Crispr’s quest to kill Donegal Amy

In the 5th century, in early medieval Ireland, Conall Gulban, an Irish king, gave his name to an area of ​​land at the northwestern tip of the Irish coast. His kingdom was called Tír Chonall, “Conall’s land” – or today Donegal.

Somewhere along the king’s line of descent, known as Cenél Conaill or “lineage of Conall”, it is believed that an error occurred 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 mainly in the liver and is responsible for transporting vitamin A and a hormone called thyroxine around the body. But in those with hereditary ATTR amyloidosis, the genetic mutation produces an incorrect version of it. This misshapen TTR accumulates and leaves clumps of amyloid, another protein, in tissues around the body – mostly the heart muscles and nerves. These clumps of amyloid disrupt 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 native Donegal for decades.

It is estimated that there are around 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 more than 130 mutations of this gene that are thought to trigger other forms of the condition. Carriers of these mutations tend to appear in hyperlocalized clusters. The most common mutation, Val30Met, first described in 1952, is 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 usually makes itself known after the age of 60. It starts with numbness in the body’s extremities, such as the hands and feet, and moves inwards as it progresses to cause tingling, excruciating pins and needles and muscle weakness – all symptoms of polyneuropathy or damage to the peripheral nerves. The disease quickly progresses to attack the autonomic nervous system, which regulates involuntary bodily processes, triggering weight loss, diarrhoea, constipation and urinary incontinence. The polyneuropathy is also accompanied by cardiomyopathy, a disease of the heart muscle in which the heart is unable to pump blood as easily, causing breathing difficulties, chest pain and swelling in 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 have a case on their hands. A patient would not usually tell their cardiologist about the carpal tunnel syndrome, nor would the neurologist know whether to scan for a heart block. “The whole path of diagnosis is full of pitfalls,” researchers have noted.

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