title: Early energy deficit in Huntington disease: identification of a plasma biomarker traceable during disease progression.
abstract: Huntington disease (HD) is a fatal neurodegenerative disorder, with no effective treatment. The pathogenic mechanisms underlying HD has not been elucidated, but weight loss, associated with chorea and cognitive decline, is a characteristic feature of the disease that is accessible to investigation. We, therefore, performed a multiparametric study exploring body weight and the mechanisms of its loss in 32 presymptomatic carriers and HD patients in the early stages of the disease, compared to 21 controls. We combined this study with a multivariate statistical analysis of plasma components quantified by proton nuclear magnetic resonance ((1)H NMR) spectroscopy. We report evidence of an early hypermetabolic state in HD. Weight loss was observed in the HD group even in presymptomatic carriers, although their caloric intake was higher than that of controls. Inflammatory processes and primary hormonal dysfunction were excluded. (1)H NMR spectroscopy on plasma did, however, distinguish HD patients at different stages of the disease and presymptomatic carriers from controls. This distinction was attributable to low levels of the branched chain amino acids (BCAA), valine, leucine and isoleucine. BCAA levels were correlated with weight loss and, importantly, with disease progression and abnormal triplet repeat expansion size in the HD1 gene. Levels of IGF1, which is regulated by BCAA, were also significantly lower in the HD group. Therefore, early weight loss in HD is associated with a systemic metabolic defect, and BCAA levels may be used as a biomarker, indicative of disease onset and early progression. The decreased plasma levels of BCAA may correspond to a critical need for Krebs cycle energy substrates in the brain that increased metabolism in the periphery is trying to provide.
authors.affiliation: INSERM, Hôpital de la Salpêtrière, UMR 679, Paris, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Mochel
authors.forename: Perrine
authors.initials: P
authors.lastname: Charles
authors.forename: François
authors.initials: F
authors.lastname: Seguin
authors.forename: Julie
authors.initials: J
authors.lastname: Barritault
authors.forename: Christiane
authors.initials: C
authors.lastname: Coussieu
authors.forename: Laurence
authors.initials: L
authors.lastname: Perin
authors.forename: Yves
authors.initials: Y
authors.lastname: Le Bouc
authors.forename: Christiane
authors.initials: C
authors.lastname: Gervais
authors.forename: Guislaine
authors.initials: G
authors.lastname: Carcelain
authors.forename: Anne
authors.initials: A
authors.lastname: Vassault
authors.forename: Josué
authors.initials: J
authors.lastname: Feingold
authors.forename: Daniel
authors.initials: D
authors.lastname: Rabier
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000596:Amino Acids / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D001835:Body Weight; D003072:Cognition Disorders / Q000235:genetics; D018450:Disease Progression; D004734:Energy Metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D006816:Huntington Disease / Q000097:blood / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009043:Motor Activity; D009154:Mutation; D011237:Predictive Value of Tests; D012016:Reference Values; D015431:Weight Loss / Q000235:genetics
chemical_list: D000596:Amino Acids; D015415:Biomarkers