title: Adult metachromatic leukodystrophy: a new mutation in the schizophrenia-like phenotype with early neurological signs.
abstract: OBJECTIVE
  The adult type of metachromatic leukodystrophy can manifest itself as motor or as psycho-cognitive form, the latter is very similar to schizophrenia. We report on two sisters with adult metachromatic leukodystrophy who display symptoms of both forms.
  
  
  METHODS
  Presented are genotype analyses and 4-year follow-up data regarding clinical manifestations as well as neurocognitive and neuroimaging results for two adult sisters with metachromatic leukodystrophy.
  
  
  RESULTS
  Whereas the younger sister developed disorganized schizophrenia-like symptoms, the other exhibited schizophrenia-like, negative symptoms. In both sisters, neurological signs were already present at the onset of the disease and progression towards dementia was documented within 1-2 years. In peripheral leukocytes, the activity of arylsulphatase A was reduced to 2 and 5% of the mean normal activity in both women. Genotype analysis revealed compound heterozygosity for a known severe splice site mutation, (c.459+1G>A) together with two known polymorphisms, [(c.937G>T), (p.Trp193Asp)] and [(c.1530C>G), (p.Thr391Ser)], and a novel missense mutation, (c.1194C>T). The latter results in the exchange of a conserved polar amino acid, threonine 279, to hydrophobic isoleucine (Thr279Ileu), which could not be found among >100 control alleles. A family analysis identified T279I as the paternal allele, whereas (c.459+1G>A) as well as the two polymorphisms were inherited from the mother. This is consistent with a disease-causing effect of the novel mutation.
  
  
  CONCLUSIONS
  The novel mutation, T279I detected in our patients, correlates with a specific phenotype with schizophrenia-like symptoms, neurological signs and cognitive impairment early in the course of the disease and a relatively fast progression towards dementia. This is in contrast to previous reports on adult metachromatic leukodystrophy patients with the psycho-cognitive phenotype who did not show any neurological signs for decades, however, most of these patients were heterozygous for another specific missense mutation, I179S.
authors.affiliation: Department of Paediatrics, Maribor Teaching Hospital, Maribor, Slovenia. hojka.gregoric@guest.ames.si
authors.forename: Hojka G
authors.initials: HG
authors.lastname: Kumperscak
authors.forename: Blanka K
authors.initials: BK
authors.lastname: Plesnicar
authors.forename: Bojan
authors.initials: B
authors.lastname: Zalar
authors.forename: Peter
authors.initials: P
authors.lastname: Gradisnik
authors.forename: Tomaz
authors.initials: T
authors.lastname: Seruga
authors.forename: Eduard
authors.initials: E
authors.lastname: Paschke
mesh_terms: D000328:Adult; D017668:Age of Onset; D017398:Alternative Splicing; D002553:Cerebroside-Sulfatase / Q000097:blood / Q000235:genetics; D017931:DNA Primers; D003704:Dementia / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007962:Leukocytes / Q000201:enzymology; D007966:Leukodystrophy, Metachromatic / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000235:genetics*; D035781:Siblings
chemical_list: D017931:DNA Primers; D002553:Cerebroside-Sulfatase