Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.6.1 (sulfatase)
 3,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During 1986 and 1991, we had diagnosed 12 cases with genetic leukodystrophy including 9 cases with metachromatic leukodystrophy (MLD), 1 case with globoid cell leukodystrophy (GLD, Krabbe's disease), 1 case with neonatal adrenoleukodystrophy (NALD), and the other with probable Pelizaeus-Merzbacher disease (P-M disease). The clinical, biochemical, neurophysiological and neuroradiological features were reported. The diagnosis of MLD, GLD, NALD was confirmed by means of the measurement of serum arylsulfatase A activity, leukocyte galactocerebrosidase activity and serum very long chain fatty acids, respectively. The P-M disease was highly suspected according to clinical picture and evoked potential findings. All the brainstem auditary evoked potentials (BAEPs) and the scalp somatosensory evoked potentials (scalp SEPs) studies in 6 patients with MLD, 1 patient with GLD and 1 patient with NALD were abnormal. In patients with MLD or GLD, the nerve conduction velocity (NCV) studies showed moderate to severe slowing suggesting peripheral demyelinating neuropathy. Brain CT in patients with MLD or NALD demonstrated marked lucency in the white matter. Brain CTs in the patient with GLD showed progressive brain atrophy. In conclusion, though final diagnosis of genetic leukodystrophy should be established throughout biochemical studies, the neurophysiological and neuroimaging studies are of value as an aid to early diagnosis, prediction of clinical course and evaluation of prognosis for genetic leukodystrophy.
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PMID:A study of genetic leukodystrophies in Chinese children. 162 51

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.
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PMID:An assay for the rapid detection of the arylsulfatase A pseudodeficiency allele facilitates diagnosis and genetic counseling for metachromatic leukodystrophy. 167 69

To analyze the genetic abnormality in a Japanese patient with adult-type metachromatic leukodystrophy (MLD), we first elucidated the genomic organization of the human arylsulfatase A (ASA) gene and then compared the nucleotide sequences of exons and splice junctions of the mutant ASA gene to those of a normal control. We have identified a new mutation, a G-to-A transition in exon 2, which results in amino acid substitution of Asp for 99Gly. In a transient expression study, COS cells transfected with the mutant cDNA carrying 99Gly----Asp did not show an increase of ASA activity, which confirms that the mutation is a cause of adult-type MLD.
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PMID:Identification of a mutation in the arylsulfatase A gene of a patient with adult-type metachromatic leukodystrophy. 167 91

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.
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PMID:An 11-bp deletion in the arylsulfatase A gene of a patient with late infantile metachromatic leukodystrophy. 167 99

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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PMID:Mutations in the arylsulfatase A pseudodeficiency allele causing metachromatic leukodystrophy. 167 51

N-[7-Nitrobenz-2-oxa-1,3-diazol-4-yl]psychosine sulfate (NBD-PS), a fluorescent analog of cerebroside sulfate (CS), was synthesized and tested as an alternative to the radiolabeled forms of CS used for assaying arylsulfatase A (ASA) in its physiological role as a cerebroside sulfate sulfohydrolase. NBD-PS simulates the natural substrate for ASA. Protocols have been developed for its use in differentiating low enzyme activities in diagnostic samples. Hydrolysis of NBD-PS is specific for ASA and optimal assay parameters were identical to those determined for CS. Differentiations between each of the major phenotypes for ASA activity were possible in the set of samples tested. One particular advantage was the ability to discriminate between individuals exhibiting arylsulfatase A pseudodeficiency and the truly deficient individuals with metachromatic leukodystrophy. Differential diagnosis was possible with fibroblast extracts by an assay that is more sensitive than procedures employing radioisotopes. Reaction products may be analyzed quantitatively by HPLC, or semiquantitatively with TLC. NBD-PS provides a simpler, safer, and more cost-effective means of performing natural substrate enzyme assays for ASA. Phenotyping with the fluorescence assay is an effective alternative to the laborious radioactive CS preparations and tissue culture loading studies that have previously been necessary.
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PMID:Synthesis and characterization of NBD-PS: a fluorescent analog of cerebroside arylsulfatase A deficiency disorders. 168 Mar 31

Fragments of the arylsulfatase A (ARSA) gene from a patient with juvenile-onset metachromatic leukodystrophy (MLD) were amplified by PCR and ligated into MP13 cloning vectors. Clones hybridizing with cDNA for human ARSA were selected, examined for appropriate size inserts, and used to prepare single-stranded phage DNA. Examination of the entire coding and most of the intronic sequence revealed two putative disease-related mutations. One, a point mutation in exon 3, resulted in the substitution of isoleucine by serine. Introduction of this alteration into the normal ARSA cDNA sequence resulted in a substantial decrease in ARSA activity on transient expression in cultured baby hamster kidney cells. About 5% of the control expression was observed, suggesting a small residual activity in the mutated ARSA. The second mutation, a G-to-A transition, occurred in the other allele and resulted in an altered splice-recognition sequence between exon 7 and the following intron. The mutation also resulted in the loss of a restriction site. Apparently normal levels of mRNA were generated from this allele, but no ARSA activity or immuno-cross-reactive material could be detected. A collection of DNA samples from known or suspected MLD patients, members of their families, and normal controls was screened for these mutations. Four additional individuals carrying each of the mutations were found among the nearly 100 MLD patients in the sample. Gene segregation in the original patient's family was consistent with available clinical and biochemical data. No individuals homozygous for either of these two mutations were identified. However, combinations with other MLD mutations suggest that the point mutation in exon 3 does result in some residual enzyme activity and is associated with late-onset forms of the disease. The splice-site mutation following exon 7 produces late-infantile MLD when combined with other enzyme-null mutations, implying that it is completely silent enzymatically.
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PMID:Two new arylsulfatase A (ARSA) mutations in a juvenile metachromatic leukodystrophy (MLD) patient. 168 88

The enzyme activity of arylsulfatase A and arylsulfatase B was studied in Epstein-Barr virus-transformed lymphoid cell lines established from control individuals and patients affected with metachromatic leukodystrophy, mucopolysaccharidosis type VI (or Maroteaux-Lamy syndrome) and multiple sulfatase deficiency. Lymphoid cells derived from patients with metachromatic leukodystrophy showed a severe deficiency in cerebroside sulfatase activity, as measured using radiolabelled sulfatide, but some residual activity of arylsulfatase A when measured with the chromogenic substrate, para-nitrocatechol sulfate. Lymphoid cells from mucopolysaccharidosis type VI had virtually no arylsulfatase B activity. In cells from patients with multiple sulfatase deficiency, the activities of lysosomal sulfatases as well as steroid sulfatase were deficient. Study of the molecular forms of arylsulfatases confirmed the complete deficiency of arylsulfatase A and arylsulfatase B activities in metachromatic leukodystrophy and mucopolysaccharidosis type VI lymphoid cells, respectively. The arylsulfatase A defect in metachromatic leukodys-lymphoid cells, respectively. The arylsulfatase A defect in metachromatic leukodystrophy cells could be demonstrated on focused fractions even using the artificial substrates, para-nitrocatechol sulfate and 4-methylumbelliferyl sulfate. To investigate the discrepancy of the arylsulfatase A activity data observed between whole cell homogenates and focused fractions when using the synthetic substrates, assays were tentatively performed for optimizing the determination of arylsulfatase A on crude homogenates of lymphoid cells. Although this work has indicated methodological limitations of the enzymatic assay of arylsulfatase A in lymphoid cells using methylumbelliferyl sulfate, it emphasizes the validity of lymphoid cell lines as an experimental model for the study of inborn deficiencies of arylsulfatases A and B.
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PMID:Arylsulfatases A and B in EBV-transformed lymphoid cell lines: studies on their molecular forms in cells from patients with inborn sulfatase deficiencies. Comparative diagnostic value of enzymatic assays. 168 73

Pseudodeficiency is defined as the in vitro measurement of low activity (usually under 15% of the normal mean for controls) of an enzyme in a healthy person. They may be hard to distinguish from presymptomatic people who will present with adult-onset clinical disease. The finding of healthy people with low arylsulfatase A and galactocerebrosidase activities is well documented. This confuses the laboratory doing testing and the clinician providing the sample. Therefore confirmation of a diagnosis of metachromatic leukodystrophy and Krabbe disease, as well as accurate identification of carriers, requires additional testing including 14C-sulfatide loading in cultured skin fibroblasts, examination of urine for excretion of undegraded lipids, examination of enzyme levels in additional family members including grandparents, and molecular analysis of DNA samples for known mutations.
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PMID:Pseudodeficiencies of arylsulfatase A and galactocerebrosidase activities. 168 77

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 consists of 8 exons. The two most frequent alleles causing MLD have been characterized and the distribution of these alleles among patients with different clinical forms of MLD has revealed a simple genotype-phenotype correlation. Some individuals have low ASA activities but are healthy. This condition has been called ASA pseudodeficiency. These individuals are homozygous for the ASA pseudodeficiency allele which only encodes 5-10% of the ASA activity compared to the normal allele. The mutations in the PD allele have been characterized. Based on the knowledge of these mutations diagnostic assays have been developed to differentiate ASA deficiencies associated with PD or MLD.
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PMID:Molecular genetics of metachromatic leukodystrophy. 168 78


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