Lawrence A. Lockman

Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy.

BACKGROUND Globoid-cell leukodystrophy is caused by a deficiency of galactocerebrosidase, which results in progressive central nervous system deterioration. We investigated whether allogeneic hematopoietic stem-cell transplantation can provide a source of leukocyte galactocerebrosidase and thereby prevent the decline of central nervous system function in patients with the disease. METHODS Five children with globoid-cell leukodystrophy (one with the infantile type and four with late-onset disease) were treated with allogeneic hematopoietic stem-cell transplantation. Measurement of leukocyte galactocerebrosidase levels, neurologic examinations, neuropsychological tests, magnetic resonance imaging of the central nervous system, cerebrospinal fluid protein assays, and neurophysiologic measurements were performed before and after transplantation, with follow-up ranging from one to nine years. RESULTS Engraftment of donor-derived hematopoietic cells occurred in all patients and was followed by restoration of normal leukocyte galactocerebrosidase levels. In the four patients with late-onset disease, the central nervous system deterioration was reversed, and in the patient with the infantile form of the disease, signs and symptoms have not appeared. Magnetic resonance imaging showed a decrease in signal intensity in the three patients with late-onset disease who were assessed both before and after transplantation. Abnormalities in cerebrospinal fluid total protein levels were corrected in three patients with late-onset disease and substantially reduced in the patient with the infantile form. CONCLUSIONS Central nervous system manifestations of globoid-cell leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation.

Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy

BACKGROUND The childhood-onset cerebral form of X-linked adrenoleukodystrophy, a demyelinating disorder of the central nervous system, leads to a vegetative state and death within 3-5 years once clinical symptoms are detectable. The hypothesis to be tested was whether bone-marrow transplantation can over an extended period of time halt the inexorable progressive demyelination and neurological deterioration. METHODS 12 patients with childhood onset of cerebral X-linked adrenoleukodystrophy have been followed for 5-10 years after bone-marrow transplantation. Magnetic resonance imaging (MRI), neurological, neuropsychological, electrophysiological, and plasma very-long-chain fatty acid (VLCFA) measurements were used to evaluate the effect of this treatment. FINDINGS MRI showed complete reversal of abnormalities in two patients and improvement in one. One patient showed no change from baseline to last follow-up. All eight patients who showed an initial period of continued demyelination stabilised and remained unchanged thereafter. Motor function remained normal or improved after bone-marrow transplantation in ten patients. Verbal intelligence remained within the normal range for 11 patients. Performance (non-verbal) abilities were improved or were stable in seven patients. Decline in performance abilities followed by stability occurred in five patients. Plasma VLCFA concentrations decreased by 55% and remained slightly above the upper limits of normal. INTERPRETATION 5-10-year follow-up of 12 patients with childhood-onset cerebral X-linked adrenoleukodystrophy shows the long-term beneficial effect of bone marrow transplantation when the procedure is done at an early stage of the disease.

Neuropsychological outcomes of several storage diseases with and without bone marrow transplantation

SummaryNeuropsychological assessment is essential in providing documentation of the untreated natural history of storage diseases associated with dementia and quantifying the effectiveness of treatment on central nervous system function. Baseline characterization and outcome of bone marrow transplantation (BMT) for three leukodystrophies and three mucopolysaccharidoses are presented. Results suggests that BMT for Hurler syndrome, adrenoleukodystrophy, and globoid cell leukodystrophy can be effective in preventing dementia if done early enough in the disease. Sanfilippo and Hunter syndromes do not benefit and BMT is not recommended. For metachromatic leukodystrophy, BMT is not recommended for symptomatic early-onset forms of the disease. Further longitudinal follow-up is needed to determine whether the benefits outweigh the risks of BMT for late-onset and preclinical metachromatic leukodystrophy.

Microglia: The effector cell for reconstitution of the central nervous system following bone marrow transplantation for lysosomal and peroxisomal storage diseases

Treatment and potential cure of lysosomal and peroxisomal diseases, heretofore considered fatal, has become a reality during the past decade. Bone marrow transplantation, (BMT), has provided a method for replacement of the disease-causing enzyme deficiency. Cells derived from the donor marrow continue to provide enzyme indefinitely. Several scores of patients with diseases as diverse as metachromatic leukodystrophy, adrenoleukodystrophy, globoid cell leukodystrophy, Hurler syndrome (MPS I-H), Maroteaux-Lamy (MPS VI) Gaucher disease, and fucosidosis have been successfully treated following long-term engraftment. Central nervous system (CNS) manifestations are also prevented or ameliorated in animal models of these diseases following engraftment from normal donors. The microglial cell system has been considered to be the most likely vehicle for enzyme activity following bone marrow engraftment. Microglia in the mature animal or human are derived from the newly engrafted bone marrow. Graft-v-host disease activation of the microglia is also of importance. This article will summarize some of the pertinent literature relative to the role of microglia in such transplant processes.

The future for treatment by bone marrow transplantation for adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy and Hurler syndrome

SummaryWithin the past decade, bone marrow transplantation has been applied to over 200 patients worldwide with the intention of treating storage diseases. Bone marrow transplantation has provided a method for treatment of adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy and Hurler syndrome. After engraftment, significant improvement in the clinical course of each of these diseases occurs. Survival data of engrafted patients are superior to those of non-transplanted. Engraftment and the resulting enzymatic reconstitution are concordant. Outcomes based on neuropsychological tests indicate continued maintenance and in some cases increase in cognitive function. Magnetic resonance imaging as well as spectroscopic examinations of the brain provide further evidence that positive changes occur in the central nervous system following long-term engraftment. A better quality of life follows engraftment. Greater gains from use of bone marrow transplantation for these particular storage diseases will occur in the future. Earlier diagnosis will allow bone marrow transplantation in the presymptomatic stage at a younger age, providing an enhancement of positive effects noted from such treatment. At the same time, advances in bone marrow technology will serve to reduce the risk factors involved with the bone marrow transplantation process itself. These two factors taken together will be more than additive in providing benefits from use of bone marrow transplantation.

Thrombotic and hemorrhagic strokes complicating early therapy for childhood acute lymphoblastic leukemia

Sudden cerebrovascular insults occurred during or immediately following remission induction therapy in 4 children with acute lymphoblastic leukemia. In 3, cerebral infarction was due to thrombosis. In the fourth, an intracerebral hematoma developed representing either frank hemorrhaging or a hemorrhagic infarction. None of the patients had central nervous system leukemia or extreme leukocytosis at the time of diagnosis. Symptoms were obtundation, hemiparesis, seizures, and headache. The induction chemotherapy included L‐asparaginase which causes deficiencies of antithrombin, plasminogen, fibrinogen, and factors IX and XI. These hemostatic abnormalities may explain the thromboses and bleeding observed in these children.

Phenobarbital dosage for control of neonatal seizures

The relationship of the initial phenobarbital dose to weight, gestational age, blood level, and seizure control was studied in 39 neonates. The blood level was proportional to the dosage per kilogram, and was not related to weight or gestational age. Seizures remitted only at blood phenobarbital concentrations above 16.9 pg per milliliter. Therapeutic levels can be achieved by the intravenous or intramuscular administration of 16 to 23 mg per kilogram of phenobarbital.

Characteristics of the dementia in late-onset metachromatic leukodystrophy.

Patients with metachromatic leukodystrophy (MLD) of juvenile or adult onset present with behavioral abnormalities. In nine patients, diagnosed between ages 11 and 33 years, behavior and neuropsychological test results disclosed a pattern of dementia combining features associated with both frontal and white matter abnormalities. All the patients had been considered to have a psychiatric disorder prior to the diagnosis of MLD, even though none had any of the cardinal features of schizophrenia or other major psychosis. Early diagnosis of late-onset MLD is important to provide access to appropriate effective therapy.

Outcome of second hematopoietic cell transplantation in Hurler syndrome

Hurler syndrome (HS) is an autosomal recessive, inherited metabolic storage disorder due to deficiency of lysosomal alpha-L-iduronidase (IDU) enzyme activity. Untreated patients develop progressive mental retardation and multisystem morbidity with a median life expectancy of 5 years. Allogeneic hematopoietic cell transplantation (HCT) can achieve stabilization and even improvement of intellect, with long-term survival. However, children with HS have an increased incidence of graft failure, usually with concomitant autologous marrow reconstitution. Between 1983 and 2000, 71 Hurler children underwent HCT at the University of Minnesota. Of these 71, 19 (27%) experienced graft failure. We report HCT outcomes in all 11 Hurler patients receiving a second HCT at the University of Minnesota. Median age at second HCT was 25 months (range, 16 to 45 months); median time from first HCT was 8 months (range, 4 to 18.5 months). The conditioning regimen consisted of cyclophosphamide/TBI/ATG (n = 8) or busulfan/cyclophosphamide/ATG (n = 3). The source of bone marrow was an unrelated donor in six, matched sibling in four, and mismatched related in one. Five of the 11 grafts were T cell depleted prior to infusion. Overall, 10 of 11 patients showed donor-derived engraftment, of whom three developed grade 3 to 4 acute GVHD. Five of 11 patients are surviving a median of 25 months (range, 2 months to 12 years) with an overall actuarial survival of 50% (95% CI, 27% to 93%) at 4 years. All five show sustained donor engraftment with normalization of IDU activity levels. Three of five evaluable patients demonstrated stabilization of neuropsychological function after second HCT. Currently, allogeneic donor-derived hematopoiesis provides the only chance for long-term survival and improved quality of life in Hurler patients. While graft failure in Hurler patients requires further investigation, a timely second HCT can be well-tolerated and beneficial.Bone Marrow Transplantation (2002) 29, 491–496. doi:10.1038/sj.bmt.1703395

The Chediak-Higashi syndrome: Electrophysiological and electron microscopic observations on the peripheral neuropathy

The Chediak-Higashi syndrome is an inherited disorder characterized by huge subcellular granules in leukocytes and cells of other tissues. Neurological defects frequently occur in patients with this unusual disease. Electrophysiological and electron microscopic studies have been performed on a child with Chediak-Higashi disease and severe peripheral neuropathy. Transmission of action potentials along nerve fibers was markedly impaired, while muscle electrophysiology appeared normal. A nerve-muscle biopsy examined in the electron microscope revealed characteristic giant Chediak-Higashi granules in Schwann cells supporting peripheral nerve fibers. The possible relationship of the massive granules to the peripheral neuropathy in patients with Chediak-Higashi disease is discussed.