The management and treatment of children with Fabry disease: A United States-based perspective

Highlights

• We present consensus guidelines for the management of children with Fabry disease.

• The presence of Fabry symptoms in boys and girls of any age is a strong indication for treatment initiation.

• Treatment should be initiated before irreversible end-organ damage has occurred.

• Asymptomatic children with Fabry mutations should be followed closely.

• The management of Fabry disease requires a multidisciplinary care approach.

Abstract

Fabry disease is an inherited X-linked disorder that presents during childhood in male and female patients. Young patients may initially experience pain, hypohidrosis, and gastrointestinal symptoms. Other manifestations of Fabry disease, such as renal and cardiac disease, manifest later in adolescence or adulthood. In the pediatric population, renal damage is typically subclinical and identifiable only through biopsy. Specialists from the United States with expertise in Fabry disease convened during 2013–2014 in order to develop these consensus guidelines about the management and treatment of children with Fabry disease. The presence of symptoms in boys and girls of any age is an indication to begin therapy. Early treatment before the onset of potentially irreversible vital organ pathology is ideal. Asymptomatic children with Fabry mutations should be followed closely for the development of renal, cardiac, neurological, or gastrointestinal signs, symptoms, or laboratory changes, which would warrant treatment initiation. A comprehensive care plan should be implemented by the treating physicians to guide the management of children with Fabry disease.

Introduction

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency in the enzyme α-galactosidase A (α-GAL) due to mutations in the GLA gene. This enzyme deficiency results in an accumulation of globotriaosylceramide (GL-3) and related glycolipids, which begins a cascade of events often resulting in fatal end-organ damage to the kidneys, heart, and brain [1]. The first debilitating clinical symptoms of FD emerge in childhood and include neuropathic pain, hypohidrosis, and gastrointestinal discomfort [2], [3], [4], [5], [6] (Table 1). However, the symptoms of FD in childhood may be non-specific, often resulting in a delay in diagnosis for decades [9], [10]. Early differential diagnosis of Fabry disease is therefore important, and the testing of family members and newborn screening allows patients to be diagnosed in infancy or early childhood. Once diagnosed with FD, comprehensive regular monitoring with tracking of disease progression is important and may contribute to the decision of when to start therapy.

As expected for a rare disease, large-scale, prospective randomized controlled trials testing the long-term efficacy of proactive interventions, including assertive management of symptoms and early disease-specific treatment initiation, remain limited. Nevertheless, there is broad expert-level consensus, supported by recent and emerging studies [11], [12], [13], that treatment of FD should be initiated sufficiently early to limit or prevent significant, irreversible end-organ damage. Treatment should be started early, ideally when Fabry-related symptoms emerge or significant organ pathology is detected, in order to achieve maximal impact on the long-term consequences of FD, reduce suffering, and increase quality of life.

Timely initiation of enzyme-replacement therapy (ERT) is important because some early pathological changes are potentially reversible by ERT [11]. Importantly, the impact of ERT is reduced if extensive irreversible pathological changes (e.g., fibrosis) have already occurred in major organs [12]. A 10-year study of the effectiveness of agalsidase beta in patients with classic FD has shown that adults who initiated treatment at a younger age and with less renal involvement (urine protein to creatinine ratio ≤ 0.5 g/g and < 50% sclerotic glomeruli) benefited more from therapy [13].

Females with Fabry mutations manifesting FD clinical symptoms should be managed identically to males with symptomatic FD. It has been established that females are not just carriers of GLA mutations, but that they may develop multi-organ injury similar to male FD patients [14], [15]. In addition to active symptomatic management (see below), symptomatic female patients should be treated with ERT. However, female FD patients, including those with active renal or cardiac disease for whom treatment is clearly indicated (and long overdue), are less likely to seek treatment, and they often receive treatment much later than their male counterparts [16], thus often missing a crucial window of opportunity to intervene prior to the development of irreversible end-organ damage.

This document, which began with discussions held at a meeting of the Fabry Expert Panel of United States Fabry specialists convened in November 2013, reviews current practices and available assessment techniques for the monitoring of pediatric patients with FD, and presents consensus recommendations regarding the timing of initiation of ERT and symptomatic therapies in these patients. Other than face-to-face panel discussions, no specific method was used to reach consensus among authors, and areas of disagreement are noted in the text. Although there is considerable overlap with management practices followed in other countries [17], [18], these guidelines address the practices of Fabry specialists in the United States only.