Fumarase deficiency

Fast-forward to 1990, a century after polygyny was abandoned, and the upshot was only just beginning to emerge. In an office several hundred miles from where Young gave his speech, a 10-year-old boy was presented to Theodore Tarby, a doctor specialising in rare childhood diseases.

The boy had unusual facial features, including a prominent forehead, low-set ears, widely spaced eyes and a small jaw. He was also severely physically and mentally disabled.

After performing all the usual tests, Tarby was stumped. He had never seen a case like it. Eventually he sent a urine sample to a lab that specialises in detecting rare diseases. They diagnosed “fumarase deficiency”, an inherited disorder of the metabolism. With just 13 cases known to medical science (translating into odds of one in 400 million), it was rare indeed. It looked like a case of plain bad luck.

But there was a twist. It turned out his sister, whom the couple believed was suffering from cerebral palsy, had it too. In fact, together with colleagues from the Barrow Neurological Institute, soon Tarby had diagnosed a total of eight new cases, in children ranging from 20 months to 12 years old.

In every case, the child had the same distinctive facial features, the same delayed development – most couldn’t sit up, let alone walk – and, crucially, they were from the same region on the Arizona-Utah border, known as Short Creek.

Even more intriguingly, this region is polygynous. In this small, isolated community of Fundamentalist Church of Jesus Christ of Latter-Day Saints (FLDS), the likelihood of being born with fumarase deficiency is over a million times above the global average…

Faith Bistline has five cousins with the disease, who she used to look after until she left the FLDS in 2011. “They are completely physically and mentally disabled,” she says. The oldest started learning to walk when he was two years old, but stopped after a long bout of seizures. Now that cousin is in his 30s and not even able to crawl.

Fumarase deficiency is rare because it’s recessive – it only develops if a person inherits two faulty copies of the gene

In fact, only one of her cousins can walk. “She can also make some vocalisations and sometimes you can understand a little bit of what she’s saying, but I wouldn’t call it speaking,” she says. They all have feeding tubes and need care 24 hours a day.

Fumarase deficiency is rare because it’s recessive – it only develops if a person inherits two faulty copies of the gene, one from each parent. To get to grips with why it’s plaguing Short Creek, first we need to back to the mid-19th Century…

Followers needed somewhere to go…

They settled on the remote ranching town of Short Creek, which formed part of the Arizona Strip. This was an area larger than Belgium (14,000 sq miles, or 36,000 sq km) with only a handful of inhabitants – the perfect place to hide from the prying eyes of federal marshals.

Today it’s home to the twin towns of Hildale and Colorado City – either side of the Utah-Arizona border – and some 7,700 people. It’s the headquarters of the FLDS, which is famous for its conservative way of life and polygyny. “Most families include at least three wives, because that’s the number you need to enter heaven,” says Bistline, who has three mothers and 27 siblings.

In the end, the link to fumarase deficiency is a numbers game. Take Brigham Young. In all, his children begat 204 grandchildren, who, in turn, begat 745 great-grandchildren. By 1982, it was reported that he had at least 5,000 direct descendants.

This sudden explosion is down to exponential growth. Even with just one wife and three children, if every subsequent generation follows suit a man can have 243 descendants after just five generations. In polygynous families this is supercharged. If every generation includes three wives and 30 children, a man can – theoretically – flood a community with over 24 million of his descendants in the space of five generations, or little over 100 years. Of course this isn’t what actually happens. Instead, lineages begin to fold in on themselves as distant (and in the FLDS, not so distant) cousins marry. In polygynous societies, it doesn’t take long before everyone is related.

This is thought to be how one-in-200 men (one in 12.5 in Asia) are descended directly from super-fertile Mongol warrior Genghis Khan, who died nearly eight centuries ago. As Brigham Young said himself: “It is obvious that I could not have been blessed with such a family, if I had been restricted to one wife…”

In Short Creek, just two surnames dominate the local records – Jessop and Barlow. According to local historian Benjamin Bistline, who spoke to news agency Reuters back in 2007, 75 to 80% of people in Short Creek are blood relatives of the community’s founding patriarchs, Joseph Jessop and John Barlow…

The fumarase deficiency gene has been traced to Joseph Jessop and his first wife, Martha Yeates (14 children). One of their daughters went on to marry co-founder John Barlow – and the rest is history. Today the number of people carrying the fumarase gene in Short Creek is thought to be in the thousands…

Which brings us to the good news. Since inbreeding tends to uncover “recessive” mutations that would normally remain in hiding, studying these communities has helped scientists to identify many disease-causing genes. That’s because genetic information is useless on its own. To be meaningful to medical research, it must be linked to information about disease. In fact, more human disease genes have been discovered in Utah – with its Mormon history – than any other place in the world.

It’s not the legacy Brigham Young expected, but in the end, it’s possible that the controversial practice might have some unintended positives.

http://www.bbc.com/future/story/20170726-the-polygamous-town-facing-genetic-disaster

Courtesy of a colleague