Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca²⁺ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^-/- OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^-/- OPCs in vitro and myelination in Tmem63a^-/- mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca²⁺ influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
Animals ; Cell Differentiation/physiology* ; Oligodendroglia/metabolism* ; Mice, Knockout ; Mice ; Male ; Myelin Sheath/metabolism* ; Humans ; Child ; Cells, Cultured ; Oligodendrocyte Precursor Cells/metabolism*

Objective:To investigate the correlation between collateral circulation and infarct pattern and outcome in acute ischemic stroke patients with anterior circulation intracranial atherosclerosis.Methods:Acute ischemic stroke patients with anterior circulation intracranial atherosclerotic severe stenosis or occlusion admitted to the Department of Neurology, the First Affiliated Hospital of Xinxiang Medical College from September 2018 to March 2020 were included prospectively. According to diffusion-weighted imaging, the infarct patterns were divided into perforator pattern, territorial pattern, watershed pattern, and mixed pattern. At 90 d after onset, the modified Rankin Scale was used to evaluate the outcome. 0-2 was defined as good outcome, and >2 was defined as poor outcome. Multivariate logistic regression analysis was used to determine the independent influencing factors of clinical outcome. Results:A total of 89 patients were enrolled, 50 (56.2%) had good collateral circulation and 39 (43.8%) had poor collateral circulation. The distribution patterns of infarct: 22 patients (24.7%) were perforator pattern, 26 (29.2%) were territorial pattern, 17 (19.1%) were watershed pattern, and 24 (30.0%) were mixed pattern. The proportion of patients with good collateral circulation was 81.8%, 65.4%, 29.4% and 41.7%, respectively in the perforator pattern group, territorial pattern group, watershed pattern group, and mixed pattern group. Good collateral circulation was more common in the perforator pattern group, and poor collateral circulation was more common in the watershed pattern group. At 90 d after onset, 53 patients (59.6%) had a good outcome and 36 (40.4%) had a poor outcome. The baseline homocysteine level in the good outcome group was significantly lower than that in the poor outcome group (17.91±4.62 μmol/L vs. 20.35±4.67 μmol/L; t=2.436, P=0.017), and the proportion of patients with good collateral circulation was significantly higher than that of patients with poor outcome (73.6% vs. 30.6%; χ2=16.124, P<0.001). Multivariate logistic regression analysis showed that higher homocysteine level was an independent risk factor for poor outcome (odds ratio 1.174, 95% confidence interval 1.061-1.298; P=0.002) and good collateral circulation was an independent protective factor for good outcome (odds ratio 0.095, 95% confidence interval 0.038-0.239; P<0.001). Conclusions:Good collateral circulation was more common in patients with perforator pattern, and poor collateral circulation was more common in patients with watershed pattern. Good collateral circulation was independently associated with the good clinical outcome in acute ischemic stroke patients with anterior circulation intracranial atherosclerosis.

OBJECTIVE:To explore the efficacy and safety of probucol combined with butylphthalide in the treatment of pa-tients with acute cerebral infarction. METHODS:172 patients with acute cerebral infarction were randomly divided into observation group and control group,86 cases in each group. All patients received conventional treatment for acute cerebral infarction,includ-ing thrombolysis,anti-platelet aggregation,reducing intracranial pressure,nutritional support,intensive lipid-lowering within onset 4.5 h,timely treatment of the underlying diseases;based on it,control group received Probucol tablet,0.5 g every times,bid. Ob-servation group additionally received Butylphthalide and sodium chloride injection,100 ml every times,bid,in 9:00 and 17:00 ev-ery day,infusion within 50-90 min. Both groups lasted for 2 weeks. Lipid metabolic indexes,the changes of serum S100β,NSE and hs-CRP levels,NIHSS score,clinical efficacy before and after treatment,and the incidence of adverse reactions in 2 groups were observed. RESULTS:Compared with before treatment,triglyceride(TG),total cholesterol(TC)and low-density lipoprotein cholesterol (LDL-C) levels in 2 groups significantly decreased,high-density lipoprotein cholesterol level significantly increased, and TG,TC and LDL-C levels in observation group decreased more significantly,the differences were statistically significant(P<0.05). Serum S100β,NSE and hs-CRP levels and NIHSS scores in 2 groups significantly decreased,and NSE level NIHSS scores and in observation group decreased more significantly,the differences were statistically significant (P<0.05). The total effective rate in observation group was 89.5%,significantly higher than control group (62.8%),the difference was statistically significant (P<0.05). There were no obvious adverse reactions during treatment,and also no obvious liver and kidney function,blood coagula-tion and ECG changes. CONCLUSIONS:Probucol combined with butylphthalide can effectively improve the lipid metabolism and decrease serum NSE level in the treatment of patients with acute cerebral infarction,and plays positive role in early recovery of neu-rological function.