hereditary transthyretin amyloidosis —
Trial hints at treating, or even curing, a rare fatal disease.
In the 5th century, in early medieval Ireland, Conall Gulban, an Irish king, gave his name to an area of land at the northwest tip of the Irish coast. His kingdom was called Tír Chonall, the “land of Conall”—or, today, Donegal.
Somewhere along the king’s descendant line, known as Cenél Conaill or “kindred of Conall,” it’s thought that a mistake arose in a scion’s genome—specifically, a mutation of a gene responsible for producing a protein called transthyretin (TTR). The genetic error resulted in the birth of a rare condition known as hereditary transthyretin (ATTR) amyloidosis.
The TTR protein is made predominantly in the liver and is responsible for shuttling vitamin A and a hormone called thyroxine around the body. But in those with hereditary ATTR amyloidosis, the genetic mutation produces a botched version of it. This misshapen TTR aggregates and leaves clumps of amyloid, another protein, in tissues around the body—mostly the heart muscles and the nerves. These amyloid clumps interfere with tissues as they try to do their job, wreaking havoc.
Today, along a 15-mile strip of the coast of Donegal, where the Irish language is still predominantly spoken in many areas, the mutation is found in about 1 percent of the population. The resulting disease—colloquially known as Donegal Amy—has ravaged Donegal natives for decades.
It’s estimated that there are about 50,000 people with hereditary amyloidosis across the world, and Donegal Amy is just one type. It’s caused by a Thr60Ala mutation in the TRR gene, but there are more than 130 mutations of this gene that are thought to trigger other forms of the condition. Carriers of these mutations tend to crop up in hyperlocalized clusters. The most common mutation, Val30Met, first described in 1952, can be found in northern Portugal around the city of Porto, and has also been found in northern Sweden and Japan. Another, Val122Ile, primarily affects people of West African descent—about 4 percent of African Americans are estimated to carry it.
While each mutation produces a slightly different version of the disease, in the case of Donegal Amy, the condition typically makes itself known after the age of 60. It starts with a numbness in the body’s extremities, such as the hands and feet, and moves inwards as it progresses to causing tingling, unbearable pins and needles, and muscle weakness—all symptoms of polyneuropathy, or damage to the peripheral nerves. The disease quickly moves on to attack the autonomic nervous system, which regulates involuntary bodily processes, triggering weight loss, diarrhea, constipation, and urinary incontinence. The polyneuropathy is also accompanied by cardiomyopathy, a disease of the heart muscle where the heart isn’t able to pump blood as easily, causing breathlessness, chest pain, and swelling of the legs, ankles, and feet. Patients die between three and 15 years after diagnosis, usually due to chronic heart failure. Because the symptoms of hereditary amyloidosis are so heterogeneous, doctors rarely know when they’ve got a case on their hands. A patient wouldn’t usually tell their heart doctor about their carpal tunnel syndrome, nor would their neurologist know to scan for a heart block. “The entire diagnostic pathway is riddled with pitfalls,” researchers have noted.
…. to be continued
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