Congenital genetic defects that cause metabolic disease are one important reason why some people are born with intellectual disability. The result is that the uptake and combustion of nutrients do not work normally.

Untreated, such congenital diseases can cause intellectual disability. People can also become severely physically debilitated and eventually lose the ability to eat, talk and walk.

Phenylketonuria (PKT), also known as Følling’s disease, is the most well known of such diseases. All newborns in Norway undergo blood screening to detect metabolic diseases.

The two to five children who are diagnosed with PKT in Norway each year lack an enzyme in the liver and need to be on a strict diet all their lives.

In the past, these children developed severe intellectual disability and died young.

Can be treated with diet

In the last ten years, many more such rare genetic conditions have been discovered. They cause various metabolic disorders, which lead to intellectual disability if left untreated.

“What all these conditions have in common is that they lead to disturbances in the metabolism of certain nutrients, such as a vitamin, a mineral, part of a protein or a type of fat,” says senior consultant Sigrun Hope at Oslo University Hospital. She specializes in psychiatry.

This can either lead to people getting too little of certain important nutrients or failing to excrete waste products, which cause intellectual disability.

Hope previously discovered that people with autism have much more of the vitamin B12 than people without autism.

Creatine deficiency can cause intellectual disabilities

Creatine is an interesting substance that plays a role in normal brain development. Many fitness enthusiasts know that the drug creatine can increase the effects of exercise.

Among body builders, creatine is one of the most widely used supplements for building muscle.

But a lack of creatine does not primarily lead to decreased muscle strength.

“Creatine deficiency causes delayed language development, and is a relatively more common cause of intellectual disabilities and autism,” Hope says.

It is estimated that up to one percent of men with intellectual disability have a creatine deficiency.

Two genetic defects can cause creatine deficiency. For these patients, simply taking creatine supplements helps.

But one day, Jack Schjelderup, a neurologist at Haukeland Hospital, admitted a 34-year-old patient who was to become a new challenge.

Schjelderup works at the rehabilitation center for adults.

Two years earlier, the patient had been told that the cause of his general learning delay was due to defective creatine transporters. Already as a four-year-old he had been diagnosed with intellectual disability.

In this case the patient produces creatine, but lacks the transport mechanism to carry it into the right cells in the brain. For him, taking creatine supplements didn’t help.

Initially, the patient was relatively well-functioning. He had protected work and enjoyed playing football. But lately he had been gradually getting weaker.

He had difficulty eating, was no longer able to work and stopped talking. He was very malnourished and walked very unsteadily.

Schjelderup assessed the condition as critical.

The research literature had described only ten adults with this creatine-transporter defect up to that point. Several of them died early.

Schjelderup contacted Hope and the geneticist who had detected the condition. He knew that Hope was involved in research on treatable metabolic diseases.

“Together we contacted researcher Clara Karnebeek from the Netherlands,” says Hope.

Karnebeek originated the concept of treatable intellectual disabilities.

The collaboration was to lead to the discovery of a new treatment.

Tested out body building supplements

Painstaking biochemical detective work, combined with trial and error, ensued.

Karnebeek and Hope advised Schjelderup to give the patient a supplement with two amino acids that are the precursors to creatine, and which can be purchased at health food stores.

They also recommended supplements with cyclocreatine, another form of creatine that had recently shown positive effects in animal trials.

The patient received both the two amino acids and supplements with cyclocreatine intended for body builders. But the patient’s condition worsened.

He became weaker. His symptoms indicated side effects from the two amino acids glycine and arginine.

Improvement from supplements

Schjelderup was advised to cut out the first two supplements, and try just the dietary supplement with cyclocreatine.

Then the patient showed improvement. He gained weight, became stronger and was able to return to his protected work.

However, after ten months the supplement was sold out and could no longer be found on the market. After a few months, the patient became weaker again.

He lost weight, took a long time eating and was bedridden and weak.

What were the ingredients in the supplement, and why had it worked?

Schjelderup was able to analyze what the preparation consisted of, and surprisingly enough, the main ingredient was betaine, a substance that is abundant in beets.

The patient took supplements with betaine and recovered. His eating improved, he gained weight and started talking and walking again.

The patient has a younger half-brother with the same genetic defect, whose condition also became worse in adulthood. He had great difficulty chewing, swallowing and eating at a normal pace.

The half-brother also started taking betaine supplements and improved as his brother had.

“These cases show how doctors can discover new, important treatments by using clinical knowledge and by collaborating with researchers,” Hope says.

Over 80 conditions discovered since 2012

Karnebeek has made a great effort to map genetic causes of intellectual disability. In the last ten years alone, she has identified 81 conditions caused by genetic disorders.

More children are now being genetically examined than previously.

In questionable situations, a child can be screened for genetic disorders.

“Intellectual disability is often detected around age two due to delayed language development,” Hope says.

At Oslo University Hospital, the child can then receive metabolic screening.

The therapists can determine if a genetic defect is the cause of the delayed development.

Frambu competence center for rare diagnoses offers information, courses and guidance.

Fragile X syndrome

All told, 800 different conditions can cause metabolic “poisoning” or deficiency diseases that can lead to intellectual disabilities. Each disease is very rare.

Treatment can prevent intellectual disability or reduce its harmful effects. Hundreds of treatment methods are available.

These diseases are often due to X-linked inheritance, meaning the gene causing the disorder is on the X chromosome. They most often affect boys, because the defect is on their single X chromosome.

Girls have two X chromosomes and therefore don’t get sick because the body uses their other X chromosome. But women can pass the syndrome on to their sons.

This was the situation that resulted in the two brothers’ creatine transporter deficiency.

Will Parker (25) from Mississippi appreciates the Norwegian research work that has found a treatment for his condition.

He was diagnosed as having creatine transporter deficiency when he was 12 years old.

His mother Melissa Parker is a board member of CTD, the Creatine transporter deficiency interest organizationand is also director at the State Department og Health in Mississippi.

Lack of genetic testing

More children are being tested than before. However, many adult patients with intellectual disabilities have not been genetically screened with the latest methods.

If you determine the cause of the developmental delay, you can also in many cases treat the patient with certain supplements to prevent deterioration.

“For this reason, it’s important to find the cause of developmental disabilities if possible,” says Hope.

She also believes that some adults who have an ambiguous psychiatric disorder may actually be suffering from ailments due to an undiagnosed genetic cause.

More patients could be helped

If therapists hadn’t known that the patient in Bergen had a creatine transporter defect, they wouldn’t have known which supplements to try.

Hope believes there is reason to believe that more patients than just the two brothers from Bergen could benefit from betaine supplements.

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