Abstract
Fabry disease (FD), a rare X‐linked disease, can be treated with bi‐monthly infusion of enzyme replacement therapy (ERT) to replace deficient α‐galactosidase A (AGAL‐A). ERT reduces symptoms, improves quality of life (QoL), and improves clinical signs and biochemical markers. ERT initiation in childhood could slow or stop progressive organ damage. Preventative treatment of FD from childhood is thought to avoid organ damage in later life, prompting a French expert working group to collaborate and produce recommendations for treating and monitoring children with FD. Organ involvement should be assessed by age 5 for asymptomatic boys (age 12‐15 for asymptomatic girls), and immediately for children diagnosed via symptoms. The renal, cardiac, nervous and gastrointestinal systems should be assessed, as well as bone, skin, eyes, hearing, and QoL. The plasma biomarker globotriaosylsphingosine is also useful. ERT should be considered for symptomatic boys and girls with neuropathic pain, pathological albuminuria (≥3 mg/mmol creatinine), severe GI involvement and abdominal pain or cardiac involvement. ERT should be considered for asymptomatic boys from the age of 7. Organ involvement should be treated as needed. Early diagnosis and management of FD represents a promising strategy to reduce organ damage, morbidity and premature mortality in adulthood.
Highlights
Fabry disease (FD; OMIM#301500) is a rare X-linked lysosomal disease caused by pathogenic variants in the GLA gene
enzyme replacement therapy (ERT) initiation criteria currently follows the current Summary of Product Characteristics (SmPC) that indicates treatment initiation from the age of 7 or 8 years or over, in the absence of data in younger population. It is the opinion of this group that asymptomatic boys may benefit from an earlier initiation of ERT based on the following criteria: presence of a pathogenic GLA variant responsible for the classic phenotype, family history of disease severity in males, undetectable AGAL-A activity in peripheral blood leukocytes and plasma lysoGb3 over 20 nmol/L
Opinion diverges regarding the age of ERT initiation in asymptomatic boys, with recommendations ranging from 8-10 years in the 2016 US guidelines[38] to 10-13 years in the 2006 international guidelines[32] to 16 years in the 2015 European guidelines.[34]
Summary
Fabry disease (FD; OMIM#301500) is a rare X-linked lysosomal disease caused by pathogenic variants in the GLA gene. Children do not suffer from renal insufficiency until adulthood, when renal failure accounts for much of the morbidity and mortality associated with FD, in males.[57] Accumulation of Gb3 in kidney cells and podocytes foot process effacement can be observed in kidney biopsies from children with FD, even before pathological albuminuria and proteinuria manifest as early signs of renal involvement.[25,58,59] Performing routine renal biopsy in children remains an area of debate within the community of physicians involved in the care of patients with FD.[57] Renal biopsy has been proposed and shown to be safe by several authors[57,58,59,60] and should be considered in selected paediatric cases, when the decision to start ERT is questioning or in children with significant proteinuria or decline in renal function; in whom renal biopsy is essential to rule out a second renal disease.[38]. Monitoring (annual in boys, every 2-3 years in girls, unless otherwise indicated) X X X (for children aged >5 years) X (if no renal involvement at baseline) X X (for boys and girls with renal involvement at baseline) X X — X X If indicated by baseline ECG; optional depending on symptoms and clinical availability of test from aged 15
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