Infantile hypercalcemia type 1 is a rare genetic condition that affects the regulation of calcium levels in the body. People with infantile hypercalcemia type 1 usually have high levels of calcium in the blood, which can lead to a range of symptoms including vomiting, constipation, dehydration, irritability and delayed development. In severe cases, infantile hypercalcemia type 1 can lead to life-threatening complications such as kidney failure and cardiac arrhythmias.
Scientists at the University of East Anglia have solved a long-standing medical mystery that causes kidney damage in children and can be fatal in babies. Affected individuals are unable to properly metabolize vitamin D. This leads to a buildup of calcium in the blood and causes kidney damage and the formation of kidney stones.
This led to an increase in infant deaths in the 1930s and 1940s, due to the fortification of foods such as milk, bread, cereals and margarine with vitamin D in an attempt to eliminate the rickets in children.
Recent research has shown that the condition, now known as infantile hypercalcemia type 1, is caused by a genetic mutation. But curiously, about 10% of patients with symptoms do not have the genetic mutation.
“It really intrigued us,” said lead researcher Dr Darrell Green, from UEA’s Norwich Medical School. “So we wanted to know exactly why those 10% seemed to have the disease, but without the genetic mutation that caused it.”
The conundrum began in the early 1900s, when more than 80% of children in industrialized Europe and North America were affected by rickets, which causes bone pain, poor growth, and soft, weak and deformed.
The discovery that sunlight prevented rickets led to the fortification of foods with vitamin D, which virtually eradicated the disease in the 1930s. But epidemics of vitamin D poisoning in infants led to enrichment bans in many European countries in the 1950s.
Dr Green said: ‘Foods such as dairy products had been fortified with vitamin D but this led to a number of infant deaths and was eventually banned in many countries, with the exception of infant cereals. -breakfast 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 calcium to build up in the blood, leading to kidney stones and kidney damage, which can be fatal in babies. This was the reason why foods fortified with vitamin D in the 1930s caused poisoning in some people.
He continues: “Today, some people do not realize that they have a CYP24A1 mutation until they are adults, after years of recurring kidney stones and other problems. In most cases, these patients are screened and found that they have the CYP24A1 mutation and the disorder now known as infantile hypercalcemia type 1, or HCINF1. However, in approximately 10% of patients with suspected HCINF1, they do not have an obvious mutation in CYP24A1 and continue to have lifelong problems without a proper diagnosis.
The UEA team collaborated with colleagues at Norfolk and Norwich University Hospital, where they worked with 47 patients.
They used a combination of next-generation genetic sequencing and computer modeling to study blood samples from those puzzling “10%” of patients.
Dr Green said: ‘A Ph.D. student in my lab, Nicole Ball, performed further genetic analysis of six patient blood samples and we found that the fitness of the CYP24A1 in these patients apparent HCINF1 is abnormal.
“This tells us that the shape of genes is important in gene regulation – and that’s 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 produce the correct protein, but in an added layer of complexity, we now know that genes must also have a physical form. correct,” added Dr. Green.
Professor Bill Fraser, from 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 revealing themselves during pregnancy when vitamin D fortification of mothers occurs. We also see patients with undiagnosed causes of recurring kidney stones who have been suffering from 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 of certain antifungal drugs includes impaired vitamin D metabolism by lowering 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. .
Researchers now plan to study the role of gene shapes in other disorders such as cancer.
Case Study – Shelley O’Connor
Shelley O’Connor, 34, from Norwich, was diagnosed with childhood hypercalcaemia type 1 eleven years ago when she became pregnant with her first child aged 23.
She had started taking pregnancy supplements, which included vitamin D. But she began to experience such severe pain that midwives thought she was going into early labor at just 23 weeks.
“It was very scary,” she said. “I was in terrible pain and the midwives thought I was going to give birth. 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 pregnancy supplement.
Fortunately, her son was born safe at term, and Shelley has since had two more children.
“I was diagnosed with HCINF1 and that explained a lot because I had experienced things like abdominal pain and urinary tract infections as a child,” she said.
But the condition took its toll. Shelley now regularly passes kidney stones and has to take painkillers. She also has to have an operation every six months to remove the calcium buildup that leads to kidney stones.
“I was really thrilled to be asked to participate in the research, and I hope the results will continue to help others like me,” she said.
Reference: “3′ Untranslated region structural elements in CYP24A1 Are associated with childhood hypercalcemia type 1″ by Nicole Ball, Susan Duncan, Yueying Zhang, Rocky Payet, Isabelle Piec, Eloise Whittle, Jonathan CY Tang, Inez Schoenmakers, Berenice Lopez, Allison Chipchase, Arun Kumar, Leslie Perry, Heather Maxwell, Yiliang Ding, William D. Fraser and Darrell Green, January 10, 2023, Journal of Bone and Mineral Research.
DOI: 10.1002/jbmr.4769
This research was carried out by UEA in collaboration with the John Innes Centre, Norfolk and Norwich University Hospital, Croydon University Hospital and the Royal Hospital for Children, Glasgow.