Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder caused by deficiency of the enzyme arylsulphatase A which catalyses the first step in the degradation of the sphingolipid 3-O-Sulphagalactosyl ceramide (sulphatide). Accumulation of sulphatide in the brain leads to progressive demyelination of the central and peripheral nervous systems causing a variety of neurological symptoms including gait disturbances, ataxias, optical atrophy, dementia, seizures and spastic tetraparesis. Disease severity can range from mild to severe and can be broadly grouped into 3 subtypes (late-infantile, juvenile and adult). The majority of patients with arylsulphatase A deficiency and signs of MLD will have mutations in the ARSA gene however there is a much less common form of MLD caused by deficiency of Saposin B, a non-enzymatic sphingolipid activator protein.
Arylsulphatase A is also defective in multiple sulphatase deficiency due to mutations in SUMF1. The ARSA gene (22q13.31-qter) comprises 8 exons. Although many novel mutations are known, there are �common� mutations within the gene, particularly the c.459+1G>A and c.1277C>T (p.Pro426Leu) which account for around 50% of disease alleles in the Northern European population. Pseudodeficiency of arysulphatase A is a condition of reduced arylsulphatase A activity (<15% normal) without clinical consequence which can complicate the biochemical diagnosis of MLD. PDASA is caused by sequence variants in the ARSA gene, namely PD2 (Poly A) and PD1 (NGly). PD2 (c.*96A>G in the 3�UTR, exon 8) destroys the first downstream polyadenylation site and causes subsequent loss of the 2.1kb mRNA species; this variant is clearly associated with decreased ASA activity. PD2 is almost invariably seen on a background with PD1. PD1 (c.1788A>G (p.Asn350Ser), exon 6) destroys an N-glycosylation site, causing a change in protein size, but having little effect on stability or activity. PD1 can occur independently of PD2 and its effect in causing PDASA is controversial.
Also known as
arylsulphatase A deficiency, ARSA deficiency, cerebroside sulphatase deficiency
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When requesting this test please use the referral form provided. Please also refer to any additional information provided for this test.
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PDASA testing is used to assist the interpretation of arylsulphatase A activity results. Referrals are generally via the Enzyme Unit, Great Ormond Street Hospital however referrals may be accepted from other centres who carry out biochemical testing for arylsulphatase A. Biochemical confirmation of arylsulphatase A deficiency can only be confirmed after PDASA testing. In families with PDASA, prenatal testing by enzyme analysis can be complicated and in many cases impossible. For these families genetic testing is particularly useful but this can also mean that in some cases testing for MLD may have to be performed without biochemical confirmation. In these cases a very strong clinical picture of MLD must be present. PDASA: Testing for the presence of PD1 and PD2 by PCR and restriction enzyme digest. MLD Level 1 Analysis: Detection of the common mutations c.459+1G>A and c.1277C>T (p.Pro426Leu) by PCR and restriction enzyme digest. MLD Level 2 Analysis: Direct sequencing of all 8 coding exons and intron-exon boundaries.
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Great Ormond Street Hospital NE Thames Regional Genetics Service Laboratories
Great Ormond Street Hospital for Children
37 Queen Square
1ml EDTA neonates, 5ml EDTA adults
Common mutations - 20 days; gene screen - 40 days
Disease / group
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Prenatals must be arranged in advance, through a Clinical Genetics department if possible. Amniotic fluid or CV samples should be sent to Cytogenetics for dissecting and culturing, with instructions to forward the sample to the Regional Molecular Genetics laboratory for analysis