Xiao-Jun Huang

Background Mutations in PRRT2 and 16p11.2 microdeletion including PRRT2 have been identified as the pathogenic cause of paroxysmal kinesigenic dyskinesia (PKD). Objective The objective was to investigate the clinical and genetic features of PKD and to analyze the genotype–phenotype correlation. Methods We recruited PKD patients, recorded clinical manifestations, and performed PRRT2 screening in 150 PKD patients by unified PKD registration forms. Genotype–phenotype correlation analyses were conducted in probands. High-knee-exercise (HKE) tests were applied in one hundred and six patients. Results Eight PRRT2 mutations were detected, accounting for 22.76% of the probands. Three mutations (c.649dupC, c.649delC, and c.510_513delTCTG) were already reported, while four mutations (c.252_264delCACAGACCTCAGC, c.503_504delCT, c.679C > T, and c.804C > A) were first reported. One heterozygous microdeletion of 606 kb in 16p11.2 was detected in one patient. Compared with non-PRRT2 mutation carriers, the PRRT2 mutation carriers were younger at onset, experienced longer attacks, and tended to present with complicated PKD, combined phenotypes of dystonia and chorea. 57.01% of patients could effectively induce movement disorders through the HKE test. A good response was shown in 81.93% of the patients prescribed with antiepileptic drugs. 13.54% (13/96) had abnormal EEG results. Conclusions PRRT2 mutations are common in patients with PKD and are significantly associated with an earlier age at onset, longer duration of attacks, a complicated form of PKD, combined phenotypes of dystonia and chorea. Patients with microdeletion of 16p11.2 may have more severe manifestations. The HKE test could contribute to the diagnosis of PKD. Carbamazepine is still the first choice for PKD patients, but individualized treatment should be formulated.

Background: Paroxysmal kinesigenic dyskinesia (PKD) is the most common type of paroxysmal dyskinesias. Only one‐third of PKD patients are attributed to proline‐rich transmembrane protein 2 (PRRT2) mutations.Objective: We aimed to explore the potential causative gene for PKD.Methods: A cohort of 196 PRRT2‐negative PKD probands were enrolled for whole‐exome sequencing (WES). Gene Ranking, Identification and Prediction Tool, a method of case–control analysis, was applied to identify the candidate genes. Another 325 PRRT2‐negative PKD probands were subsequently screened with Sanger sequencing.Results: Transmembrane Protein 151 (TMEM151A) variants were mainly clustered in PKD patients compared with the control groups. 24 heterozygous variants were detected in 25 of 521 probands (frequency = 4.80%), including 18 missense and 6 nonsense mutations. In 29 patients with TMEM151A variants, the ratio of male to female was 2.63:1 and the mean age of onset was 12.93 ± 3.15 years. Compared with PRRT2 mutation carriers, TMEM151A‐related PKD were more common in sporadic PKD patients with pure phenotype. There was no significant difference in types of attack and treatment outcome between TMEM151A‐positive and PRRT2‐positive groups.Conclusions: We consolidated mutations in TMEM151A causing PKD with the aid of case–control analysis of a large‐scale WES data, which broadens the genotypic spectrum of PKD. TMEM151A‐related PKD were more common in sporadic cases and tended to present as pure phenotype with a late onset. Extensive functional studies are needed to enhance our understanding of the pathogenesis of TMEM151A‐related PKD. © 2021 International Parkinson and Movement Disorder Society

Background: CSF1R-related leukoencephalopathy, also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS), is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few of CSF1R mutations have been functionally testified and the pathogenesis remains unknown. Methods: In order to investigate clinical and pathological characteristics of patients with CSF1R-related leukoencephalopathy and explore the potential impact of CSF1R mutations, we analyzed clinical manifestations of 15 patients from 10 unrelated families and performed brain biopsy in 2 cases. Next generation sequencing was conducted for 10 probands to confirm the diagnosis. Sanger sequencing, segregation analysis and phenotypic reevaluation were utilized to substantiate findings. Functional examination of identified mutations was further explored. Results: Clinical and neuroimaging characteristics were summarized. The average age at onset was 35.9 ± 6.4 years (range 24–46 years old). Younger age of onset was observed in female than male (34.2 vs. 39.2 years). The most common initial symptoms were speech dysfunction, cognitive decline and parkinsonian symptoms. One patient also had marked peripheral neuropathy. Brain biopsy of two cases showed typical pathological changes, including myelin loss, axonal spheroids, phosphorylated neurofilament and activated macrophages. Electron microscopy disclosed increased mitochondrial vacuolation and disorganized neurofilaments in ballooned axons. A total of 7 pathogenic variants (4 novel, 3 documented) were identified with autophosphorylation deficiency, among which c.2342C > T remained partial function of autophosphorylation. Western blotting disclosed the significantly lower level of c.2026C > T (p.R676*) than wild type. The level of microtubule associated protein 1 light chain 3-II (LC3-II), a classical marker of autophagy, was significantly lower in mutants expressed cells than wild type group by western blotting and immunofluorescence staining. Conclusions: Our findings support the loss-of-function and haploinsufficiency hypothesis in pathogenesis. Autophagy abnormality may play a role in the disease. Repairing or promoting the phosphorylation level of mutant CSF1R may shed light on therapeutic targets in the future. However, whether peripheral polyneuropathy potentially belongs to CSF1R-related spectrum deserves further study with longer follow-up and more patients enrolled. Trial registration: ChiCTR, ChiCTR1800015295. Registered 21 March 2018.