Glutamate dehydrogenase hyperinsulinism: mechanisms, diagnosis, and treatment.

Congenital hyperinsulinism (CHI) is a genetically heterogeneous disease, in which intractable, persistent hypoglycemia is induced by excessive insulin secretion and increased serum insulin concentration. To date,15 genes have been found to be associated with the pathogenesis of CHI. Glutamate dehydrogenase hyperinsulinism (GDH-HI) is the second most common type of CHI and is caused by mutations in the glutamate dehydrogenase 1 gene. The objective of this review is to summarize the genetic mechanisms, diagnosis and treatment progress of GDH-HI. Early diagnosis and treatment are extremely important to prevent long-term neurological complications in children with GDH-HI.

Genetic pathogenesis, diagnosis, and treatment of short-chain 3-hydroxyacyl-coenzyme A dehydrogenase hyperinsulinism.

Congenital hyperinsulinism (CHI), a major cause of persistent and recurrent hypoglycemia in infancy and childhood. Numerous pathogenic genes have been associated with 14 known genetic subtypes of CHI. Adenosine triphosphate-sensitive potassium channel hyperinsulinism (KATP-HI) is the most common and most severe subtype, accounting for 40-50% of CHI cases. Short-chain 3-hydroxyacyl-coenzyme A dehydrogenase hyperinsulinism (SCHAD-HI) is a rare subtype that accounts for less than 1% of all CHI cases that are caused by homozygous mutations in the hydroxyacyl-coenzyme A dehydrogenase (HADH) gene. This review provided a systematic description of the genetic pathogenesis and current progress in the diagnosis and treatment of SCHAD-HI to improve our understanding of this disease.

Retrospective analysis of 23 Chinese children with congenital hyperinsulinism undergoing pancreatectomy.

INTRODUCTION: The aim of the study was to discuss therapeutic effect and prognosis of pancreatectomy in the treatment of congenital hyperinsulinism (CHI). MATERIAL AND METHODS: A total of 23 Chinese children with CHI, who had undergone pancreatectomy, were selected as the study objects. The clinical data, the results of the ¹8Fluoro-L-3-4 dihydroxyphenylalanine positron emission tomography/computerized tomography (¹8F-DOPA PET/CT) scanning, and the diagnosis, treatment, and follow-up were analysed retrospectively. RESULTS: Among the 23 cases, 14 patients were diagnosed with focal-type CHI via a ¹8F-DOPA PET/CT scan prior to the operation, with the lesions removed via partial pancreatectomy. After the operation, ten patients (71%) had normal blood glucose levels, while frequent feeding was required in four patients (29%) to control the hypoglycaemia. Three cases were diagnosed as diffuse-type CHI via preoperative scanning, two of which were treated by subtotal pancreatectomy. The other case was treated by near-total pancreatectomy, and the blood glucose level was normal following the operation. The remaining six cases were not diagnosed via the pancreatic scanning prior to the operation due to the limitation of certain conditions. Here, pancreatectomy was performed directly due to severe hypoglycaemia. CONCLUSIONS: ¹8F-DOPA PET/CT scanning was a reliable method for determining the histological type and localizing the lesion before the operation. Partial pancreatectomy for focal-type CHI had a high cure rate.

Analysis of clinical and genetic characteristics of Chinese children with congenital hyperinsulinemia that is spontaneously relieved.

OBJECTIVE: This study aimed to analyze the clinical and genetic characteristics of Chinese children with congenital hyperinsulinemia (CHI) that is spontaneously relieved. METHODS: The patient group comprised 200 children with CHI that were treated at the Beijing Children's Hospital from January 2006 to December 2018. The patients were divided into two groups according to their prognosis: the spontaneous remission group (n = 92) and the nonspontaneous remission group (n = 108). The clinical characteristics, pathogenic genes, diagnosis and treatment process, and follow-up data of both groups were analyzed retrospectively. RESULTS: Of the 200 children with CHI, 92 achieved spontaneous remission. The age of spontaneous remission was between one month and nine years, and 47 of the children were relieved before the age of one year. The median age of onset was 85 days (range: 1-2825 days) in the spontaneous remission group and 2 days (range: 1-210 days) in the nonspontaneous remission group (P < 0.05). The mean birth weight was 3.44 ± 0.76 kg for the spontaneous remission group and 3.95 ± 0.75 kg for the nonspontaneous remission group (P < 0.05). Of the 92 children in the spontaneous remission group, 65 were treated with diazoxide with effective rate of 81.5% (53/65). In 12 cases in which diazoxide treatment failed, octreotide was used with an effective rate of 83.3% (10/12). Of the 108 children in the nonspontaneous remission group, 88 were treated with diazoxide with an effective rate of 43.2 % (38/88), and 29 children were treated with octreotide with an effective rate of 48.28% (14/29). Of the 30 children in the spontaneous remission group that underwent mutation analysis of CHI-related pathogenic genes, 10 children (10/30, 33.3%) carried mutations. Of the 48 children in the nonspontaneous remission group that underwent mutation analysis of CHI-related pathogenic genes, 37 children (37/48, 77.1%) were found to carry mutations. All of the differences in the indices mentioned above were statistically significant. CONCLUSIONS: The rate of spontaneous remission of CHI was significantly higher in children with late age of CHI onset, light birth weight, effective diazoxide treatment, and no common pathogenic gene mutations. Spontaneous remission was also possible for a small number of children that carried mutations in the ABCC and KCNJ11 genes and in whom diazoxide treatment failed.

MODY10 caused by c.309-314del CCAGCT insGCGC mutation of the insulin gene: a case report.

OBJECTIVE: This study aims to report the clinical features and gene mutation of a rare MODY10 patient in China. METHODS: This study summarizes the clinical data of a MODY10 child in the Endocrine Department of our hospital and an analysis and discussion of the results of the gene sequencing of the child. RESULTS: The child was a two-year-old boy. The main reason for his visit to our hospital was "founding hyperglycemia for 3 days". The fasting blood glucose was between 8.1-10.7 mmol/L, and two-hour postprandial blood glucose was between 10.6-12.6 mmol/L. Glycosylated hemoglobin was 8.5%, fasting C-peptide was 0.6 ng/mL, fasting insulin was 2.9 µIU/mL, and the islet antibody series were all negative. Whole-genome/exon sequencing results: Exon 3 of the insulin gene in the child carried a c.309-314del CCAGCT insGCGC heterozygous mutation. The mutation was a nonsense mutation, and family sequencing showed that the mutation originated from the mother of the child. The mother of the child was diagnosed with diabetes when she was a year old and developed bilateral fundus hemorrhage and right retinal detachment at the age of 23. CONCLUSION: Among Chinese children, the insulin gene c.309-314del CCAGCT insGCGC mutation may induce MODY10. For diabetic children with a negative islet autoantibody, gene detection and analysis is helpful for the diagnosis and typing of MODY.

[Floating-Harbor syndrome: a case report and literature review].

Floating-Harbor syndrome (FHS) is an autosomal dominant genetic disease caused by SRCAP mutation. This article reports the clinical features of a boy with FHS. The boy, aged 11 years and 7 months, attended the hospital due to short stature for more than 8 years and had the clinical manifestations of unusual facial features (triangularly shaped face, thin lips and long eyelashes), skeletal dysplasia (curvature finger), expressive language disorder, and retardation of bone age. Genetic detection revealed a novel heterozygous mutation, c.7330 C>T(p.R2444X), in the SRCAP gene. The boy was diagnosed with FHS based on these clinical manifestations and gene detection results. FHS is rare in clinical practice, which may lead to missed diagnosis and misdiagnosis, and gene detection may help with the clinical diagnosis of FHS in children.

Analysis on the pathogenic genes of 60 Chinese children with congenital hyperinsulinemia.

This study aims to summarize and analyze the clinical manifestations, genetic characteristics, treatment modalities and long-term prognosis of congenital hyperinsulinemia (CHI) in Chinese children. Sixty children with CHI, who were treated at Beijing Children's Hospital from January 2014 to August 2017, and their families, were selected as subjects. The CHI-related causative genes in children were sequenced and analyzed using second-generation sequencing technology. Furthermore, the genetic pathogenesis and clinical characteristics of Chinese children with CHI were explored. Among the 60 CHI children, 27 children (27/60, 45%) carried known CHI-related gene mutations: 16 children (26.7%) carried ABCC8 gene mutations, seven children (11.7%) carried GLUD1 gene mutations, one child carried GCK gene mutations, two children carried HNF4α gene mutations and one child carried HADH gene mutations. In these 60 patients, 8 patients underwent 18F-L-DOPA PET scan for the pancreas, and five children were found to be focal type. The treatment of diazoxide was ineffective in these five patients, and hypoglycemia could be controlled after receiving partial pancreatectomy. Conclusions: ABCC8 gene mutation is the most common cause of CHI in Chinese children. The early genetic analysis of children's families has an important guiding significance for treatment planning and prognosis assessment.

[ABCC8, KCNJ11 and GLUD1 gene mutation analysis in congenital hyperinsulinism pedigree].

OBJECTIVE: To explore the ABCC8, KCNJ11, and GLUD1 gene mutations of the 11 patients diagnosed as congenital hyperinsulinism (CHI). METHODS: A total of 11 CHI children hospitalized in Beijing Children's Hospital from November 2008 to February 2012 and their parents were chosen as the study subjects. Direct sequencing of PCR-DNA was used to analyze the 39 exons of ABCC8 gene, non-translational region and exon of KCNJ11 gene and 6, 7, 10, 11 and 12 exons of GLUD1 gene. RESULTS: An P629PfsX17 heterozygous mutation of ABCC8 gene was detected in case 1 and his father, an W288X heterozygous mutation of ABCC8 gene was detected in case 4 and his father, A640V and Q1196X mutations in ABCC8 gene in case 5 whose father only carried the Q1196X mutation. In case 6 and his father, an R269H mutation was found in GLUD1 gene. The genotype of 4 children's mothers was normal. No mutations were found in other 7 patients and their parents. CONCLUSIONS: The ABCC8 gene mutations are the main pathogenic mechanisms of Chinese children with CHI. In Chinese, P629PfsX17, W288X, A640V and Q1196X heterozygous mutation of ABCC8 gene and R269H heterozygous mutation of GLUD1 gene may lead to CHI. The inheritance mode of the mutations may be paternally or de novo.

[Mutation analysis of the GLUD1 gene in patients with glutamate dehydrogenase congenital hyperinsulinism].

OBJECTIVE: To investigate the glutamate dehydrogenase 1 (GLUD1) gene mutation of three patients diagnosed as glutamate dehydrogenase congenital hyperinsulinism (GDH-HI). METHODS: Three patients diagnosed as GDH-HI and their parents were involved in the study. PCR-DNA direct sequencing was used to analyze the exons 6,7,10,11 and 12 of the GLUD1 gene. RESULTS: In the first case, an R269H heterozygous mutation was found in the GLUD1 gene, with autosomal dominant inheritance. In the second case, there was a de novo S445L heterozygous mutation of the GLUD1 gene. No mutation was detected in the third case. CONCLUSION: In Chinese, R269H, S445L heterozygous mutation of the GLUD1 gene can lead to GDH-HI. Genetic analysis is necessary in making genetic diagnosis of congenital hyperinsulinsm.

[The prevalence of diabetes in children and adolescents of Beijing].

OBJECTIVE: To study the prevalence of Diabetes mellitus (DM) in children and adolescents and to describe the characteristics on age, gender and district distribution of schoolchildren, in Beijing. METHODS: A cross-sectional screening program the fasting capillary blood glucose (FCBG) was carried out in 19,593 schoolchildren in 7 areas of Beijing from March to October, 2004. According to the WHO diagnostic criteria: DM was set as FCBG < or = 6.1 mmol/L, impaired fasting glucose (IFG) was set as 5.6 mmol/L < or = FCBG < 6.1 mmol/L. RESULTS: The total aggregate age-adjusted prevalence rates of DM and IFG were 5.7 per thousand and 13.5 per thousand, respectively. The prevalence rates of DM and IFG in males were significantly higher than that in females (7.7 per thousand vs. 3.6 per thousand and 26.8 per thousand vs. 11.3 per thousand. DM X2 = 12.27, P = 0.0005; IFG X2 =47.29, P = 0.0000). Among seven districts, East District had the highest prevalence rates of DM and IFG, 8.9 per thousand and 27.4 per thousand (companied high obesity 28.68%) while Ping-Gu District having the lowest ones as 2.0 per thousand and 7.5 per thousand (obese 12.75%) respectively (X2 = 13.75, and X2 = 32.65, P = 0.0002 and P < 0.0001). The DM prevalence rates between districts ranged from 2.0 per thousand to 8.9 per thousand, X2 = 18.94, P = 0.004 and the IFG prevalence of districts ranged from 7.5 per thousand to 27.4 per thousand (X2 = 52.05, P < 0.0001). The prevalence rates of DM among different age groups increased with age, with the highest prevalence of IFG on the 10-14 age group. Among boys, the highest prevalence rates of DM and IFG fell in the 15-18 and 10-14 age groups respectively while the highest prevalence rates on both DM and IFG among girls were in the same age group 10-14. CONCLUSION: The high prevalence rates on DM and IFG were seen in Beijing and showed significant discrimination on age, gender and district distribution. More developed urban district and males had a higher prevalence, companied by higher obesity prevalence. Age seemed to be a high risk factor on DM for boys while the puberty development seemed a high risk factor for girls.

[Association of human leukocyte antigen non-classical genes with type 1 diabetes].

OBJECTIVE: HLA-DMA and DMB are non-classical genes whose product (DM molecules) plays an important role in antigen presentation. Our present study was designed to investigate the relationship between human leukocyte antigen-DMA, -DMB and clinical status heterogeneity of type 1 diabetes. METHODS: A total of 80 children (male 36, female 44) with type 1 diabetes were selected as research subjects. Diagnosis of type 1 diabetes was made according to WHO criteria. The range of age at onset of type 1 diabetes was 2.5 - 14 years. Ninety-one healthy adult blood donors were selected as normal controls. Polymerase chain reaction and dot blot hybridization techniques were used to classify DMA and DMB alleles. Patients with type 1 diabetes were classified into different groups according to different clinical status, including sex, age of onset, ketosis onset situation on diagnosis, remained function of islet beta cell, etc. Then distribution of DM susceptive alleles and heterodimer in different clinical groups were studied. RESULTS: The frequencies of DMA * 0103 and DMB * 0103 alleles in patients were significantly increased (50% vs. 8%, 43% vs. 22%, respectively), these two alleles confer susceptibility to type 1 diabetes in Chinese. The frequencies of DMA * 0103/DMB * 0102, DMA * 0103/DMB * 0103 and DMA * 0103/DMB * 0101 heterodimers were also increased in the patients. The above heterodimers confer predisposition to type 1 diabetes. Both DMB * 0103 allele and DM susceptive heterodimers are related to islet beta cell function on diagnosis. The patients with DMB * 0103 allele or DM susceptive heterodimers were significantly increased in the patients with lower C-peptide level on diagnosis (56% vs. 29%; 58% vs. 34% respectively). DM heterodimes were also related to onset age and ketosis-onset-situations of the patients. The patients carrying DM susceptive heterodimers had higher probability to suffer type 1 diabetes before 10 years of age and had the predisposition to ketosis or ketoacidosis on diagnosis. CONCLUSION: HLA- class II non-classical alleles-DMA and DMB may play an important role in pathogenesis of type 1 diabetes, and clinical status heterogeneity of type 1 diabetes may be related to genetic mechanism.