Huntington’s disease (HD) is a rare disorder affecting about 30,000 Americans; it is a progressive, neurodegenerative disorder that is inherited through an autosomal dominant gene, meaning the inheritance of only one mutated allele (a part of a gene) is sufficient to cause the trait of the disease (Vonsattel et al., 1985). If an individual inherits the mutated allele, they are at high risk and are very likely to be affected by HD sometime in life (Prof, 2007). Children of individuals with HD have a 50% chance of inheriting the mutated allele. 

HD is characterized by a late onset of physical, cognitive, and psychiatric symptoms that typically appear in middle-age (Prof, 2007). There is a juvenile form of HD that occurs in those under 20 years of age, but it is incredibly rare and only accounts for approximately 10% of all cases of HD (Huntington Society of Canada, n.d.). Distinct symptoms of HD include chorea (involuntary and unpredictable muscle movements), dystonia (involuntary muscle contraction causing repetitive or twisting movements), incoordination, cognitive decline, and behavioural difficulties (Prof, 2007). As the disease progresses, difficulties with walking, swallowing, verbal communication, and thinking become severe (Huntington Society of Canada, n.d.). Patients typically die from complications following a fall, lack of nourishment due to dysphagia, or pneumonia/lung infection as a result of improper swallowing causing food particles to accumulate in the lungs (Prof, 2007). HD occurs in all ethnicities and both males and females have the same risk of inheriting it (Huntington Society of Canada, n.d.). 

The gene in question in HD is huntingtin, which normally codes for a protein that is expressed in all human cells (Prof, 2007). In HD, the CAG sequence at the beginning of the huntingtin gene is repeated too many times, which results in a toxic gain of function (Prof, 2007). There is an inverse relationship between the number of repeats and age of onset; the more repeats there are, the earlier the age of onset and increased rate of progression (Prof, 2007).

There are several diets outlined in the literature that show promising results in slowing neurodegeneration (the death of brain cells) and loss of abilities for individuals with HD. The first of which is the ketogenic (keto) diet. The keto diet is high in fat and low in carbohydrates and has been shown to provide neuroprotective effects against acute and chronic brain injury, specifically in rodent models of neurodegeneration (Ruskin et al., 2011). Transgenic mouse models of HD who were fed a keto diet did not experience adverse effects in locomotor activity, coordination, and working memory (Ruskin et al., 2011). There were no significant changes in lifespan either; however, weight loss was delayed (Ruskin et al., 2011). A hallmark feature of HD is progressive weight loss, yet there was a delay in the reduction of body weight in the transgenic mice models, despite the keto diet typically resulting in weight loss (Ruskin et al., 2011). Slower progression of HD has been associated with high body weight; therefore, it is important for patients with HD to maintain their weight. (Myers et al., 1991). The keto diet is able to provide that benefit, while also having no negative effects on locomotor activity and memory (Ruskin et al., 2011).

Intermittent fasting is an eating pattern that has been shown to confer positive effects in HD patients (Duan et al., 2003). Although it is not a diet, this pattern of eating has been linked to positive outcomes in HD mice models (Duan et al., 2003). Intermittent fasting is characterized by cycling through periods of eating and fasting and it has been shown to delay the onset of motor dysfunction, suppress neuropathological alterations, and increase lifespan in huntingtin mutant mice (Duan et al., 2003). Studies show that this way of eating increases cellular stress resistance and reduces brain atrophy and apoptosis (cell death) in huntingtin mutant mice (Duan et al., 2003). Furthermore, intermittent fasting, without reducing caloric intake, activates autophagy (removal of unnecessary cellular components) in the huntingtin mouse model, which reduces the large amounts of mutant huntingtin protein (Ehrnhoefer et al., 2018). This contributes to protein clearance and reduces aggregate formation, which is otherwise known to progress the disease (Ehrnhoefer et al., 2018).

The Mediterranean Diet (MD) is a highly researched diet and has been shown to provide great benefits in various pathological conditions, with HD being one of those conditions (Christodoulou, Demetriou, & Zamba-Papanicolaou, 2020). The MD consists of a high consumption of plant-based foods (i.e. fruits, vegetables, nuts, and legumes), fish, olive oil, low to moderate intake of wine, and low intake of red meat, poultry, and dairy products (Marder et al., 2013). Studies have found that HD patients who had moderate/high adherence to the MD had a slight improvement in their Unified Huntington’s Disease Rating Scale and Total Functional Capacity (Christodoulou et al., 2020). This is a tool that measures the overall functional capacity and clinical performance of an individual. HD patients who had high adherence to the diet showed improvement in both cognitive and motor scores, compared to those who had low adherence (Christodoulou et al., 2020). Overall, studies show even moderate adherence to the MD can result in improved quality of life, lower comorbidity, and lower motor impairment in HD patients, compared to patients with low adherence to the diet (Rivadeneyra et al., 2016). Of all the diets suggested to individuals with HD, the MD is the most effective because it provides the greatest benefits.

The MD has large amounts of data supporting its beneficial effects in many pathological conditions (Christodoulou et al., 2020). The MD emphasizes a high intake of fruits and vegetables; plant-based foods are loaded with micronutrients and antioxidants, such as vitamin E and C, carotenoids, and flavonoids, which have been shown to eliminate free radicals that contribute to neurodegeneration (Gillette-Guyonnet, Secher, & Vellas, 2013). Meanwhile, consuming more meats and fats, which is not part of the MD, is associated with increased disease development (Sofi et al., 2013). 

Dairy products are also not a staple of the MD, seeing as only low intakes are recommended on this diet (Christodoulou et al., 2020). High consumption of dairy products has been linked to lower urate levels, which are shown to increase the risk of faster clinical onset of HD by two-fold (Marder et al., 2013). Uric acid (urate) is an antioxidant that is known to eliminate oxygen radicals, which typically contribute to neurodegeneration (Auinger, Kieburtz, & Mcdermott, 2010). Higher urate levels are associated with slower HD progression as measured by the Total Functional Capacity scale due to its protective effect (Auinger et al., 2010). Extra virgin olive oil, which is high in monounsaturated fatty acids, has also been shown to protect the brain against antioxidant stress in HD rat models (Tasset et al., 2011).

Polyphenols (i.e. found in fruits, nuts, legumes, etc.), resveratrol (found in red wine), and olive oil are all inducers of autophagy (Corella et al., 2018). Autophagy is a natural cellular mechanism that removes unnecessary components; in HD, excess huntingtin proteins form aggregates that contribute to neurodegeneration (Ehrnhoefer et al., 2018). Inducing autophagy helps to eliminate mutant huntingtin protein (Ehrnhoefer et al., 2018). Additionally, polyphenols provide neuroprotective effects by interacting with transition metals, inactivating free radicals, modulating the activity of different enzymes, and impacting intracellular signaling pathways and gene expression to slow neurodegeneration (Obrenovich et al., 2010).

Adherence to any diet can be challenging, especially if an individual is already struggling with a debilitating condition. Therefore, future research should continue assessing the impact of the MD and other types of diets to greatly increase the quality of patient care. 

References

Auinger, P., Kieburtz, K., & Mcdermott, M. P. (2010). The relationship between uric acid levels and Huntington’s disease progression. Movement Disorders, 25(2), 224-228. 10.1002/mds.22907

Christodoulou, C. C., Demetriou, C. A., & Zamba-Papanicolaou, E. (2020). Dietary intake, Mediterranean diet adherence and caloric intake in Huntington’s disease: A review. Nutrients, 12(10), 2946. 10.3390/nu12102946 

Corella, D., Coltell, O., Macian, F., & Ordovas, J. M. (2018). Advances in understanding the molecular basis of the Mediterranean diet effect. The Annual Review of Food Science and Technology, 9, 227-249. 10.1146/annurev-food-032217-020802

Duan, W., Guo, Z., Jiang, H., Ware, M., Li, X-J., & Mattson, M. P. (2003). Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. PNAS, 100(5), 2911-2916. 10.1073pnas.0536856100

Ehrnhoefer, D. E., Martin, D. D. O., Schmidt, M. E., Qiu, X., Ladha, S., Caron, N. S., Skotte, N. H., Nguyen, Y. T. N., Vaid, K., Southwell, A. L., Engemann, S., Franciosi, S., & Hayden, M. R. (2018). Preventing mutant huntingtin proteolysis and intermittent fasting promote autophagy in models of Huntington disease. Acta Neuropathologica Communications, 6(1). 10.1186/s40478-018-0518-0

Gillette-Guyonnet, S., Secher, M., & Vellas, B. (2013). Nutrition and neurodegeneration: epidemiological evidence and challenges for future research. British Journal of Clinical Pharmacology, 75(3), 738-755. 10.1111/bcp.12058

Huntington Society of Canada. (n.d.). What is Huntington disease? Retrieved from https://www.huntingtonsociety.ca/learn-about-hd/what-is-huntingtons/

Marder, K., Gu, Y., Eberly, S., Tanner, C. M., Scarmeas, N., Oakes, D., & Shoulson, I. (2013). Relationship of Mediterranean diet and caloric intake to phenoconversion in Huntington’s disease. JAMA Neurology, 70(11), 1382-1388. 10.1001/jamaneurol.2013.3487

Myers, R. H., Sax, D. S., Koroshetz, W. J., Mastromauro, C., Cupples, A., Kiely, D. K., Pettengill, F. K., & Bird, E. D. (1991). Factors associated with slow progression in Huntington’s disease. Arch Neurol, 48(8), 800–804. 10.1001/archneur.1991.00530200036015 

Obrenovich, M. E., Nair, N. G., Beyaz, A., Aliev, G., & Reddy, V. P. (2010). The role of polyphenolic antioxidants in health, disease, and aging. Rejuvenation Research, 13(6). 10.1089/rej.2010.1043

Prof, F. O. W. (2007). Huntington’s disease. The Lancet, 369(9557), 218-228. 

Rivadeneyra, J., Cubo, E., Gil, C., Calvo, S., Mariscal, N., & Martinez, A. (2016). Factors associated with Mediterranean diet adherence in Huntington’s disease. Clinical Nutrition ESPEN, 12, e7-e13. 10.1016/j.clnesp.2016.01.001

Ruskin, D. N., Ross, J. L., Kawamura, M., Ruiz, T. L., Geiger, J. D., & Masino, S. A. (2011). A ketogenic diet delays weight loss and does not impair working memory or motor function in the R6/2 1J mouse model of Huntington’s disease. Physiology and Behavior, 103(5), 501-507. 

Sofi, F., Macchi, C. & Casini, A. (2013). Mediterranean diet and minimizing neurodegeneration. Current Nutrition Reports, 2, 75–80. 10.1007/s13668-013-0041-7

Tasset, I., Pontes, A. J., Hinojosa, A. J., de la Torre, R., & Túnez, I. (2011) Olive oil reduces oxidative damage in a 3-nitropropionic acid-induced Huntington’s disease-like rat model. Nutritional Neuroscience, 14(3), 106-11. 10.1179/1476830511Y.0000000005 

Vonsattel, J-P., Myers, R. H., Stevens, T. J., Ferrante, R. J., Bird, E. D., & Richardson, E. P. (1985). Neuropathological classification of Huntington’s disease. Journal of Neuropathology and Experimental Neurology, 44(6), 559-577.