title: Molecular basis of different forms of metachromatic leukodystrophy.
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 (greater than 16).
  
  
  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 both alleles were present, the juvenile form resulted (seven of seven instances). Heterozygosity for allele I (with the other allele unknown) is usually associated with late-infantile disease, and heterozygosity for allele A with a later onset of the disease. The clinical variability can be explained by the different levels of residual arylsulfatase A activity associated with these genotypes.
  
  
  CONCLUSIONS
  Like many lysosomal storage disorders, metachromatic leukodystrophy shows clinical heterogeneity that seems to reflect genetic heterogeneity. One of the known alleles (allele I) is associated with earlier and more severe disease than the other (allele A).
authors.affiliation: Department of Biochemistry II, Georg-August-Universität Göttingen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Polten
authors.forename: A L
authors.initials: AL
authors.lastname: Fluharty
authors.forename: C B
authors.initials: CB
authors.lastname: Fluharty
authors.forename: J
authors.initials: J
authors.lastname: Kappler
authors.forename: K
authors.initials: K
authors.lastname: von Figura
authors.forename: V
authors.initials: V
authors.lastname: Gieselmann
mesh_terms: D000293:Adolescent; D000483:Alleles; D001483:Base Sequence; D002553:Cerebroside-Sulfatase / Q000172:deficiency / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000032:analysis; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007966:Leukodystrophy, Metachromatic / Q000145:classification* / Q000201:enzymology / Q000235:genetics; D008969:Molecular Sequence Data
chemical_list: D004247:DNA; D002553:Cerebroside-Sulfatase