Diagnosis of arylsulfatase A deficiency

Li, Z. G.; Waye, John S.; Chang, Patricia L.

doi:10.1002/ajmg.1320430614

Cited by 6 publications

(2 citation statements)

References 38 publications

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“…Six European families carrying PD or PDg (Hohenschutz et al 1989;Li et al 1992;Shen et al 1993; one family each from clinics of McMaster University and Dr. D. Rodenhiser) and four European PD homozygotes (kindly provided by Drs. J.…”

Section: Haplotype Analysismentioning

confidence: 99%

Evolutionary origins of two tightly linked mutations in arylsulfatase-A pseudodeficiency

1997

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Deficient arylsulfatase A activity causes the neurodegenerative disease metachromatic leukodystrophy. However, some individuals with deficient enzyme activity appear clinically normal. This "pseudodeficiency" allele commonly found among many reported populations (frequency approximately 0.10) is associated with two A-->G transitions in cis in the arylsulfatase A gene causing the simultaneous loss of an N-glycosylation and a polyadenylation signal. To understand the evolutionary relationship between such common and tightly linked mutations, we studied 400 individuals in the African, European, Indian and East Asian populations and found none carrying the polyadenylation mutation alone. However, the N-glycosylation mutation could occur independently. Its frequency varied from 0.01 in Indians, 0.06 in Europeans, 0.21 in East Asians to 0.32 in Africans. The frequencies of both mutations occurring together ranged from almost non-existent in the Africans and East Asians, to 0.075 in the Europeans and 0.125 in the Indians. These frequencies were significantly different among populations. Haplotype analysis among homozygous pseudodeficiency individuals and eight multi-generation families with six polymorphic enzymes showed that, of the five haplotypes found in the general population, only one was linked to the double mutations. Alleles among the four populations with only the N-glycosylation mutation also supported linkage to the same haplotype except in some Europeans whose alleles were discordant. These results are consistent with the hypothesis that the N-glycosylation mutation may be a recurrent event among the Europeans but first occurred in an ancestral allele before the emergence of modern Homo sapiens from Africa at approximately 100,000-200,000 years ago. Subsequently, the polyadenylation mutation occurred in this ancient allele with the N-glycosylation mutation, an event that likely took place after the divergence between the European and East Asian lineages.

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Section: Haplotype Analysismentioning

confidence: 99%

Evolutionary origins of two tightly linked mutations in arylsulfatase-A pseudodeficiency

1997

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“…Cellulose electrophoresis of ARSA activity was performed using the method described by Chang To specifically detect the presence of the PD allelle (double point mutation) [9}, DNA analysis, using 3'-mismatch polymerase chain reaction (PCR) amplification techniques based on the method of Gieselmann {28], was performed as described previously [22]. In brief, PD mutations 191 were detected by amplifying the genomic DNA with primers specific for either the N or the PD allele together with primers for an internal control fragment.…”

Section: Laboratory Examinations (Seementioning

confidence: 99%

Metachromatic leukodystrophy: Multiple nonfunctional and pseudodeficiency alleles in a pedigree: Problems with diagnosis and counseling

Francis

Bonni

Shen

et al. 1993

Annals of Neurology

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Metachromatic leukodystrophy is due to deficient activity of arylsulfatase A, an enzyme important in myelin catabolism. The deficiency can be caused by different point mutations in the gene coding for arylsulfatase A (nonfunctional alleles). In addition, certain mutations result in low levels of enzyme activity detectable with artificial substrates in vitro but no clinical dysfunction (pseudodeficiency alleles). The described family has various combinations of normal, nonfunctional, and pseudodeficiency alleles that presented diagnostic and counseling dilemmas which were resolved at the genomic level. We find no evidence that compound heterozygote individuals have subclinical involvement of the nervous system. We report the clinical, pathological, electrophysiological, imaging, biochemical, and genetic data of this family and discuss the difficulties in analyzing such pedigrees.

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Complications in the genotypic molecular diagnosis of pseudo arylsulfatase A deficiency

Shen

Waye

et al. 1993

Am. J. Med. Genet.

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Metachromatic leukodystrophy (MLD) is a severe neurodegenerative disease associated with deficient arylsulfatase A activity. Biochemical confirmation of this disorder has been complicated by a clinically normal but enzymatically deficient variant, pseudo arylsulfatase-A deficiency (PD). The PD mutation is associated with two A-->G transitions in the arylsulfatase A gene. They can be detected simultaneously with a recently developed 3'-mismatch polymerase chain reaction, hence providing a rapid method for genotypic identification and resolving ambiguities of carrier identification based solely on enzyme analyses. However, we now report further genotypic complexities in the molecular diagnosis of PD due to the occurrence of another variant in which only one of the two A-->G mutations of the PD allele was present. This variant confers reduced but readily detectable enzyme activity and behaves as a silent allele in the 3'-mismatch polymerase chain reaction, thus leading to conflicting and erroneous genotype assignments in a family in which both variants and MLD co-exist. The inconsistency was resolved after pedigree validation and further molecular analyses in which the two A-->G mutations were assayed separately with allele-specific oligonucleotides. Because arylsulfatase A analysis is one of the most commonly requested lysosomal enzyme assays and the PD mutant allele frequency is high in the general population, complexities as described in this family may be a recurrent problem that can be solved only with combined enzymatic and detailed molecular analyses.

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Diagnosis of arylsulfatase A deficiency

Cited by 6 publications

References 38 publications

Evolutionary origins of two tightly linked mutations in arylsulfatase-A pseudodeficiency

Evolutionary origins of two tightly linked mutations in arylsulfatase-A pseudodeficiency

Metachromatic leukodystrophy: Multiple nonfunctional and pseudodeficiency alleles in a pedigree: Problems with diagnosis and counseling

Complications in the genotypic molecular diagnosis of pseudo arylsulfatase A deficiency

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