Researchers at the University of East Anglia have solved an 80-year-old medical mystery that causes kidney damage in children and can be deadly in babies.
Those who suffer from the condition cannot properly metabolize vitamin D, causing calcium to build up in the blood and causing kidney damage and kidney stones.
It led to a wave of infant deaths in the 1930s and 1940s, after foods such as milk, bread, cereals and margarine were fortified with vitamin D in an effort to eradicate rickets in children.
Recent research had shown that the condition, now known as infantile hypercalcemia type 1, is caused by a gene mutation. But curiously, about 10 percent of patients who experience symptoms do not have the genetic mutation.
This really surprised us. So we wanted to know exactly why this 10 percent appeared to have the condition, but without the gene mutation that caused it.”
Dr. Darrell Green, Principal Investigator, UEA’s Norwich Medical School
The puzzle began in the early 1900s, when more than 80 percent of children in industrialized Europe and North America suffered from rickets, which causes bone pain, poor growth, and soft, weak, misshapen bones.
The discovery that sunlight prevented rickets led to the fortification of foods with vitamin D, virtually eradicating the disease by the 1930s. But outbreaks of vitamin D intoxication in infants led to fortification bans in many European countries by the 1950s.
Dr. Green said: “Foods such as dairy products were fortified with vitamin D, but it led to a number of infant deaths and was eventually banned in many countries, except in breakfast cereals and margarine.
In 2011, researchers discovered that some people are born with a mutation in the CYP24A1 gene, meaning they cannot metabolize vitamin D properly. This causes a buildup of calcium in the blood, leading to kidney stones and kidney damage, which can be fatal in babies. It was why vitamin D-fortified foods caused drunkenness in some people in the 1930s.
“Today some people don’t realize they have a CYP24A1 mutation until adulthood, after years of recurring kidney stones and other problems. In most cases, these patients are screened and discovered that they have the disease CYP24A1 mutation and the condition now known as infantile hypercalcemia type 1 or HCINF1.
“However, in approximately 10 percent of suspected HCINF1 patients, they do not show a clear mutation in CYP24A1 and continue to have lifelong problems without a proper diagnosis.”
The UEA team worked with colleagues at 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 those “10 percent” puzzling patients.
Dr. Green said: “A PhD student in my lab, Nicole Ball, performed 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 the shape of genes is important in gene regulation – and that’s why some people lived 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 produce the correct protein, but in an added layer of complexity, we now know that genes must also have a correct physical shape,” added. Doctor Green.
Prof Bill Fraser, from both Norwich Medical School and Norfolk and Norwich University Hospital, co-led the study and is treating HCINF1 patients in metabolic bone clinics.
He said: “Genetic causes of vitamin D toxicity can go undiagnosed for long periods of time, well into adulthood, sometimes emerging during pregnancy when maternal vitamin D enrichment occurs. We also see patients with undiagnosed causes of recurrent kidney stones who have had this condition for many years.
“Treatment involves avoiding vitamin D supplementation in subjects with the specific genetic abnormalities we identified.
“A beneficial side effect of some antifungal medications includes an alteration of vitamin D metabolism, which lowers active vitamin D, which lowers calcium levels and may give patients a more normal quality of life, which we have begun to prescribe for some patients, he added. .
The researchers now plan to investigate the role of gene forms in other conditions such as cancer.
This research was led by UEA in collaboration with the John Innes Centre, Norfolk and Norwich University Hospital, Croydon University Hospital and the Royal Hospital for Children in Glasgow.
‘3’ untranslated region of structural elements CYP24A1 are associated with infantile hypercalcaemia type 1′ has been 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 11 years ago when she became pregnant with her first child at the age of 23.
She had begun taking pregnancy supplements, including vitamin D. But she began to experience pain so severe that midwives believed she would go into early labor as early as 23 weeks.
“It was very frightening,” she said. “I was in a lot of pain and the midwives thought I was going into labor. I was really scared for the baby, but when I had an MRI they found out it was actually a kidney stone caused by taking vitamin D as a medicine. pregnancy supplement.”
Fortunately, her son was born safe and sound at full term, and Shelley has since gone on to have two more children.
“I was diagnosed with HCINF1 and it explained a lot because I had experienced things like stomach aches and urinary tract infections in my childhood,” she said.
But the situation has taken its toll. Shelley now regularly passes kidney stones and has to take pain medication. She also has to have surgery every six months to remove the calcium deposits that lead to kidney stones.
“I was very pleased to be invited to participate in the study, and I hope the findings will help others like me,” she said.
University of East Anglia