Permanent Neonatal Diabetes Mellitus Patients Research Articles

Genotype and Phenotype Heterogeneity in Neonatal Diabetes: A Single Centre Experience in Turkey

Objective:Neonatal diabetes mellitus (NDM) may be transient or permanent, and the majority is caused by genetic mutations. Early diagnosis is essential to select the patients who will respond to oral treatment. In this investigation, we aimed to present the phenotype and genotype of our patients with NDM and share our experience in a single tertiary center.Methods:A total of 16 NDM patients from 12 unrelated families are included in the study. The clinical presentation, age at diagnosis, perinatal and family history, consanguinity, gender, hemoglobin A1c, C-peptide, insulin, insulin autoantibodies, genetic mutations, and response to treatment are retrospectively evaluated.Results:The median age at diagnosis of diabetes was five months (4 days-18 months) although six patients with a confirmed genetic diagnosis were diagnosed >6 months. Three patients had KCNJ11 mutations, six had ABCC8 mutations, three had EIF2AK3 mutations, and one had a de novo INS mutation. All the permanent NDM patients with KCNJ11 and ABCC8 mutations were started on sulfonylurea treatment resulting in a significant increase in C-peptide level, better glycemic control, and discontinuation of insulin.Conclusion:Although NDM is defined as diabetes diagnosed during the first six months of life, and a diagnosis of type 1 diabetes is more common between the ages of 6 and 24 months, in rare cases NDM may present as late as 12 or even 24 months of age. Molecular diagnosis in NDM is important for planning treatment and predicting prognosis. Therefore, genetic testing is essential in these patients.

Genotype-phenotype correlation of KATP channel gene defects causing permanent neonatal diabetes in Indian patients.

There are very few reports pertaining to Indian patients with neonatal diabetes mellitus (NDM). Activating or gain of function mutations of KATP channel genes namely KCNJ11 and ABCC8 are most predominant cause of permanent neonatal diabetes mellitus (PNDM). To identify the genotype-phenotype correlation of KATP channel gene defects in a large series of (n = 181) Indian PNDM patients. Direct sequencing of all exons of KCNJ11 and ABCC8 genes in all 181 patients with PNDM were performed. Clinical and biochemical data were collected. We have identified the molecular basis of KATP -NDM in 39 out of 181 patients (22%). Of these, 20 had KCNJ11 mutations and 19 had ABCC8 mutations, thus comprising 51% of KCNJ11 and 49% of ABCC8. There were four novel mutations (D1128Tfs*16, Y1287C, S1422T, and H1537R) in ABCC8 gene. Three patients with KCNJ11 mutations had developmental delay with DEND syndrome. In patients with ABCC8 mutations developmental delay was seen in seven out of 19 (36.8%). Of this, three patients (15.7%) had DEND phenotype and four (21%) had iDEND. Of the 39 patients, 33 (84%) patients were shifted to sulfonylurea therapy (glibenclamide). Of this, 19(57.5%) patients harbored KCNJ11 mutations and 14(42.1%) ABCC8 mutations. This is the first largest study in NDM patients in India demonstrating the importance of KATP channel gene mutation screening in PNDM and efficacy of glibenclamide for Indian patients with KATP -PNDM. The success rate of transfer is more in patients with KCNJ11 mutations compared with those with ABCC8 mutations.

Rare form of Permanent Neonatal Diabetes Mellitus (PNDM) due to novel mutation in EIF2AK3 gene (Wolcott—Rallison syndrome)

Wolcott—Rallison syndrome (WRS) is a rare genetic disease inherited in autosomal recessive way. Сlinical manifestations develop in early infancy with symptoms of permanent neonatal diabetes mellitus (PNDM), skeletal dysplasia, short stature and hepatic dysfunction. The condition has poor prognosis and most patients die at a young age due to episodes of acute liver or renal failure. To date about 60 genetically proved cases of WRS have been reported worldwide. The disease is most common in countries where consanguineous marriages are frequent, such as the Saudi Arabia (60% cases of PNDM patients), India, Turkey, Pakistan and North Africa. In Russian Federation WRS patients have not been described earlier.

Gain-of-Function Mutations in the KATP Channel (KCNJ11) Impair Coordinated Hand-Eye Tracking

BackgroundGain-of-function mutations in the ATP-sensitive potassium channel can cause permanent neonatal diabetes mellitus (PNDM) or neonatal diabetes accompanied by a constellation of neurological symptoms (iDEND syndrome). Studies of a mouse model of iDEND syndrome revealed that cerebellar Purkinje cell electrical activity was impaired and that the mice exhibited poor motor coordination. In this study, we probed the hand-eye coordination of PNDM and iDEND patients using visual tracking tasks to see if poor motor coordination is also a feature of the human disease.MethodsControl participants (n = 14), patients with iDEND syndrome (n = 6 or 7), and patients with PNDM (n = 7) completed three computer-based tasks in which a moving target was tracked with a joystick-controlled cursor. Patients with PNDM and iDEND were being treated with sulphonylurea drugs at the time of testing.ResultsNo differences were seen between PNDM patients and controls. Patients with iDEND syndrome were significantly less accurate than controls in two of the three tasks. The greatest differences were seen when iDEND patients tracked blanked targets, i.e. when predictive tracking was required. In this task, iDEND patients incurred more discrepancy errors (p = 0.009) and more velocity errors (p = 0.009) than controls.ConclusionsThese results identify impaired hand-eye coordination as a new clinical feature of iDEND. The aetiology of this feature is likely to involve cerebellar dysfunction. The data further suggest that sulphonylurea doses that control the diabetes of these patients may be insufficient to fully correct their neurological symptoms.

Efficacy and Safety of Sulfonylurea Use in Permanent Neonatal Diabetes Due to KCNJ11 Gene Mutations: 34-Month Median Follow-Up

Recently, many patients with Kir6.2-related permanent neonatal diabetes mellitus (PNDM) have been successfully transferred from insulin therapy to sulfonylurea (SU) treatment. The long-term efficacy and safety of SU treatment in PNDM patients, however, have not yet been determined. We monitored glycemic control and the occurrence of potential side effects in 14 Kir6.2-related PNDM patients from Poland (median age, 12.0 years; range, 5-50 years) who were transferred to SU therapy at least 2 years ago. Three of the 14 patients were lost to follow-up, whereas for the remaining 11 individuals the median follow-up was 34 months (range, 27-51 months). The initial reduction of glycated hemoglobin (HbA1c) after the switch to SU (approximately 3-6 months post-transfer) was 1.68% (range, 0.3-3.7%), and good metabolic control was maintained over the entire period of observation with an average HbA1c level of 6.0% (range, 5.3-6.7%) at the last visit. This was accompanied by a substantial drop in SU dose by 0.24 mg/kg, which constituted a 38.0% decrease. A rapid progression of retinal changes was observed in one patient, a 34-year-old woman at the beginning of the observation, with preexisting proliferative diabetic retinopathy. No causal relationship between these changes and SU treatment could be proven. Neither serious side effects nor progression of diabetes complications was observed in any other patients. No detrimental effect on growth in the observed minors was recorded. In summary, the switch from insulin therapy to SU treatment in PNDM related to KCNJ11 mutations was found to be an efficient and safe therapeutic method over a period of 34-month median follow-up. Although no serious side effects were associated with SU treatment, their use in Kir6.2 PNDM requires further attention, particularly in children, adolescents, and patients with advanced chronic diabetes complications.

Prevalence of Permanent Neonatal Diabetes in Slovakia and Successful Replacement of Insulin with Sulfonylurea Therapy in KCNJ11 and ABCC8 Mutation Carriers

Mutations in the KCNJ11 and ABCC8 genes encoding the pancreatic beta-cell K(ATP) channel have recently been shown to be the most common cause of permanent neonatal diabetes mellitus (PNDM). Information regarding the frequency of PNDM has been based mainly on nonpopulation or short-term collections only. Thus, the aim of this study was to identify the incidence of PNDM in Slovakia and to switch patients to sulfonylurea (SU) where applicable. We searched for PNDM patients in the Slovak Children Diabetes Registry. In insulin-treated patients who matched the clinical criteria for PNDM, the KCNJ11 or ABCC8 genes were sequenced, and mutation carriers were invited for replacement of insulin with SU. Eight patients with diabetes onset before the sixth month of life without remission were identified since 1981, which corresponds to the PNDM incidence in Slovakia of one case in 215,417 live births. In four patients, three different KCNJ11 mutations were found (R201H, H46Y, and L164P). Three patients with the KCNJ11 mutations (R201H and H46Y) were switched from insulin to SU, decreasing their glycosylated hemoglobin from 9.3-11.0% on insulin to 5.7-6.6% on SU treatment. One patient has a novel V86A mutation in the ABCC8 gene and was also substituted with SU. PNDM frequency in Slovakia is much higher (one in 215,417 live births) than previously suggested from international estimates (about one in 800,000). We identified one ABCC8 and four KCNJ11 mutation carriers, of whom four were successfully transferred to SU, dramatically improving their diabetes control and quality of life.

KCNJ11activating mutations in Italian patients with permanent neonatal diabetes

Permanent neonatal diabetes mellitus (PNDM) is a rare condition characterized by severe hyperglycemia constantly requiring insulin treatment from its onset. Complete deficiency of glucokinase (GCK) can cause PNDM; however, the genetic etiology is unknown in most PNDM patients. Recently, heterozygous activating mutations of KCNJ11, encoding Kir6.2, the pore forming subunit of the ATP-dependent potassium (K(ATP)) channel of the pancreatic beta-cell, were found in patients with PNDM. Closure of the K(ATP) channel exerts a pivotal role in insulin secretion by modifying the resting membrane potential that leads to insulin exocytosis. We screened the KCNJ11 gene in 12 Italian patients with PNDM (onset within 3 months from birth) and in six patients with non-autoimmune, insulin-requiring diabetes diagnosed during the first year of life. Five different heterozygous mutations were identified: c.149G>C (p.R50P), c.175G>A (p.V59M), c.509A>G (p.K170R), c.510G>C (p.K170N), and c.601C>T (p.R201C) in eight patients with diabetes diagnosed between day 3 and 182. Mutations at Arg50 and Lys170 residues are novel. Four patients also presented with motor and/or developmental delay as previously reported. We conclude that KCNJ11 mutations are a common cause of PNDM either in isolation or associated with developmental delay. Permanent diabetes of non autoimmune origin can present up to 6 months from birth in individuals with KCNJ11 and EIF2AK3 mutations. Therefore, we suggest that the acronym PNDM be replaced with the more comprehensive permanent diabetes mellitus of infancy (PDMI), linking it to the gene product (e.g., GCK-PDMI, KCNJ11-PDMI) to avoid confusion between patients with early-onset, autoimmune type 1 diabetes.

Glibenclamide Treatment in Permanent Neonatal Diabetes Mellitus due to an Activating Mutation in Kir6.2

Permanent neonatal diabetes mellitus (PNDM) is a rare form of diabetes characterized by insulin-requiring hyperglycemia that is diagnosed within the first months of life. Recently, activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 were identified in 10 PNDM patients. Tolbutamide-stimulated insulin secretion, demonstrated in 3 of these patients suggested that some PNDM patients may respond to oral sulfonylurea treatment. In this report, we describe an infant with PNDM due to an arginine-to-histidine substitution at position 201 (R201H) of the gene encoding Kir6.2. After insulin pump therapy for six months, he was shifted to oral glybenclamide therapy at a daily dose of 0.8 mg/kg. Basal c-peptide level increased by two fold during glybenclamide treatment, but no further elevation was observed following intravenous glucose administration. Outpatient, continuous glucose monitoring while on a normal infant diet demonstrated a marked improvement in glycemic control. This study demonstrates the feasibility of oral sulfonylurea treatment in PNDM patients with Kir6.2 mutations even during infancy, and the superiority of this approach over insulin administration.

Neonatal diabetes mellitus: Chromosomal analysis in transient and permanent cases

Objectives: To describe a large cohort of patients with transient neonatal diabetes mellitus (TNDM) and permanent neonatal diabetes mellitus (PNDM), and to investigate whether chromosome 6 analysis helps to distinguish TNDM from PNDM. Study design: Patients with TNDM (n = 29) (insulin therapy for <3 years) and 21 with PNDM were identified through a nationwide study. Results: Although patients with PNDM were less likely to have had intrauterine growth restriction (36% vs 74% for TNDM, P <.006), were older at diagnosis (median: 27 vs 6 days, P <.01), and had higher initial insulin requirements (1.4 U/kg/day vs 0.6 U/kg/day, P <.006), no clinical features were reliable in distinguishing PNDM from TNDM on an individual case basis. Permanent insulin-dependent diabetes developed in 5 TNDM patients after 8 years of age, emphasizing the need for prolonged follow-up. Among the 19 TNDM patients tested, two had paternal isodisomy of chromosome 6, seven from 4 families had paternally-derived trisomy of the 6q region, and two had a methylation defect in the 6q24 region. No chromosome 6 anomalies were found in the 9 PNDM patients tested. Conclusion: When present, a chromosome 6 abnormality is strongly in favor of the “transient” form of the disease. (J Pediatr 2002;141:483-9)