title: Metabolic profiling reveals biochemical pathways and potential biomarkers associated with the pathogenesis of Krabbe disease.
abstract: Krabbe disease (KD) is caused by mutations in the galactosylceramidase (GALC) gene, which encodes a lysosomal enzyme that degrades galactolipids, including galactosylceramide and galactosylsphingosine (psychosine). GALC deficiency results in progressive intracellular accumulation of psychosine, which is believed to be the main cause for the demyelinating neurodegeneration in KD pathology. Umbilical cord blood transplantation slows disease progression when performed presymptomatically but carries a significant risk of morbidity and mortality. Accurate presymptomatic diagnosis is therefore critical to facilitate the efficacy of existing transplant approaches and to avoid unnecessary treatment of children who will not develop KD. Unfortunately, current diagnostic criteria, including GALC activity, genetic analysis, and psychosine measurement, are insufficient for secure presymptomatic diagnosis. This study performs a global metabolomic analysis to identify pathogenetic metabolic pathways and novel biomarkers implicated in the authentic mouse model of KD known as twitcher. At a time point before onset of signs of disease, twitcher hindbrains had metabolic profiles similar to WT, with the exception of a decrease in metabolites related to glucose energy metabolism. Many metabolic pathways were altered after early signs of disease in the twitcher, including decreased phospholipid turnover, restricted mitochondrial metabolism of branched-chain amino acids, increased inflammation, and changes in neurotransmitter metabolism and osmolytes. Hypoxanthine, a purine derivative, is increased before signs of disease appear, suggesting its potential as a biomarker for early diagnosis of KD. Additionally, given the early changes in glucose metabolism in the pathogenesis of KD, diagnostic modalities that report metabolic function, such as positron emission tomography, may be useful in KD. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Hunter James Kelly Research Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.|Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Nadav I
authors.initials: NI
authors.lastname: Weinstock
authors.affiliation: Hunter James Kelly Research Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.|Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.|Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Wrabetz
authors.affiliation: Hunter James Kelly Research Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.|Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.|Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York.
authors.forename: M Laura
authors.initials: ML
authors.lastname: Feltri
authors.affiliation: Hunter James Kelly Research Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York. daesungs@buffalo.edu.|Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York. daesungs@buffalo.edu.
authors.forename: Daesung
authors.initials: D
authors.lastname: Shin
mesh_terms: D000367:Age Factors; D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism*; D002389:Catatonia / Q000235:genetics / Q000378:metabolism*; D002853:Chromatography, Liquid; D015331:Cohort Studies; D003704:Dementia / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005698:Galactosylceramidase / Q000172:deficiency* / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D019271:Hypoxanthine / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018377:Neurotransmitter Agents / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D000597:Amino Acids, Branched-Chain; D015415:Biomarkers; D018377:Neurotransmitter Agents; D019271:Hypoxanthine; D005952:Glucose-6-Phosphatase; D005698:Galactosylceramidase; D005947:Glucose
keywords: Krabbe disease; biomarker; globoid cell leukodystrophy; glucose metabolism; metabolomics; mitochondrial dysfunction; oxidative stress; twitcher