Persistent bone disease in adult type 1 Gaucher disease despite increasing doses of enzyme replacement therapy.

In Gaucher disease type I (GD, OMIM #230800), deficient activity of the enzyme glucocerebrosidase results in hepatosplenomegaly, cytopenia and skeletal disease. Skeletal disease leads to chronic bone pain and/or severe complications such as pathological fractures, avascular necrosis and bone crises. Enzyme Replacement Therapy symptoms of the disease with doses ranging between 15 and 120 U/kg/4weeks. Recently, it has been shown that high dose ERT results in a more robust response in Gaucher associated markers, such as chitotriosidase and the bone marrow burden score. 2 Although symptomatic bone disease is usually treated with a relatively high dose (60-120 U/kg/4weeks), bone marrow involvement may persist. 2 Whether it is useful to continue high dose or increase the dose in these cases is currently unknown. We describe one illustrative case and compared GD patients with and without persistent bone disease with respect to disease markers and the effect of dose. A male patient was diagnosed with GD (genotype N370S/ G202R) at the age of 19 because of persistent splenomegaly during an EBV infection. His first bone crisis occurred at the age of 22 followed by recurrent crises in the femurs, lumbar spine and septic arthritis of his right knee. Splenectomy was performed at age 25 because of gross splenomegaly. ERT was started in 1991 (40 U/kg/4weeks) and normalization of liver volume and modest decrease in chitotriosidase was observed. No new bone complications occurred, although bone pain persisted. Therefore, the dose of ERT was increased step-wise to 120 U/kg/4weeks. After 14 years of ERT, chi-totriosidase was still high (8018 nmol/mL/hr) and bone marrow fat fraction low. In 2007 he underwent hip replacement. Pathology of the femoral head showed minimal hematopoietic tissue, large necrotic areas in the center and extensive fields of Gaucher cells (Figure 1). The files of all adult patients at the Academic Medical Centre receiving ERT for >5 years (N=40), were reviewed. Data on age, sex, splenectomy, severity score index (SSI) 3 , weight, hemoglobin, platelet count, liver and spleen volume, QCSI, chitotriosidase, dose and bone complications were collected. Bone response was defined as follows: adequate skeletal response (Group 1): absence of bone complications and chronic bone pain during ERT; treatment failure (Group 2): occurrence of bone complications (avascular necrosis, bone crisis or pathological fractures) or chronic bone pain (requiring analgesics and attributable to GD in the opinion of the physician) during ERT. Chitotriosidase activity was measured as previously described. 4 Liver …