Enzyme replacement therapy and monitoring for children with type 1 Gaucher disease: consensus recommendations (original) (raw)

2004, The Journal of Pediatrics

ype 1 Gaucher disease is the most common lysosomal storage disease and the most common genetic disorder among persons of Ashkenazi Jewish descent. It is caused by deficiency of the enzyme glucocerebrosidase, which is necessary for the intralysosomal catabolism of glucocerebroside (GC), and is inherited in an autosomal recessive fashion. 1,2 This results in accumulation of GC (most of which is derived from phagocytosed cell membranes) in the lysosomes of monocyte-derived macrophages in tissues of the reticuloendothelial system. 3,4 Accumulation in the Kupffer cells of the liver and in splenic macrophages is associated with enlargement of these organs. The resulting hypersplenism produces progressive anemia and thrombocytopenia. Accumulation of GC in bone marrow is associated with osteopenia, lytic lesions, pathologic fractures, chronic bone pain, acute episodes of excruciating ''bone crisis,'' bone infarcts, and osteonecrosis. Although anemia and thrombocytopenia may be severe, it is usually bone disease that results in the greatest morbidity and long-term disability. Type 1 Gaucher disease responds well to enzyme replacement therapy (ERT) with recombinant human macrophage-targeted recombinant human glucocerebrosidase (imiglucerase, Cerezyme, Genzyme Corporation, Cambridge, Mass). 5-7 Treatment results in breakdown of stored GC, reduction in liver and spleen size, amelioration or resolution of anemia and thrombocytopenia, decreased bone pain, and increased bone mineralization and remodeling over a period of several years. 7-9 Although type 1 Gaucher disease is often referred to as the ''adult type,'' the age of onset and rate of progression vary widely, and more than half of all patients are diagnosed before the age of 10 years. Among those diagnosed before age 10, 68% are diagnosed even before age five. 10 When children with type 1 Gaucher disease exhibit symptoms, the disease is more severe, requiring more frequent monitoring and early intervention. In addition to the effects of the disease described previously, children with type 1 Gaucher disease are frequently growth-restricted and have delayed onset of puberty; 50% of symptomatic children are at or below the third percentile for height, and another 25% are shorter than expected based on their midparental height. 11 The organomegaly is particularly noticeable in young children, who often have markedly protuberant abdomens. Chronic pain and fatigue may affect school performance and participation in physical activities. That children with type 1 Gaucher disease are different than adults with this disorder is also evident from the genotypes observed (Table I). Homozygosity for the N370S mutation, commonly found in mildly affected adults, is much less common in symptomatic children. In contrast, genotypes including the 84GG or L444P alleles, typically associated with more severe disease, are more common in patients who exhibit signs of Gaucher disease during childhood, than in patients who first exhibit symptoms later in life.