Monogenic diabetes is highly prevalent in patients referred to Italian pediatric diabetes centers. A genetic diagnosis guided the therapeutic decisions, allowed the formulation of a prognosis regarding chronic diabetic complications for a relevant number of patients (i.e.,GCK/MODY), and helped to provide genetic counseling.
Interpretation: The study suggests an increase in the incidence of pediatric T1D in Lombardy throughout the past five years. Pandemic waves may have affected the clinical presentation at onset.
SAP therapy is effective and feasible in preschool children with T1D. In patients with high HbA1c at baseline it provide a 0.9% decrease, sustained for at least 6 months.
Mutations in the WFS1 gene, encoding wolframin (WFS1), cause endoplasmic reticulum (ER) stress and are associated with a rare autosomal recessive disorder known as Wolfram syndrome (WS). WS is clinically characterized by childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological signs. We identified two novel WFS1 mutations in a patient with WS, namely, c.316-1G > A (in intron 3) and c.757A > T (in exon 7). Both mutations, located in the N-terminal region of the protein, were predicted to generate a truncated and inactive form of WFS1. We found that although the WFS1 protein was not expressed in peripheral blood mononuclear cells (PBMCs) of the proband, no constitutive ER stress activation could be detected in those cells. In contrast, WS proband’s PBMCs produced very high levels of pro-inflammatory cytokines (i.e. TNF-α, IL-1β, and IL-6) in the absence of any stimulus. WFS1 silencing in PBMCs from control subjects by means of small RNA interference also induced a pronounced pro-inflammatory cytokine profile. The same cytokines were also significantly higher in sera from the WS patient as compared to matched healthy controls. Moreover, the chronic inflammatory state was associated with a dominance of pro-inflammatory T helper 17 (Th17)-type cells over regulatory T (Treg) lymphocytes in the WS PBMCs. The identification of a state of systemic chronic inflammation associated with WFS1 deficiency may pave the way to innovative and personalized therapeutic interventions in WS.
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