Weight loss in Huntington disease increases with higher CAG repeat number

• Published in: Neurology Vol. 71; no. 19; pp. 1506 - 1513
• Main Authors: AZIZ, N. A, VAN DER BURG, J. M. M, LANDWEHRMEYER, G. B, BRUNDIN, P, STIJNEN, T, ROOS, R. A. C
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 04-11-2008
• Subjects: Adult; Aged; Animals; Biological and medical sciences; Body Mass Index; Body Weight; Clinical Medicine; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Energy Intake; Female; Humans; Huntingtin Protein; Huntington Disease - drug therapy; Huntington Disease - genetics; Huntington Disease - physiopathology; Klinisk medicin; Male; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurologi; Neurology; Neuroprotective Agents - therapeutic use; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Placebos; Riluzole - therapeutic use; Trinucleotide Repeats; Weight Loss - genetics; Nervous system diseases; Central nervous system disease; Huntington disease; Weight loss; Degenerative disease; Genetic disease; Cerebral disorder; Extrapyramidal syndrome
• ISSN: 0028-3878; 1526-632X; 1526-632X
• DOI: 10.1212/01.wnl.0000334276.09729.0e

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.
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.
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.
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.