A, 1B, 1C. M.J.H.: 1C, 3B. C.R.: 1C, 3B. V.K.: 1C. Ethical Compliance Statement: The authors confirm that institutional review board approval was not required for this case report. Written informed consent for publication, including clinical data and images, was obtained from the patient's legal guardians. The authors affirm that they have read the Journal's position on issues involved in ethical publication and confirm that this work is consistent with those guidelines. Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: DM-Ch has no financial disclosures to report. MT-S has no financial disclosures to report. AM has no financial disclosures to report. MH has no financial disclosures to report. CR has no financial disclosures to report. VK has no financial disclosures to report. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.