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At least 19 recordsLinked to original sources
PubMed1999

Bone marrow transplantation as effective treatment of central nervous system disease in globoid cell leukodystrophy, metachromatic leukodystrophy, adrenoleukodystrophy, mannosidosis, fucosidosis, aspartylglucosaminuria, Hurler, Maroteaux-Lamy, and Sly syndromes, and Gaucher disease type III.

Over 400 patients with lysosomal and peroxisomal storage diseases have received hematopoietic stem cell transplantation from normal donors. Without treatment, all of these diseases have an inexorable fate leading to central nervous system deterioration and early death. On the other hand, all of the engrafted hosts have had a remarkable positive clinical improvement in response to normalization of previously deficient enzymatic activity. Survival data for those engrafted indicates continued life-span as long as two decades beyond transplantation. The particular diseases treated in this way are included in this article. The specific indications and methods for transplantation are also included in this article.

Bone Marrow Transplantation↗
PubMed1990

Advances in the molecular genetics of metachromatic leukodystrophy.

Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulphatase A (EC 3.1.6.1). This results in the intralysosomal storage of cerebroside sulphate, which leads to a progressive demyelination of the nervous system. The patients usually die within a few years from the onset of symptoms. Clinically, there are different forms of the disease and the molecular basis for this heterogeneity is unknown. The gene for arylsulphatase A has recently been cloned and provides a necessary tool for the exact description of the molecular defects occurring in the different forms of metachromatic leukodystrophy. Metachromatic leukodystrophy can also be caused by the deficiency of an arylsulphatase A activator protein (sphingolipid activator protein B). The cDNA for the precursor of this protein has been isolated and a mutant cDNA of one patient has been analysed. A substantial arylsulphatase A deficiency can also occur in healthy individuals, a phenotype termed pseudodeficiency. Two concurrent mutations have been identified in this low arylsulphatase A activity allele. This permitted the development of a rapid assay which allows the detection of the pseudodeficiency allele. Bone marrow transplantation has been tried in several metachromatic leukodystrophy patients and there is evidence that this treatment might slow or even halt the progression of the disease. A final conclusion as to whether bone marrow transplantation is a suitable therapy for metachromatic leukodystrophy cannot be drawn yet.

Amino Acid Sequence↗
PubMed1983

Pseudo arylsulfatase-A deficiency in healthy individuals: genetic and biochemical relationship to metachromatic leukodystrophy.

Metachromatic leukodystrophy is a hereditary neurodegenerative disorder in man associated with deficient arylsulfatase-A activity (aryl-sulfate sulfohydrolase, EC 3.1.6.1). The same enzyme deficiency has been noted in clinically normal individuals, a condition known as pseudo arylsulfatase-A deficiency. With a nonselective method, somatic cell hybrids were obtained from cultured fibroblasts of these two types of individuals; the hybrids showed no restoration of arylsulfatase-A activity. Thus, metachromatic leukodystrophy and pseudo arylsulfatase-A deficiency are allelic conditions. Although these conditions cannot be distinguished by simple quantitative arylsulfatase-A activity assays, they can be differentiated with sucrose density gradient centrifugation, Cellogel electrophoresis, or isoelectric focusing in polyacrylamide gels. In each case, a small amount of activity with characteristics of arylsulfatase-A was found only from fibroblasts of pseudo arylsulfatase-A-deficient individuals and not from those of metachromatic leukodystrophy patients. This residual enzyme has the same pH optimum, heat stability, inhibitor sensitivity, and Km as the normal enzyme but slightly different isoelectric points. In conclusion, although pseudo arylsulfatase-A deficiency and metachromatic leukodystrophy have very different clinical outcomes, they are due to mutations of the same structural gene, coding for arylsulfatase-A. These two conditions can be differentiated now by simple electrophoretic analysis of the residual arylsulfatase-A activity.

Arylsulfatases↗
PubMed1994

Molecular genetics of metachromatic leukodystrophy.

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.

Base Sequence↗
PubMed1991

An 11-bp deletion in the arylsulfatase A gene of a patient with late infantile metachromatic leukodystrophy.

Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A. Examination of the arylsulfatase A gene in a patient suffering from late infantile metachromatic leukodystrophy revealed an 11-bp deletion in exon 8. Although this allele produces normal amounts of ASA mRNA, no arylsulfatase A cross-reacting material could be detected in cultured fibroblasts from the patient. The patient was found to be a compound heterozygote, the other allele is also known to generate no ASA polypeptides. This patient is another example where absence of ASA polypeptides correlates with the severe late infantile form of metachromatic leukodystrophy.

Amino Acid Sequence↗
PubMed1994

Complex arylsulfatase A alleles causing metachromatic leukodystrophy.

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 (Gly122 > Ser). The splice donor site mutation and the Gly122 > Ser substitution have been described recently but on different alleles. The other allele carries two missense mutations causing a Gly154 > Asp and a Pro167 > 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.

Alleles↗
PubMed1994

[Neuropathy in adult metachromatic leukodystrophy].

Metachromatic leukodystrophy is a rare autosomal recessive disorder with deficient arylsulphatase A activity. Different forms occur according to the age at onset of symptoms. Adult forms generally present with presenile dementia and/or psychiatric symptoms. We report a case of a 45-year-old woman, without a family history of neuropsychiatric disorders, presenting with complaints of numbness and weakness of the lower limbs. No intellectual or behavioral disturbances were clinically detectable. Electrophysiological investigation was compatible with severe demyelinating neuropathy in upper and lower limbs. MRI of the brain showed multiple white matter lesions. Adult metachromatic leukodystrophy was diagnosed on the basis of low leucocyte arylsulfatase-A-activity and accumulation of metachromatic material in the sural nerve. Pseudo-deficiency was excluded by DNA analysis. This case indicates that adult metachromatic leukodystrophy should be considered in patients with symptoms and signs resembling multiple sclerosis with peripheral neuropathy and in patients with neuropathy of unknown etiology.

Brain Diseases↗
PubMed1994

Molecular genetics of metachromatic leukodystrophy.

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.

Cerebroside-Sulfatase↗
PubMed1993

An arylsulfatase A (ARSA) missense mutation (T274M) causing late-infantile metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of arylsulfatase A (ARSA; EC 3.1.6.8). The 8 ARSA exons and adjacent intron boundaries from a patient with late-infantile metachromatic leukodystrophy were polymerase chain reaction (PCR) amplified in seven discrete reactions. Amplified ARSA exons were analysed for the presence of sequence alterations by single-strand conformation polymorphism analysis, followed by direct sequencing of PCR products. The patient was found to be homozygous for a C-->T transition in exon IV that results in the substitution of a highly conserved threonine residue at amino acid 274 with a methionine (T274M). Analysis of a further 29 MLD patients revealed the presence of five additional homozygotes for T274M. All 6 T274M homozygotes (representing four families) were of Lebanese descent, and all were known to be the result of consanguineous marriages. The altered amino acid is rigidly conserved among 10 sulfatases from Escherichia coli to humans; therefore, it is most likely that the resultant mutant protein will have little or no enzyme activity. This is consistent with the very low ARSA activity measured in these patients and their uniformly severe clinical presentation.

Amino Acid Sequence↗
PubMed2000

Characterization of four arylsulfatase A missense mutations G86D, Y201C, D255H, and E312D causing metachromatic leukodystrophy.

Metachromatic leukodystrophy is a lysosomal storage disease caused by the deficiency of arylsulfatase A. Here we describe a hitherto unknown arylsulfatase A allele carrying a E312D missense mutation and characterize the effects of this and three previously described missense mutations, G86D, Y201C, and D255H, on arylsulfatase A. In transfection experiments no enzyme activity can be expressed from arylsulfatase A cDNAs coding for the D255H substituted enzyme, whereas Y201C and E312D mutations were associated with low amounts of residual enzyme activity. All amino acid substitutions lead to a decreased stability of the mutant enzyme, and metabolic labeling experiments indicated that except for the E312D substitution the mutations cause arrest of the mutant arylsulfatase A polypeptides in a prelysosomal compartment.

Adolescent↗
PubMed1996

Characterization of two arylsulfatase A missense mutations D335V and T274M causing late infantile metachromatic leukodystrophy.

Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A. We describe a novel missense mutation in exon 6 causing the substitution of Asp335 by Val. In transient transfections no enzyme activity could be expressed from the arylsulfatase A cDNA carrying this mutation. Examination of the effects of the mutation in cells stably overexpressing the mutant enzyme revealed, that the mutant enzyme is catalytically inactive and degraded in an early biosynthetic compartment. We have also investigated the effects of a previously identified mutation (T274M). The specific catalytic activity of the Met274 substituted arylsulfatase is reduced to about 35% of the normal enzyme when measured with an artificial substrate. Most of this enzyme is also degraded in an early biosynthetic compartment.

Age of Onset↗
PubMed1991

An assay for the rapid detection of the arylsulfatase A pseudodeficiency allele facilitates diagnosis and genetic counseling for metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulfatase A (ASA). A substantial ASA deficiency has also been described in clinically healthy persons, a condition for which the term pseudodeficiency was introduced. The discrimination of both kinds of deficiencies based on ASA activity determination is difficult and unreliable. This creates a serious problem in the genetic counseling and diagnosis of MLD. The mutations characteristic for the pseudodeficiency (PD) allele have recently been identified. A non-radioactive assay based on the polymerase chain reaction is described, which allows the rapid detection of the ASA pd allele. The assay utilizes pairs of primers that allow either the amplification of the ASA PD allele or of other ASA alleles, since their 3' residues match either the ASA PD allele or other ASA alleles.

Alleles↗
PubMed1991

The mechanism for a 33-nucleotide insertion in mRNA causing sphingolipid activator protein (SAP-1)-deficient metachromatic leukodystrophy.

Metachromatic leukodystrophy is a severe autosomal recessive disorder caused by accumulation of sulfatide resulting from deficient lysosomal degradation. While most patients have mutations in the lysosomal enzyme arylsulfatase A, some patients have mutations in a required heat stable sphingolipid activator protein, we call SAP-1. One patient with SAP-1 deficiency was previously demonstrated to have a 33-nucleotide insertion in her mRNA. This resulted in the production of mature SAP-1 with 11 extra amino acids, which was unstable during intracellular processing. In this manuscript we demonstrate that the 33 nucleotides are present near the middle of a 4-kb intron, and that a single base change, c to a, in the second position preceding the 33-nucleotide insertion, coupled with the presence of a string of pyrimidines immediately upstream from this change, creates a new 3' splice junction. The presence of a string of pyrimidines within the 33-nucleotide insertion, which has three cag trinucleotides near the 3' end, leads to alternative splicing in normal people as found in this laboratory and by others. The insertion region is followed by a gt dinucleotide that is spliced to a typical 3' consensus sequence. The single nucleotide change, c to a, was confirmed by identifying normal and mutant sequence in the consanguineous parents and a sister, previously identified as a carrier of this disorder.

Base Sequence↗
PubMed1982

Somatic cell hybridization studies on the genetic regulation and allelic mutations in metachromatic leukodystrophy.

Metachromatic leukodystrophy is a hereditary neurodegenerative disease associated with deficient arylsulfatase A activity. Clinical variants differ in onset times and severity of the disease but each breeds true within families. Somatic cell hybridization techniques were used to clarify the genetic relationship among these mutants. Hybrid clones isolated with a nonselective method from fusing fibroblasts of an infantile and a juvenile variant did not show complementation of arylsulfatase A activity. Hence, these clinical variants are allelic mutants. Previous somatic cell hybridization studies suggested that "arylsulfatase A-deficiency" is a dominant phenotype, in contrast to its apparent recessive mode of inheritance. To resolve this discrepancy, hybrid clones from fusing normal and arylsulfatase A-deficient fibroblasts were isolated nonselectively. They continued to express arylsulfatase A activity. Hence, even in vitro, "arylsulfatase A-deficiency" remains as a recessive phenotype.

Adult↗
PubMed1996

A D255H substitution in the arylsulphatase A gene of two unrelated Belgian patients with late-infantile metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an autosomal recessive disease of myelin metabolism caused by a deficiency in the lysosomal enzyme arylsulphatase A (ARSA). We have identified a new mutation in exon 4 of the ARSA gene of two unrelated Belgian patients with late-infantile MLD. The mutation predicts an aspartic acid-to-histidine substitution at position 255 in arylsulphatase A (D255H), in a highly conserved region among sulphatases. Transient expression of the mutation in COS cells did not show an increase in ARSA activity. Both patients were compound heterozygotes carrying the frequent splice site mutation in intron 2 (459 + IG -->A) on the other allele.

Animals↗
PubMed2006

Novel mutations in the arylsulfatase A gene in eight Italian families with metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. We analysed the ARSA gene in eight unrelated Italian families with different clinical variants of MLD and identified three novel mutations: two Ser406Gly, (Glu329Ter) associated with late infantile MLD and one (Leu52Pro) with juvenile MLD. Only one family carried a pseudodeficiency allele (Asn350Ser). The IVS2+1G>A mutation occurred in four families. We also identified three polymorphisms, all in heterozygosis: Thr391Ser was present in five families, Trp193Cys in four families, and Ala210Ala in one family. We could identify 100% of the alleles causing MLD in the families, involving 12 different mutations, resulting in improved prognosis and genetic counselling.

Adolescent↗
PubMed2003

Novel mutations in arylsulfatase A gene in three Ukrainian families with metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by the deficiency of arylsulfatase A (ARSA) or saposin B. The majority of mutations identified in patients with MLD are unique within individual families. Here, we report on the novel missense mutations (F247S, D381E, and A469G) and the known mutations "A" allele and P136S in the ARSA gene in three unrelated Ukrainian families with MLD. The mutations F247S and P136S were found in compound heterozygous with the "A" allele in two patients with juvenile onset MLD. The clinical features of the typical patient with genotype D381E/A469G (early onset with very rapid manifestation of disease) suggest the reason to distinguish an early infantile MLD variant.

Amino Acid Sequence↗
PubMed1985

HPLC analysis of urinary sulfatide: an aid in the diagnosis of metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) presents as six separate variant forms, four allelic and two non-allelic. It is diagnosed in the laboratory by a decrease in the fibroblast or leukocyte arylsulfatase A activity, generally against an artificial substrate. Since residual enzyme activity is not always an indicator of presence or absence of disease, it may be helpful to supplement this information with that of the presence or absence of sulfatide storage in the body. We have improved the HPLC analysis of sulfatide by the use of a sulfated internal standard, sulfatoxymonoalkylmonoacylgalactosylglycerol. Normal urines contain approximately 0 to 0.2 nmol sulfatide/mg creatinine, whereas MLD urines may contain 5 to 7.5 nmol/mg. There is no increase in plasma sulfatide compared to controls in the age group of MLD patients which we studied (up to 4 years).

Cerebroside-Sulfatase↗