Effect of Body Weight on Age at Onset in Huntington Disease: A Mendelian Randomization Study.

OBJECTIVE: Weight loss is associated with clinical progression in Huntington disease (HD), but whether body weight causally affects disease onset or progression is unknown. Therefore, we aimed to assess whether genetically determined variations in body weight are causally related to age at onset in HD. METHODS: Using data from different recent genome-wide association studies, we performed a 2-sample mendelian randomization (MR) analysis to assess whether genetic markers of body mass index (BMI) are causally related to residual age at onset in HD, i.e., the difference between observed and expected age at onset based on mutation size. Our study had a statistical power of 90% to detect a causal effect of ≥3.8 months per BMI unit change at a type I error rate of 0.05. RESULTS: Inverse-variance weighted MR estimates showed that a higher genetically determined BMI was not causally related to residual age at onset in HD (ß = -0.44 years per unit increase in BMI, confidence interval: -1.33 to 0.46, p = 0.34). All other complementary (nonparametric) MR regression methods yielded similar results. CONCLUSIONS: Although maintaining a healthy and stable body weight remains important in patients with HD, promoting weight gain with the aim of delaying disease onset or slowing down disease progression should be discouraged. Our findings point toward the existence of underlying pathologic processes that dictate both the rate of clinical progression and weight loss in HD, which need further elucidation as targeting these pathways, rather than body weight per se, could be of therapeutic value.

Overlap between age-at-onset and disease-progression determinants in Huntington disease.

OBJECTIVE: A fundamental but still unresolved issue regarding Huntington disease (HD) pathogenesis is whether the factors that determine age at onset are the same as those that govern disease progression. Because elucidation of this issue is crucial for the development as well as optimal timing of administration of novel disease-modifying therapies, we aimed to assess the extent of overlap between age-at-onset and disease-progression determinants in HD. METHODS: Using observational data from Enroll-HD, the largest cohort of patients with HD worldwide, in this study we present, validate, and apply an intuitive method based on linear mixed-effect models to quantify the variability in the rate of disease progression in HD. RESULTS: A total of 3,411 patients with HD met inclusion criteria. We found that (1) about two-thirds of the rate of functional, motor, and cognitive progression in HD is determined by the same factors that also determine age at onset, with CAG repeat-dependent mechanisms having by far the largest effect; (2) although expanded HTT CAG repeat size had a large influence on average body weight, the rate of weight loss was largely independent of factors that determine age at onset in HD; and (3) about one-third of the factors that determine the rate of functional, motor, and cognitive progression are different from those that govern age at onset and need further elucidation. CONCLUSION: Our findings imply that targeting of CAG repeat-dependent mechanisms, for example through gene-silencing approaches, is likely to affect the rate of functional, motor, and cognitive impairment, but not weight loss, in manifest HD mutation carriers.

Body weight is a robust predictor of clinical progression in Huntington disease.

Unintended weight loss is a hallmark of Huntington disease (HD), but it is unknown to what extent weight loss impacts the rate of disease progression. Therefore, using longitudinal data from the Enroll-HD study, we assessed the association between baseline body mass index (BMI) and the rate of clinical progression in 5,821 HD mutation carriers. We found that high baseline BMI was associated with a significantly slower rate of functional, motor, and cognitive deterioration (all p < 0.001), independent of mutant HTT CAG repeat size. Our findings provide strong rationale for exploration of systemic metabolism as a therapeutic target in HD. Ann Neurol 2017;82:479-483.

[A man who is not able to straighten his knee]. / Een man die zijn knie niet kan strekken na een val.

An 86-year-old man presented at the Emergency Department with pain in his right leg and the inability to extend his knee after a fall. An ultrasound of the leg revealed a quadriceps tendon rupture. Surgical repair was performed and we expect complete recovery.

[A boy with a wart-like lesion of the toe]. / Een jongen met een verruceuze afwijking van de teen.

A 10-year-old boy consulted a dermatologist with a painful, subungual tumour on one of his toes. X-ray showed an outgrowth of the distal phalanx and histopathological investigation showed osteochondromatous proliferation. The patient was diagnosed with exostosis. Subungual exostoses are benign osteocartilaginous tumours that occur beneath the nail bed. Excision was performed, the patient recovered well.

Gastrointestinal dysfunction contributes to weight loss in Huntington's disease mice.

Weight loss is the most important non-neurological complication of Huntington's disease (HD). It correlates with disease progression and affects the quality of life of HD patients, suggesting that it could be a valuable target for therapeutic intervention. The mechanism underlying weight loss in HD is unknown. Mutant huntingtin, the protein that causes the disease, is not only expressed in the brain, but also along the gastrointestinal (GI) tract. Here we demonstrate that the GI tract of HD mice is affected. At the anatomical level we observed loss of enteric neuropeptides, as well as decreased mucosal thickness and villus length. Exploring the functions of the GI system we found impaired gut motility, diarrhea, and malabsorption of food. The degree of malabsorption was inversely associated with body weight, suggesting that GI dysfunction plays an important role in weight loss in HD mice. In summary, these observations suggest that the GI tract is affected in HD mice and that GI dysfunction contributes to nutritional deficiencies and weight loss.

Beyond the brain: widespread pathology in Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a polyglutamine stretch in the huntingtin protein. Today, more than 15 years after the genetic defect underlying HD was discovered, the pathogenesis is still not well understood and there is no adequate treatment. Research into this disorder has conventionally focused on neurological symptoms and brain pathology, particularly neurodegeneration in the basal ganglia and cerebral cortex. Mutant huntingtin is, however, ubiquitously expressed throughout the body. Indeed, contrary to earlier thinking, HD is associated with abnormalities in peripheral tissues. These abnormal changes are not all secondary to brain dysfunction, but most seem to be directly caused by expression of mutant huntingtin in peripheral tissues. In this article, we highlight this emerging field of research and how it might affect our understanding of the pathogenesis of this disease, the development of novel biomarkers of disease progression, and the identification of new potential treatments.

Increased thirst and drinking in Huntington's disease and the R6/2 mouse.

While Huntington's disease (HD) is a condition that primarily involves the basal ganglia, there is evidence to suggest that the hypothalamus is also affected. Because the osmoreceptors regulating thirst are situated in the circumventricular region of the hypothalamus, we were interested in whether altered thirst is a part of the HD phenotype. We used the LABORAS behavioural monitoring system and water consumption to show that drinking behaviour was abnormal in R6/2 mice. By 10 weeks of age, R6/2 mice spent significantly more time drinking and drank a greater volume than their wild-type (WT) littermates. The numbers of immunoreactive vasopressin neurons in the paraventricular nucleus (PVN) of the hypothalamus in R6/2 mice were significantly decreased from 8 weeks of age, suggesting that the change in drinking behaviour may be the result of hypothalamic dysfunction. We gave a xerostomia (dry mouth) questionnaire to HD patients and control subjects, and also measured their urine osmolality and serum vasopressin. The mean total xerostomia score was significantly higher in HD patients than in controls, indicating greater thirst in HD patients. Urine osmolality was unaffected in HD patients up to clinical stage III, and none of the patients had diabetes. However, serum vasopressin was increased, suggesting a dysregulation in the control of hypothalamic vasopressin release. A dry mouth can affect taste, mastication and swallowing, all of which may contribute to the significant weight loss seen in both HD patients and R6/2 mice, as can dehydration. We suggest that increased thirst may be an important and clinically relevant biomarker for the study of disease progression in HD.

Increased metabolism in the R6/2 mouse model of Huntington's disease.

Huntington's disease (HD) is a hereditary disorder characterized by personality changes, chorea, dementia and weight loss. The cause of this weight loss is unknown. The aim of this study was to examine body weight changes and weight-regulating factors in HD using the R6/2 mouse model as a tool. We found that R6/2 mice started losing weight at 9 weeks of age. Total locomotor activity was unaltered and caloric intake was not decreased until 11 weeks of age, which led us to hypothesize that increased metabolism might underlie the weight loss. Indeed, oxygen consumption in R6/2 mice was elevated from 6 weeks of age, indicative of an increased metabolism. Several organ systems that regulate weight and metabolism, including the hypothalamus, the stomach and adipose tissue displayed abnormalities in R6/2 mice. Together, these data demonstrate that weight loss in R6/2 mice is associated with increased metabolism and changes in several weight-regulating factors.

Localized brain activation specific to auditory memory in a female songbird.

Song acquisition in songbird males is a prominent model system for the study of the brain mechanisms of memory. Male zebra finches (Taeniopygia guttata) learn their songs from an adult conspecific tutor early in life. Previous work has shown that exposure of males to their tutor song leads to increased expression of immediate early genes (IEGs) in the caudomedial nidopallium (NCM) and in the caudomedial mesopallium (CMM). In addition, IEG expression in the NCM correlates significantly with the strength of song learning. Interpretation of these findings is complicated, as males both learn the characteristics of tutor song and learn to produce a similar own song. Female zebra finches do not sing, but nevertheless they learn the characteristics of a song to which they were exposed when young, and form a preference for it. Here, adult zebra finch females reared with their fathers showed a significant preference for their father's song. Females that were later reexposed to their father's song showed significantly greater expression of Zenk, the protein product of the IEG ZENK, than controls that were exposed to a novel song, in the CMM, but not in the NCM or hippocampus. These results suggest that in female zebra finches the CMM may be (part of) the neural substrate for the representation of the memory of their father's song.