Abstract：
Fabry disease (FD) is an X-linked condition caused by variants in the GLA gene. Since females have two X chromosomes, they were historically thought to be carriers. Although increased knowledge has shown that females often develop the disease, data from Spain and other countries reported that females were undertreated. The aim of this study was to provide a wider and more recent description of the disease characteristics and associated management of females with a GLA variant in a Spanish cohort.
Ninety-seven females from 12 hospitals were included in this retrospective study. Mean age was 50.1 ± 17.2 years. Median follow-up time from GLA variant identification was 36.1 months, and most (70.1%) were identified through family screening. Variants associated with classic/non-classic phenotypes were similarly distributed (40.2%/53.6%). Missense variants were the most prevalent (n = 84, 86.6%). In the overall group, 70.4% had major organ involvement (i.e., cardiac, renal, cerebrovascular, peripheral nervous system or gastrointestinal), and 47.3% also had typical Fabry signs (angiokeratoma, cornea verticillata or increased plasma lyso-Gb3). Cardiac involvement was the most prevalent (49.5%) and the main reason for treatment initiation. A total of 33 (34%) patients received disease-specific therapy, 55% of whom were diagnosed by family screening. Females carrying variants associated with a classic phenotype had higher frequencies of clinical manifestations (92.3%) and were predominant in the treated subgroup (69.7%). Despite this, there were 34 untreated females (56.7% of total untreated), with both phenotypes represented, who had major organ involvement, with 27 of cardiac, renal or cerebrovascular nature. Age or comorbidities in this subgroup were comparable to the treated subgroup (P = 0.8 and P = 0.8, respectively).
Efforts have been made in recent years to diagnose and treat timely Fabry females in Spain. A high percentage of females with pathogenic variants, regardless of their associated phenotype, will likely develop disease. A proportion of females with severe disease in this cohort received specific treatment. Still a significant number of females, even with same profile as the treated ones, who may be eligible for treatment according to European recommendations, remained untreated. Reasons for this merit further investigation.
Ninety-seven females from 12 hospitals were included in this retrospective study. Mean age was 50.1 ± 17.2 years. Median follow-up time from GLA variant identification was 36.1 months, and most (70.1%) were identified through family screening. Variants associated with classic/non-classic phenotypes were similarly distributed (40.2%/53.6%). Missense variants were the most prevalent (n = 84, 86.6%). In the overall group, 70.4% had major organ involvement (i.e., cardiac, renal, cerebrovascular, peripheral nervous system or gastrointestinal), and 47.3% also had typical Fabry signs (angiokeratoma, cornea verticillata or increased plasma lyso-Gb3). Cardiac involvement was the most prevalent (49.5%) and the main reason for treatment initiation. A total of 33 (34%) patients received disease-specific therapy, 55% of whom were diagnosed by family screening. Females carrying variants associated with a classic phenotype had higher frequencies of clinical manifestations (92.3%) and were predominant in the treated subgroup (69.7%). Despite this, there were 34 untreated females (56.7% of total untreated), with both phenotypes represented, who had major organ involvement, with 27 of cardiac, renal or cerebrovascular nature. Age or comorbidities in this subgroup were comparable to the treated subgroup (P = 0.8 and P = 0.8, respectively).
Efforts have been made in recent years to diagnose and treat timely Fabry females in Spain. A high percentage of females with pathogenic variants, regardless of their associated phenotype, will likely develop disease. A proportion of females with severe disease in this cohort received specific treatment. Still a significant number of females, even with same profile as the treated ones, who may be eligible for treatment according to European recommendations, remained untreated. Reasons for this merit further investigation.
摘要：
背景：法布里病（FD）是由GLA基因变体引起的X连锁病症。因为雌性有两条X染色体,历史上被认为是航母。尽管越来越多的知识表明女性经常患上这种疾病，来自西班牙和其他国家的数据报告称,女性治疗不足.这项研究的目的是提供对西班牙队列中GLA变异女性的疾病特征和相关管理的更广泛和最新的描述。
结果：这项回顾性研究纳入了来自12家医院的97名女性。平均年龄为50.1±17.2岁。GLA变异体鉴定的中位随访时间为36.1个月,大多数(70.1%)是通过家庭筛查确定的。与经典/非经典表型相关的变异分布相似(40.2%/53.6%)。错义变异是最普遍的(n=84,86.6%)。在整个群体中，70.4%有主要器官受累(即，心脏,肾,脑血管,周围神经系统或胃肠道)，47.3%也有典型的法布里征象(血管角化瘤，角膜斜视或血浆lyso-Gb3增加）。心脏受累是最普遍的（49.5%），也是开始治疗的主要原因。共有33名(34%)患者接受了疾病特异性治疗，其中55％是通过家庭筛查诊断的。携带与经典表型相关的变异的女性临床表现频率较高（92.3％），在治疗亚组中占主导地位（69.7％）。尽管如此,有34位未经治疗的女性（占未治疗总数的56.7％），两种表型都代表，有主要器官参与的人，有27个心脏，肾或脑血管性质。该亚组的年龄或合并症与治疗亚组相当（分别为P=0.8和P=0.8）。
结论：近年来，西班牙已经做出了及时诊断和治疗法布里女性的努力。有致病变异的女性比例很高，不管它们的相关表型，可能会患上疾病。该队列中有一部分患有严重疾病的女性接受了特定治疗。仍然有相当数量的女性，即使与被治疗的相同，根据欧洲的建议，他们可能有资格接受治疗，仍未处理。这一原因值得进一步调查。
结果：这项回顾性研究纳入了来自12家医院的97名女性。平均年龄为50.1±17.2岁。GLA变异体鉴定的中位随访时间为36.1个月,大多数(70.1%)是通过家庭筛查确定的。与经典/非经典表型相关的变异分布相似(40.2%/53.6%)。错义变异是最普遍的(n=84,86.6%)。在整个群体中，70.4%有主要器官受累(即，心脏,肾,脑血管,周围神经系统或胃肠道)，47.3%也有典型的法布里征象(血管角化瘤，角膜斜视或血浆lyso-Gb3增加）。心脏受累是最普遍的（49.5%），也是开始治疗的主要原因。共有33名(34%)患者接受了疾病特异性治疗，其中55％是通过家庭筛查诊断的。携带与经典表型相关的变异的女性临床表现频率较高（92.3％），在治疗亚组中占主导地位（69.7％）。尽管如此,有34位未经治疗的女性（占未治疗总数的56.7％），两种表型都代表，有主要器官参与的人，有27个心脏，肾或脑血管性质。该亚组的年龄或合并症与治疗亚组相当（分别为P=0.8和P=0.8）。
结论：近年来，西班牙已经做出了及时诊断和治疗法布里女性的努力。有致病变异的女性比例很高，不管它们的相关表型，可能会患上疾病。该队列中有一部分患有严重疾病的女性接受了特定治疗。仍然有相当数量的女性，即使与被治疗的相同，根据欧洲的建议，他们可能有资格接受治疗，仍未处理。这一原因值得进一步调查。
