Altoon Dweck

Bone density changes with enzyme therapy for Gaucher disease

Gaucher disease is the most common lysosomal storage disease. Enzyme replacement therapy engenders improvement in hematological and visceral parameters; however, improvement in bone density (BMD) with treatment has not been confirmed. This study presents follow-up of BMD in the first ten patients in Israel treated with low-dose recombinant enzyme for up to 108 months. BMD at femoral neck and lumbar spine was determined by dual-energy X-ray absorptiometry (DEXA) at the start of the trial, after 3–6 months, after 18–24 months, and at the most recent follow-up. BMD in all patients was very low at onset and never normalized. There was a decrease in BMD in all patients at 3–6 months. Older patients (four women, two men; >30 years of age) showed some improvement in BMD during treatment. Younger patients (four females; 18–23 years of age) did not show a statistically significant improvement. These findings might reflect the failure of patients with Gaucher disease to achieve expected peak bone density at appropriate chronological milestones despite treatment. Nonetheless, the z-scores of the older patients were better than those of the younger patients, implying some catch-up period. Yet, some patients with Gaucher disease evince rapid onset of osteoporosis in early adulthood. Enzyme treatment per se, as well as attendant improved well-being and increased physical activity, may induce amelioration in BMD at this later stage. One may consider adding anti-osteoporosis therapy in young adults to induce earlier “catch up” to peak bone mass, and then enzyme replacement in later adulthood to prevent decrements in bone mass related to Gaucher cell infiltration.

Gaucher disease: pediatric concerns.

Gaucher disease, the most prevalent lysosomal storage disorder, is inherited as an autosomal recessive condition. The gold standard for diagnosis is decreased acid β-glucosidase activity in the lymphocytes or fibroblasts; molecular analysis of mutations allows for some prognostication of disease severity. Prenatal diagnosis and carrier testing for at-risk families are currently available.There is tremendous phenotypic heterogeneity in the non-neuronopathic form (type I), ranging from clinically asymptomatic to massive hepatomegaly, hypersplenism, growth retardation in children and extensive involvement of bone and lungs. Presence on one allele of the most common mutation, N370S, which is the most prevalent among Ashkenazi Jews for whom there is a predilection for Gaucher disease, is protective of neurological involvement. Some mutations, such as 84GG and IVS2+1, are associated with more severe disease manifestations when appearing as compound heterozygotes with N370S, but when occurring in the homozygous state are not compatible with life. Other mutations, such as L444P, are associated with severe non-neurological disease when occurring as compound heterozygotes with N370S, but when occurring in the homozygous state may be predictive of neurological disease of either acute (type II) or subacute (type III) forms.In the past decade, enzyme replacement therapy has become available which has resulted in a reduction in liver and spleen volume and consequently improved anemia and thrombocytopenia in most patients. It has also engendered catch-up growth in many children, induced improvement in lung involvement secondary to Gaucher disease, and to some extent ameliorated episodes of bone pain. By virtue of treatment, many children who may have been severely affected no longer need to undergo splenectomy to treat hypersplenism, and therefore they are not at risk of bone involvement consequent to the loss of the preferred reservoir for lipid-laden ‘Gaucher cells’. However, enzyme treatment is ineffective in reversing neurological signs, requires a lifelong commitment to intravenous infusions, thereby reducing quality of life, and is relatively expensive for many national health schemes. Hence, alternative forms of treatment, such as substrate balance, are being explored. Symptomatic management, including orthopedic surgery, pain relief for bone pain and even splenectomy, still has importance for patients with Gaucher disease. In addition, there is the potential for bone marrow transplantation and, in the future, gene therapy to be curative, particularly for patients with the neuronopathic forms.

TYPE I GAUCHER DISEASE IN CHILDREN WITH AND WITHOUT ENZYME THERAPY

This retrospective study describes the course of 56 children with non-neuronopathic Gaucher disease who presented at <16 years and were followed at 6- to 12-month intervals for 3-9 years. Massive splenomegaly and height retardation marked those who required treatment. Enzyme replacement significantly increased hemoglobin levels; platelet counts were divergent at presentation and follow-up, regardless of therapy. Among treated patients there was a significant reduction in liver and spleen index volumes, and a significant increase in height z-scores. None of the children required splenectomy or developed lung involvement. Many patients diagnosed due to large-scale screening were very mildly affected and remain untreated.

Thrombocytosis Associated with Enzyme Replacement Therapy in Gaucher Disease

We describe a patient with an intact spleen and moderately severe symptoms of Gaucher disease in whom, after initiation of (low-dose) enzyme replacement therapy (ERT), thrombocytosis (720 × 109/l) was documented. Checking the International Gaucher Registry database revealed that this patient is the only nonsplenectomized patient of more than 1,000 treated patients to experience ERT-induced thrombocytosis. Platelet counts dropped immediately after the discontinuation of ERT.