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Abstract

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.

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Letters to the Editor
29 January 2009
Weight loss in Huntington disease increases with higher CAG repeat number
Gordon J. Gilbert

I read the article by Aziz et al. with interest. [1] The authors present a strong case for a hyper-metabolic link between expanding CAG repeat number and the characteristic weight loss in Huntington disease (HD). It is notable that such recognized hyper-metabolic disorders as thyrotoxicosis may also cause chorea. Perhaps therapeutic efforts to lower the metabolic rate by suppressing thyroid function should be investigated in patients with HD.

Reference

1. Aziz NA, van der Burg GB, Landwehrmeyer GB et al. Weight loss in Huntington disease increases with higher CAG repeat number. Neurology 2008;71:1506-1513.

Disclosure: The author reports no disclosures.

29 January 2009
Reply from the authors
N. Ahmad Aziz, Leiden University Medical Center, Department of Neurology
Jorien M.M. van der Burg, G. Bernhard Landwehrmeyer, Patrik Brundin, Theo Stijnen, and Raymund A.C. Roos

We appreciate Dr. Gilbert's interest in our findings. [1] The concept of suppressing thyroid function in HD in order to counteract weight loss is intriguing. In addition, as Dr. Gilbert also points out, thyroid hormone excess has been associated with chorea so altering thyroid function might also influence the choreactic movements in HD. [2] However, a number of caveats should be considered.

First, although we found an increased rate of weight loss in HD patients with higher CAG repeat number, the precise mechanisms underlying this association are still unclear. [1] A higher metabolic rate due to mitochondrial dysfunction may be involved, but whether mitochondrial dysfunction in HD would respond to changes in thyroid hormone levels has yet to be investigated. [1]

Second, the hypothalamic-pituitary-thyroid axis function has been rarely studied in HD patients. [3] Although normal basal levels of thyroxine, triiodothyronine and thyroid-stimulating hormone (TSH) have been reported in HD patients, others have found an impaired TSH response to thyrotropin-releasing hormone stimulation. [3] Therefore, more detailed studies of thyroid function in HD are needed.

Third, besides regulating bodies metabolic rate, thyroid hormones have also a myriad of other effects, including the regulation of normal brain function, heart rate and myocardial contractility, gastrointestinal motility and renal water clearance. Moreover, as thyroid hormones affect protein synthesis and degradation, they can also alter the production, responsiveness and metabolic clearance of other hormones. Therefore, iatrogenically induced changes in thyroid function are likely to entail complex alterations in systemic physiology.

However, the concept of direct modulation of the metabolic rate in HD remains intriguing and should be tested in the transgenic disease models now available. It is interesting that caloric restriction, which is known to lower basal metabolic rate, has been shown to slow disease progression, ameliorate weight loss, and increase survival in an HD transgenic mouse model.[4]

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2. Sudo K, Tashiro K. Hyperthyroidism-associated chorea. Lancet 1998;352:239.

3. Aziz NA, Swaab DF, Pijl H, Roos RA. Hypothalamic dysfunction and neuroendocrine and metabolic alterations in Huntington's disease: clinical consequences and therapeutic implications. Rev Neurosci 2007;18:223-251.

4. Duan W, Guo Z, Jiang H, Ware M, Li XJ, Mattson MP. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci USA 2003; 100:2911-2916.

Disclosure: The authors report no disclosures.

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Published In

Neurology®
Volume 71Number 19November 4, 2008
Pages: 1506-1513
PubMed: 18981372

Publication History

Published online: November 3, 2008
Published in print: November 4, 2008

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Affiliations & Disclosures

N. A. Aziz, MSc
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.
J.M.M. van der Burg, MSc
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.
G. B. Landwehrmeyer, MD
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.
P. Brundin, MD
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.
T. Stijnen, PhD
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.
EHDI Study Group
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.
R. A.C. Roos, MD
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.

Notes

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 [email protected]

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