medwireNews: Researchers have identified probable type 1 diabetes in children of an age more commonly associated with diagnosis of monogenic diabetes, raising the possibility that polygenic disease processes can begin in utero.
“This extreme form of autoimmune diabetes is the first polygenic autoimmune disease demonstrated to present before the age of 6 months, challenging current understanding of the early immune system,” write Richard Oram (University of Exeter Medical School, UK) and study co-authors in Diabetologia.
However, they stress the continued need for comprehensive genetic testing of infants diagnosed with diabetes when younger than 6 months, because the vast majority will have monogenic diabetes and a precise diagnosis can guide treatment decisions in many cases.
The team studied 166 children who had been referred to them for genetic testing when less than 6 months old, but proved to have no pathogenic variants in the 26 genetic loci known to cause monogenic diabetes.
However, 63 (38%) of these children had a type 1 diabetes genetic risk score (T1D-GRS) that was above the 95th centile for people without diabetes, indicating a high risk for type 1 diabetes.
The Exeter team previously developed the T1D-GRS score, based on the top 30 risk alleles for type 1 diabetes, and they explain that if the children had monogenic diabetics caused by as yet undiscovered variants then just 5% of them would be expected to have a T1D-GRS above the 95th centile, because the distribution of scores in children with monogenic diabetes is similar to that in the general population without diabetes.
The team was able to obtain serum for islet autoantibody testing from 22 of the children who had a high T1D-GRS and no alternative explanation for their diabetes and found that nine (41%) of these were positive for at least one of GADA, IA2A, or ZnT8A, when tested after a median diabetes duration of 3.0 years.
This was not significantly different to the 58% rate of positivity found in 152 children diagnosed with type 1 diabetes between the ages of 6 and 24 months (51 of 88 children tested after a median diabetes duration of 4.0 years).
Consistent with a diagnosis of type 1 diabetes, children with a high T1D-GRS also had very low C-peptide levels, at a median of less than 3 pmol/L. The median level in children diagnosed between 6 and 24 months was 24.5 pmol/L, whereas the median level in children who were diagnosed when younger than 6 months but had a low T1D-GRS score was 117 pmol/L.
“The combination of high levels of islet autoantibody positivity, reduced C-peptide and high type 1 diabetes genetic susceptibility makes a strong case that these individuals have polygenic type 1 diabetes,” say Oram and team.
Of note, the children who were diagnosed before 6 months of age, and had a high T1D-GRS, also had a reduced birthweight, at a median z score of –0.89. This was particularly marked in those diagnosed within the first 3 months of life, who had a median birthweight z score of –1.98.
Children diagnosed with type 1 diabetes between 6 and 24 months of age did not have a reduced birthweight, but those with monogenic diabetics did, at a median z score of –1.39, which the researchers say reflects the effect of genetic beta-cell defects, which “reduce insulin secretion and therefore insulin-mediated growth in utero.”
They say: “This raises the possibility that there is a common explanation for the low birthweight and extremely early onset of diabetes” in the children with high T1D-GRS.
Oram and team therefore believe “that a major failure of early immune tolerance mechanisms may underlie type 1 diabetes diagnosed before the age of 6 months.”
And they suggest: “This failure may be triggered by environmental factors such as specific viral infection during pregnancy or in the first few months of life.”
By Eleanor McDermid
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