Mutations in K ATP channel genes and congenital hyperinsulinemic hypoglycemia / 国际儿科学杂志

Congenital hyperinsulinemic hypoglycemia(CHH)is a group of rare heterogeneous diseases with hypoglycemia as the main clinical manifestation caused by insulin imbalance and excessive secretion.It is the most common cause of persistent hypoglycemia in infants and children.Related gene mutations were detected in about 40% of patients, among which inactivating mutations in ABCC8 or KCNJ11 genes are the most common.Delay in diagnosis and improper treatment can cause permanent brain damage in infants and children with CHH.Therefore, early identification and correct diagnosis and treatment are important and essential to prevent brain damage in infants and children with CHH.This article reviews the molecular pathogenesis of CHH caused by K ATP gene inactivation mutations, the impact of ABCC8 or KCNJ11 gene mutations on the pathological types of pancreas, the severity of hypoglycemia and the choice of clinical treatment options in children with CHH, as well as the latest progress in clinical diagnosis and treatment of CHH, in order to improve clinicians′ awareness of CHH.

Expression and Prognostic Value of Inward Rectifier Potassium Channel Subfamily J Member 11 mRNA in Gliomas / 肿瘤防治研究

Objective To analyze the expression of KCNJ11 mRNA in gliomas and its prognostic value. Methods The clinical, histopathological and molecular pathological features of 273 patients with gliomas were collected from CGGA. We analyzed the differences of KCNJ11 mRNA expression in different types of gliomas and the survival time of patients with high and low expression of KCNJ11 mRNA in different subtypes of gliomas. Results The expression levels of KCNJ11 mRNA in young glioma and primary glioma patients were higher than those in old glioma and recurrent glioma patients, respectively (P=0.008, 0.001). The expression of KCNJ11 mRNA in oligodendroglioma was the highest, astrocytoma was the second, and glioblastoma was the lowest (P=0.000). The expression of KCNJ11 mRNA in WHOⅡ grade glioma was the highest, WHOⅢ was the second, and WHOⅣ was the lowest (P=0.000). The expression levels of KCNJ11 mRNA in IDH-mutant type glioma patients were higher than those in IDH-wild type glioma patients (P=0.000). The expression of KCNJ11 mRNA in deletion of 1p/19q glioma patients was higher than that in non-deletion of 1p/19q ones (P=0.000). The expression of KCNJ11 mRNA in MGMT methylated glioma patients was higher than that in non-methylated ones (P=0.036). The survival time of patients with high expression of KCNJ11 mRNA (≥2.77) was longer than that with low expression (P=0.000). Multivariate Cox analysis showed that the high expression of KCNJ11 mRNA was an independent factor affecting the good prognosis of patients with glioma. Conclusion The expression of KCNJ11 mRNA is negatively related to the malignant degree of the tumor. The high expression of KCNJ11 mRNA is an independent factor affecting the good prognosis of patients with glioma.

Successful switching from insulin to sulfonylurea in a 3-month-old infant with diabetes due to p.G53D mutation in KCNJ11

Permanent neonatal diabetes mellitus is most commonly caused by mutations in the ATP-sensitive potassium channel (KATP) subunits. Prompt initiation of sulfonylurea treatment can improve glycemic control in children with KCNJ11 mutation. In this report, we present a case of permanent neonatal diabetes caused by a mutation in the KCNJ11 gene that was successfully treated via early switching of insulin to sulfonylurea treatment. A 53-day-old female infant presented with diabetic ketoacidosis. Insulin was administered for the ketoacidosis and blood glucose regulation. At 3 months of age, using genomic DNA extracted from peripheral lymphocytes, direct sequencing of KCNJ11 identified a heterozygous mutation of c.158G>A (p.G53D) and confirmed the diagnosis of permanent neonatal diabetes mellitus. Subsequently, treatment with sulfonylurea was initiated, and the insulin dose was gradually tapered. At 4 months of age, insulin therapy was discontinued, and sulfonylurea (glimepiride, 0.75 mg/kg) was administered alone. At 6 months after initiation of administration of sulfonylurea monotherapy, blood glucose control was stable, and no hypoglycemic events or developmental delays were reported. C-peptide levels increased during treatment with sulfonylurea. Early switching to sulfonylurea in infants with permanent diabetes mellitus owing to a KCNJ11 mutation could successfully help regulate glycemic control, which suggests the need for early genetic testing in patients presenting with diabetes before 6 months of age.

Clinical characteristics and gene mutations analysis of 56 patients with congenital hyperinsulinism / 中华实用儿科临床杂志

Objective To analyze the clinical characteristics and gene mutations of 56 patients with congenital hyperinsulinism(CHI)and to provide a theoretical basis for clinical diagnosis and treatment of CHI.Methods Fifty-six children who were diagnosed as CHI between February 2002 and January 2016 in Beijing Children's Hospital Affiliated to Capital Medical University were selected as research subjects.A retrospective study was done about the clinical data and the treatment procedures of the 56 patients,such as perinatal conditions,clinical manifestations,laboratory data,treatments,prognosis and so on.Polymerase chain reaction(PCR)-DNA technology or next-generation sequencing technology was used to analyze the CHI relevant genes of the 56 patients.Results Thirty of the 56 patients carried CHI gene mutation.(1)Twenty-three of 56 patients(41.0％)carried ABCC8/KCNJ11 gene mutations:4 of 23 patients carried complex heterozygous mutation,1 of 23 patients carried both ABCC8 and KCNJ11 gene mutation,1 of 23 patients carried maternally inherited ABCC8 gene mutation,12 of 23 patients carried paternally inherited ABCC8 gene mutation,1 of 23 patients carried paternally inherited KCNJ11 gene mutation,3 of 23 patients carried de novo ABCC8 gene mutation,1 of 23 patients had unknown genetic way,19 of 23 patients were treated with Diazoxide,2 of 19 patients were responsive to Diazoxide,7 of 19 patients were unresponsive to Diazoxide and 10 of 19 patients were uncertain to Diazoxide.(2)Five of 56 patients(8.9％)carried GLUD1 gene mutation,4 of 5 patients were treated with Diazoxide and they were all responsive to Diazoxide.(3)One of 56 patients(1.7％)carried de novo GCK gene mutation,responsive to Diazoxide treatment.(4)One of 56 patients(1.7％)carried maternally inherited SLC16A1 gene mutation,responsive to Diazo-xide treatment.Conclusions The ABCC8 gene and GLUD1 gene mutation are the main causative genes of CHI.The GCK gene and SLC16A1 gene mutation are in the minority.Most ABCC8 gene and KCNJ11 gene mutation are unresponsive to Diazoxide treatment.

Clinical features of two patients with neonatal diabetes mellitus caused by KCNJ11 gene V59A/V59M mutations / 中华内分泌代谢杂志

Two patients with neonatal diabetes tested as V59A and V59M mutations were chosen for the study. Clinical data were analyzed retrospectively. The results showed that the patient with V59A mutation was characteristic of spasm and hyperglycemia at the age of three month, and treated with insulin for a long time as unresponsive to the glibenclamide at the beginning. Myasthenia and delay of development were observed during the follow-up. At the age of two years, glibenclamide was tried for the second time with a high dose and fairly-controlled glucose level. The patient with V59M mutation was diagnosed with diarrhea, hyperglycemia, and ketosis at the age of two month, and was responsive to glibenclamide at a relatively low dose with well-controlled glucose level. These results suggest that KCNJ11 V59M mutation would show some milder clinical manifestations and better glibenclamide efficacy as compared with V59A mutation.

DEND Syndrome with Heterozygous KCNJ11 Mutation Successfully Treated with Sulfonylurea

Permanent neonatal diabetes mellitus (PNDM) is caused by mutations in the ATP-sensitive potassium channel (K(ATP) channel) subunits. Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome is the most severe form of PNDM and is characterized by various neurologic features. We report on a patient with DEND syndrome following initial misdiagnosis with type 1 DM, who was successfully switched from insulin to sulfonylurea therapy. A 50-day-old male presented with fever and seizure, complicated by persistent hyperglycemia. Insulin therapy was initiated. At 10 months of age, the patient was unable to hold his head up and make eye contact with others. At 17.9 years of age, direct sequencing of KCNJ11 identified a heterozygous mutation of c.602G>A (p.R201H). Since then, treatment with gliclazide was initiated and the insulin dose was gradually reduced. Following 3 months, insulin was discontinued with a gliclazide dose of 2.4 mg/kg. The patient continued to have excellent glycemic control with a glycated hemoglobin (HbA1c) level of 5.8% after 5 months. However, the patient's psychomotor retardation did not improve. This study reports the first case of DEND syndrome in Korea caused by a KCNJ11 mutation and emphasizes the necessity to screen mutations in KATP channel genes in patients with neonatal diabetes.

Successful sulfonylurea treatment in a patient with permanent neonatal diabetes mellitus with a novel KCNJ11 mutation / 소아과

Permanent neonatal diabetes mellitus refers to diabetes that occurs before the age of 6 months and persists through life. It is a rare disorder affecting one in 0.2-0.5 million live births. Mutations in the gene KCNJ11, encoding the subunit Kir6.2, and ABCC8, encoding SUR1 of the ATP-sensitive potassium (K(ATP)) channel, are the most common causes of permanent neonatal diabetes mellitus. Sulfonylureas close the K(ATP) channel and increase insulin secretion. KCNJ11 and ABCC8 mutations have important therapeutic implications because sulfonylurea therapy can be effective in treating patients with mutations in the potassium channel subunits. The mutation type, the presence of neurological features, and the duration of diabetes are known to be the major factors affecting the treatment outcome after switching to sulfonylurea therapy. More than 30 mutations in the KCNJ11 gene have been identified. Here, we present our experience with a patient carrying a novel p.H186D heterozygous mutation in the KCNJ11 gene who was successfully treated with oral sulfonylurea.

Association of the KCNJ11 Variant E23K with Type 2 Diabetes in Indo-Trinidadians / La Asociación de la Variante E23K de KCNJ11 con la Diabetes de Tipo 2 en Indo-Trinitenses

OBJECTIVE: To examine the effect of genetic variation in KCNJ11 on the risk of Type 2 diabetes mellitus in Trinidadians. METHODS: The coding and bordering intronexon regions of the KCNJ11 gene were sequenced in 168 diabetic and 61 non-diabetic subjects who historically were thought to be of South Asian Indian ancestry, as well as 66 diabetic and 59 non-diabetic subjects of African ancestry. Allele and haplotype frequency differences were calculated between cases and controls and linkage equilibrium was assessed across the KCNJ11 region. RESULTS: We identified novel missense mutations in both subject groups including A94P and R369C in a diabetic Indo-Trinidadian subject, S113G in a non-diabetic Indo-Trinidadian subject, and S118L in a diabetic Afro-Trinidadian subject. It is unknown if these mutations are pathogenic as other family members were not available for study. Additionally, the common variant E23K was associated with Type 2 diabetes in the Indo-Trinidadian group (OR = 1.797 [1.148-2.814], p = 0.0098). CONCLUSIONS: Rare variants in KCNJ11 are segregating in the Indo- and Afro-Trinidadian populations and further studies are needed to determine their contribution, if any, to the overall prevalence of diabetes in these groups. Common variants such as E23K may increase the risk in the Indo-Trinidadian population.

OBJETIVO: Examinar el efecto de la variación genética en KCNJ11 sobre el riesgo de la diabetes tipo 2 en trinitenses. MÉTODOS: Las regiones codificantes y las regiones de la frontera intrón-exón del gen KCNJ11 fueron secuenciadas en 168 sujetos diabéticos y 61 no diabéticos - históricamente de ascendencia del sur de la India - así como 66 sujetos diabéticos y 59 no diabéticos, de ascendencia africana. Se calcularon las diferencias de la frecuencia de los aleles y los haplotipos entre los casos y los controles, evaluándose asimismo el equilibrio de ligamiento de la región de KCNJ11. RESULTADOS: Se identificaron novedosas mutaciones de sentido erróneo en ambos grupos de sujetos, incluyendo A94P y R369C en un sujeto indo-trinitense diabético, y S118L en un sujeto afro-trinitense diabético. No se sabe si estas mutaciones son patogénicas ya que no se disponía de otros miembros de la familia para estudiar el caso. Además, la variante E23K estaba asociada con la diabetes tipo 2 en el grupo indo-trinitense (OR = 1.797 (1.148-2.814), p = 0.0098). CONCLUSIONES: Variantes raras en el KCNJ11 se están segregando en las poblaciones indo - y afro-trinitenses, y se requieren estudios ulteriores para determinar si de algún modo contribuyen a la prevalencia general de la diabetes en estos grupos. Las variantes comunes como la E23K pueden aumentar el riesgo en la población de indo-trinitense.

Genetic analysis of neonatal diabetes mellitus and its influence on treatment outcome / 中华内分泌代谢杂志

Fourteen neonatal diabetes mellitus(NDM)patients were recruited. 9 patients were treated with glyburide and the other 5 with insulin. ABCC8, KCNJ11, and INS genes were sequenced in 6 of them. Gene mutations were found in 2, 1, and 1 cases in these genes, respectively. One case with 6q24 hypomethylation and another without known mutation were also found. 8 out of 9 patients treated with glyburide reached euglycemia(88.9%). The other 5 patients with insulin therapy either died or lost contact. The results suggest that glyburide therapy is effective in neonatal diabetes mellitus, while insulin therapy may contribute to poor compliance.

Long-term response to sulfonylurea in a patient with diabetes due to mutation in the KCNJ11 gene / Resposta a longo prazo com sulfonilureia em um paciente com diabetes associado à mutação no gene KCNJ11

OBJECTIVE: To report the long-term (30-month) effect of the switch from insulin to sulfonylurea in a patient carrying the p.G53D (c.158G>A) mutation in KCNJ11 gene. SUBJECT AND METHOD: A 29-year-old male patient was diagnosed with diabetes in the third month of life and after identification of a heterozygous p.G53D mutation in the KCNJ11 gene, the therapy was switched from insulin to sulfonylurea. RESULTS: Long-term follow-up (30 months) showed that good metabolic control was maintained (HbA1c: 6.6 percent) and the glibenclamide dose could be reduced. CONCLUSION: Long-term therapy with sulfonylureas in patients with neonatal diabetes due to mutation in the KCNJ11 gene is safe and promotes sustained improvement of glycemic control.

OBJETIVO: Reportar o efeito a longo prazo (30 meses) da substituição de insulina por sulfonilureia em um paciente com a mutação p.G53D (c.158G>A) no gene KCNJ11. SUJEITO E MÉTODO: Paciente do sexo masculino, atualmente com 29 anos de idade, foi diagnosticado com diabetes melito no terceiro mês de vida e, após identificação da mutação p.G53D (c.158G>A) em heterozigose no gene KCNJ11, a terapia foi substituída de insulina para sulfonilureia. RESULTADOS: Seguimento a longo prazo (30 meses) mostrou que o bom controle metabólico foi mantido (HbA1c: 6,6 por cento) e a dose de glibenclamida pode ser reduzida. CONCLUSÃO: A terapia com sulfonilureia a longo prazo em pacientes com diabetes neonatal decorrente de mutações no gene KCNJ11 é segura e promove uma melhora persistente no controle metabólico.

Persistent hyperinsulinemic hypoglycemia of infancy due to homozygous KCNJ11 (T294M) mutation.

Hyperinsulinemic hypoglycemia is the most common cause of persistent hypoglycemia in infancy. While most of the cases are sporadic more than 100 mutations have been reported in the familial type. The authors report a case of familial hyperinsulinemic hypoglycemia with homozygous T294M mutation of the KCNJ11 gene, which responded to diazoxide therapy.

KCNJ11 activating mutation in an indian family with remitting and relapsing diabetes.

Objective. To identify the genetic cause of transient neonatal diabetes mellitus in three siblings from an Indian family. Methods. Case reports with clinical and molecular evaluation of an activating mutation in the KCNJ11 gene are presented. We describe an Indian family with two asymptomatic parents with 3 children presenting with hyperglycemia at 6, 1.5 and 1 month of age respectively. Blood glucose levels at presentation were 22.2, 18.3 and 20 mmol/L and the diabetes remitted in all three children by 5 years of age. None of the affected siblings had dysmorphism or neurological abnormalities. Diabetes relapsed in the oldest sibling at 9.4 years of age and she is now euglycemic on 1mg/Kg of Glibenclamide twice a day. Results. A novel heterozygous missense mutation (G53V) in the KCNJ11 gene was identified in all 3 affected children and the father. Conclusions. The report suggests that screening for KCNJ11 mutations is appropriate in patients diagnosed with neonatal diabetes as it provides valuable information concerning possible course of the disease and choice of treatment.

KCNJ11 gene mutation in 3 cases with neonatal diabetes mellitus / 中华内分泌代谢杂志

KCNJ11 gene mutation was searched in 3 families with neonatal diabetes. A KCNJ11 175 G>A (V59M) mutation was found in one child, while no KCNJ11 gene mutation was found in his parents. No mutation was found in the other two families. The result indicated that KCNJ11 gene mutation might lead to the onset of neonatal diabetes mellitus in Chinese.

Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene / Falha de resposta à glibenclamida em criança brasileira com diabetes melito neonatal permanente e síndrome DEND devido a mutação C166Y no gene KCNJ11 (Kir6.2)

Heterozygous activating mutations of KCNJ11 (Kir6.2) are the most common cause of permanent neonatal diabetes mellitus (PNDM) and several cases have been successfully treated with oral sulfonylureas. We report on the attempted transfer of insulin therapy to glibenclamide in a 4-year old child with PNDM and DEND syndrome, bearing a C166Y mutation in KCNJ11. An inpatient transition from subcutaneous NPH insulin (0.2 units/kg/d) to oral glibenclamide (1 mg/kg/d and 1.5 mg/kg/d) was performed. Glucose and C-peptide responses stimulated by oral glucose tolerance test (OGTT), hemoglobin A1c levels, the 8-point self-measured blood glucose (SMBG) profile and the frequency of hypoglycemia episodes were analyzed, before and during treatment with glibenclamide. Neither diabetes control nor neurological improvements were observed. We concluded that C166Y mutation was associated with a form of PNDM insensitive to glibenclamide.

As mutações ativadoras, heterozigóticas do gene KCNJ11 (Kir6.2) são a causa mais freqüente de diabetes melito neonatal permanente (DMNP) e a terapêutica oral com sulfoniluréias tem sido bem sucedida em muitos destes casos. Relatamos o processo de substituição da insulinoterapia convencional para o tratamento oral com glibenclamida em uma paciente de 4 anos, portadora de DMNP e síndrome DEND devido a uma mutação C166Y no gene KCNJ11. A insulina NPH (0,2 U/kg/dia) foi substituída pela glibenclamida (1 mg/kg/dia e 1,5 mg/kg/dia) durante internação hospitalar. As respostas de glicose e peptídeo-C no teste de tolerância oral à glicose (OGTT), os níveis de hemoglobina glicada, o perfil de glicemias capilares de 8 pontos e a freqüência de hipoglicemias foram comparados antes e durante o tratamento com glibenclamida. Não houve melhora no controle glicêmico, nem no quadro neurológico. Concluímos que a mutação C166Y associa-se a uma forma de DMNP insensível à glibenclamida.

Correlation between KCNJ11 gene polymorphism and type 2 diabetes mellitus / 解放军医学杂志

0.05).Conclusion The polymorphism of rs2285676 in KCNJ11 may not be associated with T2DM in Hanethnic population in Chongqing.