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 are unable to metabolize vitamin D properly, which causes a buildup of calcium in the blood, leading to kidney damage and kidney stones.
It led to a wave of infant deaths in the 1930s and 1940s, after foods like milk, bread, cereal, and margarine were fortified with vitamin D in an attempt to eradicate rickets in children.
Recent research has shown that the condition, now known as type 1 infantile hypercalcemia, is caused by a genetic mutation. But interestingly, about 10 percent of patients who experience symptoms do not have the gene mutation.
This really puzzled us. So we wanted to find out exactly why this 10 percent seemed to have the condition, but without the genetic mutation that was found to cause it.”
Dr Darrell Green, Principal Investigator, UEA Norwich Medical School
The puzzle began in the early 1900s, when more than 80 percent of children in industrialized Europe and North America were affected by rickets, which causes bone pain, poor growth, and soft, weak, and misshapen bones.
The discovery that sunlight prevented rickets led to the fortification of foods with vitamin D, which nearly eradicated the disease in the 1930s. But outbreaks of vitamin D poisoning in infants led to a ban on fortification in many European countries in the 1950s.
Dr Green said: “Foods such as dairy products had been fortified with vitamin D, but it led to the deaths of several babies and was eventually banned in many countries, except for breakfast cereals and margarine.
“In 2011, researchers discovered that some people are born with a mutation in the CYP24A1 gene, which means they cannot properly metabolize vitamin D. This causes a buildup of calcium in the blood, leading to kidney stones and kidney damage, which can be fatal in babies. It was the reason that vitamin D-enriched foods in the 1930s caused food poisoning in some people.
“Today, some people don’t realize they have a CYP24A1 mutation until they are adults, after years of recurring kidney stones and other problems. In most cases, these patients are evaluated and discover that they have the CYP24A1 mutation and the disorder now known as infantile hypercalcemia type 1, or HCINF1.
“However, in about 10 percent of patients suspected of HCINF1, they do not show an obvious mutation in CYP24A1 and continue to have lifelong problems without proper diagnosis.
The UEA team collaborated with colleagues from Norfolk and Norwich University Hospital, where they worked with 47 patients.
They used a combination of next-generation genetic sequencing and computational modeling to study blood samples from that ’10 percent’ of puzzling patients.
Dr Green said: “A PhD student in my lab, Nicole Ball, carried out a more extensive genetic analysis of six patient blood samples and we found that the physical form 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 why some people were living with HCINF1 but without a definitive diagnosis,” he added.
“On a broader scale relevant to genetics and health, we know that genes must have the correct sequence to make the correct protein, but in an added layer of complexity, we now know that genes must also have the correct physical shape.” he added. Dr Green.
Professor Bill Fraser, from Norwich Medical School and 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, and sometimes come to light during pregnancy when vitamin D fortification of mothers occurs. Also We see patients with undiagnosed causes of recurrent kidney stones who have had this condition for many years.
“Treatment includes avoiding vitamin D supplementation in subjects with particular genetic abnormalities that we have identified.
“A beneficial side effect of some antifungal medications includes altered vitamin D metabolism, which reduces active vitamin D, which lowers calcium levels and may give patients a more normal quality of life, which we have begun to prescribe in some patients,” he added. .
The researchers now plan to investigate the role of the gene shapes in other disorders such as cancer.
This research was led by the UEA in collaboration with the John Innes Centre, Norfolk and Norwich University Hospital, Croydon University Hospital and the Royal Children’s Hospital in Glasgow.
‘3’ structural elements of the untranslated region in CYP24A1 are associated with infantile hypercalcemia type 1′ is published in the Journal of Bone and Mineral Research.
Case Study – Shelley O’Connor
Shelley O’Connor, 34, from Norwich, was diagnosed with infantile hypercalcaemia type 1 eleven years ago when she became pregnant with her first child at the age of 23.
She had started taking pregnancy supplements, which included vitamin D. But she began experiencing such severe pain that the midwives thought she was going into preterm labor at just 23 weeks.
“It was very scary,” he said. “I was in a lot of pain and the midwives thought I was going to give birth. I was really scared for the baby, but when they did an MRI they found out it was actually a kidney stone caused by taking vitamin D as a pregnancy supplement. “.
Fortunately, their son was born safely at term, and Shelley has since had two other children.
“I was diagnosed with HCINF1 and it explained a lot because I had experienced things like abdominal pain and urinary tract infections in childhood,” he said.
But the condition has taken its toll. Shelley now passes kidney stones regularly and needs to take painkillers. She also has to have surgery every six months to remove the calcium buildup that causes kidney stones.
“I was very pleased to be invited to participate in the research, and I hope the findings help others like me,” he said.
University of East Anglia