Clinical management of female patients with Fabry disease based on expert consensus

Abstract

Fabry disease is an X-linked lysosomal storage disorder that causes accumulation of glycosphingolipids in body tissues and fluids, leading to progressive organ damage and life-threatening complications. It can affect both males and females and can be classified into classic or later-onset phenotypes. The disease severity in females ranges from asymptomatic to the more severe, classic phenotype. Most females are hemizygous and the X-linked inheritance is associated with variable X-activation pattern and residual enzymatic activity. The heterogeneity of clinical presentation in females requires different approaches to diagnosis and management than males. A European group of 7 physicians, experienced in the management of Fabry disease, convened to discuss patient perspectives and published guidelines. The experts discussed the need to focus on psychological treatment in relation to individual coping styles when monitoring targets, and the lack of data supporting the use of plasma globotriaosylsphingosine over enzyme activity in the diagnosis of these patients. It was suggested that the high phenotypic variability in female patients may be related to the dynamic nature of the X-chromosome inactivation process and further understanding of this process could help predict the progression of Fabry disease in females and facilitate timely intervention. Due to the range of disease severity they exhibit, female patients with Fabry disease may require a more individualized treatment approach than males. Despite current recommendations, the experts agreed that early disease-specific treatment initiation in high-risk females could improve clinical outcome.

Background

Fabry disease (FD; OMIM 301500) is a rare, X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene encoding the enzyme α-galactosidase A (α-Gal A) [1]. Deficient or absent α-Gal A enzyme and the subsequent lysosomal accumulation of glycosphingolipids cause progressive organ damage with life-threatening complications and increased risk of premature death [2].

FD can be broadly classified into two phenotypes: “classic” and “non-classic” (including later-onset) [2]. The phenotypic variability of disease manifestations is high in female patients, with symptoms/manifestations usually occurring later in life and exhibiting slower disease progression [3]. Clinical experience of females carrying GLA pathogenic variants has shown a range of phenotypes – from an asymptomatic to a severe classical phenotype, with cardiac, renal, and neurologic involvement, as well as impaired quality of life (QoL) [4, 5]. In addition, among female patients with FD bearing the same mutation, different organs can be affected to different degrees.

This variability could be, in part, due to the proportion of random X-chromosome inactivation (XCI) of the X chromosome carrying the allele with pathogenic mutation which may differ between individuals globally or even within a particular organ in the same individual [6, 7]. In the case of FD, there are conflicting results regarding the XCI profiles of heterozygous females [8]. A possible explanation for the apparent discrepancies is offered by emerging evidence on the dynamic nature and complexity of the XCI phenomenon and potential methodological issues in XCI assessments [6, 7].

Since 2001, enzyme replacement therapy (ERT) with human α-Gal A has been the mainstay of FD-specific treatment to prevent or slow disease progression and in 2016, in Europe, a chaperone therapy was granted marketing authorization for treatment in patients with amenable GLA variants [9, 10]. More recently, the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have approved a pegylated ERT (pegunigalsidase alfa) for the treatment of adults with confirmed FD [11, 12]. Due to the heterogeneous clinical picture of female patients with FD, including those affected females with near normal or normal plasma α-Gal A activity, the optimal time for treatment initiation remains controversial. Current guidelines and recommendations suggest ERT should be initiated after the onset of the first FD-typical renal, cardiac, and/or cerebral clinical manifestations in female patients with classic mutations [2, 13]. However, published evidence has shown ERT to be most effective when started before the onset of irreversible tissue damage [2].

Seven European clinical experts were presented with the results of interviews with female patients with FD conducted by Sanofi (details of which are presented in Supplementary Material). They discussed current guidelines and reasonable response to therapy relevant to female patients with the aim of developing a set of organ-specific management goals for these patients. As the presentation and severity of FD in females is variable, this report aims to provide expert opinion and guidance on the management of females with FD, based on published evidence and insights into the experience of these patients.

Published guidance on management and monitoring of females with FD

The diagnosis of FD should involve a detailed patient history, family history, physical examination, genetic testing, and identification of clinical and biochemical findings suggestive of FD [14]. The clinical manifestations and symptoms suggestive of FD in female patients are summarized in Table 1. In patients with a genetic variant of unknown significance or in patients where it is difficult to interpret the GLA variant (e.g., non-specific clinical manifestations or symptoms), family segregation, manifestations in a male family member, as well as various imaging procedures, renal and/or skin biopsy, and expert consultation, may be useful to confirm or exclude the pathogenic nature of the GLA variant [15]. In addition, blood concentrations of globotriaosylsphingosine (lyso-GL3), a deacylated form of the main storage molecule globotriaosylceramide (GL3) and a biologically active and water-soluble marker, may be used to stratify high-risk patients who require intensive monitoring and treatment [16]. Although not all female patients will exhibit a high plasma lyso-GL3 concentration [17, 18], studies by Ouyang et al. and Duro et al. found that plasma lyso-GL3 concentrations can be more useful than enzyme assays in diagnosing female patients with FD [18, 19]. However, it is important to note that the data supporting the use of plasma lyso-GL3 over enzyme activity in the diagnosis of these patients is limited. Additional biomarkers for monitoring cardiac and renal disease in all patients with FD can be found in the recent expert consensus paper by Burlina et al. on the recommendations for the use of biomarkers in FD and appear in Table 1 [20]. It is important to note that although female patients tend to have a milder disease phenotype than men, they can still experience cardiac manifestations but these generally appear later in life compared to men [21]. Furthermore, female patients may develop myocardial fibrosis without the accompanying hypertrophy observed in men, which can complicate diagnosis and monitoring [22].

Table 1 Clinical findings suggestive of Fabry disease and differential diagnosis for female patients with Fabry disease

Current guidelines recommend that female patients with FD should be treated when the first clinically relevant Fabry disease-associated manifestations occur. Evidence from studies of patients receiving ERT suggests that early diagnosis and timely initiation of therapy can prevent further disease progression which could otherwise lead to irreversible tissue damage and organ failure [2]. The initiation of treatment depends on a patient’s sex, phenotype, and the manifestation of signs and symptoms characteristic of FD. However, due to the range of disease severity they exhibit, female patients with FD may require a more individualized treatment approach than males (Table 2) [2]. The degree of patient monitoring is influenced more by disease severity than by type of treatment. Patients are classed according to their stage of renal disease based on the Kidney Disease Improving Global Outcomes guideline for the management of glomerular diseases [23]. Patients should therefore be monitored at appropriate intervals to effectively track disease progression, particularly adult patients without FD-related clinical symptoms, and guidance suggests that a switch in therapy may be appropriate in patients who do not achieve their treatment goals [2, 24,25,26].

Table 2 Organ-specific management goals for females with Fabry disease based on published guidelines and expert opinion [2, 35, 36]

Expert opinion on treatment and management goals: results from the clinical experts’ advisory board

The advisors discussed the guidelines and their experience in diagnosing, treating, and monitoring female patients with FD. All advisors agreed that genetic testing to identify GLA gene variants and blood tests measuring activity of α-Gal A enzyme and lyso-GL3 concentrations are key examinations used to aid the diagnosis of FD in all patients. Most clinical experts (n = 5/7) agreed that lyso-GL3 could be a relevant prognostic marker for assessing disease severity and progression; however, it is currently only validated for use in diagnosis. The experts noted that the decrease in lyso-GL3 after treatment initiation is typically steeper in males than in females, which may be explained by males having a higher baseline lyso-GL3 value.

For female patients with FD, cardiac disease was the feature most mentioned, although it was noted that disease features can vary between individuals depending on age and type of variant. Additionally, the experts agreed that if any patient presents with low estimated glomerular filtration rate (eGFR) without albuminuria/proteinuria, the underlying cause is less likely to be FD and requires detailed investigation (Table 3). Early organ involvement and treatment-refractory neuropathic pain were the most frequently mentioned reasons for initiating treatment in female patients with FD. The clinical experts concluded that the extent of monitoring depends on the degree of organ involvement; stable patients on treatment are monitored annually, symptomatic patients with disease progression twice per year, and untreated, asymptomatic, stable female patients every other year (Table 3). Encouragingly, most experts within this group believe that female patients with FD are being treated according to current guidelines.

Table 3 Recommended monitoring schedule in female patients with Fabry disease based on guidelines and expert opinion [2, 24, 25]

Future perspectives

Importance of genetic counseling and psychological support

Psychological symptoms such as depression are highly prevalent in patients with FD. A study by Ali et al. reported a beneficial outcome from psychological treatment, with improvements in mental health and QoL in eight female patients with FD [27]. Based on this evidence and the interview responses of patients with FD, the experts agreed there is a clinical need for monitoring goals to emphasize psychological treatment tailored to individual coping styles.

XCI may help predict the progression of FD in females and facilitate timely intervention

Phenotypic variability of disease is high in female patients. This could be, in part, due to tissue-specific differences in XCI in the same individual, which may be related to cell-specific XCI [6, 7]. In the case of FD, there are conflicting results regarding the XCI profiles of heterozygous females, resulting in variable GLA gene expression [8]. A possible explanation of such apparent discrepancies is offered by emerging evidence on the dynamic nature and complexity of the XCI process, which may have more impact than previously believed [6]. This complexity includes a proportion of genes escaping XCI, tissue-specific and cell-to-cell differences of the XCI process, and the intricate gene-specific and gene region-specific role of DNA methylation, which influences gene expression, exerted on both active X (Xa) and inactive X (Xi) chromosomes [6]. A study conducted by Echevarria et al. found that patients with skewed XCI ratios and predominant expression of the pathogenic GLA allele had very low or absent residual enzyme activity [8]. This study also revealed a significant and calculable correlation between the XCI direction observed in the blood with that present in other tissues studied (skin, buccal smears, urinary epithelia). Significant differences in residual α-Gal A, disease severity scores, and cardiac and renal disease, dependent on the direction and degree of skewing, were also identified, implying that XCI could significantly impact the phenotype and natural history of FD in female patients [8].

The existence of skewed XCI in females with FD was demonstrated by analyzing the human androgen receptor (HUMARA) gene; this revealed the existence of skewed inactivation in 16 heterozygous females correlating with FD severity scores [8, 28].

A study conducted by Hossain et al. demonstrated a correlation between the methylation state of the wild-type GLA allele and the early onset and severity of disease manifestations in a heterozygous female with acroparesthesia, facial dysmorphism, left ventricular hypertrophy, and intellectual disability, in addition to a proven family history particularly relevant to FD [29]. Another study found a correlation between disease severity, lyso-GL3 accumulation, and methylation of the normal allele [28].

Most studies investigating the role of DNA methylation in FD defined the extent and direction of XCI through HUMARA testing as it is inexpensive and fast [6]. However, it is important to note that HUMARA testing cannot distinguish between the two chromosomes and thus it cannot predict disease outcome in a female patient with very skewed XCI. In addition, allele-specific DNA methylation at the promoter region of the GLA gene may also influence expression levels of the mutated allele, impacting the onset and progression of FD [6]. Therefore, approaches that distinguish between the mutated and non-mutated allele when analyzing DNA methylation at the GLA promoter may be much more informative [6]. Řeboun et al. studied XCI in 35 female patients with FD using two methylation-based and two allele-specific expression assays in combination with GLA expression analyses, and enzyme activity [7]. This study showed a good concordance of methylation and allele-specific expression assays for assessment of XCI in females with FD. Furthermore, Řeboun et al. found correlating XCI to GLA expression and α-Gal A activity facilitated identification of crossing-over between the loci used for methylation assays and the GLA locus. Combining XCI assays, GLA expression analyses, and enzyme activity may potentially minimize technical and biological pitfalls [7].

The hope for the future is that ad hoc and ultra-deep methylation analyses of the GLA gene will provide epigenetic signatures that will help predict the disease course for females with FD, thus allowing timely interventions.

Conclusions

In conclusion, the clinical heterogeneity of FD requires an individualized approach to patient care that reflects the genotype, sex, age, family history, phenotype, and specific clinical disease severity of each patient. The management of female patients with FD should involve timely disease-specific treatment (ERT or chaperone therapy, as appropriate), regular assessment of disease progression in all patients, and the use of a multidisciplinary care team to assist in the management of organ-specific complications. Currently, ERT is the cornerstone of therapy, however, randomized trials demonstrate that migalastat may also be prescribed for female patients with amenable mutations although, the response may not be uniform depending on residual enzymatic activity and degree of amenability [30]. Despite growing evidence that the clinical response to treatment in high-risk females is improved with early treatment initiation, current guidelines suggest treatment in females should be initiated after the first signs of cardiac and/or renal disease, central nervous system involvement, gastrointestinal symptoms, and/or rapidly progressive disease. Future observational studies should aim to evaluate the prognostic value of elevated plasma lyso-GL3 for ERT initiation, as a way to avoid delay in treatment initiation is considered an unmet need. In addition, psychological support during the diagnosis, management, and monitoring of FD should be offered to all patients.

In future, ad hoc and ultra-deep methylation analyses of the GLA gene should provide epigenetic signatures predictive of whether female heterozygotes will develop disease-specific symptoms, identifying opportunities for timely therapeutic intervention. Further education and increased awareness of the signs and symptoms, diagnosis, management, and monitoring of FD is needed among healthcare professionals and the public so that female patients with FD can be better supported.