Rare syndrome 'may give autism clues'

Monday November 28 2011

“A rare syndrome linked to autism could help explain the origins of the condition,” BBC News reported. The broadcaster said that in the search for clues about autism, scientists have examined a rare condition called Timothy syndrome, which can cause autistic behaviour. Although just 20 people are thought to have the condition worldwide, it is of interest because the cause has been pinpointed to a single gene defect.

In a new laboratory study, scientists took skin cells from two people with Timothy syndrome and converted them into nerve cells for use in a series of experiments. They found that the types of nerve cells that developed differed from those in people without Timothy syndrome, and that activity of specific genes varied in these cells.

Although scientists found that one of these differences in gene activity could be reversed by a particular experimental drug in the laboratory, it is unclear whether this would have any practical benefit in people with Timothy syndrome. It is also unclear to what extent the results represent what happens in most autistic spectrum disorders, which are not caused by this syndrome. Overall, further study of the Timothy syndrome nerve cells and animal studies of the syndrome will be needed to understand Timothy syndrome and its implications for autism.

Where did the story come from?

The study was carried out by researchers from Stanford University and other research centres in the US and Japan. It was funded by the US National Institutes of Health, US National Institute of Mental Health, the California Institute for Regenerative Medicine and the Simons Foundation for Autism Research. The study was published in the peer-reviewed journal Nature Medicine.

This story was covered in a balanced way by BBC News. It explained that Timothy syndrome is a rare cause of autism and included a quote from one of the researchers that put the findings of this exploratory lab research into context.

What kind of research was this?

This laboratory research looked at the effects of an extremely rare condition called Timothy syndrome, which causes a range of problems, including heart rhythm problems, developmental delay, and usually autistic spectrum disorder. People with the condition usually die in childhood from their heart problems. According to the US National Library of Medicine, there are only 20 reported cases of the condition worldwide.

The condition is caused by a mutation in a gene called CACNA1C, which is involved in the production of calcium channels, key protein structures that allow cells to control the flow of electrically charged atoms (ions) into the cells. The flow of calcium ions is involved in a range of important cellular functions, including the generation of electrical signals, cell-to-cell communication and the regulation of certain genes.

The study looked at how the Timothy syndrome mutation affects brain cells, to try to understand how this might lead to autism in the affected individuals. Although most people with autism do not have Timothy syndrome, the researchers hoped that understanding this rare syndrome would shed light on the brain changes that might cause the more common forms of autism. It may also help them eventually identify drugs that could help treat autism, but this would be a longer-term goal.

Laboratory research is the most appropriate way to investigate this type of question, as it would be difficult to do this kind of research in humans.

What did the research involve?

The researchers took skin cells from two people with Timothy syndrome and three people without Timothy syndrome (controls). They used recently developed techniques to “re-programme” the skin cells to become stem cells in the laboratory. Stem cells are “building block” cells that can develop into any form of cell in the body. The researchers treated the stem cells in a way that encouraged them to develop into types of nerve cells (neurons) found in the outer region of the human brain, in an area called the cortex. They then studied how the Timothy syndrome-derived nerve cells differed from the normal control nerve cells.

Nerve cells transmit signals using electrical impulses, which they generate by controlling the flow of electrically charged atoms (ions) across the cell’s membrane. Given that Timothy syndrome is caused by a mutation in a gene that produces one protein involved in the transport of calcium ions, the researchers were interested in whether the Timothy syndrome nerve cells performed similarly to control nerve cells, for example in how they sent electrical signals.

The flow of calcium into cells also influences which genes are switched on in the cells, so the researchers also looked at whether this was affected in Timothy syndrome nerve cells. They also looked at whether the nerve cells derived from people with Timothy syndrome were of the same types as the control nerve cells. They did this by looking for genes that are only switched on in specific types of nerve cells. The researchers also used genetically engineered mice carrying the Timothy syndrome mutation to see if their brain cells showed similar effects.

They also investigated the effect of drugs that block the flow of calcium into the cell through the protein channel affected by Timothy syndrome.

What were the basic results?

The researchers found that similar numbers of nerve cells could be obtained from the reprogrammed Timothy syndrome and control stem cells, and that the cells could divide and grow in similar ways. Nerve cells carry messages using electrical impulses, and the Timothy syndrome nerve cells had slightly different electrical properties to control nerve cells. At a specific point during electrical signalling, the Timothy syndrome nerve cells allowed more calcium to flow into them than the control nerve cells did.

The activity of certain genes was also found to differ between the Timothy syndrome nerve cells and the control nerve cells. Of these genes, it had previously been suggested that 11 play a role in autistic spectrum disorders or intellectual disability.

A greater proportion of the Timothy syndrome nerve cells than the control nerve cells were found to resemble the nerves found in the upper layer of the cortex. Also, fewer Timothy syndrome nerve cells were found to resemble the nerves found in the lower layer of the cortex. In particular, the researchers found that fewer of the Timothy syndrome nerve cells switched on a gene called SATB2, which is normally switched on in a specific type of lower layer nerve cell. The researchers also found fewer brain nerve cells producing SATB2 in mice carrying the Timothy syndrome mutation.

More human Timothy syndrome nerve cells switched on a gene called TH, which makes an enzyme that is important for normal signalling between cells in the nervous system. However, this increased TH activity was not found in the brains of mice carrying the Timothy syndrome mutation. During lab tests, the researchers were able to reduce the activity of the TH gene by treating the mice with a chemical called roscovitine.

How did the researchers interpret the results?

The researchers concluded that their findings provided “strong evidence” that the CACNA1C gene, which is mutated in Timothy syndrome, normally regulates the development of nerve cells in the cortex of the brain. They say that this offers “new insights into the causes of autism in individuals with Timothy syndrome”.


This study has furthered researchers’ understanding of the effects of the Timothy syndrome mutation on nerve cells in the laboratory. This type of research has been made possible because of recent scientific advances that allow researchers to produce different types of cell, including nerves, from stem cells derived from adult skin cells. This has granted them a supply of nerve cells that do not need to be sourced from people’s brains or from animals. The results may be more representative of what happens in humans than if the researchers only studied cells from mice that were genetically engineered to carry the Timothy syndrome mutation. Studying these individual skin-derived nerve cells is unlikely to be fully representative of the complexities of the developing human brain, but is likely to be the best method currently available.

Importantly, although the experimental drug roscovitine was found to reduce the activity of one gene in nerve cells derived from the skin of people with Timothy syndrome, whether this would produce any practical benefit for people with this syndrome is not known. Much more laboratory and animal research would be needed to assess the potential effects (including side effects) of this or similar drugs before they could be tested on people with this syndrome. It is also worth noting that Timothy syndrome is a very rare cause of autism. It is not clear to what extent these findings apply to more common forms of autism.

Overall, further study of these Timothy syndrome nerve cells and in animal models of the syndrome will be needed to confirm the results and improve our understanding of the condition.

Analysis by Bazian
Edited by NHS Choices