title: An Italian cohort study identifies four new pathologic mutations in the ARSA gene.
abstract: Metachromatic leukodystrophy is an autosomal recessive neurodegenerative disorder of the myelin metabolism due to the impaired function of the lysosomal enzyme arylsulfatase A. Three major clinical variants of metachromatic leukodystrophy (MLD) have been described: late infantile, juvenile, and late onset. The infantile form, whose clinical onset is usually before the age of 2 years, is the most frequent. The juvenile form manifests itself between 3 and 16 years and the late-onset form manifests at any time after puberty. As of today, more than 150 mutations causing MLD have been identified in the ARSA gene that encodes arylsulfatase A. In this paper, we report our experience with the diagnosis of MLD in seven Italian patients from unrelated families. We found 11 different mutations, four of which have not been previously described: c.1215_1223del9 (p.406_408del), c.601 T>C (p.Tyr201His), c.655 T>A (p.Phe219Ile), and c.87C>A (p.Asp29Glu). Our data show once more that there are still several mutations to be discovered in the ARSA gene and there are rarely repeating ones found in the population. The predictive value of the enzyme activity tests in regard to clinical manifestations is extremely limited.
authors.affiliation: Medical Genetics Unit, "Mauro Baschirotto" Institute for Rare Diseases-BIRD, Via B.Bizio, 1-36023 Costozza di Longare, Vicenza, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Galla
authors.forename: Paola
authors.initials: P
authors.lastname: de Gemmis
authors.forename: Laura
authors.initials: L
authors.lastname: Anesi
authors.forename: Silvia
authors.initials: S
authors.lastname: Berto
authors.forename: Diego
authors.initials: D
authors.lastname: Dolcetta
authors.forename: Uroš
authors.initials: U
authors.lastname: Hladnik
mesh_terms: D000595:Amino Acid Sequence; D002553:Cerebroside-Sulfatase / Q000737:chemistry / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007558:Italy; D007966:Leukodystrophy, Metachromatic / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree
chemical_list: D002553:Cerebroside-Sulfatase
references.citation: Eur J Hum Genet. 2004 Feb;12(2):150-4
references.pmid: 14571263
references.citation: Am J Med Genet. 2000 Mar 6;91(1):68-73
references.pmid: 10751093
references.citation: Bioessays. 1998 Jun;20(6):505-10
references.pmid: 9699462
references.citation: Biophys J. 2002 Dec;83(6):3066-78
references.pmid: 12496078
references.citation: FEBS J. 2005 Mar;272(5):1179-88
references.pmid: 15720392
references.citation: Biophys J. 2009 Feb;96(3):875-86
references.pmid: 19186127
references.citation: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W299-302
references.pmid: 15980475
references.citation: Arch Neurol. 2005 Feb;62(2):309-13
references.pmid: 15710861
references.citation: Clin Genet. 2008 Oct;74(4):349-57
references.pmid: 18786133
references.citation: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W529-33
references.pmid: 20478830
references.citation: Genome Res. 2002 Mar;12(3):436-46
references.pmid: 11875032
references.citation: Nat Methods. 2010 Apr;7(4):248-9
references.pmid: 20354512
references.citation: Hum Mutat. 2008 Nov;29(11):E220-30
references.pmid: 18693274
references.citation: N Engl J Med. 1991 Jan 3;324(1):18-22
references.pmid: 1670590
references.citation: FEBS Lett. 1996 Nov 18;397(2-3):225-9
references.pmid: 8955352
references.citation: Nucleic Acids Res. 2002 Sep 1;30(17):3894-900
references.pmid: 12202775
references.citation: Bioinformatics. 2002 Dec;18(12):1701-2
references.pmid: 12490462
references.citation: Hum Genet. 2002 Apr;110(4):351-5
references.pmid: 11941485
references.citation: J Biol Chem. 1999 Apr 30;274(18):12284-8
references.pmid: 10212197
references.citation: Proc Natl Acad Sci U S A. 1989 Dec;86(23):9436-40
references.pmid: 2574462
references.citation: Biophys J. 2005 Apr;88(4):2897-906
references.pmid: 15653723
references.citation: Angew Chem Int Ed Engl. 2003 Mar 17;42(11):1210-50
references.pmid: 12645054
references.citation: EMBO J. 1999 Apr 15;18(8):2084-91
references.pmid: 10205163
references.citation: Cell. 1995 Jul 28;82(2):271-8
references.pmid: 7628016
references.citation: Hum Mutat. 1995;6(2):170-6
references.pmid: 7581401
references.citation: FEBS J. 2010 Aug;277(16):3404-14
references.pmid: 20646068
references.citation: Protein Eng. 2000 Dec;13(12):849-56
references.pmid: 11239084
references.citation: Bioinformatics. 2007 May 15;23(10):1292-3
references.pmid: 17379687
references.citation: J Biol Chem. 1989 Jan 15;264(2):1252-9
references.pmid: 2562955
references.citation: Glycoconj J. 2009 Nov;26(8):1029-45
references.pmid: 19381802
references.citation: Biochemistry. 1998 Mar 17;37(11):3654-64
references.pmid: 9521684
references.citation: J Mol Biol. 2001 Jan 12;305(2):269-77
references.pmid: 11124905
references.citation: Biochem Biophys Res Commun. 2003 Jun 20;306(1):293-7
references.pmid: 12788103
references.citation: Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W306-10
references.pmid: 15980478
references.citation: Nat Protoc. 2009;4(7):1073-81
references.pmid: 19561590