Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene

Manna, Thaís Della; Battistim, Claudilene; Radonsky, Vanessa; Savoldelli, Roberta Diaz; Damiani, Durval; Kok, Fernando; Pearson, Ewan R.; Ellard, Sian; Hattersley, Andrew T.; Reis, André

doi:10.1590/s0004-27302008000800024

Cited by 19 publications

(9 citation statements)

References 30 publications

(44 reference statements)

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“…However, in patients with mutations resulting in severe DEND syndrome, sulfonylurea treatment is often ineffective ( 10 , 16 , 27 , 34 ). Although in a Brazilian patient having the same mutation as our third patient (p.C166Y mutation in the KCNJ11 gene) sulfonylurea treatment was unsuccesful in controlling blood glucose levels and neurological symptoms ( 35 ), we observed relative improvement in both blood glucose levels and neurological symptoms in the short term. Nevertheless, we cannot comment on treatment success because we were not able to follow this patient in the long term.…”

Section: Discussionmentioning

confidence: 50%

Neonatal Diabetes: Two Cases with Isolated Pancreas Agenesis due to Homozygous PTF1A Enhancer Mutations and One with Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome due to KCNJ11 Mutation

Evliyaoğlu

Ercan

Ataoğlu³

et al. 2018

Jcrpe

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Neonatal diabetes mellitus is a rare form of monogenic diabetes which is diagnosed in the first six months of life. Here we report three patients with neonatal diabetes; two with isolated pancreas agenesis due to mutations in the pancreas-specific transcription factor 1A (PTF1A) enhancer and one with developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, due to a KCNJ11 mutation. The two cases with mutations in the distal enhancer of PTF1A had a homozygous g.23508363A>G and a homozygous g.23508437A>G mutation respectively. Previous functional analyses showed that these mutations can decrease expression of PTF1A which is involved in pancreas development. Both patients were born small for gestational age to consanguineous parents. Both were treated with insulin and pancreatic enzymes. One of these patients’ fathers was also homozygous for the PTF1A mutation, whilst his partner and the parents of the other patient were heterozygous carriers. In the case with DEND sydrome, a previosly reported heterozygous KCNJ11 mutation, p.Cys166Tyr (c.497G>A), was identified. This patient was born to nonconsanguineous parents with normal birth weight. The majority of neonatal diabetes patients with KCNJ11 mutations will respond to sulphonylurea treatment. Therefore Glibenclamide, an oral antidiabetic of the sulphonylurea group, was started. This treatment regimen relatively improved blood glucose levels and neurological symptoms in the short term. Because we could not follow the patient in the long term, we are not able to draw conclusions about the efficacy of the treatment. Although neonatal diabetes mellitus can be diagnosed clinically, genetic analysis is important since it is a guide for the treatment and for prognosis.

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Section: Discussionmentioning

confidence: 50%

Neonatal Diabetes: Two Cases with Isolated Pancreas Agenesis due to Homozygous PTF1A Enhancer Mutations and One with Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome due to KCNJ11 Mutation

Evliyaoğlu

Ercan

Ataoğlu³

et al. 2018

Jcrpe

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“…We excluded individuals who had transient neonatal diabetes (n =16) as well as two participants with severely activating mutations (G334D and C166Y) who were completely unresponsive to SU treatment based on undetectable C-peptide levels after achieving a dose of at least 1 mg kg −1 day −1 of glibenclamide (known as glyburide in the USA and Canada) [13-15]. Six participants were lost to follow-up and were excluded from the study.…”

Section: Methodsmentioning

confidence: 99%

Age at the time of sulfonylurea initiation influences treatment outcomes in KCNJ11-related neonatal diabetes

et al. 2015

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Aims/hypothesis Individuals with heterozygous activating mutations of the KCNJ11 gene encoding a subunit of the ATP-sensitive potassium channel (KATP) can usually be treated with oral sulfonylurea (SU) pills in lieu of insulin injections. The aim of this study was to test our hypothesis that younger age at the time of initiation of SU therapy is correlated with lower required doses of SU therapy, shorter transition time and decreased likelihood of requiring additional diabetes medications. Methods We performed a retrospective cohort study using data on 58 individuals with neonatal diabetes due to KCNJ11mutations identified through the University of Chicago Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu/registry). We assessed the influence of age at initiation of SU therapy on treatment outcomes. Results HbA1c fell from an average of 8.5% (69 mmol/mol) before transition to 6.2% (44 mmol/mol) after SU therapy (p < 0.001). Age of initiation of SU correlated with the dose (mg kg−1 day−1) of SU required at follow-up (r = 0.80, p < 0.001). Similar associations were observed across mutation subtypes. Ten participants required additional glucose-lowering medications and all had initiated SU at age 13 years or older. No serious adverse events were reported. Conclusions/interpretation Earlier age at initiation of SU treatment is associated with improved response to SU therapy. Declining sensitivity to SU may be due to loss of beta cell mass over time in those treated with insulin. Our data support the need for early genetic diagnosis and appropriate personalised treatment in all cases of neonatal diabetes.

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“…The best known examples include the aminoacidopathies phenylketonuria (PKU) and nonketotic hyperglycinemia (NKH); the organic acidemias methylmalonic acidemia (MMA), proprionic acidemia (PA) and maple-syrup urine disease (MSUD); and a disorder of copper metabolism, Menkes disease [71–77]. Mutations of KCNJ11 cause DEND syndrome (developmental delay, epilepsy, neonatal diabetes), which commonly features ISS and is a rare example of an ion channel gene associated with spasms [78–80]. The genetically-characterized mitochondrial disorders appear to be infrequently associated with ISS, with very few clinical reports available [81].…”

Section: Iss With Predisposing Genotype Knownmentioning

confidence: 99%

Genetic and Biologic Classification of Infantile Spasms

Paciorkowski

Thio

Dobyns

2011

Pediatric Neurology

146

125

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Infantile spasms are an age-dependent epilepsy that are highly associated with cognitive impairment, autism, and movement disorders. Previous classification systems have focused on a distinction between symptomatic and cryptogenic etiologies, and have not kept pace with the recent discoveries of mutations in genes in key pathways of central nervous system development in patients with infantile spasms. Children with certain genetic syndromes are much more likely to have infantile spasms, and we review the literature to propose a genetic classification of these disorders. Children with these genetic associations with infantile spasms also have phenotypes beyond epilepsy that may be explained by recent advances in the understanding of underlying biological mechanisms. We therefore also propose a biologic classification of the genes highly associated with infantile spasms, and articulate models for infantile spasms pathogenesis based on that data. The two best described pathways of pathogenesis are abnormalities in the gene regulatory network of GABAergic forebrain development, and abnormalities in molecules expressed at the synapse. We intend for these genetic and biologic classifications to be flexible, and hope that they will encourage much needed progress in syndrome recognition, clinical genetic testing, and ultimately the development of new therapies that target specific pathways of pathogenesis.

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Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene

Cited by 19 publications

References 30 publications

Neonatal Diabetes: Two Cases with Isolated Pancreas Agenesis due to Homozygous PTF1A Enhancer Mutations and One with Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome due to KCNJ11 Mutation

Neonatal Diabetes: Two Cases with Isolated Pancreas Agenesis due to Homozygous PTF1A Enhancer Mutations and One with Developmental Delay, Epilepsy, and Neonatal Diabetes Syndrome due to KCNJ11 Mutation

Age at the time of sulfonylurea initiation influences treatment outcomes in KCNJ11-related neonatal diabetes

Genetic and Biologic Classification of Infantile Spasms

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