Protracted course of Krabbe disease in an adult patient bearing a novel mutation

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 ou tcome in childhood, adult patients have been identified, showing progressiv e spastic hemiparesis to tetraparesis, followed by optic atrophy, dementia, and neuropathy. The disease can be diagnosed by detecting the deficiency o f GALC activity (less than 5% of normal) in any available tissue sample. Th e cloning of the human GALC gene allowed the molecular characterization of newly diagnosed patients. More than 75 disease-causing mutations and polymo rphisms 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 gen e. Methods: Clinical investigation was enriched by neurophysiological and neur oimaging data. The activity of GALC was assayed in white blood cells using radiolabeled natural substrate. Genomic DNA was isolated from peripheral bl ood, and the GALC gene was sequenced. The mutated gene was expressed and GA LC 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 previ ously unreported missense mutation (T1886G), which leads to low, but not to tally deficient, GALC activity. Conclusions: Expression of this mutation in COS-1 cells using the pcDNA3 ex pression vector (Invitrogen, Carlsbad, Calif) resulted in low, although not null, GALC activity, which can explain the protracted clinical course in t his patient. Patients carrying the mutation described herein might be poten tial candidates for therapeutic trials, such as bone marrow transplantation or gene therapy.