Scientists discover a disease of constant fevers after finding a DNA mutation in seven patients

A never-before-seen condition that causes constant fevers and swollen lymph nodes has been discovered by scientists.

Doctors spotted the disease – called CRIA – after a two-decade investigation into the cause of a mystery affliction that struck seven patients.

All of the American patients – whose ages ranged from 10 to 82 and came from three different families – suffered headaches, chills and fevers from birth.

Tests of their entire DNA showed they all carried the same DNA mutation, which the researchers branded a ‘remarkable’ finding.

Academics found this then drove a ‘super killer protein’ to cause ‘uncontrollable cell death’, leading to severe inflammation. 

The disease, reported in the journal Nature, has now been named cleavage-resistant RIPK1-induced autoinflammatory syndrome, or CRIA. 

At this point it is unclear how to treat it. But the Australian and US experts who found it have said it is not life-threatening. 

It is not currently clear how many people may suffer from the inflammatory disease worldwide. More investigations are needed, the researchers said.

Tests of the patients began in 1999, when doctors were baffled by the cause of one family’s continuous fevers.

Investigations were led by Dr Dan Kastner, of the National Human Genome Research Institute at the US National Institutes of Health (NIH).  

Dr Kastner and his team evaluated patients from two different families with the same symptoms. It is not clear how many years later this was.

The patients would all suffer fevers of up to 41°C (106°F) for between two and seven days. The majority were struck down every fortnight.

Some patients also reported extreme chills, severe headaches, mouth ulcers, joint pain, diarrhoea, constipation, loss of appetite, weight loss, and hallucinations. 

Tests also showed patients had larger spleens and livers, which experts said was more prominent early in life. 

Scientists looked at all seven of the patients’ exomes – a part of the genome that encodes proteins in the body.

Dr Steven Boyden was at the forefront of finding the first clue to the disease at NIH. He and colleagues found each family had a mutation in the RIPK1 gene.   

Dr Boyden said: ‘It is remarkable, like lightning striking three times [the discovery of the genetic mutation in each family] in the same place. Each of the three mutations has the same result.’

Despite the findings, the team at NIH were unsure how the mutation was related to the symptoms.

In 2017, NIH were contacted by researchers at The Walter and Eliza Hall Institute of Medical Research in Parkville, Melbourne.

Professor John Silke and Dr Najoua Lalaoui were experts in RIPK1 genetics and were keen to merge their research once they found out about the existence of these patients on scientific forums. 

Together, the teams found the mutation in RIPK1 blocks a molecule of the same name from working properly. 

RIPK1 usually regulates inflammation in the body by being split in half. But when blocked by a genetic mutation, tests revealed it is unable to split. This causes uncontrollable cell death, which leads to inflammation. 

Dr Lalaoui told MailOnline: ‘We found this mutation turns RIPK1 into a “super killer molecule” which overcomes the normal checks and balances that exist to regulate an acceptable amount of cell death. 

‘During inflammatory processes, this mutation causes too much cell death and a consequent uncontrolled inflammation.’

The findings were confirmed in mice genetically engineered to have the same mutations. They showed a ‘similar exacerbation of inflammation’, Dr Laloui said. 

Professor Silke said RIPK1 was a complex molecule to understand, but is known to be a critical regulator of inflammation and cell death.

He said: ‘Mutations in RIPK1 can drive both too much inflammation – such as in autoinflammatory and autoimmune diseases – and too little inflammation, resulting in immunodeficiency. 

‘There is still a lot to learn about the varied roles of RIPK1 in cell death, and how we can effectively target RIPK1 to treat disease.’

Dr Dan Kastner, an NIH distinguished investigator involved in the research, said anti-inflammatory drugs corticosteroids and biologics had been given to the CRIA patients.

But they haven’t been successful so far and the patients have complained of side effects. Corticosteroids can lead to a larger appetite and acne while biologics can cause infections. 

Dr Kastner noted that RIPK1 inhibitors may be appropriate for patients diagnosed in the future, but these are still being researched.

He said: ‘RIPK1 inhibitors may be just what the doctor ordered for these patients.’ 

Dr Lalaoui said more patients have been identified recently, but details have not been revealed yet.