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At least 19 recordsLinked to original sources
PubMed2002

Substrate-reduction therapy enhances the benefits of bone marrow transplantation in young mice with globoid cell leukodystrophy.

Globoid cell leukodystrophy is an autosomal recessive disease with progressive demyelination caused by a deficiency of the lysosomal enzyme galactosylceramidase. Bone marrow transplantation (BMT) is a therapeutic option for patients with late-onset disease and for patients with early onset disease that had an early diagnosis owing to an affected sibling. This therapy, however, typically is not effective for early onset disease when the diagnosis occurs after several months of life. In an effort to enable a broader range of patients to benefit from BMT, we tested whether combining substrate-reduction therapy with BMT would result in a greater benefit than either treatment alone in the twitcher mouse model of globoid cell leukodystrophy. Twitcher mice treated with L-cycloserine, an inhibitor of 3-ketodyhydrosphingosine synthase, and transplanted with 50 +/- 5 x 10(6) bone marrow cells on d 10 had a mean life-span of 112 d compared with 51 d for BMT alone (p < 0.001) or L-cycloserine alone, which was previously reported to be 56 d. L-Cycloserine treatment also was initiated neonatally to determine whether it would allow for a delayed BMT to have therapeutic value. Twitcher mice given only BMT at 18 d or only a short course of L-cycloserine died at 36 and 37 d, respectively. Twitcher mice given a short course of L-cycloserine + BMT at 18 d lived to 58 d (p = 0.0006). In conclusion, substrate-reduction therapy enhanced the value of BMT in twitcher mice, suggesting that this combination strategy might benefit patients with globoid cell leukodystrophy.

Animals↗
PubMed1999

Molecular basis of late-life globoid cell leukodystrophy.

Globoid cell leukodystrophy is an autosomal recessive inherited disease caused by deficiency of the lysosomal enzyme galactocerebrosidase (GALC). Although the severe, rapidly progressing infantile form is the most common, late-onset forms have been described. We investigated the molecular basis of GALC deficiency in a patient with a late-life mild form of globoid cell leukodystrophy who survived into the eighth decade. Since material suitable for mutation analysis was no longer available from the proband, her GALC genotype was reconstructed by analyzing this gene in her six obligate carrier offspring. One allele contained the mutation 809G>A (G270D) in the 1637C background, while the other allele contained three sequence variants: 1609G>A (G537R), 1873G>A (A625T), and 1650T>A (V550V) in the 1637T background. These mutations were confirmed in the proband's genomic DNA isolated from a sural nerve biopsy. Expression studies indicated that the G537R is a disease-causing mutation, as it resulted in no GALC activity, either alone or together with the A625T. This A625T sequence variant did not affect the enzyme activity, at least when expressed in the 1637T background. The mild clinical phenotype was likely to be associated with the 809G>A, since residual GALC activity, about 17% of the control activity, was detected in the expression studies of this mutation. This mutation has been found in several other patients with late-onset GLD.

Age of Onset↗
PubMed1993

Cloning and expression of cDNA encoding human galactocerebrosidase, the enzyme deficient in globoid cell leukodystrophy.

Globoid cell leukodystrophy (Krabbe disease) is an autosomal recessive disorder resulting from the deficiency of galactocerebrosidase (GALC) activity. GALC is responsible for the lysosomal catabolism of galactosylceramide, a major lipid in myelin, kidney and epithelial cells of small intestine and colon. We describe the molecular cloning of human GALC cDNA and its expression in COS-1 cells. Degenerate PCR primers, derived from N-terminal amino acid sequence from the 51 kDa band from human brain, were used to amplify cat testes RNA, and the resulting product was used to screen human testes and brain libraries. Two overlapping clones contained the total protein coding region, while additional clones and PCR amplification were needed to obtain the complete 3' end of the cDNA. The 3795 bp obtained include 47 bp 5' to the initiation start site, 2007 bp of open reading frame (coding for 669 amino acids), and 1741 bp of 3' untranslated sequence. Modification of the sequence surrounding the initiation codon to one more favorable for expression, resulted in a 6-fold increase in GALC activity in transfected COS-1 cells. The isolation of this clone will permit investigations into the causes for GALC deficiency in humans and available animal models, development of more accurate tests for patient and carrier identification, and evaluation of methods for effectively treating GALC deficiency, initially using the animal models.

Amino Acid Sequence↗
PubMed2005

Enzyme replacement therapy results in substantial improvements in early clinical phenotype in a mouse model of globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD) or Krabbe disease is a devastating, degenerative neurological disorder caused by mutations in the galactosylceramidase (GALC) gene that severely affect enzyme activity. Currently, treatment options for this disorder are very limited. Enzyme replacement therapy (ERT) has been shown to be effective in lysosomal storage disorders with predominantly peripheral manifestations such as type I Gaucher's and Fabry's disease. Little however is known about the possible benefit of ERT in GLD, which has a substantial central nervous system component. In this study, we examined the effect of peripheral GALC injections in the twitcher mouse model of the disease. Although we were unable to block the precipitous decline that normally occurs just before death, we did observe significant early improvements in motor performance, a substantial attenuation in the initial failure to thrive, and an increase in life span. Immunohistochemical and activity analyses demonstrated GALC uptake in multiple tissues, including the brain. This was associated with a decrease in the abnormal accumulation of the GALC substrate psychosine, which is thought to play a pivotal role in disease pathology. These results indicate that peripheral ERT is likely to be beneficial in GLD.

Animals↗
PubMed2005

AAV-mediated expression of galactocerebrosidase in brain results in attenuated symptoms and extended life span in murine models of globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD) or Krabbe disease is a neurodegenerative disorder caused by a deficiency of galactocerebrosidase (GALC) activity. GALC is required for the lysosomal degradation of galactosylceramide, psychosine, and possibly other galactolipids. This process is extremely important during active myelination. In the absence of functional GALC, psychosine accumulates, resulting in the apoptotic death of myelin-producing cells. While most patients are infants who do not survive beyond 2 years of age, some older patients are also diagnosed. Hematopoietic stem cell transplantation has proven to have a positive effect on the course of some patients with late-onset Krabbe disease. Murine models of this disease provide an excellent opportunity to evaluate therapeutic alternatives including gene therapy. In this study we used serotype 1 AAV to express mouse GALC under the control of the human cytomegalovirus promoter. Direct administration of these viral particles into the brains of neonatal mice with GLD resulted in sustained expression of GALC activity, improved myelination, attenuated symptoms, and prolonged life span. While this treatment also resulted in significant pathological improvements, the treated mice died with symptoms similar to those of the untreated mice. Additional initiatives may be required to prevent the onset of disease and reverse the course of the disease in animal models and human patients.

Animals↗
PubMed1994

Absence of MHC class II molecules reduces CNS demyelination, microglial/macrophage infiltration, and twitching in murine globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD) is a severe genetic demyelinating disorder with an increased number of Ia (immune response antigen) positive brain microglia/macrophages. To assess the role of aberrant Ia expression in the central nervous system (CNS), twitcher mice, which represent the murine model for GLD, were mated with Ia- transgenic mice. Compared with the Ia+ controls, Ia- twitcher mice showed a profound reduction in the severity of demyelinating lesions correlated with significantly fewer microglia/macrophages. Most importantly, Ia- twitcher mice showed significantly reduced twitching compared with ia+ twitcher mice. In contrast with experimental allergic encephalomyelitis (EAE), there was no significant amount of inflammatory T cell infiltrates, implying that T cells may not play a predominant role in this disease. These findings may have broad therapeutic implications for Alzheimer's disease, Parkinson's disease, and Huntington's disease, which display enhanced Ia expression in the CNS without obvious T cell infiltrates.

Animals↗
PubMed1992

Thalamic and basal ganglia hyperdensities--a CT marker for globoid cell leukodystrophy?

Globoid cell leukodystrophy (Krabbe's disease) is a rare autosomal recessive lipidosis, with signs restricted to the nervous system, and is caused by deficiency of the lysosomal hydrolase galactocerebroside beta-galactosidase (galactocerebrosidase). In recent years there have been reports of neurological variants, where age of onset and manifestations differed from the classical form. In other cases, specific CT findings, mainly hyperdensities, have been seen. We report a case of late-infantile Krabbe's disease where thalamic and basal ganglia hyperdensities have been seen on CT scan. We also stress that clinicians should be aware of the possibility of Krabbe's disease in infants who display progressive encephalopathy and these CT findings.

Basal Ganglia↗
PubMed1995

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

Within 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.

Adrenoleukodystrophy↗
PubMed1984

Biochemical pathogenesis of genetic leukodystrophies: comparison of metachromatic leukodystrophy and globoid cell leukodystrophy (Krabbe's disease).

Among the genetic leukodystrophies known to occur in man, the fundamental genetic defects have been clarified in two disorders, metachromatic leukodystrophy and globoid cell leukodystrophy (Krabbe's disease). Nevertheless, the biochemical sequences with which the underlying genetic defects lead to the clinical and pathological features of the diseases and to disruption of the normal brain function are not well understood. Comparison of the two classical leukodystrophies provides us an opportunity to consider the biochemical pathogenesis of these disorders, some common between them and others apparently unique. That both metachromatic leukodystrophy and globoid cell leukodystrophy manifest themselves almost exclusively as diseases of the myelin sheath is relatively easy to understand because both are caused by genetic abnormalities in the metabolism of the characteristic constituents of myelin, sulfatide and galactosylceramide. The presence of the abnormal and characteristic globoid cells in the white matter of Krabbe's disease patients appears to be due to a unique property of galactosylceramide in that, when present in free form in the brain, it elicits infiltration of macrophages which transform themselves to globoid-like cells. No other lipids, including sulfatide, are known to induce similar tissue reactions. The most conspicuous difference between the two diseases is the presence or absence of abnormal accumulation of the substrates, the degradation of which is genetically blocked in the respective diseases. In metachromatic leukodystrophy, sulfatide accumulates to abnormally high levels, as logically expected for a "lysosomal storage disease". In Krabbe's disease, on the other hand, galactosylceramide is always much less than normal despite the genetic block in its catabolic pathway. This paradoxical finding can be explained by the "psychosine hypothesis".(ABSTRACT TRUNCATED AT 250 WORDS)

Brain↗
PubMed1996

Molecular heterogeneity of late-onset forms of globoid-cell leukodystrophy.

Globoid-cell leukodystrophy (GLD) is an autosomal recessive inherited disorder caused by the deficiency of galactocerebrosidase, the lysosomal enzyme responsible for the degradation of the myelin glycolipid galactocerebroside. Although the most common form of the disease is the classical infantile form (Krabbe disease), later-onset forms also have been described. We have analyzed the galactocerebrosidase gene in 17 patients (nine families) with late-onset GLD and in 1 patient with classical Krabbe disease. Half of the patients were heterozygous for the large gene deletion associated with the 502C-->T polymorphism, the most common mutation in infantile patients. Several novel mutations that result in deficient galactocerebrosidase activity were also identified in these patients. They include the missense mutations R63H, G95S, M101L, G268S, Y298C, and I234T; the nonsense mutation S7X; a one-base deletion (805delG); a mutation that interferes with the splicing of intron 1; and a 34-nt insertion in the RNA, caused by the aberrant splicing of intron 6. All of these genetic defects are clustered in the first 10 exons of the galactocerebrosidase gene and therefore affect the 50-kD subunit of the mature enzyme. Studies on the distribution and enzymatic activity of the polymorphic alleles 1637T/C (I546/T546) provided support for previous data that had indicated the existence of two galactocerebrosidase forms with different catalytic activities in the general population. Our data also indicate that the mutations occur preferentially in the "low activity" 1637C allele.

Adolescent↗
PubMed2007

Central nervous system-directed AAV2/5-mediated gene therapy synergizes with bone marrow transplantation in the murine model of globoid-cell leukodystrophy.

Globoid-cell leukodystrophy (GLD) is a rapidly progressing inherited neurodegenerative disorder caused by a deficiency in galactosylceramidase activity. Previous studies in the murine model of GLD (Twitcher mouse) have shown that both bone marrow transplantation (BMT) and central nervous system (CNS)-directed gene therapy can be moderately effective at ameliorating certain aspects of GLD. As BMT and CNS-directed gene therapy target fundamentally different tissues, we tested the hypothesis that combining these disparate therapies would be more efficacious than either therapy alone. Mice receiving myeloreductive conditioning at birth followed by syngeneic BMT had approximately 25-35% donor chimerism. Untreated Twitcher mice, Twitcher mice treated with BMT alone, AAV2/5 alone, or a combination of BMT and AAV2/5 had mean lifespans of 39, 44, 49, and 104 days, respectively. Twitcher mice treated with a combination of BMT and AAV2/5 also had significantly improved performance in several behavioral tests and greater reduction in demyelination, astrocytosis, and macrophage infiltration compared to untreated Twitcher mice or mice that received either therapy alone. These data suggest that CNS-directed gene therapy synergizes with BMT. The combination of these disparate therapeutic approaches may form the basis for more effective treatment of this inherited neurodegenerative disorder.

Animals↗
PubMed1988

Metabolism of cerebroside sulfate and subcellular distribution of its metabolites in cultured skin fibroblasts from controls, metachromatic leukodystrophy, and globoid cell leukodystrophy.

With pulse-chase study of 1-[14C]stearic acid-labeled cerebroside sulfate (14C-CS) and subsequent subcellular fractionation by Percoll gradient, the metabolism of CS and translocation of its metabolites in human skin fibroblasts from controls, metachromatic leukodystrophy (MLD), and globoid cell leukodystrophy (GLD) were studied. In control skin fibroblasts, CS was transported to lysosome and metabolized there to galactosylceramide (GalCer) and ceramide (Cer) within 1 h. During the chase period, radioactivity was increased at plasma membrane plus Golgi as phospholipids and no accumulation of GalCer or Cer was found in lysosome. In MLD fibroblasts, 95% of 14C-CS taken up was unhydrolyzed at 24 h-chase and accumulated at not only lysosome but also plasma membrane. In GLD fibroblasts, GalCer was accumulated throughout the subcellular fractions and more accumulated mainly at plasma membrane plus Golgi with longer pulse. This translocation of lipid from lysosome seems to have considerable function, even in lipidosis, which may result in an imbalance of the sphingolipid pattern on the cell surface and these changes might be one of causes of neuronal dysfunction in sphingolipidosis.

Cell Compartmentation↗
PubMed1982

Globoid cell leukodystrophy: specialized contact of globoid cell with astrocyte in the brain of twitcher mouse.

Subplasmalemmal linear densities (Yajima et al. 1977 a) were the membrane specializations observed in globoid cells in globoid cell leukodystrophy (GLD) and in the cells of the mononuclear phagocytic system (Kawanami et al. 1980). In the spinal cord of the twitcher mouse, an authentic murine model of GLD, somewhat similar membrane specializations were noted in astrocytes, and on some occasions, a spot desmosome-like cellular contact was observed between globoid cells, which were likely to be mesodermal in origin, and astrocytes, which are of ectodermal origin. Possible significance of such apparent cellular contact is discussed briefly.

Animals↗
PubMed1998

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.

Central Nervous System Diseases↗
PubMed2000

L-cycloserine slows the clinical and pathological course in mice with globoid cell leukodystrophy (twitcher mice).

Globoid cell leukodystrophy (Krabbe's disease) is an autosomal recessive disease that affects the lysosomal enzyme galactosylceramidase. Galactosylceramidase removes galactose from galactosylceramide and psychosine, which are derived from sphingosine. In the present study, L-cycloserine (an inhibitor of 3-ketodyhydrosphingosine synthase) was administered to the twitcher mouse, an authentic model of globoid cell leukodystrophy. Twitcher mice treated with L-cycloserine had a significantly longer life span and a delayed onset of weight loss than vehicle-injected twitcher mice. Pathological features such as macrophage infiltration and astrocyte gliosis also were less in treated twitcher mice. These results indicate that substrate reduction therapy may have therapeutic value for individuals with residual enzymatic activity, e.g., individuals with late onset disease or individuals with partial enzyme replacement via bone marrow transplantation. In these cases, a reduction in galactosylceramide and psychosine synthesis would enable residual enzymatic activity to keep up with the accumulation of these substrates that would otherwise lead to pathology.

Animals↗
PubMed2001

Generation of a mouse with low galactocerebrosidase activity by gene targeting: a new model of globoid cell leukodystrophy (Krabbe disease).

Globoid cell leukodystrophy (Krabbe disease) is a severe leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene leading to extremely low (less than 5% of normal activity) GALC activity. Human patients include primarily severely affected infants as well as patients with a later onset of symptoms. The infants usually die before 2 years of age, but it is difficult to predict the clinical course in older patients. In addition to these patients, additional individuals identified in this laboratory have 10--20% of normal GALC activity measured in accessible tissues. These individuals have a wide range of clinical presentations involving neurological degeneration. On molecular analysis of the GALC gene they all have three or more mutations considered to be normal polymorphisms resulting in amino acid changes in the two copies of the GALC gene. In order to investigate the role these amino acid changes may play on clinical, biochemical, and pathological findings, a new transgenic mouse was generated by homologous recombination. After preliminary studies determined what effect each amino acid change had on mouse GALC activity in transient transfection experiments, mice containing a cysteine residue at codon 168 instead of histidine (H168C) were produced. These mice developed symptoms, but they were delayed by 10--15 days from the well-characterized twitcher (twi) mouse. They accumulated psychosine slightly slower than twi mice, showed pathological changes less severe than twi mice in the central and peripheral nervous systems, and live about 15 days longer than twi mice. They have large litters and will play a role in therapy trials using new procedures currently under development.

Age Factors↗
PubMed1975

Globoid cell leukodystrophy in a Beagle.

Globoid cell leukodystrophy was diagnosed in a purebred Beagle bitch. Clinical signs and histopathologic and ultrastructural features were consistent with those reported in globoid cell leukodystrophy in man, cat, and other breeds of dogs. The occurrence of the disorder in 2 clinically affected females from a related litter and a familial history of inbreeding support the existence of a familial pattern.

Animals↗