背景:由PLA2G6基因突变引起的磷脂酶相关神经变性(PLAN)是一种罕见的神经变性疾病,有四个亚组。婴儿神经轴索营养不良(INAD)和PLA2G6相关的肌张力障碍-帕金森病是主要的两个亚型。在这个队列中,我们回顾了临床,成像,以及25例PLA2G6变异的成人和儿童患者的遗传特征。
方法:对患者数据进行了广泛的回顾。应用婴儿神经轴索营养不良评定量表(INAD-RS)评价INAD患者的严重程度和进展。使用全外显子组测序来确定疾病的潜在病因,然后使用Sanger测序进行共分离分析。基于ACMG建议的计算机预测分析用于评估遗传变异的致病性。除了使用HGMD数据库和卡方统计方法,我们的目的是调查PLA2G6中考虑所有报告的致病变异的基因型相关性。
结果:纳入18例INAD和7例晚发性PLAN。在18例INAD患者中,运动粗大消退是最常见的表现症状.考虑到INAD-RS总分,症状的平均进展率为每月0.58分(标准误差0.22,低于95%-1.10,高于95%-0.15).INAD-RS最大潜在损失的60%发生在INAD患者症状发作的60个月内。在7例成人计划中,运动功能减退,震颤,共济失调门,认知障碍是最常见的临床特征。在这些患者的26个成像系列中也观察到各种脑成像异常,小脑萎缩是50%以上最常见的发现。在25例PLAN患者中检测到20种独特变体,包括9种新变体。总之,分析了来自87名患者的107种不同的致病变异以建立基因型-表型相关性。卡方检验的P值表明疾病发作年龄与PLA2G6上报告的变体分布之间没有显着关系。
结论:计划表现出从婴儿期到成年期的广泛临床症状。对于患有帕金森病或认知功能减退的成年患者,应考虑PLAN。根据目前的知识,不可能根据确定的基因型来预测疾病的发病年龄。
Phospholipase-associated neurodegeneration (PLAN) caused by mutations in the
PLA2G6 gene is a rare neurodegenerative disorder that presents with four sub-groups. Infantile neuroaxonal dystrophy (INAD) and
PLA2G6-related dystonia-parkinsonism are the main two subtypes. In this cohort, we reviewed clinical, imaging, and genetic features of 25 adult and pediatric patients harboring variants in the
PLA2G6.
An extensive review of the patients\' data was carried out. Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS) was used for evaluating the severity and progression of INAD patients. Whole-exome sequencing was used to determine the disease\'s underlying etiology followed by co-segregation analysis using Sanger sequencing. In silico prediction analysis based on the ACMG recommendation was used to assess the pathogenicity of genetic variants. We aimed to survey a genotype-genotype correlation in
PLA2G6 considering all reported disease-causing variants in addition to our patients using the HGMD database and the chi-square statistical approach.
Eighteen cases of INAD and 7 cases of late-onset PLAN were enrolled. Among 18 patients with INAD, gross motor regression was the most common presenting symptom. Considering the INAD-RS total score, the mean rate of progression was 0.58 points per month of symptoms (Standard error 0.22, lower 95% - 1.10, and upper 95% - 0.15). Sixty percent of the maximum potential loss in the INAD-RS had occurred within 60 months of symptom onset in INAD patients. Among seven adult cases of PLAN, hypokinesia, tremor, ataxic gate, and cognitive impairment were the most frequent clinical features. Various brain imaging abnormalities were also observed in 26 imaging series of these patients with cerebellar atrophy being the most common finding in more than 50%. Twenty unique variants in 25 patients with PLAN were detected including nine novel variants. Altogether, 107 distinct disease-causing variants from 87 patient were analyzed to establish a genotype-phenotype correlation. The P value of the chi-square test did not indicate a significant relationship between age of disease onset and the distribution of reported variants on
PLA2G6.
PLAN presents with a wide spectrum of clinical symptoms from infancy to adulthood. PLAN should be considered in adult patients with parkinsonism or cognition decline. Based on the current knowledge, it is not possible to foresee the age of disease onset based on the identified genotype.