Dietary Association with Phenoconversion in Huntington’s Disease Carriers
Abstract & Commentary
By Claire Henchcliffe, MD
Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College
Dr. Henchcliffe reports she is on the speakers bureau and advisory board for Allergan and Teva; speakers bureau for Boehringer-Ingelheim, GlaxoSmitKline, and Novartis; advisory board for Merz; and is a consultant for Gerson Lehman Group and Guidepoint Global.
Synopsis: Dairy intake, but not adherence to Mediterranean diet, was associated with increased risk of phenoconversion from mutation carrier to manifesting status in individuals with Huntington’s disease.
Source: Marder K, et al. Relationship of Mediterranean diet and caloric intake to phenoconversion in Huntington disease. JAMA Neurol 2013; online doi:10.1001/jamaneurol.2013.3487.
This study aimed to identify dietary risk factors in developing symptoms of Huntington’s disease (HD) in individuals carrying the mutation for this disorder. The Prospective Huntington At Risk Observational Study (PHAROS) enrolled approximately 1000 individuals over almost 5 years. Participants were deemed at 50:50 risk of developing HD based on their family history, but 93% of those enrolled had non-specific or no motor abnormalities. The present study describes a subset of 211 individuals in this cohort who were known to have a significant expansion of CAG repeats in the huntingtin gene. Of these 211 individuals, 31 reached the point of at least 99% confidence in clinically definite HD using the Unified Huntington Disease Rating Scale (UHDRS), which was defined as phenoconversion for this study. Mean time to phenoconvert was 2.5 ± 1.7 years. Those who did not phenoconvert were followed for 4.3 ± 1.7 years, that is until the end of the study or until lost to follow up. All data were reported according to degree of adherence to the Mediterranean diet, in which fruits, fish, cereals, legumes, and vegetables are considered beneficial, and meat and dairy are considered detrimental. Mean age ranged from 42.8-44.1 years, with no significant difference between groups. Age and CAG repeat length were both significantly associated with increased risk of phenoconversion during the time period studied. Although Mediterranean diet adherence did not associate in a statistically significant manner with altered risk of phenoconversion, when broken into subcomponents, high dairy intake was significantly associated with a hazard ratio of 2.36 (1.00-5.57, P = 0.05) for phenoconversion.
HD is caused by a CAG repeat expansion, encoding glutamine, in the huntingtin gene. The expansion mutation is highly penetrant, is inherited in an autosomal dominant fashion, and thus allows identification of a high-risk cohort for developing HD that is ideal for studying factors that may associate with phenoconversion. In this regard, the PHAROS study and similar studies enrolling at-risk individuals for neurodegenerative diseases are invaluable. It is disappointing that the Mediterranean diet was not found to be associated with decreased risk of phenoconversion from HD carrier to manifesting status. A potential problem is that diet was self-reported and not validated, and the questionnaire was administered more than 30 months after study start up. The authors state that there was just 50-85% power to detect hazard ratios of 2.0 to 3.0, meaning that some signals may have been lost. The same type of dietary analysis has previously demonstrated a positive association of the Mediterranean diet with decreased risk of Alzheimer’s disease, mild cognitive impairment, Parkinson’s disease, and cerebrovascular disease. However, after adjustment for age, caloric intake, and CAG repeat expansion, there was approximately a 2-fold greater risk of phenoconversion associated with higher dairy intake. A similar finding has been reported for risk of Parkinson’s disease. The authors highlight the association of higher urate levels with lower dairy intake: Of note, higher urate levels have been associated with slower progression of HD over a 2.5 year period in one study and also with decreased risk and slower progression of Parkinson’s disease (at least in men). Whether this is indeed a valid explanation or whether dairy intake is a surrogate marker for intake of another harmful substance (pesticides, hormones, or other chemicals used in the U.S. agricultural industry) remains to be seen. Nonetheless, this study supports an idea that is gaining traction — that genetic factors in neurodegeneration may be modulated by diet and/or lifestyle. This potentially presents ideal opportunities for developing preventive strategies.
