Weight loss in HD

HD Lighthouse Contributing Editor's Comment: 

Weight loss is a characteristic symptom in Huntington's Disease and also a clue to unraveling its mysteries.  European researchers followed 517 early stage HD patients for three years and found that weight loss was significant and positively correlated with the CAG count.  In other words, the higher the number of CAG repeats, the faster weight loss occurred.

What accounts for this weight loss?  Of course, as the disease progresses and swallowing becomes more difficult, there may be a decreased intake of calories, contributing to weight loss.  But this study shows that weight loss actually occurs early on in HD patients just as it does in the R6/2 mice, before there is any decrease in caloric intake.   The researchers didn't collect information about caloric intake in their patients, but we know that as weight loss occurs, patients and their families will work on increasing calories to get weight back to normal.  The HD mice have also been found to increase their caloric intake.

Could the decrease be a result of increased movements?  Chorea does use up additional calories.  However, weight loss was not correlated with the total motor score on the United Huntington's Disease Rating Scale (UHDRS) and chorea does not correlate with the CAG count.

What about medication?   Neuroleptic use can cause changes in energy homeostasis but patients taking neuroleptics were exclued from this study.

The patients studied were in the clinical trial for riluzole.   However, the trial showed that riluzole did not affect clinical outcome; in other words, it is not an effective treatment for HD.  The researchers also confirmed that riluzole use does not affect weight loss.

It appears then that Huntington's Disease causes a metabolic problem.  This study builds on earlier research by Marcy MacDonald and colleagues who were working with cell models and a knock in mouse model.  They showed that CAG counts are negatively correlated with mitochondrial energy production.  The higher the number of CAG repeats, the less energy is produced to power the cell. 

This research is encouraging because it shows that work with cell and animal models can yield insights that are confirmed in human HD patients.  It also suggests that attempts to boost energy metabolism may result in treatments for the disease.  Two supplements that boost energy, creatine and CoQ10, and are now in Phase III clinical trials.

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 01-01-2009

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

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.

COonclusions:

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.

Source: Neurology 2008;71:1506-1513