Molecular analysis of ARSA and PSAP genes in twenty-one Italian patients with metachromatic leukodystrophy: identification and functional characterization of 11 novel ARSA alleles

Hum Mutat. 2008 Nov;29(11):E220-30. doi: 10.1002/humu.20851.


Metachromatic leukodystrophy (MLD), the demyelinating disorder resulting from impaired sulfatide catabolism, is caused by allelic mutations of the Arylsulfatase A (ARSA) locus except for extremely rare cases of Saposin-B (Sap-B) deficiency. We characterized twenty-one unrelated Italian patients among which seventeen were due to ARSA activity deficiency and 4 others resulted from Saposin-B defect. Overall, we found 20 different mutant ARSA alleles and 2 different Sap-B alleles. The eleven new ARSA alleles (c.53C>A; c.88G>C; c.372G>A; c.409_411delCCC; c.634G>C; [c.650G>A;c.1108C>T]; c.845A>G; c.906G>C; c.919G>T; c.1102-3C>G; c.1126T>A) were functionally characterized and the novel amino acid changes were also modelled into the three-dimensional structure. The present study is aimed at providing a broader picture of the molecular basis of MLD in the Italian population. It also emphasizes the importance of a comprehensive evaluation in MLD diagnosis including biochemical, enzymatic and molecular investigations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Animals
  • COS Cells
  • Catalytic Domain
  • Cerebroside-Sulfatase / genetics*
  • Child, Preschool
  • Chlorocebus aethiops
  • DNA Mutational Analysis
  • Humans
  • Infant
  • Italy
  • Leukodystrophy, Metachromatic / genetics*
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Mutation*
  • Protein Structure, Tertiary
  • Saposins / genetics*


  • PSAP protein, human
  • Saposins
  • Cerebroside-Sulfatase