摩洛哥的 Wilson 病表型和分子特征。

Phenotype and molecular characterization of Wilson's disease in Morocco.

机构信息

Université Cadi Ayyad, Faculté des Sciences Semlalia, LHEAC, 40000, Marrakech, Morocco; Université Claude Bernard Lyon 1, INSERM-U1060, INRA, INSA, Laboratoire CarMeN, 69500, Lyon, France.

Université Cadi Ayyad, Faculté de Médecine et de pharmacie, Laboratoire de recherche de l'enfance, la santé et le développement, 40000, Marrakech, Morocco; CHU Mohammed VI de Marrakech, Hôpital Mère-Enfant, Service de Pédiatrie, 40080, Marrakech, Morocco.

出版信息

Clin Res Hepatol Gastroenterol. 2024 May;48(5):102335. doi: 10.1016/j.clinre.2024.102335. Epub 2024 Apr 6.

DOI:10.1016/j.clinre.2024.102335

PMID:38588792

Abstract

BACKGROUND AND STUDY AIMS

In Morocco the prevalence of Wilson disease (WD) and the spectrum of mutations are not known. The aim of the present study was to estimate the prevalence of WD in Morocco, to evaluate the phenotype among a large cohort of WD patients, and to characterize ATP7B variants in a subgroup of WD patients.

PATIENTS AND METHODS

We collected data from 226 patients admitted to five university hospital centers in Morocco between 2008 and 2020. The diagnosis was based on clinical manifestations, function tests and biochemical parameters. The genotype was characterized in 18 families diagnosed at the University Hospital Center of Marrakesh, by next generation sequencing.

RESULTS

The mean annual prevalence in Morocco was 3.88 per 100,000 and the allele frequency was 0.15 %. Among the 226 patients included (121 males and 105 females), 196 were referred for a hepatic or neurological involvement and 30 were asymptomatic. The mean age at diagnosis was 13 ± 5.1 years (range: 5 - 42 years). Consanguinity was found in 63.3 % of patients. The mean duration of illness was 2.8 ± 1.9 years. Kayser-Fleischer rings were found in 131 (67.9 %) of 193 patients. Among the 196 symptomatic patients, 141/159 (88.7 %) had low serum ceruloplasmin (<0.2 g/L) and a high 24-hours urinary copper (>100 μg/day) was found in 173/182 (95.1 %) patients. The initial treatment was D-penicillamine in 207 patients, zinc acetate in five, zinc sulfate in five, and nine patients were not treated; 60/207 (29 %) patients have stopped treatment. A total of 72 patients died; the mortality rate was 31.9 %. Eight different ATP7B variants were identified among the 18 patients studied, of which two were novel (p.Cys1104Arg and p.Gln1277Hisfs*52), and six previously published (p.Gln289Ter, p.Cys305Ter, p.Thr1232Pro, p.Lys1020Arg, p.Glu583ArgfsTer25 and c.51+4A>T). All informative patients were homozygous for the disease-causing mutation.

CONCLUSION

In Morocco, a high prevalence due to consanguinity and a high mortality rate due to the difficulty of diagnosis and lack of treatment were observed in WD patients. NGS sequencing identified new ATP7B variants in WD patients from Morocco.

摘要

背景和研究目的

在摩洛哥，Wilson 病（WD）的流行率和突变谱尚不清楚。本研究的目的是估计 WD 在摩洛哥的流行率，评估大样本 WD 患者的表型，并对 WD 患者亚组的 ATP7B 变异进行特征分析。

患者和方法

我们收集了 2008 年至 2020 年间在摩洛哥五所大学医院中心就诊的 226 名患者的数据。诊断基于临床表现、功能试验和生化参数。在马拉喀什大学医院中心诊断的 18 个家庭中，通过下一代测序对基因型进行了特征分析。

结果

摩洛哥的年平均患病率为 3.88/100000，等位基因频率为 0.15%。在包括的 226 名患者中（121 名男性和 105 名女性），196 名因肝脏或神经系统受累就诊，30 名无症状。诊断时的平均年龄为 13±5.1 岁（5-42 岁）。63.3%的患者有近亲结婚。疾病的平均病程为 2.8±1.9 年。193 名患者中有 131 名（67.9%）发现 Kayser-Fleischer 环。在 196 名有症状的患者中，141/159（88.7%）血清铜蓝蛋白低（<0.2 g/L），182/182（95.1%）患者 24 小时尿铜高（>100 μg/天）。初始治疗为 207 名患者使用 D-青霉胺，5 名患者使用醋酸锌，5 名患者使用硫酸锌，9 名患者未治疗；60/207（29%）名患者停止治疗。共有 72 名患者死亡；死亡率为 31.9%。在研究的 18 名患者中发现了 8 种不同的 ATP7B 变异，其中 2 种是新发现的（p.Cys1104Arg 和 p.Gln1277Hisfs*52），6 种是以前发表过的（p.Gln289Ter、p.Cys305Ter、p.Thr1232Pro、p.Lys1020Arg、p.Glu583ArgfsTer25 和 c.51+4A>T）。所有信息患者均为致病突变的纯合子。