Agnieszka Zmysłowska

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.

Delayed recognition of Wolfram syndrome frequently misdiagnosed as type 1 diabetes with early chronic complications.

AIMS Improvements in diagnostic methods and greater genetic awareness have brought remarkable progress in the recognition of monogenic forms of diabetes, including Wolfram syndrome (WFS). WFS is diagnosed based on clinical criteria of coexistence of diabetes mellitus and optic atrophy, and confirmed by molecular analysis; however, the condition is still sometimes misdiagnosed. To begin to understand the reasons for misdiagnosis, we conducted a retrospective analysis of WFS patients who were originally misdiagnosed. MATERIALS AND METHODS The medical histories of 13 pediatric patients with clinical misdiagnosis of type 1 diabetes and early chronic complications made in the years 1995-2010 and who were subsequently correctly diagnosed with WFS based on genetic testing in 2008-2011 were analyzed. RESULTS The average age of the patients at diabetes onset was 5 (4.4-6.3) years, and the mean HbA1c level at diagnosis was 9.1±2.3%. Initially, all of these patients were treated as having type 1 diabetes with progressive visual impairment despite good metabolic control (mean HbA1c 7.5±1.3%). Diagnosis of optic atrophy was made at an average age of 9 (5.9-11.5) years, which corresponds to 4 years after diabetes recognition (p=0.002). At the time of genetic analysis, the average age of the patients was 16 (12-18.7) years, which corresponds to 7 years after recognition of coexistence of diabetes mellitus and optic atrophy (p=0.007). CONCLUSIONS Delays of at least 7 years occurred before recognition of WFS among a cohort of pediatric patients with diabetes. All patients with WFS were primarily misdiagnosed as having type 1 diabetes.

Immunogenicity of different brands of human insulin and rapid-acting insulin analogs in insulin-naïve children with type 1 diabetes.

Mianowska B, Szadkowska A, Pietrzak I, Zmysłowska A, Wegner O, Tomczonek J, Bodalski J, Młynarski W. Immunogenicity of different brands of human insulin and rapid‐acting insulin analogs in insulin‐naïve children with type 1 diabetes.

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.

The prevalence of Wolfram syndrome in a paediatric population with diabetes

INTRODUCTION Wolfram syndrome (WFS) is the most frequent syndromic form of monogenic diabetes coexisting with optic atrophy and many other disorders. The aim of this study was to estimate the prevalence of Wolfram syndrome among children with diabetes in Poland. MATERIAL AND METHODS These calculations were performed among Polish diabetic children, aged 0-18 years, from three administrative regions between January 2005 and December 2011. Epidemiological data was obtained by matching the results from the EURO-WABBPoland Project and the PolPeDiab Registry. RESULTS Throughout the study period, we confirmed genetic diagnosis of Wolfram syndrome in 13 patients from Poland. Three patients originated from the studied regions with complete epidemiological data on paediatric diabetes. The total number of patients with diagnosed diabetes in the study equalled 2,568 cases. The prevalence of Wolfram syndrome among Polish children with diabetes is 0.12% (95% Confidence Interval 0.04-0.34%). CONCLUSIONS We estimate that Wolfram syndrome is: 26 to 35 times less frequent than monogenic diabetes (MODY and neonatal diabetes) in the Polish paediatric population.

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.

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.

The Stricter the Better? The Relationship between Targeted HbA1c Values and Metabolic Control of Pediatric Type 1 Diabetes Mellitus

Introduction. It remains unclear how HbA1c recommendations influence metabolic control of paediatric patients with type 1 diabetes mellitus. To evaluate this we compared reported HbA1c with guideline thresholds. Materials and Methods. We searched systematically MEDLINE and EMBASE for studies reporting on HbA1c in children with T1DM and grouped them according to targeted HbA1c obtained from regional guidelines. We assessed the discrepancies in the metabolic control between these groups by comparing mean HbA1c extracted from each study and the differences between actual and targeted HbA1c. Results. We included 105 from 1365 searched studies. The median (IQR) HbA1c for the study population was 8.30% (8.00%–8.70%) and was lower in “6.5%” than in “7.5%” as targeted HbA1c level (8.20% (7.85%–8.57%) versus 8.40% (8.20%–8.80%); p = 0.028). Median difference between actual and targeted HbA1c was 1.20% (0.80%–1.70%) and was higher in “6.5%” than in “7.5%” (1.70% (1.30%–2.07%) versus 0.90% (0.70%–1.30%), resp.; p < 0.001). Conclusions. Our study indicates that the 7.5% threshold results in HbA1c levels being closer to the therapeutic goal, but the actual values are still higher than those observed in the “6.5%” group. A meta-analysis of raw data from national registries or a prospective study comparing both approaches is warranted as the next step to examine this subject further.