Pediatrics: implementing the promise of early intervention for fabry disease

Pediatrics: implementing the promise of early intervention for fabry disease

Clinical Therapeutics/Volume 29, Supplement A, 2007 Pediatrics: Implementing the Promise of Early Intervention for Fabry Disease Annick Raas-Rothschil...

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Clinical Therapeutics/Volume 29, Supplement A, 2007 Pediatrics: Implementing the Promise of Early Intervention for Fabry Disease Annick Raas-Rothschild, MD

Department of Human Genetics, Hadassah-Hebrew University Hospital, Ein Kerem, Jerusalem, Israel Fabry disease (FD) is an X-linked sphingolipidosis that is treatable with enzyme replacement therapy (ERT). The revitalized interest among the medical community in patients with FD, who now come to the clinic to receive therapy, has resulted in new clinical insights. Novel therapy dilemmas have also emerged, particularly in the field of pediatrics. Early diagnosis and treatment of FD may provide the opportunity to clear the accumulated substrate and prevent further accumulation before irreversible cell and organ damage has occurred. But what is meant by "early treatment"? Should we treat a newborn who was just diagnosed based on family history, or wait for symptoms to appear? The limited understanding of the underlying pathophysiology and the lack of accurate biomarkers suggest a conservative approach to initiating treatment when children are symptomatic. All the treated patients reported in the Fabry Registry ( were symptomatic; most of them were boys aged >8 years (as of October 2006). In our experience, family history has been the most effective tool for early diagnosis, and we therefore recommend that a medical geneticist be included in the multidisciplinary team treating the patient with FD. However, educational efforts should be directed at pediatricians, as the diagnosis of FD in children is possible, even if it is not straightforward. The pediatric phenotype of FD was recently reported in detail) -3 The most recent data from the Fabry Registry (October 2006) found that first symptoms had occurred at the mean (SD) age of 6.5 (3.3) years among 113 boys and at 8.3 (3.9) years in 46 girls. Among the pediatric symptoms, acroparesthesia is the most frequent, followed by skin manifestations (hypohidrosis, angiokeratoma) and the less-recognized gastrointestinal symptoms. Identification of baseline abnormalities is essential for evaluating the severity and progression of the disease. We recommend a brain magnetic resonance imaging scan and a detailed cardiologic evaluation using tissue velocity and strain rate imaging. The kidney evaluation should be conducted in a consistent manner and adapted to the pediatric population. We propose establishing an international severity score adapted to children that will include the physical, emotional, and cognitive developmental aspects. Recent studies suggest that ERT for children with FD is safe and effective. An open-label study done in Europe included 16 patients (14 boys, 2 girls) using agalsidase betaa and another study used agalsidase alfa in 24 patients (19 boys, 5 girls), s Results from both studies concluded that treatment is well tolerated and efficacious in children. We already have long-term experience with one boy receiving home therapy using agalsidase beta, with no adverse reactions, good compliance, and no additional school absences (A. Raas-Rothschild, MD, unpublished data, January 2007). In summary, we recommend treating symptomatic children when they are old enough to understand and cooperate with the team, and when their family is ready to cope with a chronic IV treatment. We should keep in mind that the treatment burden should be less than the disease burden. Future challenges include finding the optimal dose for effective treatment, discovering accurate biomarkers, and establishing pediatric guidelines to accurately evaluate the treatment efficacy in children affected with FD.

REFERENCES 1. Ries M, Ramaswami U, Parini R, et al. The early clinical phenotype of Fabry disease: A study on 35 European children and adolescents. EurJ Pediatr. 2003;162:767-772. 2. Ries M, Gupta S, Moore DF, et al. Pediatric Fabry disease. Pediatrics. 2005;115:e344-e355. 3. Desnick RJ, Brady RO. Fabry disease in childhood.J Pediatr. 2004;144(Suppl 5):$20-$26. 4. Vijay S, Wraith JE, Germain DP, et al. An international open-label study offabrazyme (recombinant alpha galactosidase A) therapy in pediatric patients with Fabry disease. Preliminary results. Presented at: 6th European Round Table on Fabry Disease; October 21-22, 2005; Geneva, Switzerland. 5. Ries M, Clarke JT, Whybra C, et al. Enzyme-replacement therapy with agalsidase alfa in children with Fabry disease. Pediatrics. 2006;118:924-932.

Address correspondence to: Annick Raas-Rothschild, MD, Department of Human Genetics, Hadassah-Hebrew University Hospital, Jerusalem 91120. E-maih [email protected] Printed in the USA.Reproductionin wholeor part is not permitted. Copyright¬© 2007 ExcerptaMedica,Inc.


ClinTher.2007;29(SupplA):S6 0149-2918/$32.00

Volume 29 SupplementA