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Volkmar Gieselmann - One of the best experts on this subject based on the ideXlab platform.
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Metachromatic Leukodystrophy: genetics, pathogenesis and therapeutic options.
Acta paediatrica (Oslo Norway : 1992), 2008Co-Authors: Volkmar GieselmannAbstract:Metachromatic Leukodystrophy is a lysosomal storage disease caused by the deficiency of arylsulphatase A (ASA). This leads to storage of the membrane lipid sulphatide, which is abundant in myelin. A pathological hallmark of the disease is demyelination, causing various and ultimately lethal neurological symptoms. Today more than 110 mutations in the ASA gene have been identified, of which only three are frequent. Patients homozygous for alleles, which do not allow for the synthesis of functional ASA always suffer from the severe form of the disease, whereas alleles allowing the expression of residual enzyme activity are associated with the later onset juvenile or adult forms of Metachromatic Leukodystrophy. In addition, there are other as yet unknown genetic or epigenetic factors modifying the phenotype substantially. ASA-deficient mice have been generated as a model of Metachromatic Leukodystrophy. These mice store sulphatide and show progressive neurological symptoms, but do not demyelinate. This animal model was recently improved using a transgenic approach, which generated mice in which sulphatide synthesis in myelin-producing cells is enhanced. This new animal model reflects the pathological characteristics of the human disease. ASA-deficient mice have been used in various therapeutic trials involving enzyme replacement, haematopoietic stem-cell-based gene therapy and direct injections of ASA-expressing viral vectors into the brain. These animal studies have paved the way for future clinical studies of enzyme replacement and gene therapy. Conclusion: For many years this devastating disorder was considered untreatable and the outlook for patients was poor. Within a comparatively short period of time since the ASA gene was cloned in 1989, genetic and biochemical studies and data generated from newly developed animal models have led to the first clinical trials. It is hoped that these developments will prove beneficial for patients.
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Metachromatic Leukodystrophy: consequences of sulphatide accumulation
Acta paediatrica (Oslo Norway : 1992). Supplement, 2007Co-Authors: Volkmar Gieselmann, Sebastian Franken, Diana Klein, Jan-eric Månsson, R. Sandhoff, R. Lüllmann Rauch, Dieter Hartmann, V. P. M. Saravanan, P.p. De Deyn, Rudi D'hoogeAbstract:Metachromatic Leukodystrophy is a lysosomal lipid storage disorder. It is caused by mutations in the gene for arylsulphatase A, an enzyme involved in the degradation of the sphingolipid 3'-O-sulphogalactosylceramide (sulphatide). This membrane lipid can be found in various cell types, but in particularly high concentrations in the myelin of the nervous system. Patients suffer from progressive, finally lethal, demyelination due to accumulation of sulphatide. In the nervous system, lipid storage not only affects oligodendrocytes but also neurons and, in addition, leads to astrogliosis and activation of microglia. At the cellular level, lysosomal sulphatide storage also affects the lipid composition of myelin itself and has consequences for the amount and localization of particular myelin membrane-associated proteins. Here we review data, largely based on an arylsulphatase A knock-out mouse model of Metachromatic Leukodystrophy. CONCLUSION: The knock-out mouse model of Metachromatic Leukodystrophy has provided insights into the histopathological and cellular consequences of sulphatide storage.
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Complex arylsulfatase A alleles causing Metachromatic Leukodystrophy
Human Mutation, 1994Co-Authors: Joachim Kappler, Hans Jörg Sommerlade, Kurt Von Figura, Volkmar GieselmannAbstract:Metachromatic Leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A. Sequencing of the arylsulfatase A genes of a patient affected with late infantile Metachromatic Leukodystrophy revealed that the patient is a compound heterozygote of two alleles carrying two deleterious mutation each. One allele bears a splice donor site mutation together with two polymorphisms and an additional missense mutation (Gly 122>Ser). The splice donor site mutation and the Gly 122>Ser substitution have been described recently but on different alleles. The other allele carries two missense mutations causing a Gly 154>Asp and a Pro 167>Arg substitution. When arylsulfatase A cDNAs carrying these mutations separately or in combination were transfected into baby hamster kidney cells expression of arylsulfatase A activity could not be detected. Linkage of mutations was verified by sequencing of the parental DNAs. Biosynthesis studies performed with the patients' fibroblasts show that the enzyme carrying both mutations is synthesized in almost normal amounts but is rapidly degraded in an early biosynthetic compartment. The occurence of two disease causing mutations on the same allele is a novel phenomenon in Metachromatic Leukodystrophy and as far as lysosomal storage diseases are concerned have so far only been described in Fabry disease and in the complex glucocerebrosidase alleles associated with Gaucher disease. © 1994 Wiley-Liss, Inc.
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MOLECULAR GENETICS OF Metachromatic Leukodystrophy
Journal of inherited metabolic disease, 1994Co-Authors: Volkmar Gieselmann, A. Polten, J. Kreysing, Kurt Von FiguraAbstract:Metachromatic Leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulphatase A. The disease is characterized by a progressive demyelination that causes a variety of neurological symptoms. Patients die within a few years after the age of onset. Clinically the disease is heterogeneous and according to the age of onset three different forms can be distinguished. The gene of arylsulphatase A has been cloned and several mutations causing Metachromatic Leukodystrophy have been characterized. The distribution of these alleles among patients with different clinical forms of the disease has revealed a genotype-phenotype correlation. A major determinant of the clinical phenotype is the residual enzyme activity that it associated with a particular genotype. Homozygosity for alleles that do not allow the synthesis of arylsulphatase A polypeptides causes the most severe form of disease, whereas homozygosity for alleles that encode arylsulphatase A with low residual enzyme activity is found in the mild late-onset forms of disease. A substantial arylsulphatase A deficiency can also be found in healthy individuals at high frequency. This phenomenon has been termed pseudodeficiency. It is often difficult to distinguish whether an arylsulphatase A deficiency is due to Metachromatic Leukodystrophy or harmless pseudodeficiency. The characterization of the mutations causing pseudodeficiency has allowed the detection of the pseudodeficiency allele in the DNA of probands and has thus improved the diagnosis and genetic counselling for Metachromatic Leukodystrophy.
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Molecular genetics of Metachromatic Leukodystrophy
Human mutation, 1994Co-Authors: Volkmar Gieselmann, David A. Wenger, Joël Zlotogora, Ann Harris, C. Phillip MorrisAbstract:Metachromatic Leukodystrophy is an autosomal recessive inherited lysosomal storage disease. It can be caused by mutations in two different genes, the arylsulfatase A and the prosaposin gene. These genes encode two proteins that are needed for the proper degradation of cerebroside sulfate, a glycolipid mainly found in the myelin membranes. Deficiency of arylsulfatase A or of a proteolytic product of prosaposin leads to the accumulation of cerebroside sulfate, which causes a lethal progressive demyelination. Mutations in the arylsulfatase A gene are far more frequent than those of the prosaposin gene. So far 31 amino acid substitutions, one nonsense mutation, three small deletions, three splice donor site mutations, and one combined missense/splice donor site mutation have been identified in the arylsulfatase A gene. Two of these mutant alleles are frequent, accounting for about one-half of all mutant alleles, whereas the remainder are heterogeneous. Amino acid substitutions cluster in exons 2 and 3, a region that shows a high degree of conservation among sulfatases of different function and origin. Different mutations are associated with phenotypes of different severity, but there is a remarkable variability of severity when patients with identical genotypes are compared. Demonstration of an arylsulfatase A deficiency is not a proof of Metachromatic Leukodystrophy, since a substantial deficiency without any clinical consequences is frequent in the general population. This deficiency is caused by an arylsulfatase A allele, which due to certain mutations encodes greatly reduced amounts of functional enzyme. However, these amounts are sufficient to sustain a normal phenotype. In the diagnosis and genetic counseling, these deficiencies must be differentiated from those causing Metachromatic Leukodystrophy. So far only six patients with mutations in the prosaposin gene have been described, in which three defective alleles two with amino acid substitutions and one with a 33-bp insertion have been identified. © 1994 Wiley-Liss, Inc.
Kurt Von Figura - One of the best experts on this subject based on the ideXlab platform.
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Complex arylsulfatase A alleles causing Metachromatic Leukodystrophy
Human Mutation, 1994Co-Authors: Joachim Kappler, Hans Jörg Sommerlade, Kurt Von Figura, Volkmar GieselmannAbstract:Metachromatic Leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A. Sequencing of the arylsulfatase A genes of a patient affected with late infantile Metachromatic Leukodystrophy revealed that the patient is a compound heterozygote of two alleles carrying two deleterious mutation each. One allele bears a splice donor site mutation together with two polymorphisms and an additional missense mutation (Gly 122>Ser). The splice donor site mutation and the Gly 122>Ser substitution have been described recently but on different alleles. The other allele carries two missense mutations causing a Gly 154>Asp and a Pro 167>Arg substitution. When arylsulfatase A cDNAs carrying these mutations separately or in combination were transfected into baby hamster kidney cells expression of arylsulfatase A activity could not be detected. Linkage of mutations was verified by sequencing of the parental DNAs. Biosynthesis studies performed with the patients' fibroblasts show that the enzyme carrying both mutations is synthesized in almost normal amounts but is rapidly degraded in an early biosynthetic compartment. The occurence of two disease causing mutations on the same allele is a novel phenomenon in Metachromatic Leukodystrophy and as far as lysosomal storage diseases are concerned have so far only been described in Fabry disease and in the complex glucocerebrosidase alleles associated with Gaucher disease. © 1994 Wiley-Liss, Inc.
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MOLECULAR GENETICS OF Metachromatic Leukodystrophy
Journal of inherited metabolic disease, 1994Co-Authors: Volkmar Gieselmann, A. Polten, J. Kreysing, Kurt Von FiguraAbstract:Metachromatic Leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulphatase A. The disease is characterized by a progressive demyelination that causes a variety of neurological symptoms. Patients die within a few years after the age of onset. Clinically the disease is heterogeneous and according to the age of onset three different forms can be distinguished. The gene of arylsulphatase A has been cloned and several mutations causing Metachromatic Leukodystrophy have been characterized. The distribution of these alleles among patients with different clinical forms of the disease has revealed a genotype-phenotype correlation. A major determinant of the clinical phenotype is the residual enzyme activity that it associated with a particular genotype. Homozygosity for alleles that do not allow the synthesis of arylsulphatase A polypeptides causes the most severe form of disease, whereas homozygosity for alleles that encode arylsulphatase A with low residual enzyme activity is found in the mild late-onset forms of disease. A substantial arylsulphatase A deficiency can also be found in healthy individuals at high frequency. This phenomenon has been termed pseudodeficiency. It is often difficult to distinguish whether an arylsulphatase A deficiency is due to Metachromatic Leukodystrophy or harmless pseudodeficiency. The characterization of the mutations causing pseudodeficiency has allowed the detection of the pseudodeficiency allele in the DNA of probands and has thus improved the diagnosis and genetic counselling for Metachromatic Leukodystrophy.
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Molecular Genetics of Metachromatic Leukodystrophy
Developmental neuroscience, 1991Co-Authors: Volkmar Gieselmann, Joachim Kappler, Arvan L. Fluharty, A. Polten, J. Kreysing, Kurt Von FiguraAbstract:Metachromatic Leukodystrophy (MLD) is a lysosomal storage disease caused by the deficiency of arylsulfatase A (ASA). The ASA cDNA as well as the gene has been cloned. The gene is about 3 kb long and c
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Mutations in the arylsulfatase A pseudodeficiency allele causing Metachromatic Leukodystrophy.
American Journal of Human Genetics, 1991Co-Authors: Volkmar Gieselmann, Thorsten Tonnesen, Arvan L. Fluharty, Kurt Von FiguraAbstract:We identified a patient suffering from late infantile Metachromatic Leukodystrophy who genetically seemed to be homozygous for the mutations signifying the arylsulfatase A pseudodeficiency allele. Homozygosity for the pseudodeficiency allele is associated with low arylsulfatase A activity but does not cause a disease. Analysis of the arylsulfatase A gene in this patient revealed a C----T transition in exon 2, causing a Ser 96----Phe substitution in addition to the sequence alterations causing arylsulfatase A pseudodeficiency. Although this mutation was found only in 1 of 78 Metachromatic Leukodystrophy patients tested, five more patients were identified who seemed hetero- or homozygous for the pseudodeficiency allele. The existence of nonfunctional arylsulfatase A alleles derived from the pseudodeficiency allele calls for caution when the diagnosis of arylsulfatase A pseudodeficiency is based solely on the identification of the mutations characterizing the pseudodeficiency allele.
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Molecular Basis of Different Forms of Metachromatic Leukodystrophy
The New England journal of medicine, 1991Co-Authors: A. Polten, Joachim Kappler, Arvan L. Fluharty, Kurt Von Figura, C. B. Fluharty, Volkmar GieselmannAbstract:Abstract Background. Metachromatic Leukodystrophy is an autosomal recessive inherited lysosomal storage disorder caused by a deficiency of arylsulfatase A. Three forms of the disease can be distinguished according to severity and the age at onset: late infantile (1 to 2 years), juvenile (3 to 16), and adult (>16). Methods and Results. To understand the molecular basis of the different forms of the disease, we analyzed arylsulfatase A alleles associated with Metachromatic Leukodystrophy. Two alleles (termed I and A) were Identified and accounted for about half of all arylsulfatase A alleles among 68 patients with Metachromatic Leukodystrophy whom we examined. Sufficient information was available for 66 of the patients to allow classification of their disease. Of the six instances of homozygosity for allele I, all were associated with the late-infantile form of the disease; of the eight instances of homozygosity for allele A, five were associated with the adult form and three with the juvenile form. When bo...
R Nuri Sener - One of the best experts on this subject based on the ideXlab platform.
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Metachromatic Leukodystrophy: Diffusion MR imaging and proton MR spectroscopy
Acta radiologica (Stockholm Sweden : 1987), 2003Co-Authors: R Nuri SenerAbstract:Metachromatic Leukodystrophy is characterized by dysmyelination caused by a deficiency of arylsulfatase-A. In a 17-month-old boy with Metachromatic Leukodystrophy, an echo-planar diffusion MR sequence revealed a restricted diffusion pattern in the deep white matter, manifested by high-signal on b = 1000 s/mm2 images, and low ADC values (0.56 × 10−3 mm2/s). Proton MR spectroscopy revealed a marked decrease in choline, a metabolite related to myelin turnover. These observations consisting of a restricted diffusion pattern on diffusion MR imaging, and decreased choline peaks on proton spectroscopy, likely represented dysmyelination in Metachromatic Leukodystrophy.
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Metachromatic Leukodystrophy: diffusion MR imaging findings
AJNR American journal of neuroradiology, 2002Co-Authors: R Nuri SenerAbstract:Herein the case of a 10-month-old boy with Metachromatic Leukodystrophy is reported. Diffusion MR imaging performed with an echo-planar trace sequence revealed a cytotoxic edema-like pattern (high signal intensity on b = 1000 s/mm(2) images and low apparent diffusion coefficient values) in the affected white matter in the absence of an ischemic condition. This finding was unchanged at a 6-month follow-up, as revealed by diffusion MR imaging. A gradient-echo diffusion sequence, reverse fast imaging in steady-state precession, revealed hyperintense changes at the corresponding regions. It is likely that the cytotoxic edematous pattern (restricted diffusion pattern) reflected restriction of mobility of the water molecules within abnormal portions of the myelin sheath, because impaired myelin breakdown and reutilization are known features of Metachromatic Leukodystrophy.
Nicole I. Wolf - One of the best experts on this subject based on the ideXlab platform.
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Metachromatic Leukodystrophy and transplantation: remyelination, no cross‐correction
Annals of clinical and translational neurology, 2020Co-Authors: Nicole I. Wolf, Marjolein Breur, Bonnie Plug, Shanice Beerepoot, Aimee S. R. Westerveld, Diane F. Van Rappard, Sharon I. De Vries, Maarten H. P. Kole, Adeline Vanderver, Marjo S. Van Der KnaapAbstract:OBJECTIVE: In Metachromatic Leukodystrophy, a lysosomal storage disorder due to decreased arylsulfatase A activity, hematopoietic stem cell transplantation may stop brain demyelination and allow remyelination, thereby halting white matter degeneration. This is the first study to define the effects and therapeutic mechanisms of hematopoietic stem cell transplantation on brain tissue of transplanted Metachromatic Leukodystrophy patients. METHODS: Autopsy brain tissue was obtained from eight (two transplanted and six nontransplanted) Metachromatic Leukodystrophy patients, and two age-matched controls. We examined the presence of donor cells by immunohistochemistry and microscopy. In addition, we assessed myelin content, oligodendrocyte numbers, and macrophage phenotypes. An unpaired t-test, linear regression or the nonparametric Mann-Whitney U-test was performed to evaluate differences between the transplanted, nontransplanted, and control group. RESULTS: In brain tissue of transplanted patients, we found metabolically competent donor macrophages expressing arylsulfatase A distributed throughout the entire white matter. Compared to nontransplanted patients, these macrophages preferentially expressed markers of alternatively activated, anti-inflammatory cells that may support oligodendrocyte survival and differentiation. Additionally, transplanted patients showed higher numbers of oligodendrocytes and evidence for remyelination. Contrary to the current hypothesis on therapeutic mechanism of hematopoietic cell transplantation in Metachromatic Leukodystrophy, we detected no enzymatic cross-correction to resident astrocytes and oligodendrocytes. INTERPRETATION: In conclusion, donor macrophages are able to digest accumulated sulfatides and may play a neuroprotective role for resident oligodendrocytes, thereby enabling remyelination, albeit without evidence of cross-correction of oligo- and astroglia. These results emphasize the importance of immunomodulation in addition to the metabolic correction, which might be exploited for improved outcomes.
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Metachromatic Leukodystrophy and transplantation remyelination no cross correction
Annals of clinical and translational neurology, 2020Co-Authors: Nicole I. Wolf, Marjolein Breur, Bonnie Plug, Shanice Beerepoot, Aimee S. R. Westerveld, Diane F. Van Rappard, Sharon I. De Vries, Maarten H. P. KoleAbstract:OBJECTIVE: In Metachromatic Leukodystrophy, a lysosomal storage disorder due to decreased arylsulfatase A activity, hematopoietic stem cell transplantation may stop brain demyelination and allow remyelination, thereby halting white matter degeneration. This is the first study to define the effects and therapeutic mechanisms of hematopoietic stem cell transplantation on brain tissue of transplanted Metachromatic Leukodystrophy patients. METHODS: Autopsy brain tissue was obtained from eight (two transplanted and six nontransplanted) Metachromatic Leukodystrophy patients, and two age-matched controls. We examined the presence of donor cells by immunohistochemistry and microscopy. In addition, we assessed myelin content, oligodendrocyte numbers, and macrophage phenotypes. An unpaired t-test, linear regression or the nonparametric Mann-Whitney U-test was performed to evaluate differences between the transplanted, nontransplanted, and control group. RESULTS: In brain tissue of transplanted patients, we found metabolically competent donor macrophages expressing arylsulfatase A distributed throughout the entire white matter. Compared to nontransplanted patients, these macrophages preferentially expressed markers of alternatively activated, anti-inflammatory cells that may support oligodendrocyte survival and differentiation. Additionally, transplanted patients showed higher numbers of oligodendrocytes and evidence for remyelination. Contrary to the current hypothesis on therapeutic mechanism of hematopoietic cell transplantation in Metachromatic Leukodystrophy, we detected no enzymatic cross-correction to resident astrocytes and oligodendrocytes. INTERPRETATION: In conclusion, donor macrophages are able to digest accumulated sulfatides and may play a neuroprotective role for resident oligodendrocytes, thereby enabling remyelination, albeit without evidence of cross-correction of oligo- and astroglia. These results emphasize the importance of immunomodulation in addition to the metabolic correction, which might be exploited for improved outcomes.
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Intrathecal baclofen in Metachromatic Leukodystrophy
Developmental medicine and child neurology, 2018Co-Authors: Nikki Van Der Veldt, Nicole I. Wolf, Diane F. Van Rappard, Marjo S. Van Der Knaap, Laura A. Van De Pol, Willem J.r. Van Ouwerkerk, Jules G. Becher, Annemieke I. BuizerAbstract:Metachromatic Leukodystrophy (MLD) is a rare progressive neurological disorder, often accompanied by motor impairments that are challenging to treat. In this case series, we report the course of treatment with intrathecal baclofen (ITB), aimed at improving daily care and comfort in children and young adults with MLD. All patients with MLD in our centre on ITB treatment for a minimum of 6 months were included (n=10; 4 males, 6 females; mean age 10y 8mo [range 6-24y]). Eight patients had MLD with a predominant spastic movement disorder (sMLD) and two were mainly dyskinetic. Patients with sMLD were compared with matched patients with spastic cerebral palsy (CP). Complication rates related to ITB treatment were similar in both groups. ITB treatment course in the first 6 months after pump implantation appears to show more dose increase in most patients MLD, compared to patients with spastic CP. This may be due to the progressive disease in MLD. ITB is a feasible therapy to improve daily care and comfort in patients with MLD and should therefore be considered early. WHAT THIS PAPER ADDS: Intrathecal baclofen (ITB) is a feasible therapy to improve comfort and daily care in children and young people with Metachromatic Leukodystrophy (MLD). In the first 6 months of ITB treatment, MLD seems to show more dose increase compared to spastic cerebral palsy.
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Metachromatic Leukodystrophy: Disease spectrum and approaches for treatment
Best practice & research. Clinical endocrinology & metabolism, 2014Co-Authors: Diane F. Van Rappard, Jaap Jan Boelens, Nicole I. WolfAbstract:Metachromatic Leukodystrophy is an inherited lysosomal disorder caused by recessive mutations in ARSA encoding arylsulfatase A. Low activity of arylsulfatase A results in the accumulation of sulfatides in the central and peripheral nervous system leading to demyelination. The disease is classified in a late-infantile, juvenile and adult onset type based on the age of onset, all characterized by a variety of neurological symptoms, which eventually lead to death if untreated. There is no curative treatment for all types and stages. This review discusses diagnostic process and efficacy of current and possible future therapies such as hematopoietic stem cell transplantation, enzyme replacement therapy and gene therapy. A systematic evaluation regarding the efficacy of hematopoietic stem cell transplantation and a longer follow up period for gene therapy are needed to come to a general conclusion and improve treatment options for Metachromatic Leukodystrophy.
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Improvement of White Matter Changes on Neuroimaging Modalities After Stem Cell Transplant in Metachromatic Leukodystrophy
JAMA neurology, 2013Co-Authors: Martje E. Van Egmond, Marjo S. Van Der Knaap, Jaap Jan Boelens, Petra J. W. Pouwels, Caroline A. Lindemans, Frederik Barkhof, Martijn D. Steenwijk, Peter M. Van Hasselt, Nicole I. WolfAbstract:IMPORTANCE: We sought to illustrate improvement of cerebral white matter changes in Metachromatic Leukodystrophy after treatment with hematopoietic stem cell transplant (HSCT). OBSERVATIONS: We conducted serial magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS) as standard follow-up after HSCT with cord blood in 1 patient with juvenile Metachromatic Leukodystrophy diagnosed before frank degenerative symptoms developed. We measured MRI and 1H-MRS changes. The white matter changes first increased after HSCT, then decreased in relation to the pre-HSCT MRI and 1H-MRS. CONCLUSIONS AND RELEVANCE: Hematopoietic stem cell transplant, if performed early in Metachromatic Leukodystrophy, can not only stabilize but even improve cerebral white matter abnormalities. Our findings suggest a biological effect of HSCT.
Arvan L. Fluharty - One of the best experts on this subject based on the ideXlab platform.
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Molecular Genetics of Metachromatic Leukodystrophy
Developmental neuroscience, 1991Co-Authors: Volkmar Gieselmann, Joachim Kappler, Arvan L. Fluharty, A. Polten, J. Kreysing, Kurt Von FiguraAbstract:Metachromatic Leukodystrophy (MLD) is a lysosomal storage disease caused by the deficiency of arylsulfatase A (ASA). The ASA cDNA as well as the gene has been cloned. The gene is about 3 kb long and c
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Mutations in the arylsulfatase A pseudodeficiency allele causing Metachromatic Leukodystrophy.
American Journal of Human Genetics, 1991Co-Authors: Volkmar Gieselmann, Thorsten Tonnesen, Arvan L. Fluharty, Kurt Von FiguraAbstract:We identified a patient suffering from late infantile Metachromatic Leukodystrophy who genetically seemed to be homozygous for the mutations signifying the arylsulfatase A pseudodeficiency allele. Homozygosity for the pseudodeficiency allele is associated with low arylsulfatase A activity but does not cause a disease. Analysis of the arylsulfatase A gene in this patient revealed a C----T transition in exon 2, causing a Ser 96----Phe substitution in addition to the sequence alterations causing arylsulfatase A pseudodeficiency. Although this mutation was found only in 1 of 78 Metachromatic Leukodystrophy patients tested, five more patients were identified who seemed hetero- or homozygous for the pseudodeficiency allele. The existence of nonfunctional arylsulfatase A alleles derived from the pseudodeficiency allele calls for caution when the diagnosis of arylsulfatase A pseudodeficiency is based solely on the identification of the mutations characterizing the pseudodeficiency allele.
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Molecular Basis of Different Forms of Metachromatic Leukodystrophy
The New England journal of medicine, 1991Co-Authors: A. Polten, Joachim Kappler, Arvan L. Fluharty, Kurt Von Figura, C. B. Fluharty, Volkmar GieselmannAbstract:Abstract Background. Metachromatic Leukodystrophy is an autosomal recessive inherited lysosomal storage disorder caused by a deficiency of arylsulfatase A. Three forms of the disease can be distinguished according to severity and the age at onset: late infantile (1 to 2 years), juvenile (3 to 16), and adult (>16). Methods and Results. To understand the molecular basis of the different forms of the disease, we analyzed arylsulfatase A alleles associated with Metachromatic Leukodystrophy. Two alleles (termed I and A) were Identified and accounted for about half of all arylsulfatase A alleles among 68 patients with Metachromatic Leukodystrophy whom we examined. Sufficient information was available for 66 of the patients to allow classification of their disease. Of the six instances of homozygosity for allele I, all were associated with the late-infantile form of the disease; of the eight instances of homozygosity for allele A, five were associated with the adult form and three with the juvenile form. When bo...