Early Energy Deficit in Huntington Disease: Identification of a Plasma Biomarker Traceable during Disease Progression

Fanny Mochel,Yves Le Bouc,Daniel Rabier,Laurence Perin,Julie Barritault,Christiane Coussieu,François Seguin,Josué Feingold,Alexandra Durr,Anne Vassault,Guislaine Carcelain,Christiane Gervais,Perrine Charles,Ulrich Mueller

doi:10.1371/journal.pone.0000647

Abstract

Huntington disease (HD) is a fatal neurodegenerative disorder, with no effective treatment. The pathogenic mechanisms underlying HD have 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 (1H 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. 1H 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.

Highlights

Huntington disease (HD) is a neurodegenerative disease with autosomal dominant inheritance
The 3 groups defined according to Unified Huntington disease rating scale (UHDRS) scores showed similar ages at examination (Table 1)
This hypermetabolic state is not explained by common mechanisms like inflammation or altered endocrine functions, both of which have been incriminated in the pathophysiology of HD [13,14]

Summary

Introduction

Huntington disease (HD) is a neurodegenerative disease with autosomal dominant inheritance. Excitotoxicity, protein aggregation and loss of normal function of huntingtin, have been hypothesized to be responsible for the symptoms in patients [1], HD remains a devastating disorder with no effective treatment. Despite the ubiquitous expression of mutated huntingtin, only the pathophysiology of brain-related symptoms, which are relatively inaccessible to investigation, have received attention. Unlike other neurodegenerative disorders, affected HD patients are known to lose weight [2], despite normal, or even increased, food intake [3,4]. The demonstration that mechanisms underlying weight loss in HD are related to disease onset would indicate that a more systemic, and possibly treatable, defect may be implicated early in the pathophysiology of HD

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Conclusion