ReviewEuropean expert consensus statement on therapeutic goals in Fabry disease
Section snippets
List of abbreviations
ACEi angiotensin-converting-enzyme inhibitor ARB angiotensin II receptor blocker BPI Brief Pain Inventory CKD chronic kidney disease CNS central nervous system ECG electrocardiogram eGFR estimated glomerular filtration rate EOW every other week ERT enzyme replacement therapy ESKD end-stage kidney disease EQ-5D EuroQoL 5 Dimensions questionnaire FOS Fabry Outcome Survey GFR glomerular filtration rate GL-3 globotriaosylceramide GSRS Gastrointestinal Symptom Rating Scale lyso-GL-3 globotriaosylsphingosine LV left
Methods
A European panel of experts was established with the objective of developing a set of detailed, organ-specific therapeutic goals for Fabry disease based on expert consensus and a systematic literature review that included articles published up to and including January 2017 [[3], [4], [5], [6]]. The development of the therapeutic goals was guided by a number of key questions:
- 1.
What are the relevant clinical parameters that should be considered?
- 2.
What is a reasonable response to therapy, and how
Plasma GL-3
Plasma GL-3 is the most widely available indicator of glycosphingolipid load in patients with Fabry disease, although it must be noted that because of their heterozygosity for Fabry mutations and their X-chromosome inactivation patterns, the majority of female patients have normal plasma GL-3 levels [7]. Evidence from placebo-controlled clinical trials indicates that ERT can reduce or normalize plasma GL-3 levels [[8], [9], [10], [11]] but no prospective studies have been carried out to date to
Heart involvement
Cardiac manifestations are common in Fabry disease, occurring in 40–60% of patients [[37], [38], [39], [40], [41]]. The spectrum of cardiac complications is similar in both the classic and the later-onset cardiac phenotype and includes left ventricular hypertrophy (LVH), conduction abnormalities, bradycardia and chronotropic incompetence, supraventricular and ventricular tachyarrhythmias, myocardial fibrosis, valve disease, and microvascular dysfunction [42,43].
Cardiac complications are the
Kidney involvement
The cellular kidney pathology is associated with progressive CKD with increasing albuminuria leading to overt proteinuria and reduced GFR, ultimately progressing to end-stage kidney disease (ESKD), if untreated [77]. Microscopic haematuria and nephrotic proteinuria are relatively uncommon manifestations of Fabry nephropathy. The renal complications of Fabry disease are key contributors to the morbidity and mortality associated with the disorder [78]. Effective management of underlying kidney
Brain and peripheral nervous system involvement
The first neurological symptoms of Fabry disease occur in the peripheral nervous system (PNS) as a result of damage to neurons. Small, unmyelinated or thinly myelinated nerve fibres are particularly affected and small fibre peripheral neuropathy contributes to peripheral neuropathic pain (chronic and acute excruciating pain), and accounts for dysaesthesias, deficits of thermal sensation and of physiologic pain perception, neuropathic pain, impaired sweating, GI dysmotility, and other sensory
Dermatological abnormalities/angiokeratoma
Dermatological abnormalities have been reported to be present in 78% of males and 50% of females with the classic phenotype of Fabry disease [157]. Angiokeratoma is the most common dermatological abnormality occurring in 66% of males and in 36% of females, and is the most visible early clinical feature of classic Fabry disease. They typically appear as either single or groups of superficial small reddish purple skin lesions that increase in number and size with age [157,161]. Lesions appear on
QoL in Fabry disease
Systematic review of clinical evidence has confirmed that patients with Fabry disease have a lower QoL compared with the general population [178]. Factors that reduce QoL in Fabry disease include Fabry-related chronic pain and pain crises, GI symptoms, hearing loss, physical inactivity, and fatigue. Importantly, the burden of organ damage also severely affects QoL. Experts note, however, that a diagnosis of Fabry disease followed by a treatment plan may improve QoL in some patients because of
Discussion and concluding remarks
The therapeutic goals in this review represent the consensus from a European panel of experts and knowledge from recent clinical studies. It is hoped that these goals will help establish an individualized approach to the management of patients with Fabry disease. The goals presented in this paper are intended to be used in conjunction with the consensus recommendations on best practice management of patients with Fabry disease with ERT [183,184]. Moreover, it is important that as our
Disclosures
The development of this publication and the meetings of the European expert panel were sponsored by Sanofi Genzyme. The authors received editorial/writing support in the preparation of this manuscript from Rosalie Gadiot, PhD, and Tom Rouwette, PhD, of Excerpta Medica, which was funded by Sanofi Genzyme. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this publication.
Conflicts of interest
- •
Christoph Wanner has received research support from Sanofi Genzyme; is a consultant for Actelion Pharmaceuticals, Protalix, Boehringer Ingelheim, and Sanofi Genzyme; is a member of the European Advisory Board of the Fabry Registry.
- •
Michael Arad has received travel support from Sanofi Genzyme and Shire.
- •
Ralf Baron has received speaker honoraria from Astellas, Bayer-Schering, Boehringer Ingelheim Pharma, Desitin, Eisai, Grünenthal, Lilly, Medtronic Inc. Neuromodulation, MSD, Mundipharma, Pfizer,
References (195)
- et al.
Fabry disease peripheral blood immune cells release inflammatory cytokines: role of globotriaosylceramide
Mol. Genet. Metab.
(2013) - et al.
Long-term safety and efficacy of enzyme replacement therapy for Fabry disease
Am. J. Hum. Genet.
(2004) - et al.
Non-invasive screening method for Fabry disease by measuring globotriaosylceramide in whole urine samples using tandem mass spectrometry
Mol. Genet. Metab.
(2005) - et al.
Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease following enzyme replacement therapy
Biochim. Biophys. Acta
(2011) - et al.
Treatment of Fabry disease with different dosing regimens of agalsidase: effects on antibody formation and GL-3
Mol. Genet. Metab.
(2008) - et al.
Influence of antibody formation on reduction of globotriaosylceramide (GL-3) in urine from Fabry patients during agalsidase beta therapy
Mol. Genet. Metab.
(2007) - et al.
Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma
Clin. Chim. Acta
(2015) - et al.
Renal biopsy findings in children and adolescents with Fabry disease and minimal albuminuria
Am. J. Kidney Dis.
(2008) - et al.
Progressive podocyte injury and globotriaosylceramide (GL-3) accumulation in young patients with Fabry disease
Kidney Int.
(2011) - et al.
Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy
Kidney Int.
(2002)