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Huntington disease (HD) has a protracted course that imparts substantial personal and economic burden.1 Disease rates vary by geographic location. In Western countries, prevalence approximates 5.7/100,000; rates are tenfold lower in Asia.2 Epidemiologic studies from the United States report on mostly white populations.2 Few studies give rates of HD among minorities, and there are no comprehensive descriptions of HD in American Indians. Better understanding of how the disease affects discrete populations could produce hypotheses for new approaches to treatment.
The goal of this study was to describe the epidemiology of HD among Navajo people living in the Navajo Nation, at 27,000 square miles, the largest reservation for American Indians in the United States.
The e-Methods on the Neurology® Web site at Neurology.org and previous articles by this group3,4 describe the methodology in detail. We sought to determine average annual incidence and point prevalence rates of HD among Navajo residents of the Navajo Nation during 2001–2011. The Indian Health Service National Patient Information Reporting System provided the data, which captured 98% of eligible Navajo during the planned study period.
Post hoc analyses estimated prevalence rates in American Indians living on or near reservations across the United States (2001–2011), determined whether any HD-associated inpatient visits occurred in the Navajo Nation from 1980–2000, and estimated the probability of the primary findings on prevalence day, July 1, 2006, under different rate assumptions. The Navajo Nation Human Research Review Board approved the study.
The primary analysis found no cases of HD (average annual incidence rate = 0.0/100,000 [95% confidence interval (CI) 0.0–0.21]; point prevalence = 0.0/100,000 [95% CI 0.0–1.8], Navajo Nation, 2001–2011). Post hoc analyses identified 57 cases among American Indians nationwide (estimated prevalence rate = 4.1/100,000); none was Navajo (estimated nationwide prevalence rate among Navajo = 0.0/100,000; estimated prevalence in non-Navajo American Indians = 4.9/100,000). Examination of Navajo Nation inpatient data, 1980–2000, found no cases.
The probability of finding no cases on prevalence day in the Navajo Nation ranged from 0.0004% assuming mutation rates found in people of European descent to 42% assuming rates in Asia (table e-1).2
We found no cases of HD among Navajo people. We initially limited the analyses to the 11-year period, 2001–2011, because the data capture nearly all 275,000 eligible people in the Navajo Nation.5 Post hoc analyses captured approximately 350,000 Navajo nationwide and extended the Navajo Nation analysis over 30 years.
We estimated the probability of finding no HD in the Navajo Nation on prevalence day under different rate assumptions to provide context for our findings. It is improbable that we missed rare cases on prevalence day but it is much less likely that we missed cases over the entire 30-year investigation.
American Indians emigrated from Asia.6 The rate of HD in non-Navajo American Indians indicates that they acquired the mutation from people of European and not Asian ancestry. Approximately 10% of HD is sporadic, due to spontaneous expansion of a CAG triplicate repeat in the HTT gene from an intermediate to a disease-causing tract size.7 CAG instability varies by haplotype, which vary according to ethnicity. A stable gene haplotype with short tract sizes explains the low prevalence in Asia.7 The absence of HD among Navajo people could be due to low spontaneous tract expansion from inheritance of the stable Asian haplotype and serendipitous avoidance of the European mutation carried by later-arriving immigrants because of an isolated existence.
Our findings deserve cautious interpretation. Cases could have been overlooked or misdiagnosed, or patients could have received health care elsewhere. However, a nationwide search found no Navajo with HD and, because of the remoteness of the reservation, essentially all eligible Navajo are captured by the Navajo Nation data. The findings were not verified by genetic investigation because American Indian tribes in the United States do not yet permit their genes to be analyzed. Genetic inheritance creates dependency between individuals; probability calculations assumed independent trials so cannot be interpreted strictly.
To our knowledge, this is the first epidemiologic study of HD in an American Indian tribe and the only report detailing the absence of HD in any population. Taken with studies of amyotrophic lateral sclerosis3 and Parkinson disease,4 these data point to differentially distributed neurodegenerative disorders among American Indians and other populations. Research into the reasons underlying these contrasts could yield better understanding of often cryptogenic and universally incurable brain disorders.
Acknowledgment: The authors thank the members of the Navajo Nation Human Research Review Board for their oversight and support; the communities of the Navajo Nation; the staffs at the participating health care facilities; the IHS National Patient Information Reporting System; Barbara Strzelczyk (IHS) for technical assistance; and Robert C. Holman (CDC) for his dedication to improving the health of American Indians. Bob traveled from Atlanta to Indian country numerous times so that he could better understand the people he studied; his support made these projects possible.
Supplemental data at Neurology.org
Author contributions: All authors had access to the data, substantially contributed to the intellectual content of the paper, contributed to the conception and design of the study, interpreted the data, and revised the manuscript for important intellectual content. J.M. Mehal acquired the data and performed the statistical analysis. P.H. Gordon drafted the manuscript.
Study funding: No targeted funding reported.
Disclosure: The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.