fifth In the early Middle Ages Ireland, Conal Galvan, King of Ireland, gave his name to a piece of land at the northwestern tip of the Irish coast. It was called today’s Donegal.
Somewhere in the descendants of the king known as Senel Connail or “a kind of Conal”, it is believed that a mistake was made in the Pion’s genome. Specifically, mutations in genes involved in the production of a protein called transthyretin (TTR). A genetic error has created a rare condition known as hereditary transthyretin (ATTR) amyloidosis.
Made primarily in the liver, the TTR protein is responsible for transporting vitamin A and a hormone called thyroxine throughout the body. However, in a person with hereditary ATTR amyloidosis, a genetic mutation produces a failed version of it: His TTR in this malformation aggregates and releases another protein, amyloid clumps, into tissues around the body (mainly heart muscle and nerves). These amyloid clumps interfere and wreak havoc when the tissue tries to do its job.
Today, the mutation is found in about 1% of the population along a 15-mile stretch of Donegal coast where Irish is still predominantly spoken in many areas. The resulting disease, commonly known as Donegal Amy, has ravaged the natives of Donegal for decades.
Donegal Amy is just one of an estimated 50,000 people worldwide with hereditary amyloidosis. This is caused by her Thr60Ala mutation in her TRR gene, although she has over 130 mutations in this gene that are thought to cause other forms of the condition. Carriers of these mutations tend to occur in hyperlocalized clusters. Val30Met, the most common mutation first reported in 1952, is found in northern Portugal around the city of Porto, and is also found in northern Sweden and Japan. The other, Val122Ile, primarily affects people of West African descent, with an estimated 4% of African Americans carrying it.
Each mutation causes a slightly different version of the disease, but for Donegal Amy, the condition usually becomes apparent after age 60. It begins with numbness in the extremities of the body, such as the hands and feet, and progresses to tingling, excruciating pins and needles, and muscle weakness.All symptoms of polyneuropathy, or damage to peripheral nerves. progresses rapidly and attacks 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 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 from chronic heart failure.
The symptoms of hereditary amyloidosis are so variable that doctors know very little of the cases in their hands. “There are many pitfalls along the diagnostic pathway,” the researchers note.
