Recently, the genetic cause of several syndromic forms of glycemia dysregulation has been described. One of them, MEHMO syndrome, is a rare X-linked syndrome recently linked to the EIF2S3 gene mutations. MEHMO is characterized by Mental retardation, Epilepsy, Hypogonadism/hypogenitalism, Microcephaly, and Obesity. Moreover, patients with MEHMO had also diabetes and endocrine phenotype, but detailed information is missing. We aimed to provide more details on the endocrine phenotype in two previously reported male probands with MEHMO carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. Both probands had a neonatal hypoglycemia, early onset insulin-dependent diabetes, and hypopituitarism due to dysregulation and gradual decline of peptide hormone secretion. Based on the clinical course in our two probands and also in previously published patients, neonatal hypoglycemia followed by early-onset diabetes and hypopituitarism may be a consistent part of the MEHMO phenotype.
- MeSH
- diabetes mellitus 1. typu vrozené genetika MeSH
- endokrinní žlázy metabolismus MeSH
- epilepsie genetika MeSH
- eukaryotický iniciační faktor 2 genetika MeSH
- fenotyp MeSH
- hypoglykemie vrozené genetika MeSH
- hypogonadismus genetika MeSH
- hypopituitarismus vrozené genetika MeSH
- lidé MeSH
- mentální retardace vázaná na chromozom X genetika MeSH
- mikrocefalie genetika MeSH
- novorozenec MeSH
- obezita genetika MeSH
- pohlavní orgány abnormality MeSH
- posunová mutace MeSH
- transkripční faktory MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
Familial hypercholesterolemia (FH) is most frequently caused by LDLR or APOB mutations. Therefore, the aim of our study was to examine the genetic background of Slovak patients suspected of FH. Patients with clinical suspicion of FH (235 unrelated probands and 124 family relatives) were recruited throughout Slovakia during the years 2011-2015. The order of DNA analyses in probands was as follows: 1. APOB mutation p.Arg3527Gln by real-time PCR method, 2. direct sequencing of the LDLR gene 3. MLPA analysis of the LDLR gene. We have identified 14 probands and 2 relatives with an APOB mutation p.Arg3527Gln, and 89 probands and 75 relatives with 54 different LDLR mutations. Nine of LDLR mutations were novel (i.e. p.Asp90Glu, c.314-2A>G, p.Asp136Tyr, p.Ser177Pro, p.Lys225_Glu228delinsCysLys, p.Gly478Glu, p.Gly675Trpfs*42, p.Leu680Pro, p.Thr832Argfs*3). This is the first study on molecular genetics of FH in Slovakia encompassing the analysis of whole LDLR gene. Genetic etiology of FH was confirmed in 103 probands (43.8 %). Out of them, 86.4 % of probands carried the LDLR gene mutation and remaining 13.6 % probands carried the p.Arg3527Gln APOB mutation.
- MeSH
- dospělí MeSH
- hyperlipoproteinemie typ II diagnóza epidemiologie genetika MeSH
- kvantitativní polymerázová řetězová reakce metody MeSH
- LDL-receptory genetika MeSH
- lidé MeSH
- mladý dospělý MeSH
- statistika jako téma metody MeSH
- zdravotnické přehledy * metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Slovenská republika epidemiologie MeSH
Úvod: Monogénová obezita je podmienená mutáciou v jednom z génov zúčastňujúcich sa regulácie leptín-melanokortínovej osi, ktorá hrá dôležitú úlohu v udržiavaní energetickej homeostázy organizmu, najmä v navodzovaní pocitu sýtosti. Cieľ: Cieľom práce je zhrnutie výsledkov DNA analýzy monogénovej obezity u detí od roku 2009 do roku 2015 v laboratóriu DIABGENE. Práca je zameraná najmä na etiológiu a epidemiológiu najčastejších foriem monogénovej obezity u detí na Slovensku. Pacienti a metódy: DNA analýza rôznych génov bola vykonaná doteraz u 565 pacientov s klinickým podozrením na monogénovú obezitu. Podľa literatúry najčastejšie sa vyskytujúci typ monogénovej obezity (v dôsledku mutácií v géne pre melanokortínový receptor 4 – MC4R) bol analyzovaný u 268 detských pacientov so vznikom obezity do 11. roku života, bez špecifickejších klinických príznakov. U pacientov so špecifickejšími príznakmi (endokrinopatie, častý výskyt infekcií, znížený vzrast, ryšavé vlasy, hypokorticizmus a iné) bola vykonaná analýza ďalších génov (SIM1, LEP, LEPR, POMC) spôsobujúcich iné typy monogénovej obezity. Výsledky: V našej štúdii sme našli 2 probandky (0,7 %) s mutáciou v MC4R. Doteraz sme našli jednu mutáciu v SIM1 géne, žiadne sme nenašli v génoch pre LEP, LEPR alebo POMC, čo radí Slovensko medzi krajiny Európy s pravdepodobne najnižším výskytom monogénovej obezity. Záver: Monogénová obezita je zriedkavou príčinou obezity na Slovensku, napriek tomu je vyhľadávanie a diagnostika týchto pacientov dôležité, pretože vyžadujú špecifický manažment ako aj reálnu možnosť kauzálnej liečby v súčasnosti alebo v budúcnosti.
Background: Monogenic obesity is caused by a mutation in on of the genes regulating leptin-melanocortin pathway, which is playing a key role by maintaining energetic homeostasis of organism, mainly inducing a feeling of satiety. Aim: The aim of this work is to conclude results of DNA analysis of monogenic obesity in laboratorium DIABGENE in years 2009–2015. This work is focused on etiology and epidemiology of the most frequent types of monogenic obesity in children. Patients and methods: DNA analysis of varios genes was performed together in 565 patients with a clinical suspicion of monogenic obesity to date. The suggested most frequent type of monogenic obesity (due to a mutation in melanocortin receptor 4 gene – MC4R) was analysed in 268 patients with obesity onset up to 11. years, without other specific clinical signs. In patients with more specific clinical signs (endocrinopathies, infections, decreased growth, red hair, hypocorticism and other) was performed DNA analysis of other genes (SIM1, LEP, LEPR, POMC) causing monogenic obesity. Results: We have found 2 probands (0.7%) with a MC4R mutation in our study. One mutation was found in SIM1 gene and no mutations in LEP, LEPR and POMC gene to date, reffering Slovakia to European countries with probably the lowest prevalence of monogenic obesity. Conclusion: Monogenic obesity is a rare cause of childhood obesity in Slovakia, however searching and diagnosing of these patients is very important, because of the need of specific management as well as real possibility of causal treatment today or in the future.
- MeSH
- časná diagnóza MeSH
- dítě * MeSH
- DNA analýza MeSH
- gen pro FTO fyziologie nedostatek MeSH
- incidence MeSH
- klinické zkoušky jako téma MeSH
- leptinové receptory genetika MeSH
- lidé MeSH
- mutace genetika MeSH
- obezita * genetika komplikace MeSH
- prevalence MeSH
- pro-opiomelanokortin genetika MeSH
- receptor melanokortinový typ 4 analýza genetika MeSH
- rizikové faktory MeSH
- Check Tag
- dítě * MeSH
- lidé MeSH
- Geografické názvy
- Slovenská republika MeSH
BACKGROUND: Inactivating mutations of the hypothalamic transcription factor singleminded1 (SIM1) have been shown as a cause of early-onset severe obesity. However, to date, the contribution of SIM1 mutations to the obesity phenotype has only been studied in a few populations. In this study, we screened the functional regions of SIM1 in severely obese children of Slovak and Moravian descent to determine if genetic variants within SIM1 may influence the development of obesity in these populations. METHODS: The SIM1 promoter region, exons and exon-intron boundaries were sequenced in 126 unrelated obese children and adolescents (2-18 years of age) and 41 adult lean controls of Slovak and Moravian origin. Inclusion criteria for the children and adolescents were a body mass index standard deviation score higher than 2 SD for an appropriate age and sex, and obesity onset at less than 5 years of age. The clinical phenotypes of the SIM1 variant carriers were compared with clinical phenotypes of 4 MC4R variant carriers and with 27 unrelated SIM1 and MC4R mutation negative obese controls that were matched for age and gender. RESULTS: Seven previously described SIM1 variants and one novel heterozygous variant p.D134N were identified. The novel variant was predicted to be pathogenic by 7 in silico software analyses and is located at a highly conserved position of the SIM1 protein. The p.D134N variant was found in an 18 year old female proband (BMI 44.2kg/m2; +7.5 SD), and in 3 obese family members. Regardless of early onset severe obesity, the proband and her brother (age 16 years) did not fulfill the criteria of metabolic syndrome. Moreover, the variant carriers had significantly lower preferences for high sugar (p = 0.02) and low fat, low carbohydrate, high protein (p = 0.02) foods compared to the obese controls. CONCLUSIONS: We have identified a novel SIM1 variant, p.D134N, in 4 obese individuals from a single pedigree which is also associated with lower preference for certain foods.
- MeSH
- detekce genetických nosičů MeSH
- dítě MeSH
- fenotyp MeSH
- lidé MeSH
- mladiství MeSH
- mutace MeSH
- nepřímá kalorimetrie MeSH
- obezita etnologie genetika MeSH
- předškolní dítě MeSH
- preference v jídle MeSH
- receptor melanokortinový typ 4 genetika MeSH
- represorové proteiny genetika MeSH
- rodokmen MeSH
- studie případů a kontrol MeSH
- stupeň závažnosti nemoci MeSH
- transkripční faktory bHLH genetika MeSH
- věk při počátku nemoci MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika etnologie MeSH
- Slovenská republika etnologie MeSH
Kongenitálny hyperinzulinizmus (congenital hyperinsulinism – CHI) je najčastejšou príčinou závažných perzistujúcich hypoglykémií u novorodencov a dojčiat. Z hľadiska prognózy je kľúčová včasná diagnostika, ktorá určí príčinu ochorenia a účinná liečba volená podľa princípov farmakogenetiky. Pri diagnostike typu CHI má dominantné postavenie DNA analýza 11 génov zasahujúcich do sekrécie inzulínu, ktoré spôsobujú izolované formy CHI. Genotyp zároveň určí aj optimálny liečebný postup, ktorý pozostáva z medikamentóznej liečby a diétnych opatrení, menej často z chirurgickej intervencie. Najmä medikamentózna liečba najťažších (na diazoxid rezistentných) foriem CHI zaznamenala v posledných rokoch výrazný posun vpred.
Congenital hyperinsulinism (CHI) is the most common cause of severe persistent hypoglycemia in neonates and infants. Early diagnosis and effective treatment (based on the principles of pharmacogenetics) play the key role for the prognosis. The DNA anlysis, which can identify mutation in one of the 11 genes causing MODY, is crutial in the diagnostics. Moreover, The genotype determines also the optimal therapy approach (medicaments, diet or rarely surgery). There was a large progress of novel medicaments treating particularly most severe (diazoxide-resistant) forms of CHI.
- MeSH
- časná diagnóza MeSH
- diazoxid aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- diferenciální diagnóza MeSH
- DNA analýza MeSH
- gastrointestinální látky terapeutické užití MeSH
- glukagon aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- glukosa aplikace a dávkování terapeutické užití MeSH
- hyperamonemie genetika MeSH
- hypoglykemie farmakoterapie komplikace MeSH
- kojenec MeSH
- lidé MeSH
- mutace genetika MeSH
- nemoci slinivky břišní MeSH
- novorozenec MeSH
- oktreotid aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- prognóza MeSH
- rizikové faktory MeSH
- somatostatin analogy a deriváty aplikace a dávkování terapeutické užití MeSH
- vrozený hyperinzulinismus * diagnóza klasifikace terapie MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- novorozenec MeSH
