Maturity-onset diabetes of the young secondary to HNF1B variants (HNF1B-MODY): a series of 10 patients from a single diabetes center

Background: Maturity-Onset Diabetes of the Young (MODY) is an autosomal dominant condition and represents 1-5% of all cases of diabetes mellitus. MODY is often misdiagnosed as type 1 or type 2 diabetes. The rare subtype 5 (HNF1B-MODY) is due to hepatocyte nuclear factor 1β (HNF1B) molecular alteration and is remarkable for its multisystemic phenotypes characterized by a broad spectrum of pancreatic and extra-pancreatic clinical manifestations. Methods: Retrospective study of patients with HNF1B-MODY diagnosis followed in the Centro Hospitalar Universitário Lisboa Central (Lisbon, Portugal). Demographic data, medical history, clinical and laboratory data, follow-up, and treatment procedures were obtained from electronic medical records. Results: We found 10 patients with HNF1B variants (7 index cases). The median age at diabetes diagnosis was 28 (IQR 24) years and the median age at HNF1B-MODY diagnosis was 40.5 (IQR 23) years. Six patients were initially misclassified as type 1 and 4 as type 2 diabetes. The average time between diabetes diagnosis and the diagnosis of HNF1B-MODY was 16.5 years. Diabetes was the first manifestation in half of the cases. The other half presented with kidney malformations and chronic kidney disease at pediatric age as the first manifestation. All these patients were submitted for kidney transplantation. Long-term diabetes complications included retinopathy (4/10), peripheral neuropathy (2/10), and ischemic cardiomyopathy (1/10). Other extra-pancreatic manifestations included liver test alterations (4/10) and congenital malformation of the female reproductive tract (1/6). History of a first-degree relative with diabetes and/or nephropathy diagnosed at a young age was present in 5 of the 7 index cases. Conclusions: Despite being a rare disease, HNF1B-MODY is underdiagnosed and often misclassified. It should be suspected in patients with diabetes and CKD, especially when diabetes appears at a young age, family history is present, and nephropathy appears before/shortly after the diagnosis of diabetes. The presence of unexplained liver disease increases the degree of suspicion for HNF1B-MODY. Early diagnosis is important to minimize complications and to allow familial screening and pre-conception genetic counseling. Trial registration is not applicable due to the retrospective nature of the study, non-interventional.info:eu-repo/semantics/publishedVersio

Avaliação de diferenças bioquímicas entre indivíduos diabéticos com e sem variantes patogénicas causadores de MODY. (PO 47)

A diabetes tipo MODY (Maturity-onset diabetes of the young) é um tipo de diabetes causada por mutações em um único gene. Existe 14 genes associados a essa doença, no entanto, a maioria dos casos de MODY é causada por alterações nos genes GCK, HNF1A, HNF1B e HNF4A. Cada subtipo desta patologia apresenta características fenotípicas, metabólicas e complicações para a saúde distintas o que exige uma adequação terapêutica diferente. Contudo a grane maioria dos casos de MODY é erroneamente diagnosticada como diabetes tipo 1 ou tipo 2, o que prejudica o diagnóstico do doente. O objetivo deste trabalho consiste na caracterização bioquímica dos participantes do Estudo Molecular de diabetes tipo MODY com base nos valores de glicémia e hemoglobina A1c inicial, indicados nos inquéritos do estudo, pelos médicos que os referenciaram, para perceber se estes valores são ou não um bom indicador de diabetes tipo MODY. Para tal foram analisados os valores de 76 participantes do estudo, com e sem mutação. Para análise estatística dos valores utilizou-se o Rstudio. Com os testes de Shapiro e Wilcox para avaliou-se e distribuição das amostras, bem como as diferenças entre os dois grupos. Os resultados desta análises não revelaram diferença estatística significativa (valor p=0.5) entre os valores de glicémia inicial dos participantes do estudo com mutação e sem mutação, nem com os valores de hemoglobina A1c (valor p= 0.19). Os resultados apresentados sustentam o argumento de que não é possível identificar corretamente pacientes com diabetes tipo MODY apenas com base nos resultados bioquímicos da glicémia e da hemoglobina A1c e que o diagnóstico genético é essencial para que o conceito de medicina personalizada seja uma realidade acessível aos pacientes diabéticos em Portugal.N/

Molecular study of MODY Diabetes: results update (2011-2019)

Investigadores do estudo Molecular de Diabetes tipo MODY Coordenação e equipa laboratorial – Departamento de Promoção da Saúde e Prevenção de Doenças não Transmissíveis do Instituto Nacional de Saúde Doutor Ricardo Jorge. Coordenadores: Mafalda Bourbon e Paulo Dario; Equipa laboratorial: Margarida Vaz e Gisela Gaspar; Equipa clínica: Ana Agapito (Serviço de Endocrinologia - Hospital Curry Cabral, Centro Hospitalar Universitário Lisboa Central), Ana Carolina Neves (APDP – Associação Protectora dos Diabéticos de Portugal), Ana Paula Bugalho (APDP – Associação Protectora dos Diabéticos de Portugal), Bruno Almeida (APDP – Associação Protectora dos Diabéticos de Portugal), Carla Pereira (Serviço de Endocrinologia – Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Central), Carolina Moreno (Serviço de Endocrinologia, Diabetes e Metabolismo – Centro Hospitalar e Universitário de Coimbra), Fernando Fonseca (Serviço de Endocrinologia – Hospital Curry Cabral, Centro Hospitalar Universitário Lisboa Central), Goreti Lobarinhas (Serviço de Pediatria – Hospital Santa Maria Maior), Henrique Vara Luiz (Serviço de Endocrinologia e Diabetes – Hospital Garcia de Orta), João Sequeira Duarte (Serviço de Endocrinologia – Hospital Egas Moniz), Maria de Lurdes Sampaio (Unidade de Endocrinologia Pediátrica, Serviço de Pediatria Médica, Departamento de Pediatria – Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Central) e Sofia Gouveia (Serviço de Endocrinologia, Diabetes e Metabolismo – Centro Hospitalar e Universitário de Coimbra).Correção: nas afiliações dos Autores e dos Investigadores do estudo Molecular de Diabetes tipo MODY (16/6/2021)A diabetes tipo MODY é uma doença monogénica que se estima que contribua para 1 a 5% de todos os casos de diabetes. Atualmente existem 14 genes associados a esta patologia cujos doentes apresentam características fenotípicas, metabólicas e genéticas muito heterogéneas. Em 2011, o Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis do Instituto Nacional de Saúde Doutor Ricardo Jorge implementou o estudo molecular da diabetes tipo MODY com o objetivo de caracterizar geneticamente estes doentes e identificar precocemente familiares em risco, de forma a contribuir para a melhor gestão do doente. O rastreio destes doentes é difícil devido a critérios clínicos pouco sensíveis e inespecíficos e por não existir um biomarcador único que nos permita fazer a diferenciação entre os vários tipos de diabetes. O estudo genético permite a correta identificação destes doentes. Entre 2011 e 2019, foram estudados 76 casos índex nos quais foram identificadas alterações patogénicas ou provavelmente patogénicas em 35,5% (27). Através do estudo em cascata dos familiares, foi possível identificar adicionalmente 17 indivíduos com MODY. Para estes doentes, o conceito de medicina personalizada é uma realidade pois, com base no diagnóstico genético, os clínicos têm a capacidade de definir uma terapêutica adequada a cada caso, bem como de estabelecer o prognóstico, aconselhamento genético e o estudo de familiares.MODY diabetes is a monogenic disease that is estimated to contribute to 1 to 5% of all diabetes cases. Currently, there are 14 genes associated with this condition whose patients present heterogeneous phenotypic, metabolic and genetic characteristics. In 2011, Department of Health Promotion and Prevention of non Communicable Diseases implemented the Molecular Study of MODY Diabetes with the aim of genetically characterizing these patients and early identify family members at risk, in order to contribute for the best management of these patients. The screening is difficult due to the low sensibility and specificity of clinical criteria, because there is no single biomarker that allows to make the differentiation between the different types of diabetes. The genetic study allows the correct identification of these patients. Between 2011 and 2019, 76 index cases were studied and in 35.5% (27) a pathogenic or probably pathogenic variant was identified. Through cascade screening of family members, it was possible to additionally identify 17 individuals with MODY. For these patients, the concept of personalized medicine is a reality because based on the genetic diagnosis, the clinicians have the ability to define an appropriate therapy for each case and establish patient prognosis, genetic counselling as well as identification of o therat risk family members.info:eu-repo/semantics/publishedVersio

Unraveling the genetic background of individuals with a clinical familial hypercholesterolemia phenotype

Familial hypercholesterolemia (FH) is a common genetic disorder of lipid metabolism caused by pathogenic/likely pathogenic variants in LDLR, APOB, and PCSK9 genes. Variants in FH-phenocopy genes (LDLRAP1, APOE, LIPA, ABCG5, and ABCG8), polygenic hypercholesterolemia, and hyperlipoprotein (a) [Lp(a)] can also mimic a clinical FH phenotype. We aim to present a new diagnostic tool to unravel the genetic background of clinical FH phenotype. Biochemical and genetic study was performed in 1,005 individuals with clinical diagnosis of FH, referred to the Portuguese FH Study. A next-generation sequencing panel, covering eight genes and eight SNPs to determine LDL-C polygenic risk score and LPA genetic score, was validated, and used in this study. FH was genetically confirmed in 417 index cases: 408 heterozygotes and 9 homozygotes. Cascade screening increased the identification to 1,000 FH individuals, including 11 homozygotes. FH-negative individuals (phenotype positive and genotype negative) have Lp(a) >50 mg/dl (30%), high polygenic risk score (16%), other monogenic lipid metabolism disorders (1%), and heterozygous pathogenic variants in FH-phenocopy genes (2%). Heterozygous variants of uncertain significance were identified in primary genes (12%) and phenocopy genes (7%). Overall, 42% of our cohort was genetically confirmed with FH. In the remaining individuals, other causes for high LDL-C were identified in 68%. Hyper-Lp(a) or polygenic hypercholesterolemia may be the cause of the clinical FH phenotype in almost half of FH-negative individuals. A small part has pathogenic variants in ABCG5/ABCG8 in heterozygosity that can cause hypercholesterolemia and should be further investigated. This extended next-generation sequencing panel identifies individuals with FH and FH-phenocopies, allowing to personalize each person’s treatment according to the affected pathway