Iceland’s Deadly Disease Mystery

For the past 100 years, there has been a mysterious disease afflicting Icelanders. Called Hereditary Cystatin C Amyloid Angiopathy (or HCCAA), it causes severe brain hemorrhages and dementia in young adults. For those individuals who have the disease, life expectancy is usually no higher than 30 years. Scientists have determined that this disease is caused by a single mutation in the cystatin C gene. But until now, they had not yet discovered how this mutation arose, why it afflicts only Icelanders, and why it suddenly appeared within the last 150 years.

A new collaboration between American and Icelandic scientists has helped to answer these puzzling questions about the origins of HCCAA by using Iceland’s Genealogical Database, which includes more than 80% of all Icelandic people who have ever lived. It also sheds light on the last 200 years of Iceland’s population history, and offers clues to understanding the interplay between genes and environment.

The researchers’ original goal – to use genetic and genealogical information to trace the common ancestor of every Icelander with HCCAA – proved unfeasible due to lack of data. But researchers did find a man born in 1684 north of Iceland’s capital, Reykjavik, who was an ancestor to most carriers of the disease. Because the lineages of so many people with HCCAA converged on that person, it can be inferred that he also carried the deadly mutation in the cystatin C gene. Yet census records show he did not have a shortened life span. In fact, through the 18th century the average life span for a person with the HCCAA mutation was in the neighborhood of 65 years, about average for the period. In addition, there are no historical records of Icelanders suffering from this disease throughout the 17th and 18th centuries. So if the mutation existed in 1684, why did no one show any symptoms until the mid-19th century? The researchers’ next task was to find out when in Iceland’s history people did start showing symptoms of HCCAA.

By again using Iceland’s extensive genealogical database, researchers found a significant change in life expectancy for those carrying the mutation, starting in the 19th century. It appears that individuals with the disease who were born after 1825 began to have significantly shorter life spans. By the year 1900, the average life span for HCCAA carriers had dropped to 30 years, where it remains today.

But why did life spans not start decreasing until the early to mid-19th century, when records show that this mutation had been present among Icelanders since the 17th century? What changed for the people of Iceland? The answer may lie in their diet. The researchers noticed that, prior to the 19th century, the diet of Icelanders consisted mostly of whey-preserved offal (animal entrails and organs) as well as meat, dried fish, and butter. In other words, a diet low in carbohydrates and salt. However, post-19th century, imports from mainland Europe increased dramatically, and a typical Icelandic diet began incorporating processed carbohydrates and salt (to preserve food). The researchers argue that the movement of imports from Reykjavik to more isolated regions in Iceland throughout the 19th century mirrors the appearance and spread of HCCAA symptoms. As these new kinds of foods spread from the capital to smaller towns and villages, the deadly symptoms of HCCAA did as well. Therefore, it appears that the traditional Icelandic diet ‘masked’ the deadly symptoms of HCCAA, and it wasn’t until they began to eat more processed foods, higher in carbohydrates and salt, that these ‘masking’ effects diminished.

The researchers did not speculate on the mechanism by which diet may be triggering the symptoms of HCCAA; but his study is significant for a variety of reasons. First, it is a fascinating example of how environment – in this case, diet – can affect a genetic mutation. In addition, this study is important due to a possible connection between the cystatin C gene and Alzheimer’s disease. Knowing more about the effects of a single mutation in this gene brings us another step toward understanding the complex genetics of Alzheimer’s.

The mystery of HCCAA’s origins was tackled jointly by scientists in Iceland and at Johns Hopkins in the United States. It is reported in June 26 issue of PLOS Genetics