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Weight loss in Huntington disease increases with higher CAG repeat number

From the Departments of Neurology (N.A.A., R.A.C.R.) and Medical Statistics (T.S.), Leiden University Medical Center, the Netherlands; Neuronal Survival Unit (J.M.M.v.d.B., P.B.), Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, Sweden; and Department of Neurology (G.B.L.), Ulm University, Germany.

Address correspondence and reprint requests to N.A. Aziz, Leiden University Medical Center, Department of Neurology, K-05-Q 110, P.O. Box 9600, Albinusdreef 2, 2300 RC Leiden, the Netherlands N.A.Aziz{at}lumc.nl

Objective: Huntington disease (HD) is a hereditary neurodegenerative disorder caused by an expanded number of CAG repeats in the huntingtin gene. A hallmark of HD is unintended weight loss, the cause of which is unknown. In order to elucidate the underlying mechanisms of weight loss in HD, we studied its relation to other disease characteristics including motor, cognitive, and behavioral disturbances and CAG repeat number.

Methods: In 517 patients with early stage HD, we applied mixed-effects model analyses to correlate weight changes over 3 years to CAG repeat number and various components of the Unified Huntington’s Disease Rating Scale (UHDRS). We also assessed the relation between CAG repeat number and body weight and caloric intake in the R6/2 mouse model of HD.

Results: In patients with HD, mean body mass index decreased with –0.15 units per year (p < 0.001). However, no single UHDRS component, including motor, cognitive, and behavioral scores, was independently associated with the rate of weight loss. Patients with HD with a higher CAG repeat number had a faster rate of weight loss. Similarly, R6/2 mice with a larger CAG repeat length had a lower body weight, whereas caloric intake increased with larger CAG repeat length.

Conclusions: Weight loss in Huntington disease (HD) is directly linked to CAG repeat length and is likely to result from a hypermetabolic state. Other signs and symptoms of HD are unlikely to contribute to weight loss in early disease stages. Elucidation of the responsible mechanisms could lead to effective energy-based therapeutics.

Abbreviations: BMI = body mass index; EHDI = European Huntington’s Disease Initiative; HD = Huntington disease; UHDRS = Unified Huntington’s Disease Rating Scale.

*See the appendix for a list of study group investigators.

N.A. Aziz is supported by The Netherlands Organisation for Scientific Research (grant #017.003.098). J.M.M. van der Burg is supported by a Marie Curie actions fellowship (European Union [RTN MRTN-CT-2003-504636]). The animal studies were supported by the Swedish Research Council.

Disclosure: The authors report no disclosures.

Received February 26, 2008. Accepted in final form July 31, 2008.