GRAPHICAL ABSTRACT

INTRODUCTION

The Korean Huntington’s Disease Society (KHDS) published a practical guide for the clinical treatment of patients with Huntington’s disease (HD) in Korea in the April issue of the Journal of Movement Disorders in 2024 [1]. This article is the second practical guide, particularly focused on essential points of genetic counseling for families of HD patients covering issues of testing minors and prenatal/preimplantation testing, and premanifest HD and useful laboratory investigations for assessing disease severity and progression. The latter part of this article addresses special issues of juvenile and very late-onset HD and common comorbidities in HD patients. Finally, the management principles of HD patients are briefly explained. The contents were drafted by the guideline task force members of the KHDS. We intended to include published literature containing data from Korea in this paper. We believe that this article will serve as a pocket guide for physicians as well as movement disorder specialists in Korea in planning diagnostic work-ups for and managing HD patients and their families.

GENETICS AND GENETIC COUNSELING OF HD PATIENTS AND FAMILIES

Genetics of HD

General characteristics

HD is an autosomal dominant condition resulting from a mutation in the huntingtin (HTT) gene on chromosome 4. The HTT gene encodes the HTT protein, which is essential for nerve function. While the precise role of HTT is not fully understood, it is implicated in cellular transport, particularly in the brain, and in the development and function of nerve cells [2].

CAG repeat number and pathogenesis

The HTT gene contains CAG repeat sequences that encode the amino acid glutamine. When the number of CAG repeats is significantly increased, an abnormal HTT protein that is toxic to brain nerve cells is produced, causing nerve cell death and resulting in HD symptoms [3]. Traditionally, alleles with up to 26 repeats are considered within the normal range, whereas those with 27–35 repeats are classified as “intermediate” alleles. Intermediate alleles are generally nonpathogenic but can expand into the disease-causing range during germline transmission, potentially resulting in HD in offspring. In rare cases, individuals with intermediate alleles also develop late-onset HD (LoHD).

CAG repeat lengths of 36 or more are associated with HD [4]. The severity of the disease correlates with the number of repeats, with juvenile-onset HD (JHD) typically occurring at very high repeat counts (often above 60 and up to 140) [5,6]. Incomplete penetrance can occur in the 36–39 repeat range, meaning that not all carriers may manifest clinical symptoms (Figure 1) [7]. This can potentially be influenced by genetic modifiers such as MSH3 and FAN1 [8], as well as environmental factors and lifestyle choices, including physical activity and cognitive engagement [9].

Onset age prediction by CAG repeat length

CAG repeat length is inversely correlated with the age of onset [10]. Statistical models offer reasonably accurate predictions, particularly for subjects with a CAG length of 43–46.5 The Langbehn et al. [10] prediction model [mean age of diagnosis=21.54+exp (9.556–0.1460CAG)] showed reasonable accuracy when tested with the prospective diagnostic data of the PREDICT-HD longitudinal study. The model’s predictions exhibited an average error (expressed as the standard deviation of the difference between the predicted and observed onset ages) of approximately 6–7 years, with notably lower deviations observed in individuals whose CAG repeat lengths fell between 42 and 50.

To illustrate the application of this formula, for a patient with a CAG repeat length of 44, the predicted mean age of onset is approximately 44.46 years based on the model of Langbehn et al. [10]

21.54+e(9.556−0.1460×44)=21.54+e3.132≒21.54+22.92≒44.46.

Genetic counseling

Cascade screening

Although disease-modifying therapies for HD are unavailable, genetic diagnosis facilitates cascade screening and provides access to reproductive options, such as prenatal diagnosis and preimplantation genetic testing (PGT), enabling the primary prevention of HD. Therefore, we recommend genetic testing for individuals at risk of HD when informed consent is obtained.

Cascade screening involves testing family members for the mutated gene in autosomal dominant diseases such as HD [11]. Given that the typical age of HD diagnosis is approximately 40–50 years, many HD patients have children who are already married or are planning to marry and have children. Therefore, cascade screening is highly valuable for offspring of HD patients [12]. In-depth genetic counseling should precede cascade screening, providing information on the genetic basis of HD and the risks and benefits of genetic testing [13]. Given the absence of current disease-modifying treatments, providing substantial information is crucial for family members to make informed decisions about testing (Figure 1) [11].

Predictive testing in asymptomatic individuals

Predictive testing for asymptomatic individuals has significant psychological and social consequences, impacting decisions about marriage and reproduction [14]. Therefore, it is particularly important to carefully consider the potential psychological and social implications of predictive testing.

Testing minors

Testing minors raises ethical concerns due to their limited capacity to comprehend the associated risks and benefits [15]. Being diagnosed as a carrier of HD during childhood can be challenging for both the child and their family, leading to difficulties in socialization, schooling, and daily life. Emotions such as sadness, anger, fear, and anxiety may arise [12]. Therefore, delaying predictive testing until adulthood is generally advisable unless symptoms are present.

Prenatal testing and PGT

In Korea, genetic testing of fetuses or embryos is legally allowed for specific rare diseases, including HD. Another important issue in genetic counseling for HD is the option of prenatal testing and abortion [16]. Prenatal testing can identify HD risk in a fetus, but it prompts ethical concerns regarding selective abortion [17]. Medical geneticists must inform patients about reproductive options and offer unbiased, nonjudgmental support.

PGT identifies genetic conditions in embryos created through in vitro fertilization before they are implanted into the uterus [18]. The procedure involves performing an embryonic biopsy, where a small number of cells are carefully removed from the embryo at the blastocyst stage without compromising its potential for development. These cells are then genetically analyzed to detect specific mutations [19]. If the mutated HTT gene is present, the embryo can be discarded, allowing carriers or those at risk of HD to have unaffected children. PGT is a highly specialized and complex procedure and is therefore performed only by a few expert medical centers in Korea. Those considering PGT for HD should consult with a medical geneticist and a reproductive specialist to assess its appropriateness and comprehend potential risks and benefits.

Therefore, genetic counseling is pivotal in assisting individuals and families affected by HD in navigating the complex medical, psychological, and social aspects of this condition. Medical geneticists must stay informed about the latest HD research and provide unbiased, supportive care to those affected by the disease.

PREMANIFEST HD

Stages of HD

The stages of HD include HD at risk, HD carrier, HD prodrome, and diagnosed HD (manifest HD) [20]. HD at risk denotes individuals with a parent having confirmed HD but not yet tested, carrying a 50% risk for HD. HD carriers are those with a CAG repeat expansion of 36 or more, as determined by a predictive genetic test.

The premanifest period comprises the presymptomatic and prodromal phases [21]. The presymptomatic phase precedes any symptoms, whereas the prodromal phase involves mild cognitive and behavioral symptoms and subtle motor signs before typical motor symptoms emerge. Increased access to genetic testing for HD has resulted in earlier diagnosis, allowing for a better understanding of initial HD pathology. Moreover, individuals in this subgroup are valuable candidates for the testing of new treatments.

Presymptomatic HD

Brain imaging studies

Striatal atrophy, a hallmark of HD, is detectable in the premanifest stage before motor symptoms [22]. Putaminal atrophy is prominent in presymptomatic HD patients (Table 1), with a significant reduction observed in subjects ≤6 years from estimated onset, distinguishing them from those ≥7 years from estimated onset and normal controls. Caudate atrophy, which appears slightly later than putaminal atrophy, is detectable in the premanifest stage and progresses concurrently with symptoms. In addition to the decrease in volume, the rate of decrease in striatal volume may be an important factor in progression [22]. Meanwhile, it is important to note that basal ganglia hypointensity on susceptibility-weighted imaging has been reported in some HD patients [23], which can be misdiagnosed as neurodegeneration with brain iron accumulation syndrome. However, there are no systematic data on susceptibility weighted image changes in presymptomatic HD, which requires further research.

Functional imaging studies

Reduced glucose metabolism in the bilateral striatum and cortex has been described in individuals as early as the presymptomatic stage [24]. F18-FDG-PET can reveal early striatal dysfunction in presymptomatic HD when structural imaging is normal [25]. Resting-state functional magnetic resonance (MR) images reveal aberrant brain connectivity, mainly in the sensory‒motor network, in presymptomatic HD patients [26].

Huntington’s disease Young Adult Study

The Huntington’s disease Young Adult Study analyzed a presymptomatic HD cohort approximately 24 years from predicted clinical onset and revealed reduced putamen volumes in presymptomatic HD patients, unrelated to the CAG repeat length [3]. The levels of biofluid markers, such as cerebrospinal fluid (CSF) mutant huntingtin (mHTT), neurofilament light (NfL), YKL-40 and plasma NfL, are elevated from very early periods, making these potential biomarkers for monitoring disease progression and the efficacy of disease-modifying therapy (Table 1).

Prodromal HD

The earliest prodromal stage occurs when any HD sign or symptom is noted [27] up to 15 years before typical motor manifestation onset [28]. While motor symptoms are crucial for HD diagnosis, cognitive and behavioral problems are the greatest burden on HD families and are most significantly associated with functional decline.

Cognitive changes

Mild cognitive impairment (MCI) is prevalent in HD carriers before diagnosis [29], with almost 40% of individuals in the PREDICT-HD study meeting the criteria for MCI in at least one cognitive domain [30]. Processing speed decline, the most common cognitive impairment in prodromal HD, is influenced by cognitive reserve, suggesting that those with greater prodromal intellect may experience less speed decrement [31]. Attention deficits, executive function decline, and learning/memory impairment are common in prodromal HD and pose challenges in daily life. Impairments in emotion recognition, time estimation, and smell identification may also appear in prodromal HD.

Behavioral changes

Behavioral and psychiatric symptoms are significant aspects of HD and often prompt medical attention. A range of neuro-psychiatric symptoms can appear from the prodromal stage of HD [32]. Neuropsychiatric symptoms during the prodromal stage vary widely, with reported incidences influenced by study populations, diverse definitions, and assessment tools.

Many HD gene carriers experience depression throughout the disease [33]. with peak prevalence during genetic testing and a midprodromal stage when subtle changes first become apparent [34]. Suicidality is a significant concern, with 19%–26% reporting current or historical attempts. The prevalence of anxiety in prodromal HD patients is 11%–17%, increasing as motor diagnosis approaches. Obsessive‒compulsive traits range from 15%–50% in prodromal HD. Apathetic symptoms, which are 15 times more common in HD patients than in control individuals, are reported in 59% of prodromal HD patients and 70% of clinically diagnosed patients. Neuropsychiatric symptoms vary among individuals, with the severity increasing closer to motor onset.

LABORATORY INVESTIGATION AND BIOMARKERS FOR HD

Genetic biomarkers

The number of CAG repeats in the HTT gene is a well-known diagnostic indicator of HD. In addition, various interacting genes, such as huntingtin-interacting proteins (HIPs) and huntingtinassociated protein-1 (HAP-1), play potential roles in the expression of HD.

HIPs can be grouped into proteins that are involved in gene transcription and proteins. They are linked to intracellular signaling, trafficking, endocytosis or metabolism. Interestingly, many HIPs bind to the N-terminal region of HTT (amino acids 1–588) with several proteins and modulate the toxic role of mutant N-terminal HTT. For example, 12 HIPs exhibited increased binding to mHTT, whereas the other five HIPs presented decreased binding to the mutant N-terminal HTT [35].

HAP-1, which is encoded by the HAP1 gene, also has a strong and polyQ-length-dependent interaction with polyQ-expanded HTT. This relationship is supported by the correlated expression of HAP-1 and HTT in both monkey and human brains, suggesting that abnormal protein–protein interactions contribute significantly to the selective neuronal pathology observed in HD [36].

Importantly, however, measuring HIP or HAP-1 levels is not currently feasible for prodromal HD screening because of insufficient sensitivity and specificity and a lack of correlation with pathological disease burden. Therefore, these markers should not be considered early diagnostic markers without further supporting evidence.

Clinical biomarkers

Quantitative motor evaluation and cognitive assessments are valuable tools for identifying clinical biomarkers of HD [37]. Grip force, tapping speed (Q-motor battery), and tongue force variability, which are measured quantitatively, show some range of differences in HD over 24 months. Cognitive function can be evaluated with Stroop word reading, symbol digit modalities, and circle tracing tasks. These tests are useful for monitoring longitudinal changes in HD over 24 months or more. Measurements of psychiatric symptoms yield variable results, and in particular, longitudinal changes were shown with apathy symptoms in HD patients.

Biofluid biomarkers

The most useful and well-evaluated fluid biomarker is the NfL protein [38,39]. The plasma NfL level is correlated with motor and cognitive deterioration in HD patients and the progression of brain atrophy. Moreover, the baseline plasma NfL level is associated with disease onset in individuals with premanifest HD [38]. Notably, plasma NfL levels are correlated with CSF NfL levels [40]. Therefore, a peripheral blood test may be sufficient to assess NfL levels in the central nervous system.

mHTT from blood-derived monocytes has recently been evaluated as a useful biomarker for HD. These levels are correlated with the disease burden and caudate atrophy observed in the brain magnetic resonance imaging (MRI) of patients with HD [39]. mHTT in the CSF is also correlated with the disease stage of HD, as well as motor and cognitive behavior in HD patients [41].

Single-nucleus RNA sequencing data from postmortem brain samples from HD patients and HD model mice (zQ175 and R6/2) revealed abnormal expression profiles in the HD group compared with the control group [42]. However, discrepancies exist among studies due to the use of different transcriptomic approaches. Meanwhile, CSF markers such as total tau, phosphorylated tau, and NfL are also linked to the disease stage of HD [37].

Imaging biomarkers

Volumetric changes in gray and white matter on brain MR images were evaluated in TRACK-HD patients at three time points over three years [21]. In the premanifest stage, volume loss of the striatal gray matter and white matter around the striatum, corpus callosum, and posterior corona radiata was observed. These volume losses are greater in the manifest stage of HD than in the premanifest stage. A recent DTI study revealed selectively vulnerable corticostriatal white matter connections in premanifest HD, whereas the microstructural changes extended to widespread loss of white matter connections in the manifest stage [43].

SPECIAL SUBGROUPS

Juvenile HD

JHD refers to HD with an onset age ≤20 years, although the term “pediatric HD” is also used for patients under 18 (Table 2) [44]. JHD constitutes 5%–10% of HD cases, with variable prevalence rates depending on the study design and population [45]. Patients with JHD often have ≥60 CAG repeats, and those with childhood onset tend to have longer repeats (≥100) [46]. Paternal transmission is predominant, especially in patients with earlier onset or greater number of CAG repeats, which is associated with stronger anticipation, rapid progression, and shorter survival than common-onset HD (CoHD) [46].

In addition to chorea, JHD patients present with various symptoms, including parkinsonism, dysarthria, dystonia, myoclonus, ataxia, developmental delay, and seizures [46,47]. Cognitive decline and psychiatric problems may predominate in JHD patients, leading to misdiagnosis or diagnostic delay. Sleep disturbances, pain, autonomic dysfunction, and reduced weight may also be present in individuals with JHD.

Brain MRI studies of JHD patients revealed a reduction in the volume of the striatum, globus pallidus, thalamus, and cerebral cortex [48]. Additionally, T1-Rho MRI, which reflects the macromolecular environment involving proteins, pH, and water content, demonstrated increased T1-Rho relaxation times in the striatum, globus pallidus, and thalamus [49]. Neurodegeneration is markedly accelerated in the striatum and thalamus [50], and clinical parameters such as CAG repeat length, disease duration, and the Unified Huntington’s Disease Rating Scale score are associated with radiologic findings [48,49]. Pathologic investigations revealed severe volume loss in the striatum, globus pallidus, thalamus, and cerebellum [47] and increased mHTT burden in the brains of JHD patients [47].

JHD has distinctive clinicopathologic features and requires different diagnostic and therapeutic approaches than CoHD does. Longitudinal observations as well as clinical trials targeting JHD are warranted in future studies.

Late-onset HD

LoHD occurs when symptoms manifest after 60 years of age and accounts for 4.4%–25.2% of HD cases [51,52]. A recent report from Korea revealed that patients with LoHD had a mean age of onset of 68.77±5.91 years and an average of 40.54±1 [53]. (range: 38–45) CAG repeats.53 These values were significantly lower than those of CoHD patients, who presented a mean age of onset of 44.12±8.61 years and an average of 43.47±4.14 (range: 38–65) CAG repeats. A European study reported similar results: the average age at onset was approximately 65–68 years, and the number of CAG repeats was approximately 40–41 in LoHD patients, which was lower than that reported in CoHD patients [51,52]. LoHD patients were more likely to deny a family history, possibly because of parental death before symptom onset or reduced penetrance. Moreover, individuals with 36–39 CAG repeats, potentially leading to reduced penetrance, constituted a greater proportion of LoHD than CoHD.

Clinically, motor symptoms are more common than are psychiatric or cognitive features in the early stage of LoHD [51,52]. Motor function, general cognitive function, and executive function were notably more impaired in LoHD patients than in CoHD patients or age-matched healthy controls [51,52]. Striatal glucose metabolism is reported to be reduced in LoHD patients, although only limited studies are available. LoHD patients may have slower motor progression, but their functional outcome or survival seems worse than that of CoHD patients [51,54]. Diagnosing LoHD can be challenging due to an atypical family history, emphasizing the importance of clinical suspicion and genetic testing for this subgroup.

Rare presentations

HD typically presents with chorea, cognitive decline, and psychiatric features. However, rare and distinctive clinical presentations have been reported, including isolated familial cervical dystonia, levodopa-responsive parkinsonism, or multiple tics without the typical triad of symptoms [55-57]. Unusual findings, such as hung-up knee jerks or head drops, have also been reported.

Sometimes, nonmotor symptoms outweigh motor symptoms [58]. For example, HD patients with apathy, delusions, hallucinations, and cognitive decline could be initially diagnosed with a behavioral variant of frontotemporal dementia [59,60]. Although rare, oculomotor apraxia and deafness have been described in HD patients as case reports [61,62].

The clinical features of HD can mask other medical conditions, such as oral infection or subdural hemorrhage, leading to delayed diagnoses and medical intervention. Conversely, a patient with human immunodeficiency virus (HIV) infection showed involuntary movement and cognitive decline, which was initially attributed to HIV encephalopathy, but later, HD was confirmed [63]. Additionally, individuals with HD with comorbid amyotrophic lateral sclerosis, multiple sclerosis, myasthenia gravis, or spinocerebellar ataxia 8 have also been reported.

COMORBIDITIES

Diabetes mellitus

Patients with HD often exhibit glucose intolerance and insulin abnormalities, with the insulin response correlated with the number of CAG repeats [64].A study conducted in the 1980s reported that the prevalence of diabetes mellitus (DM) was significantly greater in individuals with HD than in the general Caucasian population (84.3 per 1,000 vs. 19.9 per 1,000) [65]. Similarly, a Chinese study reported a 72.7% prevalence of DM in a fivegeneration HD family [66]. Additionally, those with premanifest HD and DM tend to progress to HD earlier (Table 3) [67].

Amylin, which is cosecreted with insulin to regulate glucose levels, was found to be diminished in individuals with both premanifest and manifest HD. Postmortem brain tissue analysis revealed altered glycolytic proteins in HD [68]. Experimental research using HD transgenic mouse models supports these clinical findings of impaired glucose tolerance; however, contradictory results exist.

The association between impaired glucose metabolism and HD suggests the potential of the repurposing of DM drugs to reverse or prevent HD progression [64]. Metformin, which is used in type 2 DM, has neuroprotective effects on HD. In Enroll-HD, metformin improves cognitive function, and in transgenic mouse models, it alleviates symptoms and prolongs survival [69]. Other antidiabetic drugs, such as rosiglitazone, exendin-4, pioglitazone, and liraglutide, also exhibit promising effects [70-74].

Hypertension

The Enroll-HD study reported a lower prevalence of hypertension in patients with HD than in controls (13.85% vs. 19.34%) [75]. Additionally, hypertension was associated with a delayed age of HD onset [75]. The REGISTRY project of the European Huntington’s Disease Network (EHDN) revealed that hypertension delays HD symptoms by 7–8 years [76]. According to the Enroll-HD study, hypertension was also associated with a delayed age of HD onset [75]. However, HD patients with hypertension experience worse cognitive function and faster motor progression [75,77]. These discrepancies among studies might be due to analytic methods or controlled variables. Antihypertensive agents may mitigate clinical manifestations and delay onset, suggesting a disease-modifying effect [75]. However, further studies are needed to understand the association between HD and hypertension.

Cardio- and neurovascular abnormalities

Cardiovascular events are a leading cause of death in HD patients [78]. Electrophysiological studies revealed cardiac conduction abnormalities, nondipping nighttime blood pressure, and increased carotid intima‒media thickness in HD patients [79-81]. Exercise tests indicate earlier elevation and delayed recovery of heart rate, as well as earlier increases in cerebral perfusion in HD patients, suggesting altered cardio- or neurovascular adaptation [82,83]. Postmortem analysis of HD brain tissue revealed an increased number of small vessels and disruption of the blood‒ brain barrier in the putamen [84]. Animal studies support direct mHTT involvement in vasculatures or related mitochondrial dysfunction, oxidative stress, protein misfolding, and cell death [84]. Overall, the vascular system is affected in HD and could be a potential treatment target.

Altered cholesterol metabolism

In manifest and premanifest patients with HD, total cholesterol and high-density and low-density lipoprotein-cholesterol levels are significantly lower than those in controls [85]. Cholesterol precursors such as lathosterol, lanosterol, and 24-hydroxycholesterol (24OHC) are notably reduced [86]. Postmortem HD brain tissue shows altered putaminal 24OHC and cholesterol levels [87]. Animal HD models exhibit disrupted cholesterol homeostasis, with lipid levels decreasing as the disease progresses. Statin use in the Enroll-HD study was linked to delayed manifest HD, suggesting that cholesterol metabolism is a therapeutic target [88].

Controversies about the risk of cancer

Controversies surround cancer risk in HD. European studies indicate lower overall cancer rates in HD patients despite common risk factors such as cigarette smoking or alcohol consumption [89,90]. The link between CAG repeat length and cancer risk is inconclusive [89,90]. HTT interacts with the tumor suppressor protein p53, suggesting a potential role in breast cancer prognosis [91,92]. However, the frequency of skin cancer was higher in HD patients in a French study, whereas the prevalence of lung cancer was comparable to that reported in the general population in a British study [89,93].

HD patients exhibit various comorbidities that impact the musculoskeletal, psychiatric, cardiovascular, neurological, and gastrointestinal systems. These comorbidities may have a shared pathophysiology with HD. Presymptomatic patients with HD also present higher rates of musculoskeletal and psychiatric disorders, suggesting that expanded CAG repeats play a role in their condition [94]. Liver function test abnormalities are relatively common in HD patients and are possibly influenced by medication or mHTT [95]. Addressing comorbidities is crucial for improving HD outcomes and understanding disease pathophysiology.

MANAGEMENT

Principles of management

The purpose of HD management is to reduce the severity of symptoms, maintain patient function, and focus on optimizing quality of life, since sufficiently effective disease-modifying treatments have not yet been developed [96]. However, in HD mouse models, environmental enrichment, physical exercise, and dietary intervention can ameliorate or mitigate several HD phenotypes. Additionally, in HD gene carriers, an active lifestyle has been reported to delay the age at onset and reduce the severity of symptoms [97]. Therefore, maintaining an optimal physical condition is crucial for HD gene carriers, and regular outpatient follow-up is essential for informing them about newly developed therapeutic options.

The symptoms of HD vary greatly among individuals and according to disease stage. Chorea is common in early-stage HD, but hypokinetic movement disorders such as parkinsonism and dystonia are more likely to occur in later stages. Therefore, the dose of medications should be adjusted according to the evolution of the symptoms. Patients should also be reminded that their symptoms may not follow the same course as those of their relatives do. In addition, HD patients in Korea are less likely to receive treatment for psychiatric symptoms in the early stage than are those in Western countries. Although the exact reasons have not been fully elucidated, this may be due to ethical differences or societal attitudes toward psychiatric illnesses. Therefore, these unique cultural and social factors in Korea should be considered when treating patients with HD.

Symptomatic treatment

It is important to perform personalized tailored treatment by combining medications for each symptom. It is typical to change medication according to the progression in symptoms of HD, and polypharmacy should be avoided. Another consideration is that the effects of some medications, such as antidepressants and neuroleptics, are not observed immediately and require several weeks. This should be explained to the patients for compliance. Occasionally, medications have drug interactions or even worsen the symptoms of patients, therefore sometimes, the reduction or cessation of medications may be considered depending on the symptoms of patients.

Table 4 summarizes the recommended medications for symptomatic treatment of patients with HD [96,98-105]. We recommend referring to a systematic review paper on the symptomatic treatment of HD in Korea that was conducted by the KHDS Task Force [106]. It is difficult to conduct a large-scale clinical trial in HD, so it may be difficult to treat patients if only medications with sufficient evidence are used. For example, there are no evident medications for cognitive dysfunction in HD [105]. However, clinicians may consider the use of acetylcholine esterase inhibitors or memantine for dementia in patients with HD. Therefore, for symptomatic treatment of HD, commonly used drugs for each symptom are also considered under clinical judgment.

Physical therapy

Physical therapy is a concept that starts with exercise and encompasses not only gait and balance training but also respiratory and palliative care as the disease progresses. Physical therapy should also be individualized according to the patient’s progression and condition. The Physiotherapy Working Group of the EHDN suggested 7 classifications of physiotherapy for HD [107,108] and presented the level of evidence as the content of recent systematic reviews [109,110].

Nutritional support

HD patients may develop swallowing difficulty, and weight loss is a critical problem. Furthermore, unintended weight loss is common in HD patients, and lower body weight is associated with more severe functional, motor, and cognitive deterioration [111]. Therefore, providing good nutritional support is fundamental to the treatment of patients with HD. EHDN published a clinical guideline in 2012, which is the only guideline for nutritional management of HD patients to date [112]. In this guideline, recommended standards for nutritional support for each HD stage were presented [112].

If the patient’s swallowing difficulty is significant, enteral tube feeding should be considered. In this stage, neurological dysphagia may be permanent due to disease progression, so there is a greater need to use long-term percutaneous gastrostomy rather than a nasogastric tube.

Palliative care for HD

Evidence or guidelines for palliative care for HD patients have not been properly established to date. In general, it is better to reduce unnecessary medications and drugs for long-term prevention. However, the maintenance of medications for movement disorders and psychiatric problems can relieve patients’ discomfort. In addition, continuous pain management is important for maintaining the quality of life of patients in the late stage.

Disease-modifying treatment

Early clinical trials using antisense oligonucleotides (ASOs) aimed at reducing HTT protein levels in patients with HD have demonstrated promising results. Among these, tominersen dosedependently decreased the level of HTT in CSF mutants and advanced to a phase 3 trial (GENERATION HD1, NCT03761849) [113]. Despite demonstrating sustained reductions in HTT levels in the CSF, this study was halted because of the observed clinical deterioration and a higher incidence of adverse events than those associated with the placebo. However, post hoc analysis indicated that younger participants with a lower disease burden may have benefited from tominersen treatment. Consequently, studies with revised eligibility criteria and dosing regimens are ongoing to explore the possibility of this second-generation ASO agent as a disease-modifying treatment. Additionally, gene therapies using novel vectors and disease-modifying therapies employing brain-penetrant small molecules are considered promising for HD [114]. Combination strategies and novel technological advances may lead to the development of meaningful treatments for HD in the future.

Issues and unmet needs of management for HD in Korea

The treatment of HD in Korea has been dependent on clinicians’ pharmacological therapy. In countries where the management of HD is well established, multidisciplinary team care is recommended. The disease burden and quality of life of both patients and caregivers are also underrecognized issues that require more research and attention in Korea [115]. In addition, the establishment of a well-designed prospective cohort and performing clinical trials of potential disease-modifying agents will be the next step toward better treatment of HD patients in Korea.

CONCLUSION

This guideline provides a comprehensive overview of the various clinical aspects of HD, covering genetic counseling, laboratory investigations, biomarkers, and the management of different HD subgroups and comorbidities. Genetic counseling is crucial, covering predictive testing, cascade screening, and prenatal testing to guide informed reproductive decisions. Quantitative motor and cognitive assessments, such as grip force, tapping speed, and Stroop word reading, are valuable for tracking disease progression, whereas the plasma NfL level serves as a reliable biomarker. Early interventions for premanifest HD and tailored approaches for JHD and LoHD are essential for improving outcomes. Comorbidities such as diabetes, hypertension, and cardiovascular abnormalities significantly impact HD management, highlighting the need for comprehensive care. Effective management of HD focuses on symptom relief and quality of life enhancement through tailored medical treatment, physical therapy, nutritional support, and palliative care. The KHDS guidelines advocate for a multidisciplinary approach to enhance the quality of life of HD patients and caregivers in Korea. Continued research and collaboration will be crucial for advancing HD diagnosis and management in Korea and fostering international collaboration, which will eventually benefit HD patients in Korea.

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This work was supported by a focused clinical research grant-in-aid from the Seoul Metropolitan Government-Seoul National University (SMG-SNU) Boramae Medical Center (04-2022-0014) and a research fund of the Chungnam National University Sejong Hospital (2023-S2-008).

Author Contributions

Conceptualization: Jee-Young Lee. Data curation: Jangsup Moon, Chaewon Shin, Ryul Kim, Dallah Yoo, Eungseok Oh, Minkyeong Kim. Formal analysis: Jangsup Moon, Eungseok Oh, Minkyeong Kim, Chaewon Shin, Ryul Kim, Dallah Yoo, Minkyeong Kim. Funding acquisition: Jee-Young Lee, Chaewon Shin. Investigation: Jangsup Moon, Eungseok Oh, Chaewon Shin, Minkyeong Kim, Ryul Kim, Dallah Yoo. Methodology: Jee-Young Lee, Jangsup Moon, Chaewon Shin, Ryul Kim, Dallah Yoo, Eungseok Oh, Minkyeong Kim. Project administration: Jee-Young Lee, Jangsup Moon. Resources: Jee-Young Lee. Supervision: Jee-Young Lee, Jong-Min Kim, Seong-Beom Koh, Manho Kim, Beomseok Jeon. Validation: Jee-Young Lee, Jong-Min Kim, Seong-Beom Koh, Manho Kim, Beomseok Jeon. Visualization: Jangsup Moon, Eungseok Oh, Minkyeong Kim, Chaewon Shin, Ryul Kim, Dallah Yoo. Writing—original draft: Jangsup Moon, Eungseok Oh, Minkyeong Kim, Chaewon Shin, Ryul Kim, Dallah Yoo. Writing—review & editing: Jee-Young Lee, Jong-Min Kim, Seong-Beom Koh, Manho Kim, Beomseok Jeon.

Acknowledgments

None

Figure 1.

Genetic counseling and testing strategies for HD. This figure illustrates the genetic counseling and testing strategies for HD based on HTT CAG repeat numbers. Cascade screening is required for individuals with a CAG repeat number of 36 or more; however, genetic counseling ensuring informed decision-making is crucial. The offspring of HD patients who are planning for a child must receive prenatal counseling to help ensure that they can have a healthy baby through prenatal testing or PGT. HD, Huntington’s disease; HTT, huntingtin gene; PGT, preimplantation genetic testing; IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection.

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