Children and adolescents with fabry disease

Abstract

Despite the observation that severe clinical signs and symptoms, with the exception of neuropathic pain and gastrointestinal symptoms, are rare in pediatric patients with Fabry disease, studies have shown extensive organ involvement in all pediatric patients. A recent study of renal biopsy findings in children and adolescents with Fabry disease (7 males, 2 females; age range, 7-18 years), all with normal estimated glomerular filtration rate (eGFR), found GL-3 accumulation in all patients and a broad spectrum of abnormalities, including glomerular, tubulointerstitial, and vascular changes, in many patients.? Another study in 20 children and adolescents (12 fe­ males, 8 males; age range, 6-16 years), without any overt cardiac signs or symptoms, found that all patients had a left ventricular mass indexed to height greater than the 75th percentile of healthy controls. 8 In addition, this study reported that heart rate variability in all male patients was significantly lowered (P < 0.05), suggesting a reduced parasympathetic stimulation of the heart. Results of these studies support the claim that pediatric pa­ tients with Fabry disease can have extensive renal and cardiac involvement, albeit subclinical, in addition to the overt neuropathic and gastrointestinal signs and symptoms. Enzyme replacement therapy (ERT) has been found to be well tolerated 9 ,!O and to reduce GL-3 accumulation in the dermal capillary endothelium 9 in pediatric patients with Fabry disease. However, the optimal age at which ERT should be initiated has not yet been determined. Research in adult patients with mild to moderate kidney disease found that ERT slowed the progression of the disease and was more effective in patients with less severe renal involvement, as determined by eGFR values.!! This finding supports the notion that initiation of ERT before substantial-and potentially irreversible---damage has occurred will provide greater clinical benefit. Extensive GL-3 accumulation may be present in pediatric patients with Fabry disease from an early age, result­ ing in demonstrable functional abnormalities in many patients; therefore, investigating whether initiating ERT during childhood (at least in male patients) might prevent disease progression appears justified. In addition, if ERT is started at an early stage of the disease, various dosage or dosing intervals may be efficacious. A random­ ized, multicenter, open-label study was recently initiated to evaluate the efficacy and tolerability of treating male pediatric Fabry disease patients without severe symptoms using a low-dose regimen of ERT (agalsidase beta 0.5 mg/kg every 2 weeks vs 1 mg/kg every 4 weeks).!2 This study was started in October 2008, and the goal is to include 45 patients. The study's estimated primary completion date is December 2014. In conclusion, Fabry disease can have serious clinical signs and symptoms during childhood which necessitate vigorous follow-up studies so that ERT can be initiated before irreversible damage has occurred. Studies on the efficacy of early intervention in children are greatly needed.