Genetic and clinical heterogeneity of permanent neonatal diabetes mellitus: a single tertiary centre experience

Laimon, Wafaa; El-Ziny, M.; El-Hawary, Amany; Elsharkawy, Ashraf; Salem, Nanees; Aboelenin, Hadil Mohamed; Awad, Mohammed; Flanagan, Sarah E.; Franco, Elisa De

doi:10.1007/s00592-021-01788-6

Cited by 9 publications

(15 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…26 Studies have shown that INS and GCK gene mutations are the leading causes of PNDM in communities with a high rate of consanguinity. 2,52,53 Variants in GCK are not a common cause of PNDM, being present in approximately 2.0%-3.0% of all patients with PNDM. 52,54 In this report, they were responsible for 16.7% of NDM cases.…”

Section: Ptf1a (Nm_1781613)mentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2022

View full text Add to dashboard Cite

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.

show abstract

Section: Ptf1a (Nm_1781613)mentioning

confidence: 99%

“…2,52,53 Variants in GCK are not a common cause of PNDM, being present in approximately 2.0%-3.0% of all patients with PNDM. 52,54 In this report, they were responsible for 16.7% of NDM cases.…”

Section: Ptf1a (Nm_1781613)mentioning

confidence: 99%

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

et al. 2022

View full text Add to dashboard Cite

show abstract

“…At present, no specific pharmacotherapeutic treatment options are currently suitable for CS, but glibenclamide can partially reverse the vascular symptoms of CS by inhibiting the overactivity of the K ATP channel ( McClenaghan et al, 2020 ; Laimon et al, 2021 ). Sulfonylureas can inhibit the effect of ABCC8 and KCNJ11 activation mutations that prevent the closure of K ATP channels leading to insulin deficiency, reversing a condition that has historically been treated only with insulin ( Laimon et al, 2021 ). The early ascertainment of a genetic diagnosis help us find the underlying cause which is the optimal treatment of the diseases of mutations in K ATP channels.…”

Section: Discussionmentioning

confidence: 99%

Functional Regulation of KATP Channels and Mutant Insight Into Clinical Therapeutic Strategies in Cardiovascular Diseases

et al. 2022

View full text Add to dashboard Cite

ATP-sensitive potassium channels (KATP channels) play pivotal roles in excitable cells and link cellular metabolism with membrane excitability. The action potential converts electricity into dynamics by ion channel-mediated ion exchange to generate systole, involved in every heartbeat. Activation of the KATP channel repolarizes the membrane potential and decreases early afterdepolarization (EAD)-mediated arrhythmias. KATP channels in cardiomyocytes have less function under physiological conditions but they open during severe and prolonged anoxia due to a reduced ATP/ADP ratio, lessening cellular excitability and thus preventing action potential generation and cell contraction. Small active molecules activate and enhance the opening of the KATP channel, which induces the repolarization of the membrane and decreases the occurrence of malignant arrhythmia. Accumulated evidence indicates that mutation of KATP channels deteriorates the regulatory roles in mutation-related diseases. However, patients with mutations in KATP channels still have no efficient treatment. Hence, in this study, we describe the role of KATP channels and subunits in angiocardiopathy, summarize the mutations of the KATP channels and the functional regulation of small active molecules in KATP channels, elucidate the potential mechanisms of mutant KATP channels and provide insight into clinical therapeutic strategies.

show abstract

“…NDM is a rare type of monogenic diabetes compared to MODY and it is diagnosed within the first six months of life, includes a variety of clinically and genetically diverse disorders. 26 , 27 NDM can be permanent (PNDM) and require lifetime therapy, or transient (TNDM), with insulin reliance for the first few months and spontaneous remission of diabetes by the age of 18 months. 26 , 28–30 …”

Section: Monogenic Diabetesmentioning

confidence: 99%

“… 26 , 27 NDM can be permanent (PNDM) and require lifetime therapy, or transient (TNDM), with insulin reliance for the first few months and spontaneous remission of diabetes by the age of 18 months. 26 , 28–30 …”

Section: Monogenic Diabetesmentioning

confidence: 99%

Genome Editing and Human Pluripotent Stem Cell Technologies for in vitro Monogenic Diabetes Modeling

Dabi¹,

Degechisa²

2022

DMSO

View full text Add to dashboard Cite

Diabetes is a metabolic disease characterized by chronic hyperglycemia. Polygenic diabetes, which encompasses type-1 and type-2 diabetes, is the most prevalent kind of diabetes and is caused by a combination of different genetic and environmental factors, whereas rare phenotype monogenic diabetes is caused by a single gene mutation. Monogenic diabetes includes Neonatal diabetes mellitus and Maturity-onset diabetes of the young. The majority of our current knowledge about the pathogenesis of diabetes stems from studies done on animal models. However, the genetic difference between these creatures and humans makes it difficult to mimic human clinical pathophysiology, limiting their value in modeling key aspects of human disease. Human pluripotent stem cell technologies combined with genome editing techniques have been shown to be better alternatives for creating in vitro models that can provide crucial knowledge about disease etiology. This review paper addresses genome editing and human pluripotent stem cell technologies for in vitro monogenic diabetes modeling.

show abstract

Genetic and clinical heterogeneity of permanent neonatal diabetes mellitus: a single tertiary centre experience

Cited by 9 publications

References 29 publications

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

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

Functional Regulation of KATP Channels and Mutant Insight Into Clinical Therapeutic Strategies in Cardiovascular Diseases

Genome Editing and Human Pluripotent Stem Cell Technologies for in vitro Monogenic Diabetes Modeling

Contact Info

Product

Resources

About