In the 5th century, in early medieval Ireland, Conall Gulban, the Irish king, gave his name to an area of land on the northwestern tip of the Irish coast. His kingdom was called Tir Chonall, “the land of Conall” – or, today, Donegal.
Somewhere in the line of descendants of the king, known as Senel Conail or “Kin of Conall”, it is believed that an error occurred in the genome of the scion, in particular, a mutation in the gene responsible for the production of a protein called transthyretin (TTR). A genetic error led to the birth of a rare disease known as hereditary transthyretin (ATTR) amyloidosis.
The TTR protein is produced primarily in the liver and is responsible for delivering vitamin A and a hormone called thyroxine throughout the body. But in people with hereditary ATTR amyloidosis, a genetic mutation results in a tainted version of it. This shapeless TTR aggregates and leaves deposits of amyloid, another protein, in tissues around the body, mainly in the heart muscles and nerves. These accumulations of amyloid prevent the tissues from doing their job, wreaking havoc.
Today, along the 15-mile stretch of the Donegal coast, where Irish is still predominantly spoken in many areas, the mutation has been found in about 1 percent of the population. The resulting illness, known colloquially as Donegal Amy, plagued Donegal natives for decades.
There are an estimated 50,000 people with hereditary amyloidosis worldwide, and Donegal Amy is just one type. It is caused by a Thr60Ala mutation in the TRR gene, but there are over 130 mutations in this gene that are thought to cause other forms of the disease. Carriers of these mutations usually appear as hyperlocalized clusters. The most common Val30Met mutation, the first described in 1952, can be found in northern Portugal around the city of Porto, as well as in northern Sweden and Japan. The other, Val122Ile, primarily affects people of West African descent – about 4 percent African Americans are estimated to be carriers.
While each mutation causes a slightly different version of the disease, in Donegal Amy’s case, the condition usually manifests itself after the age of 60. It begins with numbness of limbs such as arms and legs and movement. orally as it progresses, causing tingling, unbearable goosebumps, and muscle weakness—all symptoms of polyneuropathy or peripheral nerve damage. The disease quickly progresses to damage to the autonomic nervous system, which regulates involuntary bodily processes, causing weight loss, diarrhea, constipation and urinary incontinence. Polyneuropathy is also accompanied by cardiomyopathy, a disease of the heart muscle in which the heart cannot pump blood as easily, causing shortness of breath, chest pain, and swelling of the legs, ankles, and feet. Patients die between 3 and 15 years after diagnosis, usually due to chronic heart failure.
Because the symptoms of hereditary amyloidosis are so varied, doctors rarely know when they have a case. The patient usually doesn’t tell their cardiologist about their carpal tunnel syndrome, and their neurologist doesn’t know what to scan for heart block. “The whole diagnostic path is riddled with traps,” researchers noted.