Karolina Antosik

HDL cholesterol as a diagnostic tool for clinical differentiation of GCK‐MODY from HNF1A‐MODY and type 1 diabetes in children and young adults

Introduction  Confirmation of monogenic diabetes caused by glucokinase mutations (GCK‐MODY) allows pharmacogenetic intervention in the form of insulin discontinuation. This is especially important among paediatric and young adult populations where GCK‐MODY is most prevalent.

Wolfram syndrome in the Polish population: novel mutations and genotype–phenotype correlation

Objective  Wolfram syndrome is a rare form of diabetes mellitus associated with optic atrophy and disorders of different organs (e.g. diabetes insipidus, hearing loss, ataxia, anaemia and many others). This syndrome is caused by recessive mutations in the wolframin gene (WFS1) localized on chromosome 4p16·1. The aim of this study was to identify the causative mutations in WFS1 in a group of Polish patients with suspected Wolfram syndrome.

Novel glucokinase mutations in patients with monogenic diabetes - clinical outline of GCK-MD and potential for founder effect in Slavic population.

Borowiec M, Antosik K, Fendler W, Deja G, Jarosz‐Chobot P, Mysliwiec M, Zmyslowska A, Malecki M, Szadkowska A, Mlynarski W. Novel glucokinase mutations in patients with monogenic diabetes – clinical outline of GCK‐MD and potential for founder effect in Slavic population.

Retinal Thinning as a Marker of Disease Progression in Patients With Wolfram Syndrome

Wolfram syndrome (WFS), caused by recessive mutations in WFS1 , is characterized by neurodegeneration due to apoptosis provoked by increased endothelial reticulum stress (1). Currently, it is incurable and leads to a premature death at an average age of 35 years (2). Despite initial success with spectroscopy-based studies (3), there is a lack of repeatable and robust markers for monitoring the clinical course of WFS. The aim of our study was to evaluate retinal parameters, measured with optical coherence tomography, as biomarkers of WFS progression. The Ethics Committee of the Medical University of Lodz approved the project (RNN/140/13/KE). Optical coherence tomography was performed after mydriasis using the Topcon 3D OCT-2000 system. Average retinal thickness and central thickness were measured using three-dimensional disc and macula scans covering a retinal area of 6 × 6 mm. The study was performed between August 2013 and April 2014. Two cohorts were enrolled: a pediatric/adolescent group and an adult one. The first consisted of patients with genetically confirmed WFS (median age 17.25 [interquartile range …

Doubling the referral rate of monogenic diabetes through a nationwide information campaign – update on glucokinase gene mutations in a Polish cohort

Borowiec M, Fendler W, Antosik K, Baranowska A, Gnys P, Zmyslowska A, Malecki M, Mlynarski W. Doubling the referral rate of monogenic diabetes through a nationwide information campaign – update on glucokinase gene mutations in a Polish cohort.

Abnormal serum microRNA profiles in tuberous sclerosis are normalized during treatment with everolimus: possible clinical implications.

BackgroundTuberous sclerosis (TSC) is a monogenic disease resulting from defects of the TSC1 or TSC2 genes, which encode the proteins forming hamartin-tuberin tumor suppressor complex, the mammalian target of rapamycin complex (mTOR). The mTOR pathway is constitutively activated in response to tuberin or hamartin defects. The mTOR pathway is also regulated by a multitude of epigenetic mechanisms, one of which is regulation by microRNA (miRNA) inhibition. This leads us to hypothesize that organ-level abnormalities of miRNA expression patterns are widespread in TSC. The aim of the study was to evaluate the serum profiles of miRNAs in patients with TSC and subependymal giant cell astrocytoma (SEGA) treated with mTOR inhibitor (everolimus).MethodsSerum microRNA profiling was performed in 10 TSC-patients before and three months after everolimus treatment, as well as in 10 sex- and age-matched healthy controls. MicroRNAs were profiled using qPCR panels (Exiqon).ResultsOf 752 tested miRNAs, 11 showed statistically significant dysregulation in patients with TSC in comparison to controls. The following miRNAs were downregulated in TSC: miR-142-3p, miR-199a-5p, miR-142-5p and miR-136-5p; while miR-130a-3p, miR-378a-3p, miR-130b-3p, miR-192-5p, miR-25-3p, miR-215-5p and miR-222-3p were upregulated in TSC in comparison to the control group. After three months of everolimus treatment, mean dose 5.1 (2.6-9.7) mg/m2, seven miRNAs reached expression levels similar to healthy controls, with miR-142-3p and miR-136 showed significant increase over baseline levels in TSC patients. Moreover, miR-222-3p normalization due to treatment differed between patients with mutation in TSC1 and TSC2 gene.ConclusionsActivation of the mTOR pathway in TSC patients alters serum miRNA levels, which may be partially reversed by an mTOR inhibitor. This indicates the involvement of miRNA dysregulation in the pathogenesis of TSC, linking miRNA profiles with treatment efficiency.

Paternally Inherited Proinsulin Mutations May Result in Earlier Onset of Monogenic Diabetes Mutation Identity Effect in Monogenic Diabetes

Mutations within the human proinsulin gene ( INS ) have been reported to cause neonatal, maturity onset diabetes of the young (MODY), and antibody-negative idiopathic type 1 diabetes (1–3). However, because the expression of maternally or paternally transmitted INS-IGF2 alleles is different as a result of selective methylation (imprinting) (4), we surmised that the effect of INS mutations may depend on the origin of the mutated allele. To verify this hypothesis, pairs comprising an affected child and parent carrying the same heterozygous INS mutation were studied. A literature search was performed and yielded eight relevant articles reporting heterozygous INS mutations in neonatal, MODY, or antibody-negative type 1 diabetes (supplementary Table 1, available in an online appendix at http://care.diabetesjournals.org/cgi/content/full/dc10-1142/DC1). We also included an unpublished case …

Serum Metabolic Fingerprinting Identified Putatively Annotated Sphinganine Isomer as a Biomarker of Wolfram Syndrome

Wolfram syndrome (WFS) is an example of a rare neurodegenerative disease with coexisting endocrine symptoms including diabetes mellitus as the first clinical symptom. Treatment of WFS is still only symptomatic and associated with poor prognosis. Potential markers of disease progression that could be useful for possible intervention trials are not available. Metabolomics has potential to identify such markers. In the present study, serum fingerprinting by LC-QTOF-MS was performed in patients with WFS (n = 13) and in patients with T1D (n = 27). On the basis of the obtained results, aminoheptadecanediol (17:0 sphinganine isomer) (+50%, p = 0.02), as the most discriminatory metabolite, was selected for validation. The 17:0 sphinganine isomer level was determined using the LC-QQQ method in the samples from WFS patients at two time points and compared with samples obtained from patients with T1D (n = 24) and healthy controls (n = 24). Validation analysis showed higher 17:0 sphinganine isomer level in patients with WFS compared to patients with T1D (p = 0.0097) and control group (p < 0.0001) with progressive reduction of its level after two-year follow-up period. Patients with WFS show a unique serum metabolic fingerprint, differentiating them from patients with T1D. Sphinganine derivate seems to be a marker of the ongoing process of neurodegeneration in WFS patients.

Genetic Factors of Diabetes

Monogenic diabetes is a rare genetic type of diabetes caused by pancreatic β-cells dysfunction. All subtypes of monogenic diabetes are recognized in the pediatric population. They include maturity onset diabetes of the young, permanent neonatal diabetes mellitus and rare syndromic forms of diabetes. An early and proper diagnosis allows to implement an optimal treatment, leads to improved metabolic control and amelioration of related disabilities as well as increases the quality of life of the patients.

Central Nervous System PET-CT Imaging Reveals Regional Impairments in Pediatric Patients with Wolfram Syndrome

Wolfram syndrome (WFS) is inherited as an autosomal recessive disease with main clinical features of diabetes mellitus, optic atrophy, diabetes insipidus and deafness. However, various neurological defects may also be detected. The aim of this study was to evaluate aspects of brain structure and function using PET-CT (positron emission tomography and computed tomography) and MRI (magnetic resonance imaging) in pediatric patients with WFS. Regional changes in brain glucose metabolism were measured using standardized uptake values (SUVs) based on images of (18F) fluorodeoxyglucose (FDG) uptake in 7 WFS patients aged 10.1–16.0 years (mean 12.9±2.4) and in 20 healthy children aged 3–17.9 years (mean 12.8±4.1). In all patients the diagnosis of WFS was confirmed by DNA sequencing of the WFS1 gene. Hierarchical clustering showed remarkable similarities of glucose uptake patterns among WFS patients and their differences from the control group. SUV data were subsequently standardized for age groups <13 years old and>13 years old to account for developmental differences. Reduced SUVs in WFS patients as compared to the control group for the bilateral brain regions such as occipital lobe (−1.24±1.20 vs. −0.13±1.05; p = 0.028) and cerebellum (−1.11±0.69 vs. −0.204±1.00; p = 0.036) were observed and the same tendency for cingulate (−1.13±1.05 vs. −0.15±1.12; p = 0.056), temporal lobe (−1.10±0.98 vs. −0.15±1.10; p = 0.057), parietal lobe (−1.06±1.20 vs. −0.08±1.08; p = 0.058), central region (−1.01±1.04 vs. −0.09±1.06; p = 0.060), basal ganglia (−1.05±0.74 vs. −0.20±1.07; p = 0.066) and mesial temporal lobe (−1.06±0.82 vs. −0.26±1.08; p = 0.087) was also noticed. After adjusting for multiple hypothesis testing, the differences in glucose uptake were non-significant. For the first time, regional differences in brain glucose metabolism among patients with WFS were shown using PET-CT imaging.