Systemic Symptoms in Huntington's Disease: A Comprehensive Review

Abstract

Background

Although Huntington's disease (HD) is usually thought of as a triad of motor, cognitive, and psychiatric symptoms, there is growing appreciation of HD as a systemic illness affecting the entire body.

Objectives

This review aims to draw attention to these systemic non‐motor symptoms in HD.

Methods

We identified relevant studies published in English by searching MEDLINE (from 1966 to September 2023), using the following subject headings: Huntington disease, autonomic, systemic, cardiovascular, respiratory, gastrointestinal, urinary, sexual and cutaneous, and additional specific symptoms.

Results

Data from 123 articles were critically reviewed with focus on systemic features associated with HD, such as cardiovascular, respiratory, gastrointestinal, urinary, sexual and sweating.

Conclusion

This systematic review draws attention to a variety of systemic and autonomic co‐morbidities in patients with HD. Not all of them correlate with the severity of the primary HD symptoms or CAG repeats. More research is needed to better understand the pathophysiology and treatment of systemic and autonomic dysfunction in HD.

Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder manifested typically by chorea and other motor, cognitive, and psychiatric symptoms. ¹ , ² HD is caused by a CAG repeat expansion within the huntingtin (HTT) gene which produces a polyglutamine repeat that leads to protein misfolding, soluble aggregates, and the development of inclusion bodies. ³ While traditionally considered a motor and neuropsychiatric disease, recent work suggests HD is a systemic illness affecting the entire body. ⁴ , ⁵ Although autonomic symptoms (AS) are being more frequently reported, ⁶ , ⁷ , ⁸ , ⁹ there is an unmet need to better understand and treat AS associated with HD. Furthermore, AS seems be an important prodromal feature of HD, occurring in some patients 20 years prior to the predicted onset of motor symptoms of HD. ¹⁰ This article attempts to review the available literature on systemic and AS in HD, and to identify the current lapses in our knowledge of this topic.

Search Strategy

A systematic review of available literature in MEDLINE from 1966 to September 2023 with the following search terms was performed: Huntington AND each of abdominal, autonomic, bladder, blood pressure, body mass index, breathing, cardiac, constipation, diarrhea, dyspepsia, gastric, genital, hair, nausea, nutrition, reflux, sex, skin, sweat, thermoregulatory, urinary, vascular, vomiting, weight. These search terms were intentionally vague to capture the most abstracts possible and minimize the risk of missing a relevant study.

Articles were included if reporting on systemic and autonomic symptoms in Huntington's disease, and written in English. Articles were excluded from this review if not available in English, published as editorials or letters, or reported exclusively on motor, psychiatric, or cognitive symptoms in HD. We also did not include reports of treatment‐induced systemic or autonomic symptoms in HD. All abstracts were reviewed for relevance to the topic of this review. Of the 1647 abstracts reviewed, 1532 were not considered relevant to the topic of this review. Two hundred and eleven abstracts were retained and the corresponding full articles were carefully reviewed. Of these, 104 full articles were considered relevant to the topic of this review and were included. PubMed links and references from these articles were also scrutinized to identify other relevant studies as suggested by the references’ titles. Similarly to the initial search, abstracts of potentially relevant references were reviewed and, if considered relevant to the topic of this review, the corresponding full articles were reviewed. Thus, an additional 19 studies were identified from references and included in this review, bringing the total of articles reviewed to 12 (Fig. 1).

Figure 1.

Reference selection process.

Cardiovascular Disorders

While cardiovascular disease is a major cause of death in HD, ¹¹ premanifest HD mutation carriers also present with a higher risk of cardiovascular disease than healthy controls. ¹²

Electrical Abnormalities

Abnormal electrocardiogram (ECG) variables unexplained by medications or by potentially contributing medical conditions were reported at higher frequencies than in the general population in one study which included 590 subjects with early symptomatic HD ¹³ (Table 1). Another longitudinal observational study of children under 18 including 84 subjects with HD gene expansion and 238 subjects without gene expansion reported that participants with HD onset predicted in less than 15 years had a mean adjusted resting heart rate (rHR) that was almost 16 bpm higher than the group without gene expansion; furthermore, there was also a significant, positive relationship between CAG repeat length and rHR. ¹⁰ This is important as some studies have suggested that an increase in rHR of 10 bpm is associated with a 14% increased risk of cardiovascular mortality. ¹⁴ Another study reported changes in QRS‐T peak, QRS‐T mean, QT interval variability index (QTVI) and the unexplained QTV, in clinically manifest HD subjects compared to healthy controls, with these alterations greatest in patients with late HD. ¹⁵ Both QTVI and unexplained QTV are strong predictors of sudden cardiac death. ¹⁶

TABLE 1.

Reported frequency of systemic symptoms in HD subjects

System/Symptom	Reported frequency in HD	Remarks
Cardiovascular
Abnormal electrocardiogram	39% 13	More frequent than general population
Bradycardia	28.3% 13	More frequent than general population
Prolonged QRS	4.9% 13	More frequent than general population
Prolonged QTc	3.7% 13	More frequent than general population
Intraventricular conduction delay	3.4% 13	More frequent than general population
Right bundle branch block	1.3% 13	More frequent than general population
Lower heart rate variability (HRV)	11.1% 17	More frequent than control
Abnormal orthostatic BP	5.6% 17	More frequent than control
Nocturnal non‐dipper	86.7% of early HD, 47.8% of pre‐manifest HD 18	More frequent than control
Respiratory
Central or upper airway obstruction on pulmonary function test	40% of pre‐manifest and 55.3% of manifest HD 19	More frequent than control
Gastro‐intestinal
Swallowing/ choking	32.4–71% 6 , 20	More frequent than control
Dysphagia	35% 6	More frequent than control
Sialorrhea	32% 6	More frequent than control
Abnormal swallowing capacity (timed swallowing of 150 ml of water)	84.8% 19	More frequent than control
Dysphagia on FEES	35% of early‐stage 94% of moderate‐stage 100% of advanced‐stage HD. 21	Uncontrolled
Silent aspiration on FEES	7.7% of early‐stage	Uncontrolled
	11.8% of moderate‐stage
	27.8% of advanced‐stage HD. 21
	70.6% 22	Uncontrolled
Esophagitis	32.4% 17	Uncontrolled, EGD study
Gastritis	33.8% 17	Uncontrolled, EGD study
Constipation	27–43.7% 23 , 24	More frequent than control
Chronic diarrhea	25% 23	Uncontrolled
Fecal incontinence	16%–18.7% 6 , 23	More frequent than control
Defecation urgency	28% 24	Uncontrolled
Urinary
Any urinary symptom	87.5% 23	Uncontrolled
Urinary incontinence	29%–70.8% 6 , 7 , 23	More frequent than control
Urinary frequency	62.5% 23	Uncontrolled
Urinary urgency	44%–58.3% 6 , 7 , 23	More frequent than control
Impaired bladder emptying	25% men–40% women 7	Not more frequent than control
Nocturia	52.1% 23	Uncontrolled
Sexual
Any sexual symptom	75% F, 85% M 25	More frequent than control
Hypoactive SD	53–83% 26	Compounded numbers
Hyperactive SD	6–30% 26	Compounded numbers
Erectile dysfunction	48–69% 6 , 8 , 25	More frequent than control. SD with the highest difference between HD patients and control groups 25
Ejaculatory problems	30–65% 6 , 8 , 25	Conflicting results regarding relative frequency compared to controls
Vaginal lubrication	53%, 6 83% 9	Conflicting results regarding relative frequency compared to controls
Sexual aversion	15% M, 25% F 25	More frequent than control in M only
Decreased or lack of sexual enjoyment	74% M 8	More frequent than control
Failure in arousal	33–91% 9 , 25	More frequent than control
Dyspareunia	33–61% 9 , 25	More frequent than control
Orgasmic dysfunction in women	42–78% 6 , 9 , 14	As or more frequent than control
Paraphilia	19% M, 8% F 25	More frequent than control
Thermoregulatory and sweating
Abnormal sympathetic skin response	16.7% 27	More frequent than control
Hyperhidrosis during the day	37% 6	As frequent as controls
Hyperhidrosis during the night	41% 6	As frequent as controls
Heat intolerance	44% 6	As frequent as controls
Cold intolerance	38% 6	As frequent as controls

Abbreviations: BP, blood pressure; EGD, esophagogastroduodenoscopy; FEES, fiberoptic endoscopic evaluation of swallowing; HD, Huntington's disease; SD, sexual dysfunction.

One study, which included 18 early and middle stage HD patients and 60 matched controls, reported overall lower heart rate variability (HRV) in the HD group with an inverse correlation between cardiovagal activity modulation and severity of HD symptoms as assessed by the UHDRS ¹⁷ (Table 1). HRV is considered an indication of cardiovascular health, and low variability has been proposed as a predictor for cardiovascular disease and mortality. ²⁸ Decreased HRV in HD has been attributed to hyperactivity of the sympathetic system, which may occur early in the course of the disease. ²⁹

Vascular and Blood Pressure Abnormalities

HD patients often complain of dizziness and lightheadedness upon standing, suggesting baroreceptor dysregulation resulting in orthostatic hypotension. ⁶ , ³⁰ Studies on animal models of HD reported a dramatically blunted response in heart rate to transient hypotension induced by different medications, suggesting that both the sympathetic and parasympathetic arms of the baroreceptor reflex are affected. ²⁹ , ³¹ , ³²

In one study evaluating 63 patients with HD, 21 pre‐manifest mutation carriers, and 85 controls using the Parkinson's disease‐autonomic symptoms scale (SCOPA‐AUT), pre‐manifest mutation carriers experienced significantly more lightheadedness on standing up compared with controls. ⁶ Lightheadedness after standing for some time (16 vs. 3 P < 0.05) but not when standing up (33 vs. 17, P = 0.123) was also more frequent in HD patients than controls.

Nocturnal dipping of blood pressure is part of the normal circadian pattern, and its absence is associated with more severe end‐organ damage and increased risk of cardiovascular events. ¹⁶ A higher frequency of “non‐dipper” blood pressure has been reported in HD patients ¹⁸ (Table 1). Non‐dipping was significantly associated with increased thickness of carotid intima as well as poor quality of sleep in patients but not in controls. ¹⁸

There is also increasing evidence that the cerebral vasculature is affected in HD. ³³ , ³⁴ , ³⁵ Furthermore, the detrimental effect of uncontrolled hypertension in HD may occur as a result of a loading effect of hypertension‐induced cerebrovascular pathology on a weakened vascular system with increased arterial stiffness and decreased carotid compliance in the presymptomatic and early HD stages. ³⁶ However, one study showed no difference regarding the frequency of carotid plaques between HD patients and controls. ³⁶

One study from a European cohort of 630 HD patients suggested that the presence of hypertension (HTN) could delay the onset of motor HD by 5–8 years compared to normotensive patients when CAG repeats were between 40 and 44. ³⁷ However, this study did not account for the fact that the prevalence of HTN increases with age. Another study involving 3020 premanifest HD subjects from the Enroll HD database controlled for this cofounder, and reported an increased annualized hazard of motor conversion in hypertensive compared to normotensive premanifest HD patients (hazard ratio, 1.29; 95% confidence interval, 1.02–1.64; P = 0.034). ³⁸ Finally, using longitudinal observational data from the Enroll‐HD database (n = 14,534), another study suggested that the use of antihypertensives, rather that the presence of hypertension, was associated with delayed onset of the disease. ³⁹ As there was no difference between the various antihypertensive classes of drugs used, the delayed onset age and reduced motor impairment observed in the HD patients treated with anti‐hypertensives was possibly driven by a reduction in high blood pressure rather than by another direct effect from the drugs. Importantly, these results did not allow inference about causality, and no blood pressure measurement values are available in the Enroll‐HD database.

Myocadiac Abnormalities

Studies of animal models of HD found clear evidence for reduced contractility and cardiac output. ³² , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ There is, however, limited data, including ultrasonographic studies, on heart function in HD patients. ²⁹

Pathophysiology and Management of Cardiovascular Disorders

The sympathetic nervous system appears to be hyperactive very early in the progression of HD, ³⁰ as suggested by an elevated resting heart rate, blood pressure, and core body temperature. ¹⁰ , ⁴⁶ As the disease advances, the parasympathetic activity progressively decreases as well, ⁴⁷ , ⁴⁸ as suggested by the decrease in HRV and impaired heart rate recovery. ⁴⁹ This increased cardiac sympathetic activity without opposing increase in parasympathetic vagal activity could play a role in the genesis of sudden cardiac death from arrythmia in patients with HD. ⁵⁰ In addition, reduced parasympathetic HRV was associated with an increased risk of falls. ⁵¹

The mechanism of cardiovascular dysfunction in HD is not clear. It has been hypothesized to be secondary to peripheral changes by some, while other suggest it is centrally mediated.

These symptoms could, at least in theory, be linked to mutated HTT (mHTT) expression in peripheral organs. ⁵² , ⁵³ Indeed, mHTT has been detected in many peripheral organs in animal models, including the heart, liver, pancreas and kidneys. ⁵⁴ However, more recent studies could not identify mutated Htt in the diseased heart of mice HD models with symptomatic cardiomyopathy. ⁵⁵ Thus, while there may be direct effects of mHTT on the heart, ⁵⁶ removing mHTT protein from the heart is not sufficient to rescue cardiac function. ²⁹

The cortical autonomic network (CAN) is a network of brain regions consisting of the anterior insula (AI), anterior cingulate cortex (ACC), supramarginal gyri (SMG), the rostral prefrontal cortex (RPFC), along with the hypothalamus and autonomic nuclei in the brainstem ⁵⁷ , ⁵⁸ , ⁵⁹ that seems to directly control cardiac autonomic regulation. ⁶⁰ These regions may be impacted by neurodegeneration very early in HD. ¹⁰ , ⁶¹ , ⁶² Moreover, one small cross‐sectional study reported that cardiac sympathetic tone was altered in HD patients with preservation of the overall density of sympathetic nerve endings in the myocardium 123I‐metaiodobenzylguanidine (MIBG), suggesting that cardiovascular dysfunction was likely a consequence of dysfunction of the central nervous system. ⁶³ Small postmortem human studies have also shown evidence that HD alters the expression of peptides and neuromodulators as well as causes degeneration in the CAN. ⁶⁴ , ⁶⁵ , ⁶⁶ , ⁶⁷ Alternatively, neurodevelopment can be impacted by the presence of mHTT, ⁶⁸ , ⁶⁹ and abnormal development, rather than neurodegeneration, of brain regions within the CAN could explain the development of cardiovascular symptoms. The mechanism of cardiac failure remains largely unstudied in both clinical settings and experimental animal models of HD. Some authors believe heart abnormalities in HD may be secondary to CNS abnormalities because the cardiac dysfunction in HD animal models occurs much later than CNS dysfunction. ⁴⁵ , ⁵⁰ , ⁷⁰ However, there is evidence suggesting cardiac failure without neuronal involvement from cardiac‐specific expression of mHTT. ⁴⁵ , ⁵⁰ , ⁷⁰ , ⁷¹ , ⁷² Indeed, HTT is expressed strongly in the cardiac tissue, ⁵⁴ , ⁷³ , ⁷⁴ and cardiomyocyte destruction from mHTT accumulation has been reported in mouse and fly models of HD. ⁴¹ , ⁷⁵ , ⁷⁶ Overall, data from human subjects is limited, and no conclusions regarding HD‐related heart dysfunction in humans can be drawn at this time. ⁷⁷

Because of the reported increased frequency of prolonged QTc in HD, QT‐prolonging medications should be used with caution because of the risk of torsade de pointes and potentially fatal arrhythmias or sudden death. ⁵⁰ From a clinical perspective, however, routine evaluation with conventional ECG is not necessary in patients with HD and no specific cardiovascular treatment guidelines have been developed. Finally, some authors suggest that the absence of steady heart rate during low‐intensity exercise requires modification of exercise prescription for patients with HD, possibly involving submaximal intensity. ⁴⁹ , ⁷⁸

Respiratory Disorders

While aspiration pneumonia was identified as the main cause of death in 86.8% of 224 HD patients, ⁷⁹ two controlled studies including 18 and 67 HD subjects, respectively, ¹⁹ , ⁸⁰ found decrease in pulmonary function associated with the severity of motor abnormalities. The larger study further reported decreased respiratory function in the manifest group compared to healthy controls and pre‐manifest groups, but no differences between healthy controls and pre‐manifest subjects ¹⁹ (Table 1). Polysomnographically confirmed obstructive sleep apnea was also reported in HD. ⁸¹

Multiple mechanisms have been advanced to explain respiratory dysfunction in HD. Data supports reduced respiratory muscles strength and lung volumes, ⁸⁰ with influence from posture, physical activity and exercise capacity. ¹⁹ Furthermore, these changes seem to start early, with one study reporting upper airway changes in 40% premanifest HD subjects and cough effectiveness reduced in the mid stage of the disease. ¹⁹ Other authors have also suggested the role of irregular breathing patterns secondary to dysregulation within the respiratory center. ⁸² Respiratory muscles can also be affected by chorea earlier in the disease, ⁸³ and by akinesia and rigidity later on. ⁸¹ , ⁸³ Akinesia and rigidity might be more impactful on these muscles, as most HD patients do not report respiratory symptoms until later stages of the disease. Alternatively, pulmonary function disturbances might go unnoticed early in the disease as HD patients tend to adopt a sedentary life style, with limited physical activity in which impairment of pulmonary function would not be evident. ⁸⁰

Formal guidelines regarding monitoring respiratory function in HD are lacking. ⁸⁴ If pulmonary function is impaired, specific interventions such as regular breathing exercises, ¹⁹ respiratory muscle training, manually assisted coughing, or mechanical cough assistance to prevent aspiration pneumonia have been recommended. ⁸⁰ While a home‐based respiratory muscle training program might improve pulmonary function in manifest HD patients, it does not seem to improve dyspnea and exercise capacity. ⁸⁵ Further studies are needed to identify the appropriate exercises and other interventional strategies. Regarding aspiration, it can be prevented by swallow precautions and ultimately by the placement of a Percutaneous Endoscopic Gastrostomy (PEG). If obstructive apnea is present, the use of continuous positive airway pressure (CPAP) can result not only in meaningful improvement in sleep structure and nocturnal respiration, but also in daytime alertness and subjective memory. ⁸¹

Gastrointestinal Disorders

Dysphagia

Dysphagia has been reported more frequently in HD patients than in controls ⁸⁶ (Table 1), and is a leading cause of hospitalization in HD. ⁸⁷ A strong correlation was also observed between disease progression and dysphagia severity on fiberoptic endoscopic evaluation of swallowing. ²¹

Difficulty with deglutition have been reported in all phases of swallowing. ⁸⁸ , ⁸⁹ Dysphagia in HD is likely multifactorial including motor and cognitive components. Motor components include disrupted force, amplitude, and timing of the swallowing and esophageal muscles, leading to inefficient muscle contractions and failing to move food in the rostro‐caudal direction, ²⁰ , ⁸⁸ , ⁹⁰ in addition to continued respiration during the pro‐esophageal stages of swallowing. ⁹¹ Additionally, hyperkinetic tongue movements of HD can cause loss of bolus propulsion to the pharynx. ²⁰ , ⁸⁸ Cognitive impairment can also lead to eating and swallowing risky behaviors, such as food cramming or phonation while swallowing, worsening the issue. ²⁰ , ⁸⁸

The management of dysphagia in HD includes timely intervention by speech‐language pathologists to improve swallowing. ⁸⁹ , ⁹² Therapeutic interventions in mid‐ to late stages of HD can also include modifying texture, temperature and consistencies of food, and using adaptive feeding equipment. ⁸⁹ For severe swallowing disorders impacting nutrition and quality of life, the use of a PEG may be considered and should be discussed on a case‐by‐case basis with the patient and the caregivers. ⁸⁴

Esophago‐Gastritis

Esophagitis (32.4%) and gastritis (33.8%) were described in one retrospective cohort study of 68 HD patients who underwent esophagogastroduodenoscopies, ⁹³ with only 29.4% of the patients reporting gastrointestinal pain or acid reflux. This abnormality was attributed to an increase in the cell density of pepsinogen‐producing chief cells of the fundus of HD patients, ⁵² or loss of enteric neurons resulting in delayed gastric emptying. Routine upper GI endoscopy, however, is not recommended in patients with HD. ⁹¹

Weight Loss and Malabsorption

Weight loss in HD is almost universal and occurs despite adequate intake of calories, in individuals with increased appetite, hyperphagia and even in those on a diet high in fat and caloric content. ⁹¹ Although chorea may play a small role, weight loss occurs independently of chorea or other HD‐related hyperkinetic movement disorder. ⁹¹ This suggests that weight loss is an inherent symptom of HD rather than solely the result of unmet increased caloric demand from the hyperkinetic disorder. In addition, patients with HD with a higher BMI at onset of symptoms seemed to have a slower rate of disease progression in a small study with 42 patients. ⁹⁴ HD mouse models excreted a higher percentage of food consumed suggesting malabsorption of nutrients along the GI tract. ⁹⁵ While malabsorption is correlated with weight loss, it occurred after weight loss had already begun, ⁹⁵ suggesting malabsorption was not the only cause of weight loss. Whether malabsorption is also present in human HD patients needs to be further investigated.

Theories to explain weight loss in HD include disturbances in energy metabolism, malabsorption, disruption of microbiome, increased energy requirement because of chorea as well as lack of nutrition due to dysphagia. ⁹¹ Centrally, the impact of HD on thalamus, hypothalamus, and the hypothalamic–pituitary–adrenal axis has been implicated, affecting food intake and metabolism. Peripheral abnormalities in the GI wall are sometimes present prior to central abnormalities ⁹⁶ but studies have not been able to directly link these peripheral abnormalities to changes in the brain. ⁹⁷ GI anatomical abnormalities reported in HD mouse models include decreased villus length, reduced mucosal thickness, loss of neuropeptides stimulating as well as inhibiting gut motility as well as decreased ghrelin, which role is to stimulate food intake and decrease energy expenditure. ⁹⁵ Finally, expression of fat storage genes, leptin and adiponectin, is impaired because of mutant HTT expression, leading to loss of intracellular lipid stores and decline in the systemic levels of lipids and carbohydrates in animal models, which could contribute to weight loss as well. ⁹¹ In conclusion, weight loss and malabsorption in HD are likely the result of multifactorial pathophysiological processes.

Weight should be closely monitored as unintended and rapid weight loss is common in HD, even with adequate caloric intake, and may lead to cachexia and its systemic and immune consequences. ²⁰ A higher caloric intake has been shown to stabilize body weight in HD, ⁹⁸ and ketogenic diet delays reduction of weight loss in mouse models. ⁹⁹ However, whether gaining weight or increasing BMI can slow the progression of disease has yet to be established. Expert opinions suggest medical and/or social intervention in case of unintended weight loss (more than 10% in 3–6 months, or more than 5% if BMI < 20 kg/m²). ⁸⁴ Most recent therapeutic guidelines in HD ⁸⁴ recommend early assessment by a dietitian or nutritionist, and regular timely reviews of nutritional needs. Alternative causes of weight loss (dysphagia, cognitive decline, psychiatric symptoms) should be assessed for and treated. ⁸⁴ Finally, if antidepressants are needed, favoring the use of weight gaining agent is suggested. ¹⁰⁰

Lower Bowel Symptoms

Lower bowel symptoms are frequent in HD (Table 1) and increase in prevalence with increasing stage of the disease. ⁶ , ²³ Constipation is one of the most common systemic symptoms among patients with HD, ¹⁰¹ increased with disease progression and could be at least partly explained by decreased mobility in the advanced disease. ²⁴ On the other hand, fecal incontinence has also been reported, with two prevalence peaks: the first early in the disease, and probably a consequence of fecal urgency that might outline progressive deregulation between cortical and brainstem autonomic centers; the second, later in the disease, attributed to decreased mobility. ²⁴

Anorectal manometry, ²⁴ anal sphincter EMG and sacral reflex studies ⁷ , ¹⁰² in HD patients with bladder or bowel symptoms suggest a central dysregulation, probably involving basal ganglia and frontal lobes, as the etiology of lower bowel symptoms. There are no available recommendations for the management of lower bowel symptoms in HD patients.

Urinary Disorders

Urinary disorders are frequent in HD (Table 1) with increasing prevalence from early to late disease. ²³ Cytometry was performed in 12 HD patients and demonstrated detrusor‐sphincter dyssynergia in 5 (42%), detrusor overactivity in 2 (17%), and reduced detrusor capacity in 2 (17%). ⁷ Urinary dysfunction was correlated with decrease motor functioning and disease progression, suggesting a central etiology to the symptoms. ⁷ On the other hand, a study of 6 HD patents with urological complaints (5 females) reported detrusor hyperreflexia with a normal sphincter in 4 and a normal urodynamic study in 2. The authors described choreiform contractions of the abdominal perineal floor muscles during filling with selective suppression of choreiform contractions in the perineum during detrusor contraction, suggesting that the urinary complaints might be secondary to the local effect of chorea. ¹⁰³

Antipsychotics and antidepressants constitute the mainstay of pharmacological treatment of HD, but they may impair bladder function. ¹⁰⁴ However, in one uncontrolled cross‐sectional study evaluating 48 HD patients with a self‐reported questionnaire, ²³ nine of 10 subjects on no medications reported at least one pelvic organ system problem (urinary, genital or distal bowel), suggesting that medications were not the main cause of the dysfunction.

Most recent HD treatment guidelines recommend first ruling out bladder infection and/or prostate disease before using pharmacotherapy. ⁸⁴ Carbamazepine could be beneficial for episodes of complete and sudden bladder emptying without urge, and hyperactive bladder could be managed with antimuscarinics, with a careful consideration of the benefit/side effects ratio in this patient population. ⁸⁴

Sexual Disorders

Sexual disorders affect up to 85% of males and 75% of females with HD, ²⁵ and sexual activity declines severely with disease progression ²³ (Table 1). One cross‐sectional study including 156 HD subjects and 233 controls reported that SD had the highest life impact among 216 HD‐related symptoms. ¹⁰⁵

It is unclear whether SD is directly caused by HD pathophysiology or whether it is merely a byproduct of HD symptoms, such as chorea and depression, and/or their treatments. Indeed, depression is prevalent in HD ⁵ and is directly related to erectile/ejaculatory problems. ⁶ Depression can also be caused or worsened by dopamine depleting agents used to treat HD chorea. ²⁶ In addition, antidepressants, neuroleptics and benzodiazepine can also cause sexual dysfunction. ²⁶ On the other hand, there is no significant correlation between the international index of erectile function score and the number of CAG repeats in men, ⁸ , ⁹ but a positive correlation between the number of triplets and sexual desire in women. ⁸ , ⁹ Data suggests that sexual dysfunction is correlated with decreased functional capacity measured using TFC and TMS, ⁸ , ⁹ rather than disease duration. This could suggest that sexual dysfunction could be caused by dysfunctions in the hypothalamus or in the brainstem and spinal cord. ²⁶ In one uncontrolled cross‐sectional study evaluating 48 HD patients with a self‐reported questionnaire, ²³ 39% reported concomitant symptoms in all pelvic organ systems (genital, urinary and distal bowel), suggesting the central pathophysiology of HD as a possible etiology. Indeed, multiple aspects of male sexual functioning are influenced by brain regions which are known to be disrupted in HD, ¹⁰⁶ as reported in various neuro‐imaging studies. ²³ , ¹⁰⁷ , ¹⁰⁸ , ¹⁰⁹ Motor and cognitive aspects of HD, including difficulty with maintaining attention and concentration, may interfere in the ability to achieve orgasm. ²⁵ Hyposexuality in male could also be secondary to lower testosterone levels in HD, although a correlation between the two was not established. ²⁶

Most recent treatment guidelines recommend treating iatrogenic decreased libido with lower dose or alternative HD treatment, referring to an endocrinologist and psychosexual specialist in case of ED, in addition to considering symptomatic treatment such as phosphodiesterase 5 inhibitors. ⁸⁴ A psychological approach is recommended for hypersexual behavior, with the addition of neuroleptics and/or SSRI when associated with violence or social discomfort, and referral to endocrinologist or sexologist ⁸⁴ for antiandrogen treatment. In case of severe hypersexual behavior, referral to a psychiatrist is recommended. ⁸⁴

Thermoregulatory and Sweating Disorders

There is very limited data regarding thermoregulatory and sweating disorders in HD (Table 1). Hypothermia has been reported in HD animal models ¹¹⁰ and in one patient in late‐stage HD. ¹¹¹

Thermoregulatory disorders in HD could be secondary to the involvement of the brown adipose tissue, skeletal muscle, or hypothalamus. ¹¹² Brown adipose tissue has blunted heat production response of the mitochondrial uncoupling protein UCP1 to cold stimuli ¹¹³ in mouse models of HD. PGC‐1α, which mediates the expression of UCP1 and plays a role in adaptive thermogenesis, is also impaired in animal and human HD muscles biopsies. ¹¹⁴ Additionally, the ATP/ADP ratio is decreased in HD patients’ skeletal muscle as compared to controls, ¹¹⁰ with decreased muscle force and altered neuromuscular junction integrity in animal models, ¹¹⁵ , ¹¹⁶ suggesting that dysfunctional motor units might also decrease the shivering response to cold. On the other hand, loss of oxytocin and vasopressin, both of which are implicated in thermoregulation, ¹¹⁷ has been reported in post mortem HD hypothalamic tissue, ⁶⁴ with oxytocin and vasopressin loss even reported in a postmortem case study of an HD gene carrier who presented with mainly nonmotor features and where neuropathologic analysis did not reveal any striatal pathology, ¹¹⁸ suggesting an early involvement of the thermoregulatory pathway. Finally, downregulation of UCP1 and PGC‐1α in BAT in mice models was reported with a targeted expression of mutant huntingtin only in the hypothalamus, ¹¹⁹ suggesting a central role of the autonomic nervous system in the pathophysiology of hypothermia.

Discussion

Our systematic review of the literature provides evidence that systemic symptoms are frequent in patients with HD, and clearly adversely impact their quality of life. ²⁴ This highlights the view that HD is not only a neuropsychiatric disease but a systemic disorder affecting to a variable degree almost every organ.

This review has some limitations. It attempts to cover a broad topic, which might have limited the detailed coverage of all published studies. However, the intent was to synthetize the available knowledge, rather than to simply report it. Another limitation was related to the quality of the data available in the literature. Indeed, most published studies are small, use different questionnaires to assess the same symptoms, with many using non validated questionnaires, and less than half the studies using an appropriate control group. This is particularly true for sexual dysfunction, with many studies reporting that patients left blank questionnaires concerning sexual functions or marked them as “not applicable”, ⁶ , ⁹ , ¹²⁰ witnessing to the social taboo regarding sex or discussion of sex. SD are also likely to be underreported as patients with HD often are not aware of their symptoms (anosognosia), may deny their symptoms, or simply be passive and apathetic about their condition. ¹²¹ , ¹²² Additionally, a verbal assessment of sexual or urinary function, sweating or other autonomic symptoms in clinic can be awkward or uncomfortable for patients and their partners, leading to underreporting. Recent treatment guidelines did not address all the AS presented here, and almost all recommendations were assigned Grade C (low‐level of scientific proof), testifying to the paucity of well‐designed studies evaluating specific treatments for these symptoms ⁸⁴ (Fig. 2).

Figure 2.

Summary of available treatment recommendation by organ system. CPAP, continuous positive airway pressure; ED, erectile dysfunction; OSA, obstructive sleep apnea; PEG, percutanous endoscopic gastrostomy; SSRI, selective serotonin reuptake inhibitor.

However, our review has many strengths, including a comprehensive search for evidence, a criterion‐based selection of relevant evidence, and an objective quantitative summary. This review confirmed a high prevalence and wide range of AS. While some could argue that these symptoms are just comorbid conditions, we presented the relative frequency of each compared to the general population in our table, and show that the majority is reported more frequently in HD patients than controls. In addition, we identified the following shortcomings in the current state of the literature, that will need to be addressed in the future: (1) the heterogeneity in the methodology of the published studies makes it difficult to determine the exact prevalence, severity, and progression of AS; (2) the pathophysiology of each symptom is still largely understudied; (3) a marked proportion of published studies rely on patient reported outcomes rather than validated instruments, which can introduce significant bias depending on how the questions were formulated; (4) studies assessing specific treatments for these symptoms and their impact of quality of life are lacking.

Conclusion

Although HD is usually thought of as a triad of motor, cognitive, and psychiatric symptoms, the purpose of this review is to draw attention to the systemic nature of HD, and particularly to the involvement of the autonomic system in this disorder. To our knowledge, this is the first comprehensive review addressing all systemic and autonomic symptoms in HD. We hope that clinicians caring for HD patients will be able to recognize and address various systemic autonomic symptoms associated with HD, and that bringing attention to these symptoms will galvanize interest in their contribution to the clinical burden of HD, as well as their potential contribution to understanding the pathophysiology of this disease.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

R.M.: 1A, 1B, 1C, 3A

J.J.: 3B

Disclosures

Ethical Compliance Statement: This article being a review of the literature, no patient data was collected. As such, informed consent was not obtained and IRB approval was not sought. The authors confirm that they have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: No specific funding was received for this work, and the authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for Previous 12 Months: R.M. is on the speaker bureau for TEVA and Kyowa Kirin. He has received research grants from Global Kinetic Corporation, Neurocrine, and Cerevel. J.J. has received research or training grants from AbbVie Inc; CHDI Foundation; Dystonia Coalition; Medtronic Neuromodulation; Merz Pharmaceuticals; Michael J. Fox Foundation for Parkinson Research; National Institutes of Health; Parkinson's Foundation; Revance Therapeutics, Inc; Teva Pharmaceutical Industries Ltd. He has served as a consultant for AbbVie Inc; Eon BioPharma; Neurocrine; Revance Therapeutics; Teva Pharmaceutical Industries Ltd. He has received royalties from Cambridge; Elsevier; Medlink: Neurology; Lippincott Williams and Wilkins; UpToDate; Wiley‐Blackwell. He has served on the following editorial boards: Expert Review of Neurotherapeutics; Medlink; Neurology in Clinical Practice; Therapeutic Advances in Neurological Disorders; Neurotherapeutics; Toxins; Tremor and Other Hyperkinetic Movements; Journal of Parkinson's Disease. J.J. does not participate in Speaker's bureaus.