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A fragile existence

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Science  12 Oct 2018:
Vol. 362, Issue 6411, pp. 172-175
DOI: 10.1126/science.362.6411.172

Why is a remote Colombian town a hot spot of an inherited intellectual disability?

Jair Triviño has fragile X syndrome and is nearing 60, but works exhausting hours collecting fruit in local fields.

PHOTO: JUAN CRISTÓBAL COBO

It's late afternoon in this tiny town tucked into the Colombian Andes, when Mercedes Triviño, 82, lights the wood stove to start to prepare dinner. Smoke fills the two-bedroom home she shares with six of her adult children.

Francia, 38, one of the youngest, is the family's primary breadwinner. She brings home 28,000 Colombian pesos (roughly $10) a day harvesting papayas in the fields just outside town. “Really, what I earn is just enough for eating and nothing else,” she says. Four of her siblings have fragile X syndrome, a genetic condition that causes intellectual disability, physical abnormalities, and often autism. Jair, 57, works alongside Francia when he can. Hector, 45, is also somewhat able to care for himself. Victor, 55, and Joanna, 35—who has both fragile X and Down syndrome—are less independent.

In fragile X syndrome, pieces of the X chromosome appear to be falling off.

IMAGE: MONICA SCHROEDER/SCIENCE SOURCE

As Mercedes serves coffee on this July afternoon, sweetening it with a hefty dose of sugar and offering her best cups to her guests, she talks about the condition that dominates the lives of her family and many others here. Her niece, Patricia, 48, who lives a few blocks away, cares for two adult sons and a nephew with fragile X. More distant kin in town, the Quinteros, also have grown children with the condition. Other neighbors are adults with fragile X who have no caretaker and look after one another.

In Colombia, this town has long been known as the home of los bobos, “the foolish ones”—thanks in part to a 1980s novel and a later TV series that depicted families like the Triviños. More recently, scientists have caught on that it is home to the world's largest known cluster of people with fragile X. One researcher, medical geneticist Wilmar Saldarriaga-Gil of the University of Valle (Univalle) in Cali, Colombia, has made Ricaurte the focal point of his scientific inquiry. Saldarriaga-Gil, who vacationed nearby as a child, says he has visited about a hundred times since the mid-1990s to trace how fragile X affected the town and its inhabitants—and to try to understand details of the syndrome's biology. “This is a history of scientific research, a history of my community, a history of my life,” he says.

The payoff from research in this town could have global impacts. Caused by mutations in a gene called FMR1 on the X chromosome, fragile X syndrome is the leading cause of inherited intellectual disability worldwide; it affects as many as one in 2000 men and one in 4000 women. And as a single-gene cause of autism—a recalcitrantly complex condition—fragile X has been the focus of efforts to develop drugs for autism. The proteins disrupted in people with the syndrome are also key players in brain development.

In March, Saldarriaga-Gil and his colleagues reported that at least 5% of residents here carry either the full-blown fragile X mutation or less severe “premutations” that can trigger the condition in future generations. Premutation carriers usually escape cognitive problems, but some develop physical symptoms, including tremors and fertility problems. The research here might explain such variability, which could reflect how the protein FMR1 encodes, FMRP, interacts with other proteins and pathways.

The scale of Saldarriaga-Gil's investigations is small—Ricaurte only has 58 full mutation and premutation carriers, by his count—but the research benefits because the town's residents share the same environment and a similar genetic background, offering a natural control for some variables. “What you have [here] is something that certainly warrants a lot more intensive investigation,” says Jim Grigsby, a clinical health psychologist at the University of Colorado in Denver.

SALDARRIAGA-GIL'S OBSESSION with this town began in 1980. As a boy, he spent summers at a family home in Huasano, 10 kilometers away. When he attended church here, he couldn't help noticing the lanky men and women with large, flat ears who spoke very little or not at all. “Everyone who knows Ricaurte had curiosity,” Saldarriaga-Gil says. “Why is it happening here?”

Growing up, he heard many stories. According to one, nearby magnesium mines had poisoned Ricaurte's groundwater, damaging the minds of people who drank it. Protestant missionaries to the region warned residents that God had sent “the foolishness” to punish them for worshiping “El Divino,” an image of Jesus in Ricaurte's white A-frame church that draws Catholic pilgrims. “The other hypothesis was sorcery of some sort,” Saldarriaga-Gil says. In that version, women in the town prepared a love potion that sometimes went wrong, producing intellectual disability instead of undying devotion. Saldarriaga-Gil's father warned him never to drink anything offered by a woman from Ricaurte.

Saldarriaga-Gil eventually set out to discover the truth as a medical student in the late 1990s. His adviser suggested the people here might have Down syndrome. But when Saldarriaga-Gil paged through a 1000-page medical textbook, he saw photographs of people who looked eerily similar to a boy he knew in Ricaurte—Patricia Triviño's nephew Ronald. The people in the textbook had fragile X syndrome.

To confirm that the resemblance was more than coincidence, in 1997 Saldarriaga-Gil took blood samples from 28 people in town who he suspected were affected, Ronald included. He analyzed each person's karyotype—the number and appearance of their chromosomes—by inspecting their blood cells under a microscope.

In most people, FMR1 contains anywhere from six to 54 repeats of a specific set of three DNA “letters,” or bases: CGG. In people with fragile X syndrome, however, the gene has more than 200 repeats. The extra DNA disrupts the X chromosome; under the microscope, tiny islands appear to break away from the chromosome, making it look fragile. Of the 28 people whose karyotypes Saldarriaga-Gil analyzed, 19 showed those telltale islands.

In the Quinteros family in Ricaurte, Colombia, Soledad (center) and Yeison (far right) have fragile X syndrome. Rosario (second from right), her daughter Sara (second from left), and Sara's son Juan Pablo (far left) are unaffected, but Sara had her fallopian tubes cut after learning she is a carrier of the full mutation causing the syndrome.

PHOTO: JUAN CRISTÓBAL COBO

Premutation carriers, however, have between 55 and 200 CGG repeats—too few to be obvious under a microscope. In 2012, Saldarriaga-Gil decided to try to identify those carriers by building a pedigree chart to trace the condition's inheritance through Ricaurte's families. Premutation carriers often have affected children or grandchildren because in fragile X—as in other “triplet repeat” conditions such as Huntington disease—the number of repeats typically increases with successive generations. Working backward from affected individuals, Saldarriaga-Gil tried to guess at who had passed the mutation on. That approach took him only so far, however, because he had no definitive test for premutations.

The next year, his karyotype research caught the attention of experts in fragile X, including Randi Hagerman, medical director of the Medical Investigation of Neurodevelopmental Disorders Institute at the University of California, Davis. She and her colleagues offered to help spot the premutation carriers by using a polymerase chain reaction (PCR) test—which Saldarriaga-Gil wasn't equipped to do in his own lab. PCR would make it possible to amplify and sequence the residents' DNA.

Hagerman recalls being struck by Ricaurte's promise for studying fragile X: “When I first visited this town, I was surrounded by individuals with fragile X syndrome, and I said, ‘Oh, my God, this is like ground zero for fragile X.’”

THE TWO LANE ROAD TO RICAURTE from Cali traverses sugarcane fields between the cloud-shrouded Andes that enclose the town. Saldarriaga-Gil estimates he has driven the route dozens of times in the past 5 years. Before 2010, Colombia's drug trade made the trip dangerous. The region is safer now, he says, but the mountains still teem with farmers secretly growing coca, the raw material of cocaine.

Saldarriaga-Gil checks in on residents with fragile X every 2 months or so, offering routine checkups and monitoring them for complications. Over multiple visits between 2015 and 2016, he and his students also collected blood samples from 926 people, about 80% of the population. Genetic analysis of the samples led to his recent finding that about 5% of Ricaurte's residents have either the full mutation or a premutation. He supplemented the genetic work by recording oral histories and digging up centuries-old land, marriage, and birth records with help from a local historian. Ultimately, Saldarriaga-Gil reconstructed much of the town's history of the syndrome.

An unwieldy pedigree chart now dominates one of his office walls, spanning nine generations and 420 names. Two big families—the Triviños and Gordillos—form its trunk. Saldarriaga-Gil slashes lines through the deceased and scrawls notes in looping handwriting where he is still guessing at kinship.

One name is circled, with sunlike rays extending out in every direction: Manuel Triviño, who may be Mercedes's greatgrandfather. Saldarriaga-Gil says he suspects Manuel was one of the town's original settlers in the early 1880s and carried the premutation to Ricaurte. Everyone here with fragile X could be his direct descendant (although how the mutation spread to the Gordillos is still unclear). To confirm that “founder effect,” Saldarriaga-Gil's team is conducting a haplotype analysis: The scientists are looking for other genetic variants shared by people with the condition, which would imply that they all share a common forebear.

Saldarriaga-Gil and colleagues from Univalle are also sequencing the exomes—the protein-coding portions of the genome—of the people from whom they took blood samples in 2015 and 2016. They hope to learn how genetic variability outside the FMR1 gene influences how fragile X mutations manifest themselves—and why people with the same FMR1 mutations can have such different outcomes.

Among women, “mosaicism”—in which a person's cells aren't all genetically identical—explains part of it. Because women have two X chromosomes, each cell turns off one of them at random. If most of a woman's cells turn off the mutated copy, she might show few outward signs of the mutation; if the normal copy is shut down more often, she might be more severely affected. Mosaicism emerges differently in men, who have a single X chromosome: Some of their cells may have the full FMR1 mutation—200-plus CGG repeats—whereas others end up with the shorter premutation or with a complete deletion of FMR1.

The array of symptoms resulting from a mutation might also depend on how FMRP interacts with other proteins. FMRP is missing in people with the full mutation, which silences FMR1. Because FMRP controls the activity of nearly 1000 other proteins, many of which are crucial to the interactions between neurons, its loss can have far-reaching effects—particularly during brain development. But in people with the premutation, the impact of the reduced protein might be more or less severe depending on other genetic variations.

Saldarriaga-Gil and his colleagues predict that genetic analyses will reveal that people whose fragile X symptoms are similar have overlapping patterns of gene expression and protein interaction. “This type of population is ideal for this study because these people have a similar genetic background,” says Univalle geneticist Julián Andrés Ramírez Cheyne, who leads the exome study.

The ultimate goal for fragile X researchers is to develop treatments. Because of its connection to intellectual disability and autism, fragile X has been the focus of an extensive—and so far, unsuccessful—drug development program. Several candidates that showed promise in early clinical trials fizzled out in larger trials. Researchers are seeking new proteins or pathways to target—and some of those may emerge from the work done here. “Most geneticists would say there are genetic modifiers in some of these families,” says Eric Klann, director of the Center for Neural Science at New York University in New York City—clues, he says, to possible treatments.

Understanding the molecular underpinnings of fragile X might also explain why general anesthesia and some seizure medications are more toxic to premutation carriers than to typical people. Hagerman says she was struck by the number of premutation carriers here whose symptoms are unusually severe. Patricia Triviño's sister Rosaura, 60, for example, is deaf and mute; her sister Julieta, 58, has seizures and uses a wheelchair. Hagerman says pesticides, sprayed heavily in the nearby fields, might be to blame. “Looking at the environmental contaminants could tell us a lot about vulnerability” in people with the mutations, she says.

NO ONE HERE IS WAITING for radical new treatments. Even if the residents can help researchers develop drugs, they know they are likely to be among the last to receive them.

Mercedes Triviño's son Jair is one of the oldest workers in the papaya fields, but he has no complaints. Even though his work is arduous, living among others with similar symptoms has given him a degree of freedom he'd be hard-pressed to find anywhere else. At the end of his shift on a hot July day, Jair fills the back of a pickup truck with fruit. He swings the heavy crates one by one, his wiry arms flexing until he has stacked nearly 100. He stops to wipe sweat from his brow and secures the truck's door with an iron bolt. The driver starts the engine as Jair hops in the back. Jair says he looks forward to being back the next day “if it's God's wish.”

Back in town, Patricia, who is Jair's cousin, says all she wants is a good drug to control the seizures of her sister Julieta. For years, Julieta has taken phenobarbital to control her convulsions, but the drug is risky for premutation carriers like her, who may be particularly vulnerable to its neurotoxic effects. Scans that Saldarriaga-Gil took show that portions of Julieta's brain have shrunk, and in the past few weeks, she has started to complain of headaches. Another of Patricia's sisters, Esperanza, 60, who also was a premutation carrier and relied on phenobarbital for years, died in 2015 after several massive seizures. Julieta could take safer medications, such as valproate, but getting a prescription hasn't been easy.

Wilmar Saldarriaga-Gil (right) comforts Julieta Triviño (left), who has fragile X syndrome.

PHOTO: JUAN CRISTÓBAL COBO

In July, a new doctor who serves Ricaurte and three other towns arrives to make her rounds. Rubbing Julieta's temples below her cropped black hair, the doctor explains that she doesn't have the correct paperwork to prescribe valporate. She suggests Patricia take Julieta to a doctor in Bolívar, about 7 kilometers away. Patricia doesn't own a car, and walking there would take her about an hour and a half.

For months, Patricia has pleaded with a local health minister, Viviana Alvarez, to secure basic sanitary supplies and protein supplements for Julieta—but to no avail. Although the family is entitled to free care through the government, Alvarez says her hands are tied: “Health insurance takes its time; the problem is on the national level.” The Hospital Santa Ana in Bolívar can't help much, either. With just eight doctors, it fielded 15,000 appointments and 5000 emergency room visits in 2017. The hospital director has hired a physical therapist to visit about 15 people here with fragile X every weekday but he says Ricaurte will probably never have its own physician.

“I always want them to do more,” Saldarriaga-Gil says, although he understands the financial constraints. He tries to fill in the gaps during his visits and has enlisted a Colombian nonprofit to donate clothes and mattresses to many of the families.

Given the harsh realities of life here with fragile X, some residents have made difficult decisions about the future of their families. Rosario Quintero's daughter, Sara, has the full mutation but shows no signs of the syndrome. Before Sara learned that she carried the mutation, she had a son, who also seems unaffected. But afterward, she had her fallopian tubes cut so that she cannot have any more children. Another carrier, who chose to remain anonymous, also decided not to have children.

Over the past decade here, only three children with fragile X have been born, and many with the condition are older than 50. Trapped in this valley by economic hardship and unyielding geography, the population with fragile X could slowly die out, Saldarriaga-Gil says. He is racing to understand the syndrome's secrets before that happens.

  • * This story was produced in collaboration with Spectrum (spectrumnews.org), where Hannah Furfaro is a staff reporter.

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