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      Referral rates for diagnostic testing support an incidence of permanent neonatal diabetes in three European countries of at least 1 in 260,000 live births

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          To the Editor: Surveys of neonatal diabetes in the UK and Germany from more than a decade ago reported an incidence of 1 in 400,000–450,000 live births [1, 2]. The permanent form of neonatal diabetes mellitus (PNDM) accounted for about half the cases, equating to a PNDM incidence of 1 in 800,000–900,000 live births. The definition of neonatal diabetes used in these publications was a diagnosis of diabetes within 4 weeks [1] or 6 weeks [2] of birth. HLA genotype analysis has shown that permanent diabetes diagnosed within the first 6 months of life is PNDM rather than type 1 diabetes [3]. Using a definition of diagnosis before 6 months, the incidence of PNDM was recently calculated at 1 in 214,000 live births from the Slovakian diabetes register [4]. We examined the incidence rates of PNDM in three further European countries. The incidence of neonatal diabetes for a country can be calculated from the referral rate of cases to a diagnostic laboratory and the annual birth rate, if all cases are referred to that laboratory. This will be less than the true incidence if not all cases are referred, but will still reflect a minimum incidence. In 2001 the Exeter Peninsula Molecular Genetics Laboratory based at the Royal Devon and Exeter Hospital (Exeter, UK) began recruiting patients worldwide prior to the discovery reported in 2004 that KCNJ11 mutations are the most common cause of PNDM [5]. The highest referral rates are in the UK, the Netherlands and Poland, where there have been considerable educational initiatives to inform clinicians of the free-of-charge diagnostic service for patients diagnosed with diabetes before 6 months of age. Between 2001 and 2009, samples from 119 patients (50.4% male) born between 1950 and 2005, diagnosed with PNDM and with no documented remission from diabetes were referred from the UK, the Netherlands and Poland. Isolated diabetes occurred in 60 patients, three had pancreatic agenesis, six had features consistent with Wolcott–Rallison syndrome and 40 had neurological symptoms. A genetic diagnosis was obtained in 59 cases, with mutations in KCNJ11 (n = 32) and INS (n = 10) being the most common. All the procedures in the participating centres were conducted in accordance with the Declaration of Helsinki as revised in 2000, and patients or their guardians gave written informed consent. We calculated the minimum annual PNDM incidence rate from 1950 to 2005 for the UK, the Netherlands and Poland. This was calculated using the number of patients referred who were born in a given year and dividing by the number of live births in that year using data from the United Nations Population Division (http://esa.un.org/unpp/, accessed 1 March 2009). To avoid large influences of stochastic variation that could occur with the low numbers, the results from the three countries were combined and the data were analysed in 5 year groups from 1950 to 2005. Minimum observed PNDM incidence ranged from <0.5 cases per million live births between 1950 and 1970, to about one case per million between 1970 and 1985, and increased between 1985 and 2005 from 1.9 to 3.8 cases per million (Fig. 1). Fig. 1 Minimum observed annual incidence of PNDM per million live births per year for 5 year intervals from 1 January 1950 to 31 December 2004 in Poland, the Netherlands and the UK combined The most recent data (24 cases born between 2000 and 2005) showed an incidence of 3.8 cases per million live births (one in 260,000) and this is comparable to the 4.6 cases per million live births calculated from the eight cases reported to the Slovakian registry between 1981 and 2004 [4]. An incidence of at least one in 260,000 live births in these four European countries is still much lower than in Oman, which has the highest reported incidence of PNDM, with one in 45,000 live births between 1991 and 1995 [6]. In Oman, consanguineous marriages are frequent (55%) and consequently we would expect a high prevalence of recessive forms of PNDM, which are rare in outbred populations. The reported incidence of neonatal diabetes in Germany (12 cases between 1977 and 1991) and the UK (two cases in 1994 and 1995) was considerably lower at 1 in 400,000–450,000 live births [1, 2], which corresponds to a PNDM incidence of about 1 in 800,000–900,000 live births, as approximately 50% of the neonatal diabetes cases remit. One partial explanation is that the definition of neonatal diabetes for these series was diagnosis in the first 4 or 6 weeks rather than the first 6 months of life. In our dataset, 62% of patients had been diagnosed before 7 weeks. The finding that patients diagnosed with diabetes in the first 6 months have mutations in the PNDM-associated genes [7] and a similar prevalence of type 1-predisposing HLA genotypes as non-diabetic controls [3] strongly supports the view that a cut-off of 6 months is appropriate. The major limitation of our study is that the data were taken from a single referral centre, to which all referrals were voluntary. We consider it likely that we identified all patients from these three countries who had genetic testing for PNDM during this time period. However, we could not ascertain patients with PNDM who died or for other reasons were not referred for genetic testing. The calculated incidence data therefore represent the minimum incidence rather than the actual incidence and will be an underestimate. The incidence of PNDM, based on referral rates for genetic testing, appears to have progressively increased over time (Fig. 1) and was particularly low before 1985. This has many possible explanations. It could reflect increased survival with improved clinical care over time. However, the uncertainty about the referral rates for genetic testing means that the apparent increase in incidence over time may in fact merely reflect a difference in the proportion of cases referred. In support of this being a factor, we noted that 66% of the patients were born after 1985 and were therefore likely to have been referred from a paediatric rather than an adult clinic. Paediatricians are more aware of recent advances in the genetic aetiology of PNDM and the impact this has on treatment, with improved control in approximately 90% of patients with ATP-sensitive K+ channel (KATP channel) mutations when insulin is replaced by sulfonylureas [8, 9]. In addition the smaller numbers of patients in paediatric clinics make it easier to identify those patients diagnosed before 6 months and refer them for genetic testing. Adult patients with PNDM are probably under-diagnosed and more effort should be made to identify these patients, especially as some may benefit from transfer from insulin to sulfonylurea treatment. In conclusion, based on genetic testing the recent incidence of PNDM in the UK, the Netherlands and Poland is at least 1 in 260,000 live births, in keeping with a recent smaller study from Slovakia. This is considerably higher than in previous incidence studies performed in the UK and Germany 10 years ago. This is only partly explained by the widening of the diagnostic age group and therefore suggests in addition either increased survival or greater awareness of the diagnosis resulting from the therapeutic advances seen since the discovery of KATP channel mutations.

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          Most cited references 11

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          Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

          Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas. Copyright 2004 Massachusetts Medical Society
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            Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations.

            Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, cause 30 to 58 percent of cases of diabetes diagnosed in patients under six months of age. Patients present with ketoacidosis or severe hyperglycemia and are treated with insulin. Diabetes results from impaired insulin secretion caused by a failure of the beta-cell K(ATP) channel to close in response to increased intracellular ATP. Sulfonylureas close the K(ATP) channel by an ATP-independent route. We assessed glycemic control in 49 consecutive patients with Kir6.2 mutations who received appropriate doses of sulfonylureas and, in smaller subgroups, investigated the insulin secretory responses to intravenous and oral glucose, a mixed meal, and glucagon. The response of mutant K(ATP) channels to the sulfonylurea tolbutamide was assayed in xenopus oocytes. A total of 44 patients (90 percent) successfully discontinued insulin after receiving sulfonylureas. The extent of the tolbutamide blockade of K(ATP) channels in vitro reflected the response seen in patients. Glycated hemoglobin levels improved in all patients who switched to sulfonylurea therapy (from 8.1 percent before treatment to 6.4 percent after 12 weeks of treatment, P<0.001). Improved glycemic control was sustained at one year. Sulfonylurea treatment increased insulin secretion, which was more highly stimulated by oral glucose or a mixed meal than by intravenous glucose. Exogenous glucagon increased insulin secretion only in the presence of sulfonylureas. Sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy. This pharmacogenetic response to sulfonylureas may result from the closing of mutant K(ATP) channels, thereby increasing insulin secretion in response to incretins and glucose metabolism. (ClinicalTrials.gov number, NCT00334711 [ClinicalTrials.gov].). Copyright 2006 Massachusetts Medical Society.
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              Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations.

               B. Shields,  ,  M. Rafiq (2008)
              Neonatal diabetes can result from mutations in the Kir6.2 or sulfonylurea receptor 1 (SUR1) subunits of the ATP-sensitive K(+) channel. Transfer from insulin to oral sulfonylureas in patients with neonatal diabetes due to Kir6.2 mutations is well described, but less is known about changing therapy in patients with SUR1 mutations. We aimed to describe the response to sulfonylurea therapy in patients with SUR1 mutations and to compare it with Kir6.2 mutations. We followed 27 patients with SUR1 mutations for at least 2 months after attempted transfer to sulfonylureas. Information was collected on clinical features, treatment before and after transfer, and the transfer protocol used. We compared successful and unsuccessful transfer patients, glycemic control before and after transfer, and treatment requirements in patients with SUR1 and Kir6.2 mutations. Twenty-three patients (85%) successfully transferred onto sulfonylureas without significant side effects or increased hypoglycemia and did not need insulin injections. In these patients, median A1C fell from 7.2% (interquartile range 6.6-8.2%) on insulin to 5.5% (5.3-6.2%) on sulfonylureas (P = 0.01). When compared with Kir6.2 patients, SUR1 patients needed lower doses of both insulin before transfer (0.4 vs. 0.7 units x kg(-1) x day(-1); P = 0.002) and sulfonylureas after transfer (0.26 vs. 0.45 mg x kg(-1) x day(-1); P = 0.005). Oral sulfonylurea therapy is safe and effective in the short term in most patients with diabetes due to SUR1 mutations and may successfully replace treatment with insulin injections. A different treatment protocol needs to be developed for this group because they require lower doses of sulfonylureas than required by Kir6.2 patients.

                Author and article information

                Springer-Verlag (Berlin/Heidelberg )
                5 June 2009
                August 2009
                : 52
                : 8
                : 1683-1685
                [1 ]Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, EX2 5DW UK
                [2 ]Department of Cardiology, Leiden University Medical Centre, Leiden, the Netherlands
                [3 ]Care Cure Science Foundation, Amsterdam, the Netherlands
                [4 ]Department of Paediatrics, Maxima Medical Centre, Veldhoven, the Netherlands
                [5 ]Department of Paediatrics, Radboud University Medical Centre, Nijmegen, the Netherlands
                [6 ]Department of Paediatrics, 1st Institute of Paediatrics, Medical University of Lodz, Lodz, Poland
                [7 ]Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland
                © The Author(s) 2009
                Research Letter
                Custom metadata
                © Springer-Verlag 2009

                Endocrinology & Diabetes

                monogenic diabetes, neonatal diabetes, genetic testing, pndm, incidence


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