Hematopoietic Stem-Cell Transplantation in Globoid-Cell Leukodystrophy

Krivit, William; Shapiro, Elsa; Peters, Charles; Wagner, John E.; Cornu, Guy; Kurtzberg, Joanne; Wenger, David A.; Kolodny, Edwin H.; Vanier, Marie T.; Loes, D. J.; Dusenbery, Kathryn E.; Lockman, Lawrence A.

doi:10.1056/nejm199804163381605

Cited by 296 publications

(192 citation statements)

References 23 publications

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“…The kinetics of microglial repopulation, as described above, may largely explain the lack of therapeutic effectiveness of BMT in symptomatic infantile ceramidase deficiency and other rapidly progressive infantile phenotypes of sphingolipid storage diseases such as galactosylceramidase deficiency (globoid cell leukodystrophy; Krabbe disease) and arylsulfatase A deficiency (metachromatic leukodystrophy). 26,[32][33][34] Allogeneic BMT in these aggressive conditions may stabilize the neurological status only if carried out in truly presymptomatic infants within the first weeks of life, maximizing the time for replacement of microglia with enzymatically normal cells.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow transplantation for infantile ceramidase deficiency (Farber disease)

Yeager

Uhas

Coles

et al. 2000

Bone Marrow Transplant

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Summary:Infantile ceramidase deficiency (Farber disease) is an uncommon, progressive lysosomal storage disease characterized by multiple ceramide-containing nodules (lipogranulomata) in the subcutaneous tissue and upper aerodigestive tract, painful periarticular swelling, psychomotor retardation, and varying degrees of ocular, pulmonary or hepatic involvement. Management of Farber disease has been limited to symptomatic supportive care, and few affected infants survive beyond 5 years of age. We performed an allogeneic bone marrow transplant (BMT) from an HLA-identical heterozygous sister in a 9.5-month-old female with minimally symptomatic Farber disease who received a pre-transplant regimen of busulfan and cyclophosphamide. Ceramidase activity in peripheral blood leukocytes increased from 6% before transplant to 44% (donor heterozygote level) by 6 weeks after BMT. By 2 months after transplant, the patient's subcutaneous lipogranulomata, pain on joint motion, and hoarseness had resolved. Despite modest gains in cognitive and language development, hypotonia and delayed motor skills persisted. Gradual loss of circulating donor cells with autologous hematopoietic recovery occurred; VNTR analyses showed 50% donor DNA in peripheral blood cells at 8.5 months after BMT and only 1% at 21 months after transplant. Interestingly, leukocyte ceramidase activity consistently remained in the heterozygous range despite attrition of donor cells in peripheral blood. This novel observation indicates ongoing hydrolase production by non-circulating donor cells, possibly in the mononuclear phagocytic system, and uptake by recipient leukocytes. Although lipogranulomata and hoarseness did not recur, the patient's neurological and neurocognitive status progressively declined. She died 28 months after BMT (age 37.5 months) with pulmonary insufficiency caused by recurrent aspiration pneumonias. Allogeneic BMT

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Section: Discussionmentioning

confidence: 99%

Bone marrow transplantation for infantile ceramidase deficiency (Farber disease)

Yeager

Uhas

Coles

et al. 2000

Bone Marrow Transplant

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“…Significant improvements were also observed in the patients with GLD after BMT especially in the patients of the late-onset form. 9 However, the disadvantages of BMT such as shortage in donor supply and the side-effects largely limit the clinical application of this treatment. With the success in the cloning of GALC cDNA and the identification of gene mutation in twitcher, [10][11][12] gene therapy of the twitcher mouse became possible and challenging.…”

Section: Introductionmentioning

confidence: 99%

Intraventricular administration of recombinant adenovirus to neonatal twitcher mouse leads to clinicopathological improvements

Watabe

Ohashi

et al. 2001

Gene Ther

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Twitcher mouse is a murine model of human globoid cell leukodystrophy (Krabbe disease), which is characterized by a genetic deficiency in galactocerebrosidase (GALC) activity. The nervous system is affected early and severely by demyelination in the white matter. So far, there is no effective treatment for Krabbe disease except bone marrow transplantation (BMT). However, BMT has inherent limitations such as unavailability of donors and graft-versus-host disease. In this study, we injected recombinant adenovirus encoding GALC into the lateral ventricle of twitcher mice at postnatal day 0 (PND 0) and the therapeutic effects were evaluated. Our results showed slight, but significant

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“…1,2 Over the last few years, several storage diseases have been treated with hematopoietic stem cell transplantation (HSCT). [3][4][5][6] The enzymatic activity of white blood cells has been proven to rise to normal levels after HSCT. 7 Moreover, the differentiation of donor monocytes into tissue-specific cells such as Kupfer cells, Ito cells, pulmonary or peritoneal macrophages, lymphoid or histiocytic cells of the spleen and lymph nodes or dendritic cells of the skin causes the clearance of the accumulated substrate in many organs.…”

mentioning

confidence: 99%

Four year follow-up of a case of fucosidosis treated with unrelated donor bone marrow transplantation

Miano

Lanino

Gatti

et al. 2001

Bone Marrow Transplant

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Summary:Fucosidosis is a rare autosomal recessive lysosomal disorder caused by ␣-fucosidase deficiency. We report a child with fucosidosis, second daughter of non-consanguineous parents, for whom biochemical diagnosis followed clinical evidence of the disease in her older sister. Based on previous experiences, the indication to transplant was considered. Since she lacked a matched sibling, an unrelated marrow donor was found. At prehematopoietic stem cell transplantation evaluation, first signs of neurological involvement were clinically detectable. MRI showed diffuse hypomyelination and auditory brainstem responses and somatic-sensorial evoked potentials were altered. Visual evoked potentials were normal, tortuosity in the retinal veins and peripapillary hemorrhages were detected. Bone marrow transplantation conditioning was with a regimen of busulphan, thiotepa and cyclophosphamide; in vivo Campath 1G, cyclosporin A and short course methotrexate were given to prevent graft-versus-host disease. The patient engrafted rapidly and her post-transplant course was complicated by moderate graft-versus-host disease, transient episodes of idiopathic thrombocytopenic purpura, repeated septic complications and recurrent episodes of Sweet's syndrome. Sequential short tandem repeat polymorphisms on peripheral blood and bone marrow cells documented the persistence of donor engraftment. Follow-up showed a progressive rise of enzymatic levels. Over the last few years, several storage diseases have been treated with hematopoietic stem cell transplantation (HSCT). [3][4][5][6] The enzymatic activity of white blood cells has been proven to rise to normal levels after HSCT. 7 Moreover, the differentiation of donor monocytes into tissue-specific cells such as Kupfer cells, Ito cells, pulmonary or peritoneal macrophages, lymphoid or histiocytic cells of the spleen and lymph nodes or dendritic cells of the skin causes the clearance of the accumulated substrate in many organs. 8 The correction of enzymatic levels has also been demonstrated in the CNS where new microglia and astroglia were shown to originate in the donor's macrophagic system. 9-13 Persistence of engraftment makes it possible to maintain the turnover of these cells and accounts for clinical improvement after HSCT. Intracellular enzyme transfer and uptake of donor-derived enzyme in plasma contribute to improving the advantageous effects of HSCT in these diseases. In the canine model, early HSCT proved to be useful in preventing clinical onset of fucosidosis and in maintaining normal enzymatic levels. 14 Clinical improvement has been reported in human fucosidosis after HSCT. 15,16 In this paper we report on the long-term outcome of fucosidosis in a patient treated with unrelated donor (UD) HSCT. Case reportWe report on the outcome of the second daughter of nonconsanguineous parents, for whom diagnosis followed clinical evidence of the disease in her sister.At the age of 18 months, the patient's older sister underwent cranial MRI which showed a diffuse hypomyelination invo...

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Hematopoietic Stem-Cell Transplantation in Globoid-Cell Leukodystrophy

Abstract: Central nervous system manifestations of globoid-cell leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation.

Cited by 296 publications

References 23 publications

Bone marrow transplantation for infantile ceramidase deficiency (Farber disease)

Bone marrow transplantation for infantile ceramidase deficiency (Farber disease)

Intraventricular administration of recombinant adenovirus to neonatal twitcher mouse leads to clinicopathological improvements

Four year follow-up of a case of fucosidosis treated with unrelated donor bone marrow transplantation

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