Mortality trends and disparities in adults with Huntington's disease in the United States

Abstract

Background

Huntington's disease (HD), an autosomal dominant disorder, is characterized by progressive neurodegeneration, psychiatric issues, dementia, and worsening chorea over time. Its prevalence varies by ethnicity and region.

Objective

This study aims to analyze mortality trends and disparities in adults with HD in the United States (US).

Methods

This study analyzed death certificates from 1999 to 2020 for deaths due to HD (ICD-10 code G10) in individuals aged 25 and older. Age-adjusted mortality rates (AAMRs) and annual percent change (APC) were calculated by year, gender, age groups, race/ethnicity, geographics and urbanization status.

Results

Between 1999 and 2020, there were 24,121 reported deaths among patients with HD. During this period, the AAMR increased from 4.3 to 6.0 per 1,000,000 population, with a notable surge from 2018 to 2020 (APC: 9.88; 95% CI: 5.45 to 13.20). Older adults exhibited the highest AAMRs at 10.4 per 1,000,000 when analyzed by age-group. Men and women had comparable AAMRs (5.2 vs. 5.0). By race, non-Hispanic (NH) Whites had the highest AAMRs (6.0), followed by NH African Americans (3.3) and Hispanics (2.8). Additionally, non-metropolitan areas experienced higher AAMRs compared to metropolitan areas (6.6 vs. 4.8).

Conclusions

Since 1999, mortality from HD has increased, particularly from 2018 to 2020, with higher rates in older adults, men, NH Whites, and non-metropolitan areas. Further research is essential to consolidate data, standardize reporting practices, and address disparities to improve outcomes.

Keywords

mortality Huntington's disease epidemiology disparity trends neurology

Introduction

Huntington's disease (HD) is an autosomal dominant disorder characterized by neurodegeneration, psychiatric problems, and dementia.^1,2 It is caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion, which exacerbates chorea and behavioral issues over time.³ Studies indicate a worldwide prevalence of 0.48 cases per 100,000 person-years, with an increasing yearly incidence. Disease incidence varies by ethnicity and region.⁴ Additionally, the age of onset influences disease progression and outcomes, highlighting the importance of considering age and ethnicity in the management and pre-diagnosis of the disease.⁵

The global mean age of onset for HD typically ranges from 30 to 50 years old, with most people showing symptoms in their 40 s. However, this can vary depending on genetic factors, particularly the number of CAG repeats in the HTT gene.⁶ The mean age of death in individuals with HD is typically significantly lower than in the general population,⁷ generally ranging from 55 to 65 years. This usually occurs 15 to 20 years after the onset of symptoms. The exact age of death can vary widely depending on factors such as the severity of the disease, access to medical care, and other comorbid conditions.^6,8,9 Research conducted within European cohorts indicates that mortality in HD patients can result from various causes similar to those seen in other neurodegenerative diseases, including pneumonia, other infections, cancer, stroke, suicide, and trauma.^10,11 Moreover, suicide is particularly notable as a significant cause of death in those affected by HD.¹²

Studies show that HD is present in children in about 5% of cases. A notable difference in Juvenile HD is the prevalence of epilepsy, a major symptom rarely observed in adults, underscoring the distinct presentation and lower incidence of the disease in children compared to adults.^13,14 To better understand the trends in the pediatric population, a study focused exclusively on mortality and disease manifestations in Juvenile HD is needed.

Gender and racial disparities play a significant role in HD outcomes, particularly concerning diagnosis and mortality rates. While gender-based differences are generally subtle, men may experience a slightly earlier onset and shorter life expectancy, whereas women are more likely to develop psychiatric symptoms such as depression and anxiety. Despite these differences, the progression of motor and cognitive symptoms is similar across genders, with inconsistencies in survival rates and symptom severity reported across studies.^15–17 Additionally, research shows that Black patients are often diagnosed about a year later than White patients, potentially leading to worse outcomes due to delayed access to care.¹⁸

Current guidelines for HD do not account for racial and ethnic factors. However, incorporating patient counseling and specific requests is recognized. Collecting data on race and ethnicity can support the development of robust guidelines for targeted predictive screening, ultimately improving pre-diagnosis and management strategies.¹⁹ Given that HD is a genetic disease, its incidence and prevalence differ among various racial, ethnic, and gender groups. Examining mortality trends among HD patients can offer insights into disease severity and progression, potentially leading to modified pre-screening protocols for diverse populations.²⁰ Moreover, understanding these trends can shed light on the disease's prevalence and variability across regions and ethnicities, aiding in the assessment of the underlying genetic factors. This study aims to find the mortality trends in HD among US adults. The trends have been analyzed across gender, age, race, ethnicity, and geographic location.

Methods

Study setting and population

The mortality data was derived from the WONDER (Wide-Ranging Online Data for Epidemiologic Research) database of the Centers for Disease Control and Prevention (CDC).²¹ The examination of mortality rates in individuals diagnosed with HD from 1999 to 2020 in adults aged 25 years and older was conducted using the International Statistical Classification of Diseases and Related Health Problems (10th Revision) code, G10.²² The US adult population of 2000 was taken as the sample (N = 4,473,854,489). Our study specifically concentrated on mortality records found in the Multiple Causes of Death Public Use dataset.²¹ Thus, the inclusion criteria of our study consisted of adult patients whose death certificates had HD as either contributing or underlying cause of death, while the exclusion criteria consisted of non-adult patients or those not having HD as a cause of death on their death certificate. This database and method has been previously utilized in various published papers analyzing trends and disparities in mortality.^23,24 Approval from an institutional review board was not necessary, as we utilized a de-identified public-use dataset provided by the government and adhered to the guidelines of Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and utilized a de-identified public-use dataset provided by the government.²⁵

Data extraction

The data was stratified based on abstracted demographic variables, such as population size, age distribution, gender composition, location of death, racial/ethnic background, geographic location, and urbanization status. The location of death encompassed various settings, including medical facilities (consisting of inpatient facilities, outpatient centers, emergency departments, cases of death upon arrival), decedents’ homes, hospices, nursing homes/long-term care facilities, or situations where the location was unidentified. Patients were grouped racially and ethnically as either Hispanic (Latino), non-Hispanic (NH) White, NH Black/African American, NH American Indian/Alaskan Native, or NH Asian. These classifications align with those previously used in analyses from the CDC WONDER database and are based on data reported on death certificates in compliance with the US Office of Budget and Management Guidelines.²¹

The patients were also segmented into ten-year intervals based on whether they were young adults (25–44 years), middle-aged adults (45–64 years), or older individuals (65–85 + years). This age distribution was described according to previous studies examining mortality trends utilizing this database.²⁶ Our study population was classified geographically using the Urban-Rural Classification Scheme developed by the National Center for Health Statistics. Urban areas were defined as those having populations of 50,000 or more, while rural areas consisted of areas with fewer than 50,000 residents. For ease of analysis, we divided the United States into four regions according to the division given by the US Census Bureau: Northeast, Midwest, South, and West.²⁷

Statistical analysis

We examined disparities and trends in gender, race, age, urbanization, and census region-related trends by analyzing the age-adjusted mortality rates (AAMRs) per 1,000,000 persons, utilizing the 2000 US population as the baseline for standardization. The analysis of mortality rate changes over time was conducted using the Join Point Regression Program (Version 5.0.2, National Cancer Institute).²⁸ The temporal trends in AAMR were analyzed using log-linear regression models. Joinpoint regression was utilized to detect inflection points in the AAMR trends for HD from 1999 to 2020, following established methodological guidelines. For datasets spanning 17 to 21 time points, these guidelines recommend identifying up to three inflection points during the study period. Given that this study covers 22 years, the Joinpoint regression software was configured to detect up to four joinpoints where significant changes in the trend occurred. However, if fewer inflection points better captured the trend variations, the analysis allowed for the identification of between 0 and 4 joinpoints. The Grid Search method (2, 2, 0), permutation test, and parametric method were used to estimate the annual percent change (APC) and corresponding 95% confidence intervals (CIs). A change in mortality was classified as increasing or decreasing if the slope representing the APC was significantly different from 0, as determined by a 2-tailed t-test. Statistical significance was defined as p ≤ 0.05.

Results

Between 1999 and 2020, there were 24,121 deaths where HD was either the main cause or a contributing factor in the US adult population (Supplementary Table 1). The place of death was documented for 23,082 of these cases: 51% occurred in nursing homes or long-term care facilities, 20.4% in the decedents’ homes, 20% in medical facilities, and 4.1% in hospices (Supplementary Table 2).

Demographic trends in mortality

The age-adjusted mortality rate (AAMR) per 1,000,000 individuals according to the US population of 2000 was 4.3 in 1999 and increased to 6.0 in 2020. Overall, the AAMR rose significantly from 1999 to 2014 (APC: 0.81; 95% CI: 0.51 to 1.70). It then significantly declined from 2014 to 2018 (APC: −1.54; 95% CI: −4.39 to −0.03), followed by a sharp rise from 2018 to 2020 (APC: 9.88; 95% CI: 5.45 to 13.20) (Figure 1, Supplementary Tables 3 and 4).

Figure 1.

Overall and sex-stratified Huntington's disease-related age-adjusted mortality rates per 1,000,000 in adults in the United States, 1999 to 2020. * Indicates that the annual percentage change (APC) is significantly different from zero at α = 0.05. AAMR. age-adjusted mortality rate; APC, annual percent change.

Gender stratification

During the study period, men's AAMRs were slightly higher than women's (5.2 vs. 5.0). In 1999, the average AAMR for men was 4.6, which rose significantly to 6.2 in 2020 (APC: 0.69; 95% CI: 0.23 to 1.18). For women, the AAMR was 4.1 in 1999, increasing significantly to 5.8 in 2020 (APC: 0.94; 95% CI: 0.60 to 1.31) (Figure 1, Supplementary Tables 3 and 4).

Stratification by age groups

When stratified by age groups, older adults had the highest AAMRs (10.4), followed by middle-aged adults (6.7) and young adults (1.6). Among young adults, AAMRs remained relatively stable from 1999 to 2020 (APC: 0.16; 95% CI: −0.72 to 1.04). Middle-aged adults showed a significant increase in AAMRs from 1999 to 2020 (APC: 0.78; 95% CI: 0.34 to 1.26). For older adults, the AAMRs remained stable between 1999 and 2018 (APC: 0.62; 95% CI: −1.55 to 1.59), followed by a steep rise until 2020 (APC: 9.36; 95% CI: 0.92 to 13.90) (Figure 2, Supplementary Tables 3 and 5).

Figure 2.

Huntington's disease-related age-adjusted mortality rates per 1,000,000, stratified by age groups in adults in the United States, 1999 to 2020. * Indicates that the annual percentage change (APC) is significantly different from zero at α = 0.05. AAMR, age-adjusted mortality rate; APC, annual percent change.

Demographics by age groups

Among young adults, both men and women had a comparable AAMR of 1.6 per 1,000,000 individuals throughout the study period, with no significant trend changes. In the racial analysis, NH whites had the highest AAMR at 2.1. Specifically, the AAMR in NH whites increased significantly from 1999 to 2002 (APC: 10.94; 95% CI: 1.13 to 32.56), followed by a period of stability until 2020 (Supplementary Figure 1, Supplementary Tables 3 and 6).

Among middle-aged adults, men had a slightly higher AAMR compared to women (6.9 vs. 6.5), with both genders showing a significant increase in AAMRs from 1999 to 2020 (men APC: 0.64; 95% CI: 0.00 to 1.36, women APC: 0.86; 95% CI: 0.34 to 1.43). Similar to young adults, NH whites had the highest AAMRs across all races among middle-aged adults, at 8 per 1,000,000 individuals. The AAMR of NH whites increased significantly from 1999 to 2000 (APC: 1.10; 95% CI: 0.64 to 1.61) (Supplementary Figure 2, Supplementary Tables 3 and 7).

Among older adults, men had AAMRs comparable to women throughout the study period (10.4 vs. 10.3). For older men, the AAMR remained stable from 1999 to 2018, followed by a steep upward trend from 2018 to 2020 (APC: 14.26; 95% CI: 1.23 to 21.16). In older women, the AAMR showed a significant increase from 1999 to 2020 (APC: 1.23; 95% CI: 0.65 to 1.91). Similar to young and middle-aged adults, racial analysis among older adults revealed that NH whites had the highest AAMR at 11.5 per 1,000,000 individuals. This AAMR in NH whites remained stable until 2018, followed by a steep upward trend from 2018 to 2020 (APC: 8.30; 95% CI: 0.96 to 12.57) (Supplementary Figure 3, Supplementary Tables 3 and 8).

Racial stratification

When stratified by race or ethnicity, AAMRs were highest among NH white patients (6.0), followed by NH African American (3.3) and Hispanic (2.8) populations. The NH American Indian or Alaska Native and NH Asian or Pacific Islander groups had unreliable or suppressed AAMR values throughout the study period, making analysis impossible. A significant upward trend was reported from 1999 to 2020 among NH Whites (APC: 1.05; 95% CI: 0.74 to 1.39), NH African Americans (APC: 1.92; 95% CI: 1.16 to 2.86), and Hispanics (APC: 2.14; 95% CI: 0.86 to 3.93) (Figure 3, Supplementary Tables 3 and 9).

Figure 3.

Huntington's disease-related age-adjusted mortality rates per 1,000,000, stratified by race in adults in the United States, 1999 to 2020. * Indicates that the annual percentage change (APC) is significantly different from zero at α = 0.05. AAMR, age-adjusted mortality rate; APC, annual percent change.

State-wise distribution

AAMR values varied significantly by state, ranging from 1.7 in Hawaii to 8.0 in Indiana. States in the top 90th percentile (Nebraska, West Virginia, Vermont, Iowa, Montana, Indiana) had AAMRs about three to four times higher than those in the bottom 10th percentile (Hawaii, District of Columbia, Florida, New Mexico, Nevada, Virginia) (Figure 4, Supplementary Table 10).

Figure 4.

Huntington's disease-related age-adjusted mortality rates per 1,000,000, stratified by state in adults in the United States, 1999 to 2020.

Census region

During the study period, the highest AAMR was in the Midwestern region (6.5), followed by the Northeastern (4.9), Western (4.7), and Southern (4.5) regions. From 1999 to 2002, AAMRs significantly increased in the Northeastern region (APC: 9.59; 95% CI: 1.56 to 24.92), followed by a stable period till 2018, and a steep rise from 2018 to 2020 (APC: 10.38; 95% CI: 0.43 to 16.80). From 1999 to 2020, AAMRs significantly increased in the Midwestern (APC: 0.87; 95% CI: 0.34 to 1.44) and Southern (APC: 1.25; 95% CI: 0.77 to 1.80) regions. In the Western region, AAMRs remained relatively stable between 1999 and 2018, followed by a significant increase from 2018 to 2020 (APC: 8.69; 95% CI: 0.25 to 13.36) (Figure 5, Supplementary Tables 3 and 11).

Figure 5.

Huntington's disease-related age-adjusted mortality rates per 1,000,000, stratified by census regions in adults in the United States, 1999 to 2020. * Indicates that the annual percentage change (APC) is significantly different from zero at α = 0.05. AAMR, age-adjusted mortality rate; APC, annual percent change.

Urbanization

Throughout the study period, non-metropolitan areas had higher AAMRs for HD than metropolitan areas, with overall AAMRs of 6.6 and 4.8 respectively. In metropolitan areas, AAMRs increased significantly from 1999 to 2002 (APC: 3.45; 95% CI: 0.67 to 8.88), followed by a stable period from 2002 to 2018, and then a steep rise from 2018 to 2020 (APC: 7.06; 95% CI: 1.87 to 9.88). Similarly, in non-metropolitan areas, AAMRs significantly increased from 1999 to 2020 (APC: 1.38; 95% CI: 0.78 to 2.01) (Figure 6, Supplementary Tables 3 and 12).

Figure 6.

Huntington's disease-related age-adjusted mortality rates per 1,000,000 in adults in the metropolitan and non-metropolitan areas in the United States, 1999 to 2020. * Indicates that the annual percentage change (APC) is significantly different from zero at α = 0.05. AAMR, age-adjusted mortality rate; APC, annual percent change.

Discussion

Our study revealed significant findings regarding HD mortality trends. Overall mortality increased from 1999 to 2020, with the AAMR rising from 4.3 to 6.0 per 1,000,000 individuals. However, this pattern followed a non-uniform trajectory. There was a steady increase in mortality rates until 2014, with an APC of 0.81, followed by a decline until 2018 (APC −1.54), and finally, a sharp upward surge (APC 9.88). Further analysis across demographic subgroups revealed higher mortality rates among men, older adults, NH Whites, and those living in the Midwestern and non-metropolitan regions.

The steady increase in mortality rates up to 2014 is consistent with findings from other regions. For instance, a Spanish study showed a rise in AAMRs from 0.076 to 0.157 per 100,000 between 1984 and 2013,¹⁶ and similar trends were observed in Norway.⁷ This increase is likely due to advances in diagnostic testing, neuroimaging, and greater public health awareness leading to more reporting, especially among those without a family history of HD.^29,30

The decline in AAMR from 2014 to 2018 suggests potential improvements in clinical outcomes due to better disease management and enhanced healthcare access. This period likely saw advancements in symptomatic treatments and multidisciplinary care, including physical therapy, psychological support, and improved chorea management.³¹ Supporting this, Furby et al. observed that while the incidence of HD in the UK remained constant from 2000 to 2018, prevalence doubled from 4.3 to 9.2 cases per 100,000, attributed to overall increased longevity and better symptomatic care.¹¹ However, the subsequent rise in AAMR post-2018 (with APC 9.88) raises concerns about whether these improvements were sustained. This underscores the need for continuous evaluation of treatment protocols, specialized care access, and the long-term effects of interventions. Investigating the factors behind this trend is crucial to identifying areas where clinical practices may need adjustment.

Research has highlighted the significant burden of HD in North America, Europe, and Canada.^4,10,32,33 For instance, Pringsheim et al. (2012) reported a prevalence of 5.70 per 100,000 in North America, compared to a global rate of 2.71.³⁴ Insurance database studies from 2017 found high prevalence rates of 13.1 per 100,000 in Medicare and 15.2 per 100,000 in Medicaid populations, respectively. Despite these figures and the advent of genetic testing, diagnostic frequency has remained stable.³⁵ Notably, a 20-year cohort study revealed that mortality rates among HD gene carriers remain stable, depicting that the advances in medical care have not yet translated into significant mortality reductions for affected families.³⁶

Further stratification of the data revealed that men had a higher mortality rate than women. A study by Hentosh et al. analyzed the Enroll-HD database and found that sex did not significantly affect the incidence of HD.³⁷ Although female HD gene carriers exhibited worse motor, cognitive, and depressive symptoms compared to males at presentation, the progression of symptoms over the years was similar between the sexes.³⁸ This discrepancy in mortality can be explained by increased suicidality and risk-taking behavior in men than women.³⁹

Among different racial groups, NH Whites exhibited the highest mortality burden (the impact of deaths within a specific population or demographic group, often expressed in terms of the number of deaths, the rate of death, or the loss of potential life years), followed by NH African Americans and Hispanics. This finding aligns with a study by Lanska et al. (1991), which analyzed data from the National Center for Health Statistics covering the period from 1971 to 1978.⁴⁰ Populations of European descent, including many NH Whites, have historically shown higher frequencies of expanded CAG repeats associated with HD. Moreover, historical migration patterns and the founder effect have led to a higher concentration of the mutated gene within NH White populations, thereby contributing to the observed disparities.^{4,16,29,40,41}

Interestingly, despite having the lowest total mortality, Hispanics showed the greatest annual rise in mortality. The lowest total mortality can be attributed to the “Hispanic paradox” observed in all-cause mortality in the United States. Despite Hispanics’ lower socioeconomic position, including lower education and income levels and reduced access to health insurance, they demonstrate lower all-cause mortality rates compared to non-Hispanics.^42,43 However, the highest APC value can be explained by an increased aging population with poor healthcare access, migration patterns, population expansion, and late-manifest HD inflating mortality rates.⁴⁴ However, more research is needed to dive into this trend.

Mortality rates among older adults with HD are notably higher, primarily due to the substantial burden of comorbid conditions. Additionally, there has been a marked increase in mortality among middle-aged adults, despite their overall lower mortality rates. Paulsen et al. highlighted that individuals in their 30 s to 50 s, during the early and middle stages of HD, experience a higher incidence of suicidal ideation and attempts. This is attributed to the rapid onset and progression of motor, cognitive, and psychiatric symptoms, leading to significant psychological distress.^45,46 Non-metropolitan areas exhibited higher mortality rates compared to metropolitan regions. This disparity can be attributed to the uneven geographical distribution of Huntington's Disease Society of America Centers of Excellence (HDSA COEs), with 23 states and 3 US territories lacking accessible COEs for at least half of their HD population.⁴⁷ Rural areas are often characterized by limited healthcare access, lower socioeconomic status, and poorer health outcomes. Both animal and human studies have demonstrated the impact of environmental factors on CAG repeat expansions.^48,49 These factors likely contribute to the notable disparity in mortality rates between non-metropolitan and metropolitan regions. Therefore, health authorities should focus on increasing healthcare availability and improving health outcomes in rural areas.⁵⁰

The Midwestern region showed the highest HD-related AAMR among the census regions. While specific studies on mortality trends in the Midwest are limited, research suggests that genetic factors, healthcare access, and socioeconomic conditions influence regional mortality.¹⁵ Although the Northeastern region did not have the highest AAMR, it recorded the most significant APC in mortality at 9.59. The reasons behind this substantial APC are unclear, but further research is needed to identify the exact causes and to determine whether improved diagnostic practices or an increase in disease prevalence in the Northeastern region contributed to this significant rise in mortality.

These trends can inform policymakers and healthcare planners to address the complex needs of HD patients. Variations in mortality across demographics highlight the need for further investigation into specific risk and protective factors affecting HD. Longitudinal studies are also necessary to evaluate the impact of emerging therapies and healthcare strategies on HD mortality.⁵¹ Despite identifying the HD gene and mutation over two decades ago, drug development has been slow, with only two drugs approved in the past 15 years.⁵² Currently, no disease-modifying treatments exist, and symptomatic therapies remain limited.⁵³ Addressing these gaps is crucial for developing more effective interventions, improving the quality of life for patients and their families, and reducing healthcare costs and burdens.⁵⁴

Limitations

While our study provides valuable insights into HD mortality trends, it has some limitations. Firstly, our study may be affected by inaccurate reporting within the CDC WONDER database. Misclassification or underreporting of HD on death certificates can lead to inaccuracies in mortality rates. Mortality trends by place of death over the years could not be determined. Secondly, the variations in diagnostic criteria and coding practices over the years and across different regions may result in inconsistencies in the data. These discrepancies can affect the reliability of our findings. Furthermore, our study's observational nature limits the ability to draw causal inferences about the reasons behind the observed trends. Socioeconomic, environmental, and healthcare access factors, which significantly impact disease outcomes, were not fully accounted for in our analysis. Future research should address these limitations by incorporating detailed clinical data, exploring longitudinal patient outcomes, and considering broader social determinants of health. Validation studies, geospatial analysis, multi-source data integration, and standardized diagnostic criteria could enhance data accuracy, while causal inference techniques would improve the reliability and interpretability of the findings.

Conclusions

Mortality rates due to HD show considerable variation. Throughout the study period, AAMRs initially increased from 1999 to 2014, followed by a decline, and then experienced a sharp rise from 2018 onwards. Among adults aged 25 and older in the US, higher mortality rates were observed in older adults, men, NH white individuals, those residing in the Midwest, and those living in non-metropolitan areas. These findings underscore the urgent necessity for comprehensive reforms in healthcare practices and protocols to address these disparities.

Supplemental Material

sj-docx-1-hun-10.1177_18796397241287399 - Supplemental material for Mortality trends and disparities in adults with Huntington's disease in the United States

Supplemental material, sj-docx-1-hun-10.1177_18796397241287399 for Mortality trends and disparities in adults with Huntington's disease in the United States by Humza Saeed, Abdullah, Hira Hameed, Hafiz Mohammad Maaz, Abdul Wasay, Zubair Amin, Muhammad Khubaib Arshad, Hritvik Jain and Aman Goyal in Journal of Huntington's Disease

Footnotes

Acknowledgments

The authors have no acknowledgments to report.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability

The data supporting the findings of this study are openly available in CDC Wonder at [].

Supplemental material

Supplemental material for this article is available online.

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