Gaucher Disease

Abstract

Gaucher disease, the most prevalent lysosomal storage disorder, is inherited as an autosomal recessive condition. The gold standard for diagnosis is decreased acid beta-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.

Gaucher disease in Syrian children: common mutations identification and clinical futures

“…Diagnosis depended on clinical presentation and laboratory findings compatible with GD. 7 These included the presence of organomegaly, neurologic signs, growth failure, blood cytopenia, and high level of acid phosphatase and ferritin. The histologic findings of typical Gaucher cells in bone marrow, liver, or spleen biopsy 21 was the principal inclusion criteria.…”

“… 5 , 6 Gaucher-like disease presents with progressive calcification of the aorta and the aortic and/or mitral valves as its main feature. 7 …”

GBA, Gaucher Disease, and Parkinson’s Disease: From Genetic to Clinic to New Therapeutic Approaches

“…GD type 1 has been classically considered only a systemic disorder, with no neurological involvement whatsoever. Anemia, leukopenia, thrombocytopenia with frequent bleeding, osteopenia with bone pain, easy fractures, Erlenmeyer flask deformity, as well as hepatosplenomegaly, failure to grow, and puberty delay can be presenting features of this disease [11,12,13,14]. Monoclonal gammopathy has been reported as well [15].…”

Naturally Occurring Iminosugars and Related Alkaloids: Structure, Activity and Applications

“…Intracellular GCase activity increased approximately twofold when cells were incubated with IFG. The effective concentration for IFG was determined to be 10-50 M, whereas those of calystegines and DIX were 100-200 M. This two-fold increase in the residual enzyme activity is expected to have a significant impact in the disease development among the patients with the N370S mutation because this mutation results in mild clinical symptoms and some of the patients having the homozygous N370S mutations are even asymptomatic [82]. Further details on this topic are presented in Chapter 10 of this volume.…”