The Epidemiology of Huntington’s Disease in Iceland Open Access

Huntington’s disease (HD) is a rare, autosomal dominant, neurodegenerative disorder characterized by involuntary movements, cognitive impairments, and psychiatric disturbances and ultimately leads to premature death [1, 2]. It is caused by cytidine-adenosine-guanosine (CAG) trinucleotide repeat expansion in the HTT gene [3]. The disease is found worldwide but is more prevalent among Caucasians than other ethnic groups [4, 5]. In Europe, the prevalence is 6.37 cases per 100,000 inhabitants, while the global prevalence is 4.88 cases per 100,000 inhabitants [6]. The epidemiology of HD in Iceland was studied in 2007 and the prevalence (0.96 cases per 100,000 individuals) and incidence (0.14 cases per 100,000 person-years in Iceland), was found to be unusually low compared to other European countries [7]. The purpose of this study was to determine the incidence and prevalence of HD in Iceland during 2008–2022 as well as age, sex, symptoms, number of CAG repeats, treatment, and prognosis.

A retrospective descriptive nationwide study was conducted using patients’ medical records and diagnosis from the two hospitals in Iceland with neurological services as well as information from all 15 practicing neurologists, particularly those 5 managing patients with HD. Data from the Department of Genetics and Molecular Medicine, the only one in Iceland, were also used regarding the results of genetic testing and genetic counseling. The study population consisted of all individuals with the diagnosis of HD in Iceland from January 1, 2008, to December 31, 2022 (a 15-year time frame). The data analyzed included age, sex, symptoms, inheritance, number of CAG repeats, treatment, and prognosis. Symptoms were classified into three categories: motor symptoms, cognitive symptoms and psychiatric symptoms. Time of onset was defined as the time when motor, psychiatric or cognitive symptoms attributed to HD began. Drug treatment was classified into the five most common medication classes, including: antipsychotics, antidepressants, anxiolytics, specific medications for chorea, and sleep medications. Disease duration was defined as the time from symptom onset to prevalence date. The patients’ disability levels were assessed using the Shoulson Fahn staging system [2]. Statistical analysis was conducted using Microsoft Excel and R studio and demographic information was provided by Statistics Iceland (https://www.hagstofa.is/). The study was approved by the National Ethics Committee and the National Data Protection Agency of Iceland.

We identified 22 individuals with HD in Iceland between the years 2008 and 2022 (11 women and 11 men, Table 1). On the prevalence date, December 31, 2022, 17 individuals (10 men and 7 women) were alive with manifest HD, making the prevalence of the disease 4.38 cases per 100,000 inhabitants. Sixteen individuals were diagnosed with HD during the 15-year period, while 6 individuals were diagnosed before 2008. The average annual incidence was 0.314 cases per 100,000 person-years. Two individuals were presymptomatic on the prevalence date, with an average age of 37 years. On the prevalence date, the average age was 49.7 (range 24–68, median age 50 years). In this study, there were no juvenile onset cases. The oldest patient at diagnosis was 69 years (now deceased).

The average age of symptom onset was 46.3 years (19–63 years) with a median of 49 years (Table 1). The most prominent symptom was chorea, experienced by 80% of individuals during their disease course (Table 2). Other common motor symptoms were balance disturbance (50%) and impaired fine motor skills (45%). The most common psychiatric symptoms were depression (65%), anxiety (50%), and mood disturbances (50%). Sleep disturbance, suicidal thoughts, hallucinations, and obsessive and compulsive thoughts were also common symptoms (Table 2). Memory loss (60%) was the most common cognitive symptom in this study.

The initial symptoms of HD patients were examined and were also classified into motor, psychiatric, and cognitive symptoms (Fig. 1). Motor symptoms were the most common clinical presentation (63.2%), while 47.4% experienced psychiatric symptoms among their initial symptoms, and 16% cognitive symptoms. A third of the patients presented with more than one of the above-mentioned symptoms.

The disability level of patients with HD was assessed at the prevalence date using the Shoulson Fahn classification system. Seven individuals (41.2%) were classified at disease stage I; 4 (23.5%) at stage II; and 2 (11.8%) at stages III, IV, and V (Fig. 2).

Twenty-one out of 22 HD patients had HD confirmed by DNA analysis. One was diagnosed based on family history and symptoms consistent with HD. The mean number of CAG repeats was 42.3 (median 42 repeats), with a range from 40 to 45 repeats (Fig. 3). In individuals tested for HD at the Department of Genetics, there were 83 non-pathogenic alleles (less than 36 GAG repeats). The median size was 18 repeats (range 12–34).

Two individuals (9.1%) did not have a family history of HD and were, therefore, sporadic cases. Since the 2007 study, a new HD family was discovered as well as two unrelated migrants from France who had moved to Iceland with the mutation. In the study population, 13 individuals (65%) inherited the disease from their father and 7 individuals (35%) from their mother (Table 1).

Drug treatment during the research period was examined. The most common medication classes used were antidepressants (85%), while 55% of patients took antipsychotics, 45% anxiolytics, 35% sleeping medications and only 5% received dopamine-depleting agents (Table 3).

Five individuals (22.7%) died during the research period. The most common cause of death was aspiration pneumonia (60%) (Table 1). Other causes were respiratory failure and heart failure. No individual died by suicide. The average age of death was 70.4 years (55–82 years). The average disease duration was found to be 20.2 years (12–35 years).

The epidemiology of HD in Iceland was studied from January 1, 2008, to December 31, 2022. The average incidence of HD in Iceland was 0.314 cases per 100,000 person-years, compared to 0.14 per 100,000 person-years in 2007 [7]. The prevalence on December 31, 2022, was 3.84 cases per 100,000 individuals, compared to 0.96 cases per 100,000 individuals on July 1, 2007. [7]. This indicates a significant increase in both the incidence and prevalence of the disease over this 15-year period. Several factors might explain this increase. The diagnostic process has improved since 2007, with 21 out of 22 individuals being diagnosed through DNA analysis in the present study compared to only 2 in the previous study. The availability of genetic testing allows us to detect new mutations in patients with no family history, elderly patients with mild symptoms and presymptomatic individuals with a family history of HD. Previously, there was only one known, existing family with HD in Iceland in 2007; now sporadic cases have been identified, and other HD families have been discovered and migrants with the HTT mutation have moved to the country. The aging of the population and better survival rates for HD patients are also factors that could increase the prevalence, as well as better treatment options and more awareness of the disease. Today, patients have a team of healthcare professionals providing more specific care to HD patients.

The average prevalence of HD in the world is 4.88 cases worldwide per 100,000 individuals, and the incidence 0.48 cases per 100,000 person-years [6]. The prevalence and incidence of HD in Iceland is similar to what is seen in the rest of the world. However, in Europe, the prevalence is higher, 6.37 cases per 100,000 individuals and the incidence 0.38 cases per 100,000 person-years [6]. Although the prevalence of HD in Iceland has increased, it remains relatively low compared to other European countries. This low prevalence is surprising in light of Icelanders’ European origin. The Icelandic people are descended from Nordic countries, Ireland and Scotland, where the prevalence is found to be considerably higher [4, 8‒10]. A possible explanation for this is the founder effect and genetic drift, possibly acting on unstable intermediate alleles, which occur by chance when a population is created from people settling in isolated communities. Additionally, the historical migration of the Icelandic people to America may have played a role. Approximately one third of the individuals who migrated were from the northern part of Iceland, where the roots of HD in Iceland are traced. We infer that the healthcare system is robust in Iceland and the clinical spectrum is recognized by clinicians and may not be a factor in explaining the low prevalence of HD. With the rise in HD incidence in Iceland, it is possible that the prevalence will approach that seen in Europe in the coming decades. With this said, the prevalence of HD has also been increasing during the last decades in studies from Australia, North America and Western Europe [11]. The findings in the current study align with that observation.

The average age of symptom onset and age at diagnosis fell within the expected range, 40 and 50 years, aligning with findings from the 2007 study where the average age at symptom onset was 46.3 years, whereas in this study it was 46.1 years [7]. The average age of symptom onset worldwide is around 40 years old; therefore, the onset of symptoms in HD patients in Iceland appears to be higher than in other populations [12]. This could be a reflection of a relatively low number of CAG repeats in the Icelandic HD cohort.

The average number of CAG repeats observed in this study was 42.3 repeats, with a median value of 42. The range spanned from 40 to 45 repeats. The mean number of CAG repeats in studies in other countries is around 44. This suggests that the number of CAG repeats in Iceland is lower than in other countries [12, 13]. Sporadic cases were 9.1%. Possible explanations might be non-paternity or expansion of intermediate alleles. The general view is that around 10% of cases are sporadic, which aligns with these data [14].

The symptoms exhibited by HD patients in Iceland are consistent with the widely recognized manifestations of the condition. Motor symptoms were the most common while depression was the most common psychological symptom, aligning with the findings from other studies [12]. In the 2007 study, it was reported that among older HD cases, motor symptoms were more prominent; however, today it has been observed that psychiatric symptoms were very frequent, and a great majority of patients received medication for these symptoms [7]. It is likely that the psychiatric symptoms were underrecognized some decades ago [15].

Aspiration pneumonia emerged as the most prevalent cause of death, consistent with findings from other HD studies [16, 17]. The average age at death was 70.4 years old, whereas in the 2007 study it was notably lower at 61.9 years [7]. This might be explained by improved supportive treatment for HD patients today compared to 15 years ago. A Norwegian study on HD from 2018 reported that the average age at death was 63.9 years, while globally it was 58 years old. The lower age at death in the present study might be explained by the lower number of CAG repeats in Icelandic HD patients [18, 19]. The average life expectancy of the Icelandic population between 2011 and 2020 was 82.7 years, according to Statistics Iceland. Therefore, the life expectancy of HD patients is still substantially lower than in the general population.

The study had various strengths, such as its nationwide scope. We believe that we were able to identify most, if not all, patients diagnosed with HD in Iceland, and the research provided further insight into the symptoms, diagnosis and treatment of the disease in the country. Limitations of the study include the rarity of the disease and, consequently, small sample size and its retrospective nature.

The prevalence and incidence of HD in Iceland have increased compared to the 2007 study and are approaching the incidence and prevalence seen in other European populations. Results showed a lower average number of CAG repeats in the Icelandic population, potentially explaining the higher age at symptom onset and death compared to global averages.

The study was approved by the National Ethics Committee (VSN-23-118) and the National Data Protection Agency of Iceland and in compliance with the Helsinki Declaration. The Ethics Committee determined that written or oral individual informed consent was not required.

The authors have no conflicts of interest to declare.

The study did not receive any funding.

S.B. had a major role in acquisition of data, contributed to statistical analysis, and drafted the manuscript for intellectual content. V.S. and J.J.J. revised the manuscript for intellectual content. O.S. designed the study, interpreted the data, revised the manuscript for intellectual content, and had a major role in design of study.

The data that support the findings of this study are not publicly available due to information that could compromise the privacy of research participants but are available from the corresponding author (O.S.) at [email protected] upon reasonable request.