Williams Syndrome: The people who are too friendly

People with Williams Syndrome treat strangers as their new best friends. Now the condition is giving clues to our evolutionary past – and what makes us human.

Imagine walking down the street and feeling an overwhelming love and warmth for every single person that you met. That is a familiar experience for people with Williams Syndrome (WS), a rare genetic condition that affects approximately 1 in 7,500 individuals.

People with WS, often dubbed the 'opposite of autism', have an innate desire to hug and befriend total strangers. They are extremely affectionate, empathetic, talkative and gregarious. They treat everyone they meet as their new best friend, yet there is a downside to being so friendly. Individuals often struggle to retain close friendships and are prone to isolation and loneliness.

People with WS are also sometimes too open and trusting towards strangers, not realising when they are in danger, leaving them vulnerable to abuse and bullying.

"It's very easy for someone to fool a person with Williams Syndrome and take advantage of them, because they are so trusting," says Alysson Muotri, a professor of paediatrics and cellular and molecular medicine at the University of California, San Diego (UCSD). "They give themselves to anybody without prejudice, which seems like a lovely trait, but at the end of the day there is a reason why the human brain evolved to be a little bit suspicious of a new person. You don't know if that person is there to hurt you or to love you, and they [a person with WS] cannot make that distinction," he says.

Few people with WS live independently as adults, and many suffer from severe anxiety. There are also health problems that accompany the condition, such as cardiovascular disease, developmental delays, and learning disabilities. Many people with WS have a lower IQ than the average, for example.

Over the last decade, scientists have learned more about the condition, which is offering a unique window into how some of the traits that make us human – such as kindness, trust, and friendliness – evolved.

First off, some facts. Humans have 46 chromosomes, organised into 23 pairs. During sperm or egg development, a process called 'recombination' occurs where genetic material is swapped between matching pairs of chromosomes. However in WS, the process goes wrong, and a whole section of DNA from one copy of chromosome seven is accidentally deleted. As a result, people with WS are missing one copy of between 25-27 genes.

These genes serve various functions. For example one, ELN, codes for a protein called elastin, which provides flexibility and elasticity to tissues throughout the body. A lack of elastin causes the artery walls to stiffen, leading to lifelong cardiovascular problems for people with Williams Syndrome.

Another gene, BAZ1B, affects the growth of what are known as neural-crest cells. These are stem cells which eventually form the basis of many tissues, including the bones and cartilage of the face. People with Williams Syndrome have distinct facial characteristics, such as a small, upturned nose, wide mouth, and small chin.

Yet pinpointing the gene, or genes, responsible for the increased friendliness of people with WS has proved more elusive. One theory is that BAZ1B could have a role here too. Some neural-crest cells go on to form the adrenal glands, which, through their release of adrenaline are responsible for the fight or flight response. It's feasible that people with fewer or impaired neural crest cells could produce less adrenaline. This, in turn, could make them less fearful of strangers.

Meanwhile, other scientists believe that a gene called GTF2I could be responsible. For example, research has shown that individual animals who lack GTF2I tend to be more social than other members of their species. Unpublished research suggests that fruit flies who don't have the gene like to eat together. Mice without GTF2I are more likely to approach a second 'stranger' mouse. Dogs also contain a variant of the GTF2I gene thought to make it less effective, which could explain their overt sociability and friendliness compared to wolves. Meanwhile, people who have a duplication of the gene tend to develop a form of autism characterised by social phobia.

Nevertheless, the exact mechanism by which GTF2I controls sociability isn't known. The protein GTF2I codes for is a transcription factor, meaning that it helps to regulate the expression of many other genes. One theory holds that the personality profile of WS individuals could be related to an impairment of myelin, the insulating layer or 'sheath' that wraps around nerves, especially those in the brain and spinal cord.

"Just like the electrical cable in your house, which is covered by a plastic insulation layer, myelin is crucial for the proper transmission of electrical signals from one neuron to another," says Boaz Barak, an associate professor at Tel Aviv University in Israel.

Barak and colleagues recently showed that not only were mice bred to lack GTF2I more social, but that their neurons contained less myelin. Giving them a drug that improved myelination made their behaviour more like that of other mice.

As myelin dramatically speeds up the rate at which electrical signals can travel, one explanation is that the loss of myelin could lead to slower, sluggish nerve cells. This could explain some of the cognitive difficulties faced by people with Williams Syndrome, as well as the poor motor skills associated with the condition.

However, Barak believes it could also disrupt the communication between the amygdala, the tiny, walnut shaped region of the brain that processes fear and emotion, and the frontal cortex – a region responsible for decision making, personality, and emotions. This could explain why people with WS do not fear, or mistrust strangers.

"What we discovered is that when you don't have GTF2I, the myelination process is impaired, leading to weak communication between the brain regions responsible for fear, and those in charge of social decision-making," says Barak.

Intriguingly, a FDA approved drug called clemastine – commonly used to treat allergies – is known to improve myelination. As brain samples donated by people with Williams Syndrome also show impairments in myelination, Barak and his team plan to repurpose clemastine as a potential treatment for the condition. They are currently assessing its safety and effectiveness in a phase 1 clinical trial – the first stage of testing done on humans – due to complete in December 2025.

"Individuals with Williams Syndrome have amazing traits that neurotypical people could learn from, so their behaviour is not something that we need to correct necessarily," says Barak. "We meet a lot of families and it is common to hear a parent saying, 'I would never change how much love she gives to the world, or I adore how friendly and loving she is.' However what we are trying to do is to develop treatments based on drugs that are already out there for those who want to use them," he says.

Barak's lab have also found that mice bred to lack the gene GTF2I also have dysfunctional mitochondria in their neurons. Mitochondria are the powerplants present in every cell that produce energy for the body to use. Brain samples from individuals with Williams Syndrome also show that their mitochondria do not develop and function properly.

"Neurons need energy in order to do their job, and what we found is that without GTF2I, the network of mitochondria does not form correctly," says Barak. "As a result, neurons have trouble meeting their energy needs – they suffer a power outage."

As a result of this, toxic substances build up inside the neurons, potentially preventing them from firing properly, according to Barak.

Meanwhile, others have suggested that losing the GTF2I gene could increase levels of oxytocin, the so-called "love hormone", in the brain. Research shows that people with WS produce more oxytocin, and have more oxytocin receptors – proteins that recognise and bind to oxytocin – than healthy controls.

Muotri, on the other hand, believes that the increased friendliness shown by people with WS can be explained by the number of synapses – or connections – in their brains. In 2016, his team took stem cells from the discarded baby teeth of children with WS. The cells were then reprogrammed to form neurons capable of forming connections, just like those seen in developing brains. On close examination, the neurons of these lab-grown mini brains were remarkably different.

"There were more synapses than normal, so the neurons were more branched and made more contacts," says Muotri.

In the 2016 study, the team also examined post-mortem samples taken from people with WS who had donated their brains to science. The same patterns were observed – the neurons of people with WS were more branched and formed more connections with other neurons.

Although Muotri and his team haven't yet unravelled all of the circuits involved, he suggests that it's likely that in WS, the frontal cortex forms more connections with the parts of the brain involved in reward. "When you remember someone or see someone that you like, your brain releases dopamine which creates a good sensation," he says.

"I think people with Williams Syndrome might have a dysregulation in this neurotransmitter. So when they see a new face, they immediately get a release of dopamine, and they feel good about it."

On the flip side of the coin, the team found that mini brains grown using stem cells from children with autism have fewer neuronal connections.

"We showed that if you lower the expression of the [GTF2I] gene, you make more connections, and if you increase the expression of the gene, you create less connections – which is amazing," says Muotri.

As traits like trust, kindness, and friendliness are so important to human survival, Muotri believes that evolution must keep a tight rein on the expression of the GTF2I gene. Humans are a social species, and our very survival rests on collaborating with one another. We need to be able to trust each other to a certain extent.

"The specific balance [of GTF2I] is probably quite important, as being too friendly is not a good thing, but not being friendly enough is also not a good thing," says Muotri. "So what evolution has done is tune the expression of that gene – it's found the exact right amount of socialisation that we can all tolerate."

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