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INTRODUCTION: Maturity-onset diabetes of the young (MODY) is a rare disease due to a single gene mutation that affects several family members in most cases. The Krüppel-like factor 11 (KLF11) gene mutation is associated with decreased insulin sensitivity to high glucose levels. KLF 11 has been implicated in the pathogenesis of MODY type 7 but given its low prevalence, prolonged subclinical period, and the emergence of new information, doubts are raised about its association. METHODS: A literature search of the PubMed, Scopus, and EBSCO databases was performed. The terms "Diabetes Mellitus, Type 2/genetics", "Mason-Type Diabetes" , "Maturity-Onset diabetes of the young", "KLF11 protein, human", and "Maturity-Onset Diabetes of the Young, Type 7" were used"., "Diagnosis" The search selection was not standardized. RESULTS: The KLF1 mutation is rare and represents <1% of the mutations associated with monogenic diabetes. Its isolation in European family lines in the first studies and the emergence of new variants pose new diagnostic challenges. This article reviews the definition, epidemiology, pathophysiology, diagnosis, and treatment of MODY type 7. CONCLUSION: MODY type 7 diabetes represents a rare form of monogenic diabetes with incomplete penetrance. Given its rarity, its association with impaired glucose metabolism has been questioned. Strict evaluation of glycemic control and the appearance of microvascular complications are key areas in the follow-up of patients diagnosed with MODY 7. More studies will be required to characterize the population with KLF11 mutation and clarify its correlation with MODY.
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Diabetes Mellitus Tipo 2 , Fator XI , Humanos , Fator XI/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/diagnóstico , Mutação , Insulina , Proteínas Repressoras/genética , Proteínas Reguladoras de Apoptose/genéticaRESUMO
Monogenic forms of diabetes mellitus may affect a significant number of patients of this disease, and it is an important molecular cause to be investigated. However, studies of the genetic causes of monogenic diabetes, especially in populations with mixed ethnic backgrounds, such as the one in Brazil, are scarce. The aim of this study was to screen several genes associated with monogenic diabetes in fifty-seven Brazilian patients with recurrence of the disease in their families and thirty-four relatives. Inclusion criteria were: Age of onset ≤ 40 years old, BMI < 30 kg/m², at least two affected generations and negative anti-GAD and anti-IA2 antibodies. MODY genes HNF4A, GCK, HNF1A, HNF1B, NEUROD1, KLF11, PAX4, INS, KCNJ11, and MT-TL1 were sequenced by Sanger sequencing. We identified a total of 20 patients with variants, 13 GCK-MODY, four HNF1A-MODY, and one variant in each of the following genes, HNF4A, HNF1B and MT-TL1. Segregation analysis was performed in 13 families. Four variants were novel, two in GCK (p.(Met115Val) [c.343A>G] and p.(Asp365GlufsTer95) [c.1094_1095insGCGA]) and two in HNF1A (p.(Tyr163Ter) [c.489C>G] and p.(Val380CysfsTer39) [c.1136_1137insC]). Here we highlight the importance of screening for monogenic diabetes in admixed populations.
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Diabetes Mellitus Tipo 2 , Sequenciamento de Nucleotídeos em Larga Escala , Adulto , Brasil/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Humanos , MutaçãoRESUMO
BACKGROUND: Diabetes mellitus is the most common metabolic alteration in gestation. Monogenic diabetes or Maturity-Onset Diabetes of the Young (MODY) is a subtype caused by a primary defect in insulin secretion determined by autosomal dominant inheritance. OBJECTIVES: This study aimed to analyze molecular changes of the Glucokinase gene (GCK) in pregnant women with hyperglycemia during gestation and in their neonates. Case Study and Methods: We collected 201 blood samples, 128 from pregnant patients diagnosed with hyperglycemia and 73 from umbilical cord blood from neonates of the respective patients. DNA extraction and polymerase chain reaction (PCR) were performed to identify molecular changes in the GCK gene. RESULTS: In a total of 201 samples (128 from mothers and 73 from neonates), we found changes in 21 (10.6%), among which 12 were maternal samples (6.0%) and 9 were neonatal samples (4.5%). DNA sequencing identified two polymorphisms and one deleterious MODY GCK-diagnostic mutation. CONCLUSION: The prevalence of molecular changes in the Glucokinase gene (GCK) and the deleterious MODY GCK-diagnostic mutation were 9.3% and 0.7%, respectively, in women with hyperglycemia during gestation and 12.5% and 1.3%, respectively, in their neonates. The deleterious MODY GCK mutation identified is associated with a reduction in GCK activity and hyperglycemia. In the other molecular changes identified, it was impossible to exclude phenotypic change despite not having clinical significance. Therefore, these changes may interfere with the management and clinical outcome of the patients.
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Diabetes Mellitus Tipo 2 , Hiperglicemia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Glucoquinase/genética , Humanos , Hiperglicemia/diagnóstico , Hiperglicemia/genética , Recém-Nascido , Mutação , Gravidez , GestantesRESUMO
AIMS: Maturity-Onset Diabetes of the Young (MODY) caused by glucokinase (GCK) mutations is characterized by lifelong mild non-progressive hyperglycemia, with low frequency of coronary artery disease (CAD) compared to other types of diabetes. The aim of this study is to estimate cardiovascular risk by coronary artery calcification (CAC) score in this group. MATERIALS AND METHODS: Twenty-nine GCK-MODY cases, 26 normoglycemic controls (recruited among non-affected relatives/spouses of GCK mutation carriers), and 24 unrelated individuals with type 2 diabetes were studied. Patients underwent CAC score evaluation by computed tomography and were classified by Agatston score ≥ or < 10. Framingham Risk scores of CAD in 10 years were calculated. RESULTS: Median [interquartile range] CAC score in GCK-MODY was 0 [0,0], similar to controls (0 [0,0], P = 0.49), but lower than type 2 diabetes (39 [0, 126], P = 2.6 × 10-5). A CAC score ≥ 10 was seen in 6.9% of the GCK group, 7.7% of Controls (P = 1.0), and 54.2% of individuals with type 2 diabetes (P = 0.0006). Median Framingham risk score was lower in GCK than type 2 diabetes (3% vs. 13%, P = 4 × 10-6), but similar to controls (3% vs. 4%, P = 0.66). CONCLUSIONS: CAC score in GCK-MODY is similar to control individuals from the same family and/or household and is significantly lower than type 2 diabetes. Besides demonstrating low risk of CAD in GCK-MODY, these findings may contribute to understanding the specific effect of hyperglycemia in CAD.
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Cálcio/sangue , Vasos Coronários/metabolismo , Diabetes Mellitus Tipo 2/diagnóstico , Fatores de Risco de Doenças Cardíacas , Adulto , Idoso , Cálcio/análise , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , Vasos Coronários/química , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/diagnóstico , Feminino , Glucoquinase/genética , Humanos , Hiperglicemia/genética , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: Monogenic Diabetes (MFD) represents close to 2% of all the cases of diabetes diagnosed in people younger than 45 years old. Maturity-Onset Diabetes of the Young (MODY), neonatal diabetes, and several syndromic forms of diabetes are included among the most accounts for about typical forms of MDF. MODY is the most frequent type of MFD, with MODY 1, 2, 3, and 5 being the most prevalent forms. The aim of this narrative review is to describe pregnancy associated changes in the pharmacological profile of the antidiabetic drugs used in women with the most frequent MODY subtypes. METHODS: A comprehensive literature search was carried out to identify eligible studies from MEDLINE/ PubMed, EMBASE, and SCIELO databases from 1970 to 2019 first semester. RESULTS: Pregnancy introduces changes in the pharmacodynamic and pharmacokinetic profile of some of the treatments used in MODY. MODY 3 (also known as HNF1-A MODY) is the most frequent MDF. MODY 3 patients are highly sensitive to Sulfonylureas (SU). This is also the case for MODY pregnant women. This high sensitivity to SU is also registered in patients with MODY 1 (HNF4-A MODY). Pharmacodynamic changes have been proposed to explain this behavior (Epac2 hyperactivity). However, changes in expression/activity of the metabolizing CYP2C9 cytochrome and/or alterations in the drug transporters oatp1 (Slc21a1), Lst-1 (Slc21a6), OATPD (SLC21A11), and oat2 may better explain, at least in part, this phenomenon by an increase in the concentration of the active drug. CONCLUSION: The impact of changes in the pharmacological behavior of drugs like SU and other metabolized/transported by mechanisms altered in a pregnancy complicated by MODY is unknown. However, switching-to-insulin recommendation formulated for MODY 1 and 3 seems to be justified. Further research in this field is needed for a better understanding of changes in drug activity associated with this particular subset of patients with MFD.
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Diabetes Mellitus Tipo 2 , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Hipoglicemiantes/farmacologia , Recém-Nascido , Insulina , Pessoa de Meia-Idade , Gravidez , Compostos de Sulfonilureia/uso terapêuticoRESUMO
PURPOSE: The aim of this study was to sequence the coding region of the PAX4 gene in a Brazilian cohort with clinical manifestations of monogenic diabetes. PATIENTS AND METHODS: This study included 31 patients with autosomal dominant history of diabetes, age at diagnosis ≤40 years, BMI <30 kg/m2, and no mutations in GCK or HNF1A, HNF4A, and HNF1B. Screening of the PAX4 coding region was performed by Sanger sequencing. In silico algorithms were used to assess the potential impact of amino acid substitutions on protein structure and function. Additionally, PAX4-MODY family members and 158 control subjects without diabetes were analyzed for the identified mutation. RESULTS: The molecular analysis of PAX4 has detected one missense mutation, p.Arg164Gln (c.491G>A), segregating with diabetes in a large Brazilian family. The mutation was absent among the control group. The index case is a woman diagnosed at 32 years of age with polyneuropathy and treated with insulin. She did not present diabetic renal disease or retinopathy. Family members with the PAX4 p.Arg164Gln mutation have a heterogeneous clinical manifestation and treatment response, with age at diagnosis ranging from 24 years to 50 years. CONCLUSION: To the best of our knowledge, this is the first study to report a PAX4-MODY family in Brazil. The age of PAX4-MODY diagnosis in the Brazilian family seems to be higher than the classical criteria for MODY. Our results reinforce the importance of screening large monogenic diabetes families for the understanding of the clinical manifestations of rare forms of diabetes for the specific and personalized treatment.
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ABSTRACT Objective We aimed to identify the frequency of monogenic diabetes, which is poorly studied in multiethnic populations, due to GCK or HNF1A mutations in patients with suggestive clinical characteristics from the Brazilian population, as well as investigate if the MODY probability calculator (MPC) could help patients with their selection. Subjects and methods Inclusion criteria were patients with DM diagnosed before 35 years; body mass index < 30 kg/m2; negative autoantibodies; and family history of DM in two or more generations. We sequenced HNF1A in 27 patients and GCK in seven subjects with asymptomatic mild fasting hyperglycemia. In addition, we calculated MODY probability with MPC. Results We identified 11 mutations in 34 patients (32.3%). We found three novel mutations. In the GCK group, six cases had mutations (85.7%), and their MODY probability on MPC was higher than 50%. In the HNF1A group, five of 27 individuals had mutations (18.5%). The MPC was higher than 75% in 11 subjects (including all five cases with HNF1A mutations). Conclusion Approximately one third of the studied patients have GCK or HNF1A mutations. Inclusion criteria included efficiency in detecting patients with GCK mutations but not for HNF1A mutations (< 20%). MPC was helpful in narrowing the number of candidates for HNF1A screening.
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Humanos , Masculino , Feminino , Criança , Adolescente , Adulto , Adulto Jovem , Diabetes Mellitus Tipo 2 , Fator 1-alfa Nuclear de Hepatócito/genética , Glucoquinase/genética , Mutação/genética , Linhagem , Fenótipo , Brasil , Estudos Transversais , ProbabilidadeRESUMO
BACKGROUND: MODY-NEUROD1 is a rare form of monogenic diabetes caused by mutations in Neuronal differentiation 1 (NEUROD1). Until now, only a few cases of MODY-NEUROD1 have been reported worldwide and the real contribution of mutations in NEUROD1 in monogenic diabetes and its clinical impact remain unclear. METHODS: Genomic DNA was isolated from peripheral blood lymphocytes of 25 unrelated Brazilians patients with clinical characteristics suggestive of monogenic diabetes and the screening of the entire coding region of NEUROD1 was performed by Sanger sequencing. RESULTS: We identified one novel frameshift deletion (p.Phe256Leufs*2) in NEUROD1 segregating in an autosomal dominant inheritance fashion. Almost 20 years after the first report of NEUROD1-MODY, only a few families in Europe and Asia had shown mutations in NEUROD1 as the cause of monogenic diabetes. CONCLUSION: To our knowledge, we described the first case of NEUROD1-MODY in a Latin American family.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diabetes Mellitus Tipo 2/genética , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Brasil/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/metabolismo , Família , Feminino , Mutação da Fase de Leitura/genética , Testes Genéticos/métodos , Genoma Humano/genética , Humanos , América Latina/epidemiologia , Masculino , Mutação/genética , Linhagem , Análise de Sequência de DNA/métodosRESUMO
ABSTRACT Objective To verify the presence of variants in HNF1B in a sample of the Brazilian population selected according to the presence of renal cysts associated with hyperglycemia. Subjects and methods We evaluated 28 unrelated patients with clinical suspicion of HNF1B mutation because of the concomitant presence of diabetes mellitus (DM) or prediabetes and renal cysts. Genotyping was accomplished using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). In positive cases, available relatives were recruited. Results We found two patients with HNF1B mutations. The first presented the variant p.Pro328Leufs*48(c.983delC) and had DM, renal cysts, and hypomagnesemia. The second presented a heterozygous whole gene deletion in HNF1B, DM, renal cysts, body and tail pancreatic agenesis, and hypomagnesemia; this alteration was also found in his two siblings and his father. Conclusion The recruitment of suspected cases of HNF1B gene mutations in Brazilians due to hyperglycemia and renal cysts presents two positive cases. Our cases contribute to the annotation of clinical and biochemical phenotypes of this rare form of maturity-onset diabetes of the young (MODY).
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Humanos , Adulto , Pessoa de Meia-Idade , Nefropatias Diabéticas/genética , Doenças Renais Císticas/genética , Fator 1-beta Nuclear de Hepatócito/genética , Hiperglicemia/genética , Mutação , Fenótipo , Polimorfismo Genético/genética , Brasil , Estudos de Coortes , Deleção de Genes , Nefropatias Diabéticas/complicações , Doenças Renais Císticas/complicações , Hiperglicemia/complicaçõesRESUMO
AIMS: Maturity-Onset Diabetes of the Young (MODY) comprises a heterogeneous group of monogenic forms of diabetes caused by mutations in at least 14 genes, but mostly by mutations in Glucokinase (GCK) and hepatocyte nuclear factor-1 homeobox A (HNF1A). This study aims to establish a national registry of MODY cases in Brazilian patients, assessing published and unpublished data. METHODS: 311 patients with clinical characteristics of MODY were analyzed, with unpublished data on 298 individuals described in 12 previous publications and 13 newly described cases in this report. RESULTS: 72 individuals had GCK mutations, 9 described in Brazilian individuals for the first time. One previously unpublished novel GCK mutation, Gly178Ala, was found in one family. 31 individuals had HNF1A mutations, 2 described for the first time in Brazilian individuals. Comparisons of GCK probands vs HNF1A: age 16±11 vs 35±20years; age at diagnosis 11±8 vs 21±7years; BMI 19±6 vs 25±6kg/m2; sulfonylurea users 5 vs 83%; insulin users 5 vs 17%; presence of arterial hypertension 0 vs. 33%, all p<0.05. No differences were observed in lipids and C-peptide. CONCLUSIONS: Most MODY cases in Brazil are due to GCK mutations. In agreement with other studied populations, novel mutations are common. Only 14% of patients with familial diabetes carry a HNF1A mutation. Diagnosis of other rare forms of MODY is still a challenge in Brazilian population, as well as adequate strategies to screen individuals for molecular diagnosis.