title: Protracted course of Krabbe disease in an adult patient bearing a novel mutation.
abstract: BACKGROUND
  Krabbe disease, or globoid cell leukodystrophy, is an autosomal recessive disorder caused by the deficiency of galactocerebrosidase (GALC) activity. Although most cases are diagnosed in infancy and show a fatal outcome in childhood, adult patients have been identified, showing progressive spastic hemiparesis to tetraparesis, followed by optic atrophy, dementia, and neuropathy. The disease can be diagnosed by detecting the deficiency of GALC activity (less than 5% of normal) in any available tissue sample. The cloning of the human GALC gene allowed the molecular characterization of newly diagnosed patients. More than 75 disease-causing mutations and polymorphisms in this gene have been identified.
  
  
  OBJECTIVE
  To describe a 28-year-old woman with Krabbe disease, correlating clinical and biochemical abnormalities to a novel mutation on the GALC gene.
  
  
  METHODS
  Clinical investigation was enriched by neurophysiological and neuroimaging data. The activity of GALC was assayed in white blood cells using radiolabeled natural substrate. Genomic DNA was isolated from peripheral blood, and the GALC gene was sequenced. The mutated gene was expressed and GALC activity was measured in transfected COS-1 cells.
  
  
  RESULTS
  The patient had progressive and bilateral amaurosis starting at 8 years of age. Although she was experiencing weakness in all her extremities, her intellect remained intact. She was found to be homozygous for a previously unreported missense mutation (T1886G), which leads to low, but not totally deficient, GALC activity.
  
  
  CONCLUSIONS
  Expression of this mutation in COS-1 cells using the pcDNA3 expression vector (Invitrogen, Carlsbad, Calif) resulted in low, although not null, GALC activity, which can explain the protracted clinical course in this patient. Patients carrying the mutation described herein might be potential candidates for therapeutic trials, such as bone marrow transplantation or gene therapy.
authors.affiliation: Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Brazil.
authors.forename: L B
authors.initials: LB
authors.lastname: Jardim
authors.forename: R
authors.initials: R
authors.lastname: Giugliani
authors.forename: R F
authors.initials: RF
authors.lastname: Pires
authors.forename: S
authors.initials: S
authors.lastname: Haussen
authors.forename: M G
authors.initials: MG
authors.lastname: Burin
authors.forename: M A
authors.initials: MA
authors.lastname: Rafi
authors.forename: D A
authors.initials: DA
authors.lastname: Wenger
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005698:Galactosylceramidase / Q000235:genetics; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D007965:Leukodystrophy, Globoid Cell / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D017354:Point Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics
chemical_list: D005698:Galactosylceramidase