An 80-year-old mystery linked to a wave of baby deaths in the 1930s and 1940s has finally been solved by researchers.
The fatal ingredient was found in household staples – milk, bread, cereal, margarine.
But it was put there to try and make children healthier. In the early 1900s, more than 80% of children were affected by the bone condition rickets, so food was fortified with vitamin D.
The fortification all but eradicated the disease. However, there were fatal side-effects as a result of the measure, as some babies could not metabolise vitamin D properly.
They had a condition which causes a build-up of calcium in the blood, leading to kidney damage and kidney stones, which can be fatal in babies.
Outbreaks of vitamin D intoxication in infants led to fortification bans in many European countries by the 1950s.
Research in 2011 revealed the condition, now known as infantile hypercalcaemia type 1 or HCINF1, is caused by a gene mutation.
But scientists were stumped to find about 10% of patients affected by HCINF1 do not have the genetic mutation.
Many of the baby deaths, and symptoms still experienced by patients today, therefore remained unexplained.
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Now, though, researchers at the University of East Anglia (UEA) have discovered what is going on with these patients – and it’s not due to a gene mutation, but their shape.
Lead researcher Dr Darrell Green, from UEA’s Norwich Medical School, said most patients who are screened and find out they have HCINF1 also have a mutation in the CYP24A1 gene.
Where people don’t have that mutation, but still struggle to process vitamin D, they can continue to have “lifelong problems without a proper diagnosis”, he said.
Issues for patients can include recurrent renal stones and severe pain.
Shelley O’Connor, 34, from Norwich, was only diagnosed with HCINF1 11 years ago when she fell pregnant with her first child at the age of 23.
When she started taking pregnancy supplements to help her baby – which included vitamin D – she began to suffer from intense pain which made her midwives think she was going into labour at just 23 weeks.
“It was very frightening,” she said. “I was really scared for the baby, but when I had an MRI, they found out that it was actually a kidney stone caused by taking vitamin D as a pregnancy supplement.”
‘Abnormal’ gene shape solves puzzle
The UEA team collaborated with colleagues at the Norfolk and Norwich University Hospital, where they worked with 47 patients like Shelley to find out how people could have the condition without the mutation.
They used a combination of next generation genetic sequencing and computational modelling to study blood samples from those 10% 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.
Dr Green explained the difference between a genetic mutation in DNA sequencing and the shape of genes, and what this means for patients.
He said: “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.”
The researchers now plan to investigate the role of gene shapes in other disorders such as cancer.