Huntington\'s Disease Correlation of Body

HUNTINGTON'S DISEASE

CORRELATION of BODY MASS INDEX/IDEAL BODY WEIGHT WITH MORBIDITY and MORTALITY in PERSONS WITH HUNTINGTON'S DISEASE

National Institute of Neurological Disorders and Stroke

Huntington's disease "results form genetically programmed degeneration of brain cells, called neurons, in certain areas of the brain." (National Institute of Neurological Disorders and Stroke, 2009) Caused by the degeneration is "uncontrolled movements, loss of intellectual faculties and emotional disturbance." (National Institute of Neurological Disorders and Stroke, 2009) Huntington's disease is stated to be a familial disease and to be passed "from parent to child through a mutation in the normal gene." (National Institute of Neurological Disorders and Stroke, 2009) the chances of a child inheriting this disease from a parent are stated to be a 50-50 chance. If the child does not inherit this specific gene then that child will not inherit the disease and they will not pass this disease to their children. If the child does inherit the gene they will develop the disease at some point in their life. Symptoms of this disease are stated to include those of "mood swings, depression, irritability or trouble driving, learning new things, remembering a fact, or making a decision. As the disease progresses, concentration on intellectual tasks becomes increasingly difficult and the patient may have difficulty feeding himself or herself and swallowing. The rate of disease progression and the age of onset vary from person to person. A genetic test, coupled with a complete medical history and neurological and laboratory tests, helps physicians diagnose HD." (National Institute of Neurological Disorders and Stroke, 2009) According to the National Institute of Neurological Disorders and Stroke "Presymptomic testing is available for individuals who are at risk for carrying the HD gene." (2009) Prognosis reports state that there is presently no known method to "stop or reverse the course of HD..." however research is ongoing to attempt to understand this disease.

II. Hamilton et al. (2004)

The work of Hamilton, et al. (2004) entitled: "Rate and Correlates of Weight Change in Huntington's Disease" reports a study with the objective of determining the "rate and correlates of weight change in a large, well characterized sample of patients with Huntington's disease followed at 44 sites by the Huntington Study Group." (Hamilton et al., 2004) Hamilton et al. states that in the study "...weight change was assessed in 927 adults with a definite diagnosis of Huntington's disease who were followed prospectively for (mean (SD)) 3.4 (1.4) years. The unified Huntington's disease rating scale was used to assess weight, motor dysfunction (including chorea and dystonia), depressive symptoms, and functional decline." (2004) Results of the study report: "Random effects modeling determined that patients gained an average of 0.11 (1.7) kg/year and their chorea scores increased by 0.36 (0.78) points/year. There were significant but weak relations between weight loss and increasingly severe chorea (r = -0.13), worse baseline motor performance (r = -0.12), less severe baseline depressed mood (r = 0.14), and poorer baseline independence ratings (r = 0.07). Patients who were within 0 to 2 years of symptom onset at the time of the baseline visit gained more weight than those with longer disease duration." (Hamilton, et al., 2004) Conclusions are stated as follows: "Weight loss following symptom onset is not a consistent feature of Huntington's disease. The mechanisms contributing to weight change in this condition are unclear and probably multifactorial. Future studies examining asymptomatic carriers of the mutation could be helpful in identifying incipience of low body weight and may be better suited for identifying clinical correlates of weight loss than studies in symptomatic patients." (Hamilton, et al., 2004)

III. Gaba et al. (2005)

The work of Gaba et al. (2005) entitled: "Energy Balance in Early-Stage Huntington Disease" reports a study with the objective of comparing twenty-four hour "energy expenditure (EE) and energy intake in persons with early midstage HD with those of matched control subjects to determine how HD affects energy balance." (Gaba, et al., 2005) the study design was such that the energy expenditure (EE) "...was assessed in 13 subjects with early-stage HD and in 9 control subjects via indirect calorimetry in a human respiratory chamber. Energy intake was determined by weighing all food provided and all leftovers from an ad libitum diet. Body composition was measured via air-displacement plethysmography. Stage of disease was estimated on the basis of the Unified Huntington's Disease Rating Scale and modified Mini-Mental Status examinations. Regression analysis included all 13 HD subjects; t tests were used for the comparisons between matched HD and control subjects." (Gaba, et al., 2005) Study result state that the "...24-h EE was 11% higher in the HD subjects than in the control subjects (NS). This difference was due to a higher (P = 0.043) waking metabolic rate, which was related to a significantly greater displacement of the center of mass by HD subjects than by control subjects (P = 0.028). On average, both groups were in positive energy balance and exceeded their energy expenditure by 2510-2929 kJ." (Gaba, et al., 2005) Conclusions of this study report that the "Higher 24-h EE in persons with early midstage HD is due to increased physical activity, both voluntary and involuntary. However, HD subjects are able to maintain positive energy balance when offered adequate amounts of food in a controlled setting." (Gaba, et al., 2005)

IV. Djousse (2002)

The work of Djousse et al. (2002) entitled: "Weight Loss in Early Stage of Huntington's Disease" reports a study in which "Data from the Huntington Study Group were used to evaluate whether HD is associated with lower body mass index (BMI) at the earliest stage of the disease." Djousse et al. (2005) reports that there were 361 "...case subjects in whom HD had been diagnosed with an independence scale rating of 100 (no special care needed), a total functional capacity score of >or=11, and HD duration of

V. Sandoff, et al. (2003)

The work of Sandoff, et al. (2003) entitled: "Oral uridine pro-drug PN401 decreases neurodegeneration, behavioral impairment, weight loss and mortality in the 3-nitropropionic acid mitochondrial toxin model of Huntington's disease" states that Huntington's disease (HD) is "...associated with decreased activity of mitochondrial succinate dehydrogenase (complex II). De novo biosynthesis of uridine nucleotides is directly coupled to the respiratory chain. Cells with impaired mitochondrial function become uridine auxotrophs and can be maintained with high micromolar concentration of uridine and pyruvate." It is related that the therapeutic role of "pyrimidines and possible changes in uridine content has not been assessed in neurological diseases involving mitochondrial dysfunction in vivo." (Sandoff, et al., 2003) Additionally stated is: "Oral administration of PN401 delivers much higher levels of uridine to the circulation than oral administration of uridine itself. Administration of complex II inhibitor 3-nitropropionic acid (3NP) induced neuronal damage in the striatum, substantia nigra and/or thalamus in 80% of the mice and led to 38% mortality." (Sandoff, et al., 2003) PN401 treatment is stated to have "...almost completely prevented the neuronal damage due to 3NP and completely prevented mortality. In two subsequent experiments, 3NP-induced weight loss, mortality and behavioral impairment in rotarod performance and spontaneous motor activity were attenuated by treatment with oral PN401. 3NP did not reduce forebrain total uridine nucleotides (TUN), though higher doses of PN401 associated with optimal neuroprotection did elevate TUN to supranormal levels. Thus, oral PN401 treatment has neuroprotective effects in a HD model of mitochondrial dysfunction and the mechanism is more complex than correction of a pyrimidine deficit." (Sandoff, et al., 2003)

VI. Dedeoglu et al. (2003)

The work of Dedeoglu, et al. (2003) entitled: "Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington's disease transgenic mice" reports that although there have been great advances in understanding the pathogenesis of Huntington's disease "...treatment to slow or prevent disease progression remains elusive." (Dedeoglu, et al., 2003) it has been reported previously that: "...dietary creatine supplementation significantly improves the clinical and neuropathological phenotype in transgenic HD mice lines starting at weaning, before clinical symptoms appear." (Dedeoglu, et al., 2003) This report states that "...creatine administration started after onset of clinical symptoms significantly extends survival in the R6/2 transgenic mouse model of HD. Creatine treatment started at 6, 8, and 10 weeks of age, analogous to early, middle, and late stages of human HD, significantly extended survival at both the 6- and 8-week starting points. Significantly improved motor performance was present in both the 6- and 8-week treatment paradigms, while reduced body weight loss was only observed in creatine-supplemented R6/2 mice started at 6 weeks." (Dedeoglu, et al., 2003) Specifically it is stated that the "...Neuropathological sequelae of gross brain and neuronal atrophy and huntington aggregates were delayed in creatine-treated R6/2 mice started at 6 weeks. We show significantly reduced brain levels of both creatine and ATP in R6/2 mice, consistent with a bioenergetic defect. Oral creatine supplementation significantly increased brain concentrations of creatine and ATP to wild-type control levels, exerting a neuroprotective effect. These findings have important therapeutic implications, suggesting that creatine therapy initiated after diagnosis may provide significant clinical benefits to HD patients." (Dedeoglu, et al., 2003)

VII. Ferrante et al. (2002)

The work of Ferrante et al. (2002) entitled: 'Therapeutic Effects of Coenzyme Q10 and Remacemide in Transgenic Mouse Models of Huntington's Disease" states that there is "...substantial evidence that bioenergetic defects and excitotoxicity may play a role in the pathogenesis of Huntington's disease (HD). Potential therapeutic strategies for neurodegenerative diseases in which there is reduced energy metabolism and NMDA-mediated excitotoxicity are the administration of the mitochondrial cofactor coenzyme Q10 and the NMDA antagonist remacemide." (2003) Ferrante et al. states that they found "...that oral administration of either coenzyme Q10 or remacemide significantly extended survival and delayed the development of motor deficits, weight loss, cerebral atrophy, and neuronal intranuclear inclusions in the R6/2 transgenic mouse model of HD. The combined treatment, using coenzyme Q10 and remacemide together, was more efficacious than either compound alone, resulting in an approximately 32 and 17% increase in survival in the R6/2 and N171-82Q mice, respectively." (Ferrante et al., 2003) This study reports that magnetic resonance imaging "...showed that combined treatment significantly attenuated ventricular enlargement in vivo. These studies further implicate defective energy metabolism and excitotoxicity in the R6/2 and N171-82Q transgenic mouse models of HD and are of interest in comparison with the outcome of a recent clinical trial examining coenzyme Q10 and remacemide in HD patients." (Ferrante et al., 2003)

VIII. Aziz et al. (2008)

The work of Aziz, et al. (2008) entitled: "Weight Loss in Huntington Disease Increases with Higher CAG Repeat Number" states that Huntington Disease (HD) is a hereditary neurogenerative 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." Aziz et al. reports that in order to understand the mechanisms underlying weight loss in Huntington's Disease, they studied "its relation to other disease characteristics including motor, cognitive, and behavioral disturbances and CAG repeat number." (2008) the study involved 517 patients in the early stages of Huntington's Disease and "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)." (Aziz, et al., 2008) Additionally assessed was the "...relation between CAG repeat number and body weight and caloric intake in the R6/2 mouse model of HD." (Aziz, et al., 2008) Results of the study report: "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." (Aziz, et al., 2008) Conclusions state that weight loss in Huntington's Disease "...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." (Aziz, et al., 2008)