In recent years a number of disease processes have been found to be associated with the tissue deposition of ceroid-lipofuscin. These disease processes include juvenile familial amaurotic idiocy (Batten’s disease) and progressive central... more
In recent years a number of disease processes have been found to be associated with the tissue deposition of ceroid-lipofuscin. These disease processes include juvenile familial amaurotic idiocy (Batten’s disease) and progressive central nervous system degeneration.’ -‘ This is the report of a girl in whom progressive signs of dysfunction of the posterior columns of the spinal cord and fluctuating evidence of corticospinal tract involvement developed. Ceroidlipofuscin was found in her liver and rectal ganglion cells. In addition, cells in her bone marrow closely resembled the sea-blue histiocytes that have been previously reported in conjunction with cirrhosis, anemia, thrombocytopenia and splenomegaly .‘
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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... more
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 ...
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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... more
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 ...
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We studied the pharmacokinetics of phenobarbital in 15 neonates after a single intramuscular dose. The mean apparent distribution volume, half-life, and apparent total body clearance were 0.81 liter per kilogram, 103.4 hours, and 6.4 ml... more
We studied the pharmacokinetics of phenobarbital in 15 neonates after a single intramuscular dose. The mean apparent distribution volume, half-life, and apparent total body clearance were 0.81 liter per kilogram, 103.4 hours, and 6.4 ml per hour per kilogram, respectively. Substantial interpatient variation was observed in the half-life and apparent total body clearance. Maintenance doses of 3.1 and 3.8 mg per kilogram per day were projected from the mean apparent total body clearance to produce plasma concentrations of 20 and 25 micrograms per milliliter, respectively. These recommendations provide initial maintenance dosage guidelines, which should be adjusted according to plasma concentrations and clinical effects.
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Sections of dental pulp were removed from a tooth of a boy 3 years 10 months of age with myoclonic seizures. When stained with hematoxylin and eosin, these sections showed eosinophilic inclusions. Ultrastructurally, these inclusions were... more
Sections of dental pulp were removed from a tooth of a boy 3 years 10 months of age with myoclonic seizures. When stained with hematoxylin and eosin, these sections showed eosinophilic inclusions. Ultrastructurally, these inclusions were large cytosomes filled with whorls of electron-opaque substance. The opaque material consisted of bilaminate strands, approximately 15 nm in diameter, arranged in a curvilinear pattern compatible with that seen in the late infantile form of "ceroid-lipofuscinosis." Most histochemical staining reactions were compatible with ceroid or lipofuscin, with the exception of the diamine silver reaction. Late infantile ceroid-lipofuscinosis represents another disease in which asymptomatic accumulation of storage material occurs in the dental pulp.
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In children, seizures associated with status epilepticus (SE) include a number of types that are age-related. These types of seizures are not associated with SE in older patients. Likewise, etiologies of SE in children are also unique to... more
In children, seizures associated with status epilepticus (SE) include a number of types that are age-related. These types of seizures are not associated with SE in older patients. Likewise, etiologies of SE in children are also unique to this patient population, in particular those responsible for SE in the neonate. Consequently, therapy must address specific treatment of any possible underlying condition in addition to appropriate interventional and supportive measures.
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Three children with acute lymphoblastic leukemia developed sagittal sinus thrombosis. One patient was in peripheral remission. One patient survived. In neither patient who died were the walls of the dural sinuses infiltrated with leukemic... more
Three children with acute lymphoblastic leukemia developed sagittal sinus thrombosis. One patient was in peripheral remission. One patient survived. In neither patient who died were the walls of the dural sinuses infiltrated with leukemic cells. Attention is drawn to this potentially treatable cause of central nervous system symptoms in childhood leukemia. Angiography is the diagnostic test of choice and can also demonstrate intracerebral hematoma and subdural hematoma, if present. Sinus thrombosis can occur either during exacerbation or remission of the basic leukemic process. The possibility that chemotherapeutic techniques predispose toward this complication is raised.
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To study the efficacy of hematopoietic stem cell transplantation (HCT) for ameliorating the clinical manifestations of α-mannosidosis.Four patients with α-mannosidosis underwent allogeneic HCT at the University of Minnesota. Diagnosis was... more
To study the efficacy of hematopoietic stem cell transplantation (HCT) for ameliorating the clinical manifestations of α-mannosidosis.Four patients with α-mannosidosis underwent allogeneic HCT at the University of Minnesota. Diagnosis was established by assay of leukocyte α-mannosidase activity level. Physical features, donor engraftment, leukocyte α-mannosidase activity, neuropsychologic function, and hearing were monitored before and after transplantation, with follow-up ranging from 1 to 6 years.All 4 patients showed slowing of their neurocognitive development and sensorineural hearing loss before HCT. All patients are alive, with normalization of leukocyte enzyme activity after HCT. Intellectual function has stabilized, with improvement in adaptive skills and verbal memory function in 3 of 4 patients. Hearing has improved to normal or near normal for speech frequencies in 3 patients. No new skeletal abnormalities have developed.HCT can halt the progressive cognitive loss in patients with α-mannosidosis. Early diagnosis and treatment with HCT is critical for optimal results.
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Long-term survival and improved neuropsychological function have occurred in selected children with Hurler syndrome (MPS I H) after successful engraftment with genotypically matched sibling bone marrow transplantation (BMT). However,... more
Long-term survival and improved neuropsychological function have occurred in selected children with Hurler syndrome (MPS I H) after successful engraftment with genotypically matched sibling bone marrow transplantation (BMT). However, because few children have HLA-identical siblings, the feasibility of unrelated donor (URD) BMT as a vehicle for adoptive enzyme therapy was evaluated in this retrospective study. Forty consecutive children (median, 1.7 years; range, 0.9 to 3.2 years) with MPS I H received high-dose chemotherapy with or without radiation followed by BMT between January 27, 1989 and May 13, 1994. Twenty-five of the 40 patients initially engrafted. An estimated 49% of patients are alive at 2 years, 63% alloengrafted and 37% autoengrafted. The probability of grade II to IV acute graft-versus-host disease (GVHD) was 30%, and the probability of extensive chronic GVHD was 18%. Eleven patients received a second URD BMT because of graft rejection or failure. Of the 20 survivors,...
Research Interests: Survival Analysis, Treatment Outcome, Mental Retardation, Humans, Blood, and 15 moreLung Diseases, Facial Features, Infant, Bone marrow, Glycosaminoglycan, Enzyme, Clinical Sciences, Bone Marrow Transplantation, Enzyme activity, Graft Rejection, Chronic Kidney Failure, Cardiac Disease, Life tables, Neuropsychological Tests, and Child preschool
Two children with metachromatic leukodystrophy underwent bone marrow transplantation. In both patients MR subsequently showed, first, white matter changes, then later, lack of change as the patients stabilized clinically.
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To report the serial brain MR observations in patients with childhood-onset cerebral adrenoleukodystrophy 1 to 2 years after bone marrow transplantation. Eight boys with childhood-onset cerebral adrenoleukodystrophy have undergone... more
To report the serial brain MR observations in patients with childhood-onset cerebral adrenoleukodystrophy 1 to 2 years after bone marrow transplantation. Eight boys with childhood-onset cerebral adrenoleukodystrophy have undergone successful transplantation at our institution. Seven patients (mean age, 8 years 10 months; range, 5 years 3 months to 11 years 9 months) had serial MR studies before and after transplantation. An MR severity score (0 to 34) based on disease location and the presence or absence of focal atrophy was calculated for each patient scan. Posttransplantation serial MR showed improvement in two patients, stabilization in three patients, and worsening of MR signal changes in two patients. The patient with the most striking progression had systemic graft-versus-host disease. Although the adrenoleukodystrophy MR severity score did not change in three patients after transplantation, two of these patients did show improved margination of disease. Bone marrow transplant...
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To develop a scoring method for brain observations in patients with X-linked adrenoleukodystrophy. One hundred seventy-five brain MR scans in 83 male subjects less than 20 years of age with proved biochemical defects were reviewed. A... more
To develop a scoring method for brain observations in patients with X-linked adrenoleukodystrophy. One hundred seventy-five brain MR scans in 83 male subjects less than 20 years of age with proved biochemical defects were reviewed. A severity score (0 to 34), based on a point system derived from location and extent of disease and the presence of focal and/or global atrophy, was calculated for each exam. Fifty-five of the 83 patients showed MR findings consistent with adrenoleukodystrophy. Two major patterns were observed. A posterior pattern (mean score, 9; range, 0.5 to 25) was present in 80% of patients, and an anterior pattern (mean score, 10; range, 2 to 18) was present in 15% of patients. Serial MR imaging, positive for adrenoleukodystrophy in 34 patients (mean follow-up, 23 months; range, 2 months to 6 years 11 months), showed progressive disease in 52%, progressive disease with subsequent stabilization in 18%, stable disease in 24%, and minimal improvement in 6%. The adrenole...
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The childhood-onset cerebral form of adrenoleukodystrophy has a devastating neurologic prognosis. Unfortunately, there is no early method of distinguishing it from the more benign forms of adrenoleukodystrophy, such as... more
The childhood-onset cerebral form of adrenoleukodystrophy has a devastating neurologic prognosis. Unfortunately, there is no early method of distinguishing it from the more benign forms of adrenoleukodystrophy, such as adrenomyeloneuropathy. To evaluate the manner in which this disease entity may be reflected in the cerebrospinal fluid, we studied a consecutive series of 19 patients, all with biochemically proved adrenoleukodystrophy. total protein, immunoglobulin production, cytokine levels, and cerebrospinal fluid pressure were measured. In this single sample of cerebrospinal fluid, a significant correlation existed between clinical stage of the illness and cerebrospinal fluid myelin basic protein. No correlation existed with total protein, cytokines, or measures of immunoglobulin production.
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Two patients are reported with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes in whom CT documented massive focal brain swelling with midline shift concurrent with exacerbations of their conditions.... more
Two patients are reported with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes in whom CT documented massive focal brain swelling with midline shift concurrent with exacerbations of their conditions. Brain swelling producing mass effect should be recognized as a feature of MELAS.
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This article describes the typical absence attack, as well as the typical manifestations of myoclonic and atonic seizures. It reviews the usual treatment, including pharmacology, and gives the prognosis for these entities.
Research Interests: Electroencephalography, Absence epilepsy, Humans, Child, Female, and 4 moreMale, Infant, Prognosis, and Child preschool
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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... more
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. 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. 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. Central nervous system manifestations of globoid-cell leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation.
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The patient was first noted to have a clumsy gait at 13 months. She was no longer climbing steps at 17 months. Deep-tendon reflexes in the arms and legs were symmetrically depressed. Babinski signs were present at three years of age. At... more
The patient was first noted to have a clumsy gait at 13 months. She was no longer climbing steps at 17 months. Deep-tendon reflexes in the arms and legs were symmetrically depressed. Babinski signs were present at three years of age. At the time of transplantation, when the patient ...
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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... more
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.
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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... more
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.
Research Interests: Technology, Biological Sciences, Humans, Blood brain barrier, Female, and 14 moreAnimals, Microglia, Male, Central Nervous System, Animal Model, Bone marrow, Cell Transplantation, Enzyme, Bone Marrow Transplantation, Phagocytosis, Enzyme activity, Gaucher Disease, Lysosomal Storage Diseases, and Bone Marrow Cells
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Research Interests: Quality of life, Treatment, Survival Analysis, Treatment Outcome, Adolescent, and 18 moreStem Cell, Mental Retardation, Humans, Female, Male, Bone marrow, Life Expectancy, Clinical Sciences, Middle Aged, Bone Marrow Transplantation, Adult, Enzyme activity, Long Term, Autosomal Recessive, Leukocytes, Hematopoietic Cell Transplantation, Hematopoietic Stem Cell Transplantation, and Neuropsychological Tests
Cerebral X-linked adrenoleukodystrophy (X-ALD) is a disorder of very-long-chain fatty acid metabolism, adrenal insufficiency, and cerebral demyelination. Death occurs within 2 to 5 years of clinical onset without hematopoietic cell... more
Cerebral X-linked adrenoleukodystrophy (X-ALD) is a disorder of very-long-chain fatty acid metabolism, adrenal insufficiency, and cerebral demyelination. Death occurs within 2 to 5 years of clinical onset without hematopoietic cell transplantation (HCT). One hundred twenty-six boys with X-ALD received HCT from 1982 to 1999. Survival, engraftment, and acute graft-versus-host disease were studied. Degree of disability associated with neurologic and neuropsychological function and cerebral demyelination were evaluated before and after HCT. Complete data were available and analyzed for 94 boys with cerebral X-ALD. The estimated 5- and 8-year survival was 56%. The leading cause of death was disease progression. Donor-derived engraftment occurred in 86% of patients. Demyelination involved parietal-occipital lobes in 90%, leading to visual and auditory processing deficits in many boys. Overall 5-year survival of 92% in patients with 0 or 1 neurologic deficits and magnetic resonance imaging (MRI) severity score less than 9 before HCT was superior to survival for all others (45%; P <.01). Baseline neurologic and neuropsychological function, degree of disability, and neuroradiologic status predicted outcomes following HCT. In this first comprehensive report of the international HCT experience for X-ALD, we conclude that boys with early-stage disease benefit from HCT, whereas boys with advanced disease may be candidates for experimental therapies.
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The first girl in a family was affected with late infantile metachromatic leukodystrophy (MLD) and had the expected characteristic central nervous system progressive deterioration, which resulted in decerebration and death. The second... more
The first girl in a family was affected with late infantile metachromatic leukodystrophy (MLD) and had the expected characteristic central nervous system progressive deterioration, which resulted in decerebration and death. The second girl (propositus) demonstrated similar symptoms and signs at the same age. Both girls had characteristically low arylsulfatase A levels. The propositus underwent allogeneic bone marrow transplantation (BMT) from a normal histocompatible sibling. Two and a half years later, the propositus has not developed the intellectual and neurologic impairment demonstrated by the first sibling, although nerve conduction has continued to worsen. These results suggest that the induction of normal enzyme levels by BMT may be retarding or inhibiting CNS deterioration. These results, confirming earlier results of others, are sufficiently promising to warrant a larger scale critical trial of BMT early in the course of MLD.
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This is a report of a new familial neurologic disorder characterized by ceroid-lipofuscin storage, sea-blue histiocytes, and associated neurologic findings. Neurologic manifestations in the family members examined were varied, but... more
This is a report of a new familial neurologic disorder characterized by ceroid-lipofuscin storage, sea-blue histiocytes, and associated neurologic findings. Neurologic manifestations in the family members examined were varied, but posterior column involvement was the most common finding. The presence of sea-blue histiocytes was genetically determined by an autosomal dominant trait. Vitamin E blood concentrations were decreased in the absence of absorption difficulties in two sisters who were most seriously affected. The relationship of ceroid-lipofuscin, lipid peroxidation, and vitamin E is discussed.
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Intraventricular hemorrhage (IVH) can occur in full-term newborns with a variety of clinical pictures. We studied five full-term infants who suffered IVH in the neonatal period and survived. No apparent cause for hemorrhage could be found... more
Intraventricular hemorrhage (IVH) can occur in full-term newborns with a variety of clinical pictures. We studied five full-term infants who suffered IVH in the neonatal period and survived. No apparent cause for hemorrhage could be found in four. All had normal results of neurologic examinations at birth, and four had no major antecedent perinatal or postnatal difficulties. In 19 previously described full-term infants with IVH, no perinatal problems were noted in 45% of those who survived. Although more common in premature infants, IVH can occur in full-term infants and should be suspected when there is a sudden change in the neurologic status. In subsequent examinations, three of our five infants had mild spasticity and two appeared to be normal. The grading system developed for IVH in premature infants, while indicating severity of the hemorrhage, does not predict clinical outcome in full-term infants. A more definitive statement of outcome will require a longer period of observation.