ESPE Abstracts

Background: In type 1 diabetes (T1D), the pancreatic βcells are selectively destroyed by the immune system resulting in absolute insulin deficiency. It has been long established that approximately half of the genetic risk for T1D is conferred by genetic loci associated with β-cell function, apoptosis, and regeneration.

Aim: We report the case of a 6- year-old boy with new onset type T1D, and identified genetic loci predisposing to T1D and hyperlipidemia. With informed consent from the parents, DNA was isolated from the patient’s peripheral blood leukocyte, and TWIST Standard Germline Exome assay were performed. Causative variants were confirmed by Sanger sequencing.

Case presentation: The boy was admitted with severe diabetic ketoacidosis (DKA), and significant combined hyperlipidemia. He is the first child of the family, born after an otherwise full-term uneventful pregnancy. Family history was negative for cardiovascular disease and/or hyperlipidemia. The father was affected by Hashimoto thyroiditis. On examination his height and weight were above the normal range (122 cm; 97th percentile, and 19 kg; 75th percentile, respectively). There were noclinical findings associated with hyperlipidemia, e.g. hepatosplenomegaly, xanthelasma, and eruptive xanthoma. Initial laboratory findings were venous blood gas (pH 7.33, pCO2 25.1mmHg, pO2 59.5mmHg, HCO3- 13.6mM/L, SaO2 98.0%), glucose 156mg/dL, hemoglobin A1c 14.3%, C-peptide 0.112ng/mL, total cholesterol 764mg/dL, total triglycerides 5950mg/dL, low density lipoprotein cholesterol (LDL) could not be measured, high density lipoprotein cholesterol (HDL) 8 mg/dL, serum lipase 20U/L. Anti-glutamic acid decarboxylase (GAD), and anti-islet antibody-2 (IA-2) antibody were positive. Although DKA resolved within 24 hours, hyperlipidemia, and hypertriglyceridemia declined in a slower rate. Patient’s genetic analysis revealed homozygosity for the APOL4c.332_333del:p.E111fs mutation (novel) and heterozygosity for the LIPA c.546G>A:p.Q182Q mutation, both genes responsible for dyslipidemia. Additionally, he is homozygous for KLF14 c.117T>A:p.A39A, c.172C>T:p.P58S, c.140C>A:p.P47Q, FDFT1 c.199_204del:p.67_68del, MAFA c.618_620del:p.206_207del, NEUROD1 c.133A>G:p.T45A, c.596T>C:p.F199S, and GLIS3 c.902C>A:p.P301Q, c.805T>C:p.S269P. and heterozygous for the C8B c.1282C>T:p.R428X, HBD c.82G>T:p.A28S and LIPA c.546G>A:p.Q182Q, all related with β-cells dysfunction and/ or apoptosis (with a MAF<0.01).

Conclusions: In many case reports, severe quantitative hyperilipidemia is observed during DKA associated with newly diagnosed T1D or attributed to poor diabetes control with severe insulin deficiency. Diabetic hyperlipemia can be caused not only by profound insulin deficiency but also due to genetic predisposition. We suggest that its pathogenesis can be exacerbated by a co-existing genetic predisposition to hyperlipidemia.