Allogenic Bone Marrow Transplantation in Severe Gaucher Disease

Abstract

ABSTRACT. Gaucher disease is the most prevalent lysoGaucher disease is the most prevalent lysosomal storage disease soma1 storage disease. This autosomal recessive disease is (I) and the most frequent genetic disease in the Ashkenazi Jewish caused by the defective activity of the enzyme acid 8-population (2). This autosomal recessive disorder of glycosphinglucosidase and the resultant accumulation of glucosylcer-golipid metabolism results from numerous point mutations at amide primarily within cells of the reticuloendothelial SyS-the locus-encoding acid (3-glucosidase (glucocerebrosidase) (for tern. Because the primary manifestations of Gaucher review, see Ref. 3). The majority of these are missense mutations, disease are due to involvement of mono~yte/macro~hage-which lead to the defective activity of this enzyme (3-5). The derived this disease is be an resultant accumulation of the substrate, glucosylceramide, within candidate for curative intervention via bone marrow trans-m o n o c y t e~m a c r o p~a g e -~e~v e~ cells (~~~ cells) leads to the ~lantation (BMT). A is panic female with subacute neu-visceral manifestations including hepatosplenomegaly, hyperronopathic Gaucher disease and progressing splenism, and skeletal disease (6). Three variants of the disease manifestations underwent BMT at 23 m0 of age using have been delineated based on the absence (type 1, nonneuronher brother as the donor' Cytoge-opathic) or presence (neuronopathic) and severity (type 2, acute; netic analyses demonstrated complete, stable engraftment by 1 mo post-BMT. During the subsequent 24 mo, clinical, type 3 subacute) of primary CNS involvement (6). Because the biochemical, enzymatic, and histologic studies demon-major visceral manifestations of this disease result from the strated nearly complete correction in the viscera. H~~ accumulation of bone marrow-derived tissue-bound macroneuropathic manifestations did not progress. Complete re-phages, Gaucher disease type 1 has been a prime candidate for constitution of enzymatic activity in peripheral blood leu-curative intervention by BMT. In addition, demonstration of the kocytes was achieved by 1 mo. Cytogenetic analyses dem-clinical, biochemical, and histopathologic efficacy of BMT would onstrated complete engraftment by d 79 and nearly corn-provide the basis for ongoing efforts directed toward molecular plete loss of bone marrow Gaucher cells was observed by therapy for this disease.

Gaucher disease as a paradigm of current issues regarding single gene mutations of humans.

“…Allogeneic marrow transplantation has been performed a number of times in patients with type 1 Gaucher disease with marked amelioration of the disorder and with disappearance ofGaucher cells from the marrow (93,94). The response of patients with neuronopathic disease has been less definitive (95,96).…”

Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines

“…HCT performed early in the disease course may be beneficial. [74][75][76] Gaucher disease types I, II, III HCT is effective in alleviating most disease manifestations of Gaucher including arresting further neuropsychological deterioration in type III (Norbottnian) disease [77][78][79][80][81] and greatly reducing skeletal problems in severe early onset type I disease. 34,[82][83][84] HCT is not currently regarded as first-line treatment because of the low morbidity of ERT.…”

Mature monocytic cells enter tissues and engraft

“…Bone marrow transplantation (BMT) is an alternative approach used to reverse visceral abnormalities and stabilize skeletal and neurological dysfunction as tissue macrophages derived from transplanted cells provide a local source of normal enzyme (5)(6)(7). Thus, the presence of donor origin Kupffer cells in the liver and macrophages in the spleen leads to the resolution of organomegaly.…”