The Spanish Fabry women study: a retrospective observational study describing the phenotype of females with GLA variants

Abstract

Background 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. Results 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). Conclusions 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.

Increased cardiac involvement in Fabry disease using blood-corrected native T1 mapping

“…FD is a X-linked disorder, and men exhibit cardiac involvement earlier than women sometimes due to random X-chromosome inactivation, which possibly may lead to faster myocardial sphingolipid accumulation in men with a more marked T1 reduction as time progresses in pre LVH states 10 . In European recommendations, women should not be treated before onset of organ manifestation [21][22][23] , which likely contributes to that sex differences in treatment of FD patients still exist, as up 35% of females do not receive treatment despite having major organ involvement 24 . This is further underlined by this study: following blood-correction, T1 remained different between the sexes, suggesting sex differences in cardiac FD beyond that amended by T1 blood-correction.…”

Fabry disease in female patients: clinical features, outcomes and indications for enzyme replacement therapy

“…соответствовала таковой в нашей когорте [10]. В испанском исследовании частота поражения внутренних органов, в том числе сердца, почек, нервной системы или желудочно-кишечного тракта, у 97 пациенток в возрасте 50,1±17,2 лет с БФ составила 70,4%, а типичные признаки заболевания встречались в 47,3% случаев [11]. Наиболее частым проявлением БФ, служившим основным показанием к ФЗТ, было поражение сердца, выявленное у 49,5% пациенток.…”

Diferenças entre Duas Condições Cardíacas Hipertróficas Distintas: Doença de Fabry Versus Cardiomiopatia Hipertrófica

“… 5 , 15 , 16 As mulheres são subdiagnosticadas em ambas as doenças, talvez devido às características da doença ou aos métodos de triagem. 12 , 17 , 18 , 23 O reconhecimento e a diferenciação precoces são necessários para tratar a DF e a CMH, especialmente o envolvimento cardíaco. Consequentemente, esses distúrbios podem ser tratados precocemente, melhorando a qualidade de vida dos pacientes.…”

“… 11 Owing to random X-chromosomal inactivation, female patients may exhibit as severely as male patients or be asymptomatic. 1 - 4 , 12 The FD’s X-linked nature causes diagnostic disparities between genders. Lower a-Gal activity evaluation in male patients is diagnostic.…”

“…A-Gal A activity can be borderline or normal in females, so gene sequencing is sometimes the only way to diagnose. 12 , 13 …”