UEA scientists solve 80 year old medical mystery
It causes kidney damage in children and can be fatal in babies
Researchers at the University of East Anglia have solved an 80-year-old medical mystery that causes kidney damage in children and can be fatal in babies.
Those affected by the condition can't metabolise vitamin D properly, meaning calcium builds up in the blood.
This then leads to kidney damage and kidney stones.
Recent research had shown that the condition, now known as infantile hypercalcaemia type 1, is caused by a gene mutation.
But scientists noticed around 10 per cent of patients experiencing symptoms don't have the genetic mutation.
“This really puzzled us,” said lead researcher Dr Darrell Green, from UEA’s Norwich Medical School. “So we wanted to find out exactly why this 10 per cent appeared to have the condition, but without the gene mutation that was found to cause it.”
The issue led to a wave of baby deaths in the 1930s and 1940s, after foods such as milk, bread, cereal, and margarine were fortified with Vitamin D in a bid to eradicate rickets in children.
Dr Green said: “Foods such as dairy products had been fortified with vitamin D, but it led to a number of baby deaths, and was eventually banned in many countries except for in breakfast cereals and margarine.
“In 2011, researchers found that some people are born with a mutation in the CYP24A1 gene, which means they cannot metabolise vitamin D properly. This causes a build-up of calcium in the blood, leading to kidney stones and kidney damage, which can be fatal in babies. It was the reason why vitamin D-fortified food in the 1930s caused intoxication in some people.
“Today, some people do not realise they have a CYP24A1 mutation until they are adults, after years of recurrent kidney stones and other problems. In most cases, these patients are screened and find out that they have the CYP24A1 mutation and the disorder now known as infantile hypercalcemia type 1, or HCINF1.
“However, in around 10 per cent of suspected HCINF1 patients, they do not display an obvious mutation in CYP24A1 and continue to have lifelong problems without a proper diagnosis.”
The UEA team collaborated with colleagues at the Norfolk and Norwich University Hospital, where they worked with 47 patients.
They used a combination of next generation genetic sequencing and computational modelling to study blood samples from those ’10 per cent’ of puzzling patients.
Dr Green said: “A PhD student in my laboratory, Nicole Ball, carried out a more extensive genetic analysis of six patient blood samples and we found that the physical shape of the CYP24A1 gene in these apparent HCINF1 patients is abnormal.
“This tells us that gene shape is important in gene regulation - and that this is the reason why some people lived with HCINF1 but without a definitive diagnosis”, he added.
“On a wider scale relevant to genetics and health, we know that genes must have the correct sequence to produce the correct protein, but in an added layer of complexity, we now know that genes also have to have a correct physical shape,” added Dr Green.
Prof Bill Fraser, from Norwich Medical School and the Norfolk and Norwich University Hospital, co-led the study and treats HCINF1 patients in metabolic bone clinics.
He said: “Genetic causes of vitamin D toxicity can be left undiagnosed for long periods, well into adulthood, sometimes coming to light during pregnancy when fortification of mothers with vitamin D happens. We also see patients with undiagnosed causes of recurrent renal stones who have had this condition for many years.
“Treatment includes avoidance of vitamin D supplementation in subjects with the particular genetic abnormalities we have identified.
“A beneficial side effect to some anti-fungal medications includes alteration of vitamin D metabolism lowering active vitamin D, which decreases calcium levels and can give patients a more normal quality of life, which we have started to prescribe in some patients,” he added.
The researchers now plan to investigate the role of gene shapes in other disorders such as cancer.