Abstract
Background: Neonatal diabetes has not been previously studied in Ukraine. We investigated the genetic etiology in patients with onset of diabetes during the first 9 months of life.
Methods: We established a Pediatric Diabetes Register to identify patients diagnosed with diabetes before 9 months of age. Genetic testing was undertaken for 42 patients with permanent or transient diabetes diagnosed within the first 6 months of life (n=22) or permanent diabetes diagnosed between 6 and 9 months (n=20).
Results: We determined the genetic etiology in 23 of 42 (55%) patients; 86% of the patients diagnosed before 6 months and 20% diagnosed between 6 and 9 months. The incidence of neonatal diabetes in Ukraine was calculated to be 1 in 126,397 live births.
Conclusions: Genetic testing for patients identified through the Ukrainian Pediatric Diabetes Register identified KCNJ11 and ABCC8 mutations as the most common cause (52%) of neonatal diabetes. Transfer to sulfonylureas improved glycemic control in all 11 patients.
Introduction
The incidence of diabetes mellitus (DM) in pediatric population of Ukraine has greatly increased in recent years, especially in children aged from 0 to 6 years (1, 2). The Ukrainian Pediatric Diabetes Register was established in 2002 and includes 8629 children with type 1 diabetes, a prevalence of 1 in 925 for the pediatric population in 2012.
Over the last decade, it has become clear that not all cases of childhood-onset diabetes are autoimmune type 1 diabetes and patients diagnosed with neonatal diabetes in the first 6 months of life are very likely to have a monogenic form of diabetes (3, 4). The key breakthrough was the discovery that activating mutations in the KCNJ11 and ABCC8 genes [encoding the ATP-sensitive potassium channel subunit Kir6.2 and the regulatory subunit sulfonylurea receptor 1 (SUR1)] are the most common cause of neonatal diabetes (5–7). Most of these patients respond to sulfonylurea treatment with an improvement in glycemic control (5, 8–12) without hypoglycemia (13–15). Approximately, 20% of patients have more severe mutations that also cause developmental delay. Improvements in motor tone and cognition have been reported after transfer to sulfonylureas (16).
We established a new neonatal section of the Ukrainian Pediatric Diabetes Registry to identify cases of neonatal diabetes for genetic testing. The aim of the study was to determine the genetic cause of neonatal diabetes in Ukraine and investigate treatment change in patients with KCNJ11 or ABCC8 mutations.
Materials and methods
Subjects
A neonatal diabetes section of the Ukrainian Pediatric Diabetes Registry was created in 2012 to include children diagnosed with diabetes before 9 months of age identified by regional Ukrainian pediatric endocrinologists. A pediatric neurologist confirmed the presence of any abnormal neurological features.
Genetic testing
Sequencing of the KCNJ11, ABCC8, and INS genes was carried out according to previously described methods (5, 17–18). Additional testing for chromosome 6q24 methylation and GLIS3 (19) was performed according to the clinical phenotype of the patients. Analysis of the chromosome 6q24 locus was undertaken using previously described methods to detect duplications, uniparental disomy, and methylation abnormalities (20, 21). Next-generation sequencing of all known neonatal diabetes genes (22) was performed in any child diagnosed in the first 6 months of life where a mutation had not been identified.
Statistical analysis
Clinical characteristics are presented as median (range) and comparative statistics predominantly used the Friedman’s test and Fisher’s exact test.
Results
Incidence of neonatal diabetes in Ukraine
We identified 46 cases with diabetes diagnosed before 9 months of age (including 24 cases diagnosed in the first 6 months of life) from the Ukrainian Pediatric Diabetes Register. DNA samples were obtained from 42 patients for genetic testing (91.3%). Between January 2012 and December 2014 there were 12 new registered cases with neonatal diabetes (diagnosed before 6 months of age) and 1,516,760 live births, giving an incidence of neonatal diabetes of 1 in 126,397.
Patients with a genetic diagnosis
Mutations were identified in 19/22 patients (86.4%) diagnosed with diabetes in the first 6 months of life (see Table 1). Only 4/20 patients (20%) diagnosed between 6 and 9 months had a mutation. The clinical characteristics of all patients with a mutation causing neonatal diabetes are shown in Table 2.
Genetic causes of neonatal diabetes in patients from the Ukraine Pediatric Diabetes Register.
| Gene | Mutation(s) | Onset before 6 months, n=22 (52.4%) | Onset between 6 and 9 months, n=20 (47.6%) |
|---|---|---|---|
| KCNJ11 | p.R201C (n=3), p.R201H (n=2), p.G53D (n=1), p.V59M (n=1), p.E229K (n=1) | 7 (31.8%) | 1 (5%) |
| ABCC8 | p.V324M/p.R1394L (compound heterozygous), p.I585T, p.I49F (n=2) | 4 (18.2%) | – |
| INS | p.C96Y, p.G32S (n=2), p.L41P | 1 (4.5%) | 3 (15%) |
| EIF2AK3 | p.E419fs/p.G1010V (compound heterozygous), p.G1010V/p.G1010V (homozygous) | 2 (9.1%) | – |
| GLIS3 | p.P444fs/p.H647R | 1 (4.5%) | – |
| Chr6q24 | Paternal uniparental isodisomy | 3 (13.7%) | – |
| GCK | p.E395X | 1 (4.5%) | – |
| No mutation | 3 (13.7%) | 16 (80%) |
Clinical characteristics of patients with mutations causing neonatal diabetesa.
| Patient | Relative | Gene | Mutation (protein description) | Mutation (DNA description) | Birth weight, g | Gestation, weeks | Age at diagnosis of diabetes, days | Age at remission of diabetes | Age at relapse of diabetes | Current age, years | C-peptide | HbA1c, mmol/mol at Investigation | Antibodies | Developmental delay (mild/moderate/severe) | Epilepsy | Other clinical features |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | KCNJ11 | p.R201C | c.601C>T | 2500 | 40 | 93 | NA | NA | 6 | 0.05 | 54 | GAD 92,6 IE/mL (n<10) | No | No | ||
| 2 | KCNJ11 | p.R201C | c.601C>T | 2600 | 41–42 | 81 | NA | NA | 1.5 | 0.35 | 81 | NA | No | No | ||
| 3 | KCNJ11 | p.R201C | c.601C>T | 2800 | 39 | 121 | NA | NA | 0.5 | 0.17 | 148 (at diagnosis) | NA | No | No | ||
| 4 | KCNJ11 | p.R201H | c.602G>A | 2300 | 37 | 1 | NA | NA | 1 | 0.09 | 128 (at diagnosis) | NA | No | No | ||
| 5 | Mother of patient 4 | KCNJ11 | p.R201H | c.602G>A | 3600 | 37 | 90 | NA | NA | 29 | NA | 65 | NA | No | No | |
| 6 | KCNJ11 | p.G53D | c.158G>A | 2650 | 40 | 224 | NA | NA | 3 | 0.005 | 47 | ICA – neg. | No | No | ||
| 7 | KCNJ11 | p.V59M | c.175G>A | 2280 | 39 | 33 | NA | NA | 7.5 | 0.06 | 54 | NA | No | No | Multiply lipoatrophy | |
| 8 | KCNJ11 | p.E229K | c.685G>A | 2920 | 40 | 167 | NA | NA | 1.5 | 0.77 | 49 | NA | No | No | ||
| 9 | ABCC8 | p.I49F | c.145A>T | 2880 | 38 | 90 | 1 y. | 2 y. 3m | 3.5 | 0.88 | 41 | NA | Severe | Yes | Severe physical delay | |
| 10 | Sibling of patient 9 | ABCC8 | p.I49F | c.145A>T | 2750 | 39 | 180 | NA | NA | 1.5 | 0.64 | 57 | NA | Severe | No | Severe physical delay |
| 11 | ABCC8 | p.V324M | c.970G>A | 3100 | 40 | 74 | NA | NA | 6 | 0.07 | 61 | NA | Severe | No | ||
| p.R1394L | c.4181G>T | |||||||||||||||
| 12 | ABCC8 | p.I585T | c.1754T>C | 2780 | 34–35 | 4 | 10 days | NA | 0.2 | 0.6 | 100 | NA | No | No | ||
| 13 | INS | p.G32S | c.94G>A | 3580 | 41 | 244 | NA | NA | 7.5 | 0.19 | 90 | NA | No | No | ||
| 14 | INS | p.L41P | c.122T>C | 2800 | 40 | 244 | NA | NA | 2.5 | 0.14 | 77 | GAD<5 IE/mL, ICA neg. | No | No | ||
| 15 | INS | p.C96Y | c.287G>A | 3000 | 40 | 130 | NA | NA | 5.5 | NA | 81 | NA | No | No | ||
| 16 | INS | p.G32S | c.94G>A | 3000 | 40 | 222 | 8 months | 10 months | 7 | NA | 77 | NA | No | No | ||
| 17 | 6q24 | UPD | – | 2010 | 37 | 35 | 5 months | NA | 4.5 | 1.31 | 37 | ICA neg. | No | No | Macroglossia, anemia, patent foramen ovale, intrauterine growth retardation | |
| 18 | 6q24 | UPD | – | 2000 | 43 | 10 | 8 months | NA | 5 | 0.87 | 33 | NA | No | No | Macroglossia, anemia, patent foramen ovale, intrauterine growth retardation, speech development delay | |
| 19 | 6q24 | UPD | – | 2350 | 39 | 2 | 16 days | NA | 0.5 | 0.5 | 22 | NA | No | No | Anemia | |
| 20 | GLIS3 | p.P444fs p.H647R | 1900 | 39 | 7 | NA | NA | 5 | Undetectable | 76 | NA | Mild | No | Congenital hypothyroidism, patent foremen ovale, polycystic kidneys | ||
| 21 | EIF2AK3 | p.E419fs/ p.G1010V | c.1254_1257delinsCGCAATCTGTCACTAACGCAATTGGT/c.3029G>T | 2800 | 39 | 105 | NA | NA | 3 | 71.5 pmol/L | 68 | NA | No | No | ||
| 22 | EIF2AK3 | p.G1010V | c.3029G>T | 2500 | 39 | 70 | NA | NA | 0.5 | 0.27 | 81 | NA | No | No | ||
| 23 | GCK | p.E395X | c.1183G>T | 3080 | 37 | 150 | NA | NA | 6 | 0.77 | 50 | NA | No | No |
aAll mutations are heterozygous except EIF2AK3 p.G1010V in patient 22 which is homozygous.
KCNJ11 mutations (n=8 patients)
All eight patients have isolated diabetes: seven were diagnosed before 6 months and one at 7.5 months. One patient heterozygous for the transient diabetes p.E229K mutation is aged 1.5 years but has not entered diabetes remission yet. The patients with the p.G53D and p.V59M mutations are currently aged 3 and 8 years and show no evidence of developmental delay. One patient, who was diagnosed with diabetes at 3 months of age, inherited the p.R201H KCNJ11 mutation from her 29-year-old mother. Analysis of parental samples confirmed that the remaining seven probands had de novo mutations. Testing of one patient’s unaffected twin brother identified mosaicism in his leukocyte DNA at a level of ~10%.
ABCC8 mutations (n=4 patients)
One patient with transient diabetes was heterozygous for a novel p.I585T ABCC8 mutation which was inherited from his 23-year-old mother who was diagnosed with “type 2” diabetes at 21 years. The proband’s maternal grandfather and uncle are also affected (genetic testing was not undertaken in any relatives).
Three patients had severe developmental delay (two siblings with a previously reported heterozygous p.I49F mutation) (11) and one patient had compound heterozygous for the previously reported p.V324M mutation (23) and a novel p.R1394L mutation.
The parents of the two siblings with the p.I49F mutation are unaffected and the mutation was not detected in either parent’s leukocyte DNA in keeping with germline mosaicism. Both children have a severe form of developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. The proband was diagnosed with diabetes at 3 months which remitted at the age of 1 year and relapsed at 2 years 3 months after starting hypothyroidism treatment. At age 2 years, the proband had a severe generalized hypotonia, with no visual contact, no babbling, psychomotor retardation, epilepsy, and severe physical delay [height: 75 cm (<3rd centile), weight: 6000 g (<3rd centile)]. His sister at age 5 months developed convulsions and hypoglycemic coma, and at age 6 months developed neonatal diabetes and received insulin for only few days. At 18 months, she was noted to have psychomotor retardation (severely hypotonic, no babbling, poor visual contact) and growth delay (height: 75 cm [<3rd centile], weight: 8100 g [<3rd centile]).
The patient with the compound heterozygous ABCC8 mutation had inherited the p.V324M mutation from the father and the novel p.R1394L mutation from the mother. This child has severe iDEND syndrome but no epilepsy. At 7 years of age, he has a severe generalized hypotonia and is unable to sit, hold his head upright, walk or talk.
INS mutations (n=4 patients)
These included one patient diagnosed with diabetes at 4 months with a de novo p.C96Y INS mutation and three patients diagnosed between 6 and 9 months (p.L41P and p.G32S n=2). In one case, p.G32S was inherited from the unaffected father whose mutation level in leukocyte DNA is ~15%. Interestingly, the child’s diabetes had remitted for 2 months from the age of 8 months. Another child diagnosed at 8 months with a de novo p.G32S mutation is obese (BMI 19.8 kg/m², >95 p.c.) at the age of 6 years. Adding metformin (850 mg/day) to insulin treatment has improved glycemic control with HbA1c reduction from 90 to 70 mmol/mol (10.4%–8.6%), respectively, after 3 months and without any change in insulin dose.
EIF2AK3 (n=2 patients)
One patient was diagnosed with diabetes at the age of 3 months. Sanger sequencing of the ABCC8 gene identified a novel, maternally inherited, heterozygous variant of uncertain significance, p.P201L (c.602C>T). A trial with sulfonylurea was started, but no durable response was achieved. Further genetic testing of all known neonatal genes by next-generation sequencing identified compound heterozygous EIF2AK3 mutations, p.E419fs and p.G1010V. At age 3 years the child does not have additional features of Wolcott-Rallison syndrome besides mild growth retardation. Targeted next-generation sequencing in a 2nd patient born to consanguineous parents demonstrated homozygosity for the same novel EIF2AK3 p.G1010V mutation. The child is currently 8 months of age and does not have other features of Wolcott-Rallison syndrome. Identification of the same novel mutation in two probands raises the possibility that p.G1010V is a founder mutation.
GLIS3 mutations (n=1 patient)
This patient presented in the 1st week of life with diabetic ketoacidosis (glucose >20 mmol/L) and has congenital hypothyroidism, patent foramen ovale with left ventricle distention and polycystic kidneys. The patient is compound heterozygous for two GLIS3 mutations, p.P444fsdelG and p.H647R (19).
Chromosome 6q24 abnormalities (n=3 patients)
All three patients have paternal uniparental isodisomy. Two had intrauterine growth retardation, macroglossia, anemia, and patent foramen ovale.
GCK (n=1 patient)
The child had mild fasting hyperglycemia (FBG at 5 months 6.1 mmol/L, at 8 months 7.4 mmol/L). Her mother was diagnosed with gestational diabetes at 19 years of age and there is a family history of diabetes affecting the maternal grandparents. A heterozygous GCK mutation, p.E395X, was identified in both the mother and child. Neither are receiving pharmaceutical treatment.
Transfer to sulfonylurea therapy for patients with KCNJ11/ABCC8 mutations
The transfer was performed according to the protocol devised by Hattersley et al. (24) but with three to five daily doses (later reducing to two to three doses) and omission of fast-acting insulin from the outset. Infants generally needed more frequent doses than those who transferred later. A total of 11 patients with KCNJ11 and ABCC8 mutations were able to stop insulin and achieve glycemic control with sulfonylurea (glibenclamide). After 3 months of sulfonylurea treatment, the median HbA1c level decreased from 57 (49–81) to 42 (37–47) mmol/mol [7.4 (6.6–9.6)–6.0 (5.5–6.5)%). After 1 year of sulfonylurea treatment all children had HbA1c level <48 mmol/mol (<6.5%), the median HbA1c level was 38 (36–41) mmol/mol [5.6 (5.4–5.9)%], p=0.016 (see Table 3, Figure 1).
Sulfonylurea transfer in 11 patients with KCNJ11/ABCC8 gene mutationsa.
| Patient | Gene | Mutation | Age at transfer | Starting dose, mg/kg/day | Maximum dose, mg/kg/day | Dose after 3 months, mg/kg/day | HbA1c pre-transfer, mmol/mol | HbA1c 3 months later, mmol/mol | Side effects | Neurological improvement (N/A if no features) |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | KCNJ11 | p.R201C | 62 months | 0.1 | 1.1 | 0.58 | 54 | 45 | No | NA |
| 2 | KCNJ11 | p.R201C | 6 months | 0.1 | 0.7 | 0.32 | 81 | 48 | No | NA |
| 3 | KCNJ11 | p.R201C | 4 months | 0.1 | 0.2 | 0.15 | 148 | 37 | No | NA |
| 4 | KCNJ11 | p.R201H | 1 month | 0.1 | 0.25 | 0.18 | 128 | 27 | No | NA |
| 5 | KCNJ11 | p.R201H | 28 years | 5 mg/day | 15 mg/day | 15 mg/day | 65 | 57 | No | NA |
| 6 | KCNJ11 | p.G53D | 20 months | 0.1 | 0.75 | 0.75 | 47 | 42 | No | NA |
| 7 | KCNJ11 | p.V59M | 72 months | 0.1 | 1.0 | 0.68 | 54 | 41 | No | NA |
| 8 | KCNJ11 | p.E229K | 16 months | 0.05 | 0.1 | 0.075 | 49 | 43 | No | NA |
| 9 | ABCC8 | p.I49F | 25 months | 0.05 | 0.1 | 0.1 | 41 | 42 | No | No |
| 10 | ABCC8 | p.I49F | 6 months | 0.05 | 0.07 | 0.07 | 57 | 48 | No | No |
| 11 | ABCC8 | p.V324M/ p.R1394L | 57 months | 0.1 | 1.0 | 0.54 | 61 | 32 | No | No |
aPatient 12 with the p.I585T ABCC8 mutation entered remission before initiation of sulphonylurea therapy.
HbA1c (mmol/mol) before 3 months and 1 year after sulfonylurea treatment (p=0.016). The daily dose of sulfonylurea decreased from 0.48 (0.09–0.75) to 0.32 (0.1–0.59) and 0.16 (0.12–0.28) mg/kg/day after 3 months and 1 year of treatment accordingly, p>0.05. No side effects were reported.
The patient with severe DEND syndrome caused by the compound heterozygous ABCC8 mutations p.V324M and p.R1394L showed no neurological improvement after 2 years on sulfonylurea treatment (current dose 0.15 mg/kg/day).
Sulfonylurea treatment was initiated in the boy with the p.I49F ABCC8 mutation when his diabetes relapsed aged 2 years 3 months. The initial dose of 0.07 mg/kg/day was increased to 0.2 mg/kg/day after starting treatment with growth hormone (0.025 mg/kg/day). His sister has been treated with low-dose sulfonylurea (0.06 mg/kg/day) for a year.
Discussion
Establishing a neonatal diabetes section of the Ukrainian Pediatric Diabetes Register has facilitated the identification of cases for genetic testing and provided an estimate of the incidence.
Incidence of neonatal diabetes in Ukraine
The incidence of neonatal diabetes in Ukraine over a 36-month period (2012–2014) was 1 in 126,397. This figure is similar to studies from Germany [1 in 89,000 (25)] and Italy [1:90,000 (26)]. As permanent diabetes (PNDM) accounts for ~50% of neonatal diabetes cases, our incidence is also consistent with reports of PNDM in the UK, the Netherlands, and Poland, of at least 1 in 260,000 live births (27), 1 in 210,000 in Italy (28), and 1 in 214,000 live births from the Slovakian diabetes register (29). The highest incidence of permanent neonatal diabetes is observed in countries with high rates of consanguinity [1 in 21,196 (30)].
Sulfonylurea transfer in patients with KCNJ11 and ABCC8 mutations
KATP channel gene mutations were the leading cause of neonatal diabetes (52.2%). Transfer from insulin to sulfonylurea was successful in all 11 patients with these mutations with improved glycemic control within 3 months and HbA1c levels below <48 mmol/mol (<6.5%) after 1 year.
The patients with the p.G53D and p.V59M KCNJ11 mutations are currently aged 3 and 8 years. They have been treated with high-dose sulfonylureas (>0.5 mg/kg/day) and show no evidence of the mild to moderate developmental delay observed in other patients with these mutations (10, 31–34). In contrast, three patients with ABCC8 mutations (p.I49F in two siblings and one case compound heterozygous for p.V324M and p.R1394L) have severe developmental delay. The siblings with the p.I49F mutation were transferred to low-dose sulfonylurea therapy (≤0.1 mg/kg/day) because of the transient nature of their diabetes. A spike of blood glucose 1 h after eating was observed in two patients (with KCNJ11 p.R201C and the ABCC8 mutations p.V324M and p.R1394L). This was solved by increasing the interval of sulfonylurea uptake up to 50 minutes pre meals.
Other genetic causes of neonatal diabetes in Ukraine
We identified three cases of transient neonatal diabetes due to chromosome 6q24 uniparental isodisomy and eight patients with mutations in non-KATP channel genes. These included four patients with heterozygous INS mutations and one patient where sequence analysis of the GLIS3 gene was indicated by his hypothyroidism and polycystic kidneys. For three patients, the genetic analysis was achieved through testing all the known neonatal diabetes genes by targeted next-generation sequencing (22). Two probands were diagnosed with Wolcott-Rallison syndrome but have not yet developed the extra-pancreatic features. One patient with mild fasting hyperglycemia has a heterozygous GCK mutation.
Cut-off age for genetic testing to identify patients with neonatal diabetes
In this study, we performed genetic testing for any patient diagnosed with diabetes before 9 months and identified a genetic etiology in four cases diagnosed after 6 months (7.3–8.0 months), the usual definition of neonatal diabetes. Three probands had an INS mutation and one individual was heterozygous for a KCNJ11 mutation. This patient was able to transfer from daily insulin injections to sulfonylurea tablets resulting in improved glycemic control [HbA1c: 47 mmol/mol (pre-transfer) vs. 42 mmol/mol (3 months post-transfer)]. Consistent with our earlier study, the pick-up rate for mutations was significantly lower in patients diagnosed after 6 months compared to those diagnosed before 6 months (20% vs. 86%; p≤0.0001) (35). The benefits of a genetic diagnosis, in terms of improving medical management and quality of life for those with KATP channel mutations as well as providing an accurate recurrence risk, highlights the utility of testing all patients diagnosed up to 9 months of age.
In conclusion, Ukraine has a similar incidence of neonatal diabetes as other European countries and KATP channel gene mutations are the most common cause. All patients with KCNJ11 and ABCC8 mutations were successfully switched from insulin injections to oral sulfonylurea therapy with an improvement in their glycemic control. Targeted next-generation sequencing technology increased the number of patients with a confirmed genetic etiology of neonatal diabetes and provides an accurate recurrence risk for the families. The identification of a KCNJ11 mutation in a patient diagnosed at 7.5 months highlights the importance of providing genetic testing to those diagnosed between 6 and 9 months.
Acknowledgments
We would like to thank all Ukrainian regional endocrinologists for referring patients. We are grateful to M. Borowiec, K. Antosik, W. Fendler, and W. Mlynarsky from Medical University of Lodz, Poland for the molecular genetic analysis of GLIS3 in one patient. SE and ATH are supported by a Wellcome Trust Senior Investigator award. DJGM is supported by Diabetes UK project grant 12/0004501. SF has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 105636/Z/14/Z).
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