Elsevier

Seminars in Hematology

Volume 47, Issue 1, January 2010, Pages 70-78
Seminars in Hematology

Transplant Outcomes in Leukodystrophies

https://doi.org/10.1053/j.seminhematol.2009.10.006Get rights and content

Hematopoietic stem cell transplantation (HSCT) has been used for three decades as therapy for lysosomal storage diseases. Stable engraftment following transplantation has the potential to provide a source of an enzyme for the life of a patient. Recombinant enzyme is available for disorders that do not have a primary neurologic component. However, for diseases affecting the central nervous system (CNS), intravenous enzyme is ineffective due to its inability to cross the blood-brain barrier. For selected lysosomal disorders, including metachromatic leukodystrophy and globoid cell leukodystrophy, disease phenotype and the extent of disease at the time of transplantation are of fundamental importance in determining outcomes. Adrenoleukodystrophy is an X-linked, peroxisomal disorder, and in approximately 40% of cases a progressive, inflammatory condition develops in the CNS. Early in the course of the disease, allogeneic transplantation can arrest the disease process in cerebral adrenoleukodystrophy, while more advanced patients do poorly. In many of these cases, the utilization of cord blood grafts allows expedient transplantation, which can be critical in achieving optimal outcomes.

Section snippets

Metachromatic Leukodystrophy

The term “metachromatic” refers to the staining pattern of sulfatides that accumulate in the cells of individuals with metachromatic leukodystrophy.8 Metachromatic leukodystrophy is an autosomal recessive lysosomal disorder caused by a defect in ARSA activity. Defects in the ARSA gene result in accumulation of the substrate cerebroside 3-sulfate, which is found primarily in myelin membranes.9 The inability to degrade substrate leads to demyelination of the white matter of the CNS, as well as

Globoid Cell Leukodystrophy

The disorder known as globoid cell leukodystrophy was initially described in 1916 by Krabbe, and hence is also called Krabbe disease.28 The term “globoid cell” refers to multinuclear macrophages present within the brain characteristically seen in this disorder. In 1970 the enzyme defect responsible for globoid cell leukodystrophy was identified as galactocerebroside β-galactosidase (GALC), a lysosomal enzyme;29 this enzyme is also commonly referred to as galactocerebrosidase. The gene was

Clinical Manifestations of Adrenoleukodystrophy

Adrenoleukodystrophy was initially described in 1923 by Siemerling and Creutzfeld as a condition characterized by hyperpigmentation and central nervous system demyelination. In 1976 Igarashi and colleagues observed that saturated very–long-chain fatty acids, such as hexacosanoic acid (C:26:0), accumulate in the brain and adrenal tissue of patients with adrenoleukodystrophy.48 Later, it was shown that excess very–long-chain fatty acids are also present in plasma,49 especially C24 and C26 fatty

Current Controversies in Hematopoietic Cell Therapy of Leukodystrophies

Despite the experience of several decades in the use of transplantation for inherited metabolic disorders affecting the CNS, there is much that remains unclear, including the following:

  • 1

    The majority of physicians transplanting these patients would agree that, with current techniques, outcomes are poor for transplantation for symptomatic infantile globoid cell leukodystrophy and metachromatic leukodystrophy. However, whether patients transplanted very early in life (several weeks of age) will

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