Ocena częstości występowania zespołu Wolframa w populacji dzieci z cukrzycą

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. (Endokrynol Pol 2014; 65 (4): 295–297)Wstęp: Zespół Wolframa (WFS) jest najczęstszą syndromiczną formą cukrzycy monogenowej, gdzie oprócz cukrzycy występuje zanik nerwów wzrokowych oraz wiele innych zaburzeń. Celem pracy była ocena częstości występowania zespołu Wolframa na tle innych rodzajów cukrzycy w populacji pediatrycznej.Materiał i metody: Ocena chorobowości została przeprowadzona wśród dzieci chorych na cukrzycę, pochodzących z trzech polskich województw (łódzkie, pomorskie i śląskie) w wieku 0–18 lat, w okresie czasu pomiędzy styczniem 2005 roku i grudniem 2011. Dane epidemiologiczne uzyskano poprzez połączenie danych pochodzących z Rejestru EURO-WABB dla Polski oraz Rejestru PolPeDiab.Wyniki: W badanym okresie czasu potwierdzono genetycznie rozpoznanie zespołu Wolframa u 13 pacjentów na terenie Polski. Do niniejszej analizy włączono 3 pacjentów z zespołem Wolframa pochodzących z badanego regionu. Całkowita liczba przypadków cukrzycy zdiagnozowanych w tym okresie czasu wyniosła 2568. Prewalencję zespołu Wolframa wśród pacjentów pediatrycznych z cukrzycą oszacowano na 0.12% (95% Przedział Ufności 0.04–0.34%).Wnioski: Oceniono, że zespół Wolframa występuje w polskiej populacji pediatrycznej 26- do 35-krotnie rzadziej niż pozostałe typy cukrzycy monogenowej (MODY i cukrzyca noworodkowa). (Endokrynol Pol 2014; 65 (4): 295–297

Czy nieprawidłowe rozpoznanie zespołu Wolframa jako cukrzycy typu 1 i jej powikłań może być przyczyną rzadkiego rozpoznawania tego zespołu?

Wolfram syndrome (WS), also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness), is a rare autosomal recessive syndrome (1/770,000 in the United Kingdom), characterised by juvenile onset of diabetes mellitus, optic nerve atrophy, diabetes insipidus, sensorineural deafness, renal tract and neurological abnormalities, and primary gonadal atrophy. WS is caused mainly by biallelic mutations in the WFS1 gene, which encodes wolframin. Wide tissue distribution of wolframin and many mutations in the wolframin gene resulting in Wolfram syndrome may contribute to different phenotypes and the unusual combinations of clinical features. We describe a female patient with Wolfram syndrome diagnosed at the age of 25, with a previous false diagnosis of type 1 diabetes mellitus and misdiagnosed diabetic complications. The patient was found to be a compound heterozygote for two novel mutations in exon 8 of WFS1 gene: a 2-bp deletion AT at nt 1539 leading to a frameshift (Y513fs) and a single-base substitution 1174C > T resulting in a stop codon (Q392X). A detailed analysis of the patient’s medical history and a review of the literature suggest that many cases of Wolfram syndrome may remain undiagnosed due to misdiagnosis as type 1 diabetes mellitus and incorrect interpretation of clinical symptoms of neurodegenerative abnormalities, especially in their early stages. (Endokrynol Pol 2014; 65 (5): 398–400)Zespół Wolframa (WS), znany również jako DIDMOAD (moczówka prosta, cukrzyca, atrofia nerwu wzrokowego i głuchota), jest rzadkim zespołem dziedziczonym autosomalnie recesywnie (1/770000 w Wielkiej Brytanii), charakteryzującym się wystąpieniem cukrzycy w wieku młodzieńczym, zanikiem nerwu wzrokowego, moczówką prostą, głuchotą, niewydolnością oddechową i zaburzeniami neurologicznymi oraz pierwotną atrofią gonad. WS jest spowodowany głównie mutacją w genie WFS1, który koduje wolframinę. Obecność wolframiny w wielu tkankach organizmu oraz wiele różnych mutacji w genie wolframiny, których skutkiem jest wystąpienie zespołu Wolframa, może stanowić przyczynę różnych fenotypów tego zespołu oraz różnych kombinacji cech klinicznych. W poniższej publikacji opisano przypadek pacjentki z zespołem Wolframa, której choroba początkowo była błędnie zdiagnozowana jako cukrzyca typu 1 i jej powikłania. W badaniach genetycznych wykazano, że pacjentka była heterozygotą w zakresie dwóch nowych mutacji w egzonie 8 genu WFS1: 2-bp delecji AT w regionie nt 1539, prowadzącej do mutacji zmiany ramki odczytu (Y513fs) oraz substytucji pojedynczej zasady 1174 C > T, czego skutkiem był stop kodon (Q392X). Ze szczegółowej analizy historii medycznej pacjentki oraz przeglądu piśmiennictwa wynika, że duża liczba przypadków zespołu Wolframa może zostać niewłaściwie rozpoznana jako cukrzyca typu 1 lub zaburzenia neurodegeneracyjne, zwłaszcza w początkowej fazie ich rozwoju. (Endokrynol Pol 2014; 65 (5): 398–400

Next-Generation Sequencing in the Diagnosis of Patients with Bardet–Biedl Syndrome—New Variants and Relationship with Hyperglycemia and Insulin Resistance

Bardet-Biedl syndrome (BBS) is a rare autosomal recessively inherited disease with major clinical symptoms such as: obesity, retinal degeneration, polydactyly and renal abnormalities. The aim of the study was to assess the spectrum of gene variants among patients with BBS, identified on the basis of nationwide genetic studies of monogenic diabetes in Polish population. Out of 575 patients enrolled for genetic testing from February 2017 to July 2019, 25 patients with a clinical suspicion of BBS were selected. The identification of pathogenic variants was performed by using targeted next-generation sequencing (NGS) on Illumina NextSeq 550 platform involving the SureSelect assay (Agilent, Santa Clara, CA, USA). BBS was genetically confirmed in 10 of 25 suspected patients. In patients, 14 different variants were found in six genes, mainly in BBS9 and BBS10 gene, including two novel variants. A strong association between hyperglycemia and insulin resistance in patients and the presence of variants in BBS9 gene was observed. Identification of 14 variants, including two new mutations using the NGS method, is the first molecular characteristic of Polish patients with Bardet–Biedl syndrome. It gives hope for earlier proper diagnosis of BBS in future patients selected from children with early childhood obesity and their medical multidisciplinary care

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

Screening for Rare Mitochondrial Genome Variants Reveals a Potentially Novel Association between <i>MT-CO1</i> and <i>MT-TL2</i> Genes and Diabetes Phenotype

Variations in several nuclear genes predisposing humans to the development of MODY diabetes have been very well characterized by modern genetic diagnostics. However, recent reports indicate that variants in the mtDNA genome may also be associated with the diabetic phenotype. As relatively little research has addressed the entire mitochondrial genome in this regard, the aim of the present study is to evaluate the genetic variations present in mtDNA among individuals susceptible to MODY diabetes. In total, 193 patients with a MODY phenotype were tested with a custom panel with mtDNA enrichment. Heteroplasmic variants were selected for further analysis via further sequencing based on long-range PCR to evaluate the potential contribution of frequent NUMTs (acronym for nuclear mitochondrial DNA) insertions. Twelve extremely rare variants with a potential damaging character were selected, three of which were likely to be the result of NUMTs from the nuclear genome. The variant m.3243A>G in MT-TL1 was responsible for 3.5% of MODY cases in our study group. In addition, a novel, rare, and possibly pathogenic leucine variant m.12278T>C was found in MT-TL2. Our findings also found the MT-CO1 gene to be over-represented in the study group, with a clear phenotype–genotype correlation observed in one family. Our data suggest that heteroplasmic variants in MT-COI and MT-TL2 genes may play a role in the pathophysiology of glucose metabolism in humans

Searching for Effective Methods of Diagnosing Nervous System Lesions in Patients with Alström and Bardet–Biedl Syndromes

Bardet–Biedl syndrome (BBS) and Alström syndrome (ALMS) are rare multisystem diseases with an autosomal recessive mode of inheritance and genetic heterogeneity, characterized by visual impairment, hearing impairment, cardiomyopathy, childhood obesity, and insulin resistance. The purpose of our study was to evaluate the indicators of nervous system changes occurring in patients with ALMS and BBS using optical coherence tomography (OCT) and magnetic resonance spectroscopy (MRS) methods compared to a group of healthy subjects. The OCT results showed significantly lower macular thickness in the patient group compared to the control group (p = 0.002). The MRS study observed differences in metabolite levels between the study and control groups in brain areas such as the cerebellum, thalamus, and white matter. After summing the concentrations from all areas, statistically significant results were obtained for N-acetylaspartate, total N-acetylaspartate, and total creatine. Concentrations of these metabolites were reduced in ALMS/BBS patients by 38% (p = 0.0004), 35% (p = 0.0008), and 28% (p = 0.0005), respectively. Our results may help to understand the pathophysiology of these rare diseases and identify strategies for new therapies

Proteomic and Transcriptomic Landscapes of Alström and Bardet–Biedl Syndromes

Alström syndrome (ALMS) and Bardet–Biedl syndrome (BBS) are rare genetic diseases with a number of common clinical features ranging from early-childhood obesity and retinal degeneration. ALMS and BBS belong to the ciliopathies, which are known to have the expression products of genes, encoding them as cilia-localized proteins in multiple target organs. The aim of this study was to perform transcriptomic and proteomic analysis on cellular models of ALMS and BBS syndromes to identify common and distinct pathological mechanisms present in both syndromes. For this purpose, epithelial cells were isolated from the urine of patients and healthy subjects, which were then cultured and reprogrammed into induced pluripotent stem (iPS) cells. The pathways of genes associated with the metabolism of lipids and glycosaminoglycan and the transport of small molecules were found to be concomitantly downregulated in both diseases, while transcripts related to signal transduction, the immune system, cell cycle control and DNA replication and repair were upregulated. Furthermore, protein pathways associated with autophagy, apoptosis, cilium assembly and Gli1 protein were upregulated in both ciliopathies. These results provide new insights into the common and divergent pathogenic pathways between two similar genetic syndromes, particularly in relation to primary cilium function and abnormalities in cell differentiation