Genetic and clinical features of neonatal and early onset diabetes mellitus in a tertiary center cohort in Brazil

Abstract

Neonatal diabetes mellitus (NDM) is defined as the occurrence of severe hyperglycemia in infants under 6 months old and may be permanent (PNDM) or transient (TNDM).When diabetes is diagnosed at 6-12 months of age (early onset diabetes [EOD]), the etiology may be monogenic; however, most cases consist of type 1 diabetes mellitus (T1DM). Molecular diagnosis was determined in a cohort of 35 unrelated Brazilian patients with NDM or EOD based on targeted next-generation sequencing panel and/or chromosome 6q24 abnormalities. The impact of genetic testing on treatment and follow-up was evaluated. Overall, 24 patients had NDM: with 18 (75.0%) having PNDM, 5 TNDM (20.8%) and 1 case in which this information was unknown. Eleven patients had EOD. Genetic testing was positive in 20/24 patients with NDM (83.3%) and in 18.2% of cases of EOD. The commonest causes were ATP-sensitive potassium (KATP) channel genes, and GCK and IPEX mutations (37.1%, 11.4% and 5.7%, respectively). Patients with PNDM due to KCNJ11 and ABCC8 mutations transitioned successfully to sulfonylureas in almost 60% of cases, reinforcing the benefit of performing genetic testing in NDM as early as possible. This report refers to the largest series of cases of NDM (TNDM and PNDM) and EOD in Brazil in which patients were submitted to molecular investigation and in which the clinical impact of genetic diagnosis was also evaluated.

Enhancing diagnostic yield of monogenic diabetes through phenotypic and molecular reanalysis of 128 individuals with young onset hyperglycemia: highlighting the significance of accurate case characterization

“…Literature data on the proportion of unresolved cases are more substantial in MODY and neonatal DM, varying around 50-80 1 and 20-37% 5 , respectively. These figures are similar in our Brazilian monogenic DM cohort even after multiple molecular investigations by our research group [6][7][8][9] .…”

“…A cohort of 128 individuals in this study was formed between the years 2011 and 2019 (see Figure 1). These individuals exhibited clinical suspicion of monogenic diabetes mellitus (DM), and despite undergoing multiple stages of molecular investigation [6][7][8][9] , their genetic causes remained unresolved. In all these cases, no pathogenic or likely pathogenic variant was identified, while in 5 of them, they harbored a variant of uncertain significance (VUS).…”

“…For MODY, typical individuals were those diagnosed with hyperglycemia before 30 years old 7 and scored more than 60% 12 on the MODY Probability Calculator 13 . Individuals with neonatal DM were considered typical if their hyperglycemia occurred in the first 6 months of life 2,3,6 . Individuals with suspected FPLD were identified as typical when their lower limbs fat was less than 25% 14,15 , as evaluated by dual-energy X-ray absorptiometry (DXA).…”

Incidence of neonatal hypoglycemia: an insight from China

“…After the umbilical cord was severed after delivery, the mother stopped providing glucose, but the insulin concentration in the fetus was still high, resulting in hypoglycemia after birth [21] . Moreover, some gestational age women's hyperglycemia is caused by heterozygous inactivation mutations in the gene encoding glucose sensing enzyme glucokinase (GCK),this type of newborn may respond to maternal hyperglycemia by secreting higher levels of insulin from fetuses that have not inherited the mutation from the mother, thereby increasing the risk of pregnancy related complications such as macrosomia and neonatal blood glucose disorders [22][23] . Maternal hypertension is also an independent risk factor for neonatal hypoglycemia.…”

Reanálise fenotípica e genotípica de indivíduos com diagnóstico clínico de diabetes monogênico sem etiologia molecular estabelecida

“…O DMN corresponde à hiperglicemia diagnosticada até os 6 meses de vida. Em alguns casos pode ocorrer entre 6 meses a 12 meses, porém a grande maioria dos diagnósticos nessa faixa etária serão por diabetes tipo 1 12,28 . Há incidência de um caso para cada 400.000-500.000 nascidos vivos 29 .…”