Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study
Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study
复制标题
DOI：
10.1136/jnnp-2022-328921
复制
发表时间：
2022-07-27
影响因子：
11
通讯作者：
Diaz-Manera，Jordi
中科院分区：
文献类型：
--
作者：
Schiava，Marianela;Ikenaga，Chiseko;Diaz-Manera，Jordi
研究背景含瓦洛辛蛋白（Valosin-containing protein，VCP）基因突变引起的VCP病可导致肌病、佩吉特骨病（Paget 'sdisease of bone，PBD）和额颞叶痴呆（frontotemporal dementia，FTD）。自然史和基因型-表型相关性数据有限。这项研究的特点与VCPgene突变的患者，并调查基因型-表型correlations.MethodsDescriptive回顾性国际研究收集的临床和遗传数据的患者在theVCPgene.ResultsTwo和55例（70.0%男性）被列入研究。平均年龄为56.8±9.6岁，平均发病年龄为45.6±9.3岁。平均诊断延迟时间为7.7±6年。50%的患者在发病时报告对称性下肢无力，进展为全身性肌无力。其他常见症状依次为：舒张功能不全40.3%、PDB 28.2%、自主神经功能障碍21.4%、FTD 14.3%。共鉴定出57种遗传变异，其中18种以前从未报道过。c.464G>A（p.Arg155His）是最常见的变异，在28%中鉴定到。全职轮椅使用者占19.1%，从发病到成为轮椅使用者的中位时间为8.5年。变异c.463C>T（p.Arg155Cys）表现出较早的发病年龄（37.8±7.6年）和较高的轴性和上肢无力、肩胛翼和认知功能障碍的发生率。用力肺活量（FVC）低于50%的危险因素是全职轮椅用户，而FVC <70%，是一个全职轮椅用户与death.ConclusionThis研究扩大了知识的表型介绍，自然史，基因型-表型相关性和疾病进展的VCP疾病的危险因素，是有用的，以提高护理提供给患者这种复杂的疾病。
BackgroundValosin-containing protein (VCP) disease, caused by mutations in theVCPgene, results in myopathy, Paget’s disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype–phenotype correlation data are limited. This study characterises patients with mutations inVCPgene and investigates genotype–phenotype correlations.MethodsDescriptive retrospective international study collecting clinical and genetic data of patients with mutations in theVCPgene.ResultsTwo hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death.ConclusionThis study expands the knowledge on the phenotypic presentation, natural history, genotype–phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.