• Differential diagnosis;
  • monogenic disease;
  • neonatal diabetes


  1. Top of page
  2. Abstract
  3. Permanent diabetes during the first year of age
  4. Permanent neonatal diabetes mellitus – different genes, different phenotypes
  5. Genetic testing in PNDM
  6. Summary points
  7. Acknowledgements
  8. Address
  9. References

Eur J Clin Invest 2011; 41 (3): 323–333


Background  The differential diagnosis of various types and forms of diabetes is of great practical importance. This is particularly true for monogenic disease forms, where some spectacular applications of pharmacogenetics have recently been described.

Design  For many years the distinct character of diabetes diagnosed in the first weeks and months of life remained unnoticed. The results of the search for type 1 diabetes-related autoantibodies, description of the HLA haplotypes distribution and analysis of clinical features in patients diagnosed in the first 6 months of life provided the initial evidence that the etiology of their disease might be different from that of autoimmune diabetes.

Results  Over the last decade, mutations in about a dozen of genes have been linked to the development of Permanent Neonatal Diabetes Mellitus (PNDM). The most frequent causes of PNDM are heterozygous mutations in the KCNJ11, INS and ABCC8 genes. Although PNDM is a rare phenomenon (one case in about 200 000 live births), this discovery has had a large impact on clinical practice as most carriers of KCNJ11 and ABCC8 gene mutations have been switched from insulin to oral sulphonylureas with an improvement in glycemic control. In this review we summarize the practical aspects of diabetes differential diagnosis in neonates and infants.

Conclusions  Genetic testing should be advised in all subjects with PNDM as it may influence medical care in subjects with these monogenic forms of early onset diabetes.

Permanent diabetes during the first year of age

  1. Top of page
  2. Abstract
  3. Permanent diabetes during the first year of age
  4. Permanent neonatal diabetes mellitus – different genes, different phenotypes
  5. Genetic testing in PNDM
  6. Summary points
  7. Acknowledgements
  8. Address
  9. References

Clinical presentation of lifelong permanent diabetes mellitus during the first year of life is described as a rare event, with an estimated incidence of only 1·43–1·96 cases per 100 000 infants [1]. Interestingly, this group of patients is heterogeneous, with the existence of two different groups with a clear cut-off at 6 months of age at the disease onset [2]. The first group is the classic type 1 diabetes (T1DM), a T-cell-mediated autoimmune disease resulting from a selective destruction of the pancreatic insulin-producing β-cells [3]. T1DM is the commonest cause of diabetes mellitus in children, accounting for over 95% of cases [4]. The disease ultimately results from a combination of genetic predisposition and a number of largely unknown environmental factors. As a rule of thumb, the earlier the clinical onset of the disease, the stronger the genetic susceptibility. This is especially true when the disease presents before 2 years of age [5]. However, as months, or even years, can elapse between the beginning of the autoimmune response and the clinical appearance of T1DM, the onset of diabetes very early in life might not be consistent with the time required for an autoimmune response to result in overt diabetes [6,7]. Below, we present three different lines of evidence supporting the notion that a mechanism alternative to autoimmune disease has to be considered in newborns and younger infants presenting with diabetes before the age of 6 months [8].

Genetic evidence

Association studies have identified over 40 regions in the human genome that are related to T1DM, but most make only a minor contribution to the overall genetic susceptibility to this disease [9,10]. The most significant susceptibility locus (IDDM1 locus) is the HLA class II region in the major histocompatibility complex on chromosome 6p21.3, as allelic variation within this locus contributes about 50% of the inherited risk for T1DM. The disease susceptibility conferred by HLA represents the combined effect of several genes within the region, the DRB1 and DQB1 genes being the major determinants of HLA-encoded T1DM susceptibility. While several HLA genotypes confer increased risk, some other genotypes confer protection. Infants diagnosed with diabetes after the 6th month had a HLA genotype distribution similar to older classic T1DM individuals, whereas younger patients were similar to control subjects (Fig. 1) [2,11]. Newborns and infants diagnosed before 6 months of age were therefore unlikely to have classic polygenic autoimmune T1DM. However, it was difficult to be certain of an absolute cut-off at 6 months. The fact that the prevalence of high-risk HLA genotypes was slightly lower in children diagnosed between 6 and 12 months when compared to those presenting between 12 and 24 months of age, indicated that there might be some admixture of patients with nonautoimmune diabetes in the 6–12-month age range (Fig. 1) [11].


Figure 1.  Prevalence of high-risk HLA class II genotypes (DR4-DQ8/DR3-DQ2, DR4-DQ8/X and DR3-DQ2/X, where X is not DR2-DQ6) in subjects diagnosed with diabetes under 24 months of age, compared to patients with adult-onset type 1 diabetes and normal controls (modified with permission from Edghill et al. [11]).

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Autoimmunity studies

The environmental triggers that initiate pancreatic β-cell destruction remain largely unknown, but it has been proven that the process usually begins months to years before the manifestation of clinical symptoms. The presence of antibodies directed against different antigens of the β-cells, including islet cell antibodies, glutamic acid decarboxylase antibodies, islet antigen-2 antibodies, insulin autoantibodies, and/or the recently identified antibodies against the zinc transporter 8, is considered a hallmark of T1DM and precedes the clinical diagnosis of the disease by several years [12,13]. The production of autoantibodies in children who will develop T1DM may be very precocious in certain circumstances, sometimes beginning even in utero; however, these children do not develop the clinical disease until several years later on [6]. Furthermore, a number of prospective studies in newborns with a genetically defined high risk for T1DM have shown that autoantibodies rarely appear within the first 6–9 months of life, not even in children who will develop diabetes later on [7,14]. It seemed clear that, even in this context, autoimmunity generally did not evolve rapidly enough to produce clinical manifestations in the first months of life. In keeping with this, infants diagnosed with diabetes before 6 months of age were less likely to be antibody positive than infants diagnosed later (15% vs. 65%) [2]. Even though autoimmune diabetes may be rarely present in very young infants, it is now accepted that mutations in the FOXP3 gene, and not polygenic T1DM, will account for most of these cases [15].

Clinical data

Almost two-thirds of the infants diagnosed in the first 6 months were born small for gestational age (SGA), in contrast to 15% of those presenting later [2]. Because insulin exerts potent growth-promoting effects during intrauterine development [16], a low birthweight might reflect reduced insulin secretion by the foetal pancreas suggesting a more precocious damage to the β-cells in infants diagnosed soon after birth.

Permanent neonatal diabetes mellitus – different genes, different phenotypes

  1. Top of page
  2. Abstract
  3. Permanent diabetes during the first year of age
  4. Permanent neonatal diabetes mellitus – different genes, different phenotypes
  5. Genetic testing in PNDM
  6. Summary points
  7. Acknowledgements
  8. Address
  9. References

A significant progress has been made in the understanding of the molecular bases of very early onset diabetes during the last few years. It is now accepted that most neonates and infants presenting with diabetes within the first 6 months of life have a monogenic form of disease, although the responsible gene remains unknown in up to 40% of patients [17]. Because the age limit to consider a nonautoimmune, monogenic cause has been changed from the first 30–45 days of life [18], to the first 3 months [19] and finally to the first 6 months [20], the term ‘monogenic diabetes of infancy’ has been suggested to be a more appropriate name than ‘neonatal diabetes’ [20]. Although somewhat terminologically incorrect, the latter is nevertheless still extensively used and preferred by most authors. Approximately, 50% of the patients will require lifelong treatment to control hyperglycemia (permanent neonatal diabetes, PNDM). In contrast, diabetes will remit within a few weeks or months in the remaining patients (transient neonatal diabetes, TNDM), although it may relapse later in life [21].

PNDM is caused by mutations affecting genes that play a critical role in the development, survival and function of pancreatic β-cells [22]. While it is a rare phenomenon, with one case occurring in about 200 000–250 000 live births [23,24], the discovery of its genetic background has had a large impact on the clinical practice in the affected subjects. The phenotype of PNDM is highly variable depending on the genotype, as described later.


Activating mutations in the KCNJ11 gene are responsible for about one-third to half of all cases of PNDM [17, 24]. KCNJ11 encodes for Kir6.2, the inward rectifier subunit of the ATP-sensitive potassium (KATP) channel of the β-cells. Dominant activating mutations make these channels irresponsive to rise in intracellular ATP concentration, thus causing their permanent activation and opening. This leads to a sustained hyperpolarisation of the cell membrane, which prevents insulin secretion from β-cells [20]. Birthweight is low in children with PNDM – below the 10th centile for gestational age in most cases – as a result of lower foetal insulin production. Affected infants frequently present with symptomatic hyperglycemia and sometimes with ketoacidosis at diagnosis [25–30]. Most cases of KCNJ11-related neonatal diabetes are diagnosed before the age of 3 months, the rest before the end of the 6th month [26–30]. Although most individuals with KCNJ11 PNDM have isolated diabetes, about 20–25% of mutation carriers also show neurological symptoms, such as epilepsy and developmental delay (DEND syndrome, developmental delay, epilepsy and neonatal diabetes) as well as muscle weakness [30–32]. The fact that KCNJ11 is expressed in many tissues and organs, including the brain and peripheral nerves, explains the presence of these extra-pancreatic symptoms [33,34]. The majority of mutations in KCNJ11 arise de novo; thus, the family history does not have much importance for the clinical diagnosis of this PNDM form [26–30]. While most of the KCNJ11 gene mutations were linked with PNDM, the spectrum of diabetes phenotypes caused by these mutations is quite broad and includes TNDM, usually resolving during the first year of life, childhood diabetes and a young adult-onset disease that may mimic maturity onset diabetes of the young (MODY) [23–25].

The most clinically relevant feature of KCNJ11 PNDM is a very good response to sulfonylurea (SU) treatment in the majority of mutation carriers. In this form of PNDM, SU action precisely corrects the mechanism underlying this diabetes by closing the activated potassium channel [35]. Successful transfer from insulin to SU has been accomplished for both adults and children, including infants [30–32,35–38]. In most of these cases, a substantial improvement in glycemic control was seen and no major side effects were reported. Minor side effects include transitory diarrhoea [36] and tooth discoloration [39]. The doses of various SU compounds were much higher than usually therapeutically used in T2DM [31,32,35–39]. In the majority of the reported cases, glibenclamide (glyburide) was used because of its nonselective nature [30–32,35–38]. It was hypothesised that this agent might be particularly useful in the correction of some extra-pancreatic symptoms, such as muscle weakness or developmental delay. Indeed, the recently published data provided an evidence for neurological improvement in diabetic KCNJ11 mutation carriers after glibenclamide use [30–32]. Other SU seems to constitute an alternative to glibenclamide, particularly in patients without extra-pancreatic symptoms [40–42]. The use of modified release formulation of SU may improve the patient’s compliance and quality of life. Usually, a drop in the SU dose by more than one-third is seen during the first 6 months of treatment, with stabilisation during longer follow-up [36,42]. No case of ‘secondary’ failure of SU in KCNJ11 PNDM has been reported so far. The initially reported reduction in glycated hemoglobin after the switch from insulin to SU is about 1·5% [28–32,35–42]. Recently, a report of successful glibenclamide use in a woman with KCNJ11 PNDM during a high-risk pregnancy has been published [43].


ABCC8 PNDM is less frequent than KCNJ11 PNDM, and it constitutes 10–15% of the total number of cases with PNDM [24]. ABCC8 encodes SUR1, the regulatory subunit of the KATP channels in pancreatic β-cells [44,45]. Diabetes results from activation, and thus persistent opening, of the mutant channels. Heterozygous gain-of-function mutations in the ABCC8 gene have been described to cause PNDM; however, diabetes cases owing to homozygous or compound heterozygous mutations have also been reported [44]. The phenotypes linked to the ABCC8 gene activating mutations are variable, and they include clinical presentations similar to the ones associated with KCNJ11 gene alterations [26–32,35–45], including PNDM, TNDM, and permanent diabetes in childhood or adulthood [44–49]. Severe mutations within ABCC8 may produce DEND syndrome [50]. The mechanism by which mutations in the same gene, the KCNJ11 or ABCC8, may lead to so variable phenotypes is only partially understood. The severity of the clinical picture correlates with the severity of the mutations shown in functional studies [50]. The impact of a mutation depends on its localisation within a specific domain of the protein and on the character of the amino acid change [50]. However, because sometimes even the identical mutations within the same families produce sometimes a variable clinical picture [49], the influence of modifying genetic and environmental factors should also be considered.

Most of the patients with the molecular diagnosis of PNDM because of the ABCC8 gene mutations could also be transferred from insulin to SU [49,51]. In a small portion of ABCC8 PNDM, insulin cannot be stopped completely, but, even in those cases, SU usage may sometimes help decrease the insulin dose [51]. The failure of SU in some diabetic carriers of ABCC8 and KCNJ11 mutation can be, at least partially, explained by the severity of their alterations, nevertheless, additional factors, such as the age of the patient, could influence this phenomenon [36,51].


Mutations in the INS gene encoding preproinsulin seem to be the second most common cause of PNDM as they are responsible for about 15–20% of cases [24,52]. Both dominant and recessive mutations in the INS gene can result in PNDM [53–55]. Dominant mutations are thought to prevent normal folding and processing of proinsulin in the insulin secretion pathway. The abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and ultimately to β-cell apoptosis [17,53]. Recessive mutations produce diabetes by decreasing insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, altered mRNA stability and abnormal INS transcription [54].

PNDM as a result of heterozygous INS mutations presents with marked hyperglycemia and, in some cases, ketoacidosis. Newborns are born SGA (median SD score −2·0), the median age at diagnosis is 9 weeks [17]. Patients with PNDM resulting from recessive INS mutations are characterised with even lower birthweight and an earlier age of diagnosis (first week of life); about 60% of them are the offspring of consanguineous parents [54]. Such an early age of diagnosis may be explained by the disruption in insulin synthesis that occurs as soon as the foetal β-cell starts to secrete insulin. Because of the irreversible nature of the β-cell damage or dysfunction, these patients with PNDM must currently remain on insulin. Interestingly, there were some less severe heterozygous mutations described in the INS gene that resulted in a milder phenotype corresponding to MODY [56,57].


Mutations in the GCK (glucokinase) gene are a rare cause of PNDM [24]. Glucokinase is a key regulatory enzyme that catalyses the first reaction of the glycolytic pathway, i.e. the conversion of glucose to glucose 6-phosphate, of the pancreatic β-cell. Thus, it is considered its glucose sensor. It plays a crucial role in the synthesis of the ATP and, subsequently, in the regulation of insulin secretion [55]. Heterozygous inactivating mutations in the GCK gene cause one of the forms of MODY, characterised by mild fasting hyperglycemia [58]. Homozygous inactivating GCK gene mutations result in a phenotype of PNDM [58,59].

So far, only a few cases of GCK PNDM diabetes have been described. One should consider this form of PNDM when both parents, particularly from consanguineous families, have mild fasting hyperglycemia or clinically moderate diabetes corresponding to GCK MODY (formerly MODY2). All subjects with PNDM linked to the GCK gene mutations are characterised by very low birthweight, intrauterine growth retardation and large hyperglycemia, sometimes with ketoacidosis, from the first days of life [58,59].

All the children with biallelic mutations in the GCK gene must be treated with insulin. However, reportedly, in one case of a ‘milder’ mutation, the introduction of SU might lead to a decrease in insulin dose and improvement in glycemic control [58].

Other causes of PNDM

Rarely, the phenotype of PNDM may be produced by pancreatic hypoplasia or aplasia [60]; diabetes developes in these cases as the result of either a lack of or a significantly reduced mass of pancreatic β-cells. This can result from homozygous or compound heterozygous mutations in the PDX1 (pancreatic and duodenal homeobox 1) gene, also called IPF1. PDX1 has been well established as a key factor in pancreas development and function [60]. Pancreatic hypoplasia/agenesis as a result of homozygous PDX1 causes severe insulin deficiency. The birthweight of the mutation carriers is low. The family history of diabetes is usually positive for both parents, and it corresponds to PDX1 MODY (formerly MODY4) [60]. Interestingly, recently, two patients with PDX1 PNDM owing to homozygous mutations have been described, where diabetes was the only manifestation of the disease, with no clinical signs of malabsorption, although some degree of ‘biochemical’ subclinical extra-pancreatic failure was detected. The heterozygous parents of these PNDM cases were not diabetic and had normal glucose tolerance [61].

Pancreatic agenesis and PNDM may also result from homozygous mutations in the PTF1A gene encoding the pancreas transcription factor 1−α. Additional features include cerebellar aplasia or hypoplasia [62,63]. Furthermore, homozygous mutations in the NEUROD1 gene, another transcription factor critical in β-cell development, whose heterozygous mutations were earlier linked with MODY (formerly MODY6) [64], cause PNDM with neurological abnormalities but with no evidence of pancreatic exocrine dysfunction [65]. Another form of very early onset diabetes results from biallelic mutations in the RFX6 gene, a member of the RFX (regulatory factor X-box) binding family. This form of PNDM includes the clinical features of hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia [66,67].

PNDM may be also part of other composite syndromes. For example, mutations in the FOXP3 gene, encoding protein involved in development and function of regulatory T cells, produce IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome. It is a multisystemic disorder that occurs in hemizygous males. FOXP3 plays a crucial role in the generation and maturation of regulatory T cells expressing CD4+ and CD25+; in contrast to other forms of PNDM, neonatal diabetes in the IPEX syndrome is autoimmune and occurs with antibodies against β-cell antigens [68]. The clinical picture also includes hypothyroidism, enteropathy and dermatitis [68].

Biallelic mutations in EIF2AK3, the gene encoding the eukaryotic translation initiation factor 2-kinase 3, result in Wolcott–Rallison syndrome which, in addition to PNDM, includes skeletal dysplasia and liver dysfunction [69]. Neonatal diabetes is developed probably via increased rate of pancreatic β-cell apoptosis. EIF2AK3, localised exclusively in the endoplasmic reticulum, is involved in stress-induced regulation of protein synthesis, and a lack of its activity leads to accelerated cell death [69]. This gene has been found to be the most common cause of PNDM in consanguineous families, followed by recessively transmitted mutations in INS, GCK, ABCC8 and PDX1 genes [46,58–60,69,70]. Finally, neonatal diabetes may accompany some more complex, extremely rare syndromes like glycogen storage disease type XI (gene SLC2A2) [71], the syndrome of congenital hypothyroidism, hepatic fibrosis, polycystic kidneys and congenital glaucoma (gene GLIS3) [72] or thiamine-responsive megaloblastic anaemia (gene SLC19A2) [73]. The mechanisms underlying the development of diabetes in these syndromes include impaired glucose sensing of pancreatic β-cells and impaired hepatocyte carbohydrate metabolism [74], disruption of the development of mature insulin-secreting cells [75], and pancreatic intercellular thiamine deficiency resulting in attenuated secretion of insulin and β-cell apoptosis [76], respectively.

Unlike in TNDM [77], no chromosome 6 anomalies are linked to PNDM. The genotype/phenotype relationship in PNDM is summarised in Table 1.

Table 1.   Genotype/phenotype relationship in PNDM
Gene nameAffected proteinHow commonUsual age of diabetes onsetType of mutation inheritanceHyperglycemia treatmentExtrapancreatic features
  1. PNDM, permanent neonatal diabetes mellitus; SU, sulfonylurea.

KCNJ11Kir6.230–50%1–3 monthsSpontaneous/Autosomal DominantSU effective in most casesDEND syndrome in approximately 20% of cases
ABCC8Sulphonylurea receptor 113%1–3 monthsSpontaneous/Autosomal dominant or recessiveSU effective in most casesDEND syndrome in approximately 20% of cases
INSProinsulin16%1–3 monthsSpontaneous/Autosomal dominant or recessiveInsulinNo
GCKGlucokinaseRareFirst days of lifeAutosomal recessiveInsulinNo
PDX1Pancreatic and duodenal homeobox 1RareFirst days of lifeAutosomal recessiveInsulinPancreatic hypoplasia or aplasia in most cases
PTF1APancreas transcription factor 1ARareFirst days of lifeAutosomal recessiveInsulinPancreatic hypoplasia or aplasia in most cases
FOXP3Forkhead box P3RareFirst days of lifeX linkedInsulinImmune dysregulation, polyendocrino-pathy, enteropathy, X-linked (IPEX) syndrome
EIF2AK3Eukaryotic translation initiation factor 2-alpha kinase 3Rare3 monthsAutosomal recessiveInsulinWolcott–Rallison syndrome (skeletal dysplasia and liver dysfunction)
GLIS3Kruppel-like zinc finger transcription factor Gli similar 3RareFirst days of lifeAutosomal recessiveInsulinCongenital hypothyroidism, congenital glaucoma, hepatic fibrosis and polycystic kidneys
SLC2A2 (GLUT2aSolute carrier family (facilitated glucose transporter), member 2RareFirst days of lifeAutosomal recessiveInsulinGlycogen storage Disease type XI
SLC19A2Solute carrier family (thiamine transporter), member 2RareFirst months of life-adolescenceAutosomal recessiveInsulinMegaloblastic anemia and sensorineural hearing loss
RFX6Member of RFX (regulatory factor x-box) binding familyRareFirst days of lifeAutosomal recessiveInsulinIntestinal atresia, gall bladder hypoplasia

Genetic testing in PNDM

  1. Top of page
  2. Abstract
  3. Permanent diabetes during the first year of age
  4. Permanent neonatal diabetes mellitus – different genes, different phenotypes
  5. Genetic testing in PNDM
  6. Summary points
  7. Acknowledgements
  8. Address
  9. References

Sequence variants may have a variable impact on the disease occurrence in humans. In complex traits, they constitute susceptibility variants that individually have a limited contribution to the disease incidence. In monogenic forms of diabetes, however, they are causative factors that are entirely responsible for the development of the disease [78]. Only two decades ago, our, then superficial, knowledge on the molecular background of diabetes had a very limited impact on the medical practice. Currently, genetic testing for monogenic diabetes plays an important and steadily increasing role in clinics [79]. As in monogenic diabetes a single gene mutation decides about the disease phenotype, it is possible to establish a specific diagnosis based on a DNA analysis in a considered patient. The search for a mutation is typically performed by automated sequencing. Making such a diagnosis usually has significant clinical importance as it may influence diabetes treatment, explain pleiotropic features and define the prognosis in the examined subject as well as in other family members. Genetic testing in a family with monogenic diabetes may be diagnostic or prognostic in its nature [80]. Diagnostic testing applies to subjects who have already developed the disease. If a person is the first examined subject in the family, the so-called proband, then the entire gene(s) should be sequenced. If a mutation in a monogenic diabetes gene has previously been identified in another family member, the search is limited to the specific mutation. Prognostic tests apply to the subjects that are free of disease, and the justification of their referral is associated with the family history and a molecular diagnosis established in a close relative in such a case, the sequencing focuses on the earlier identified sequence difference. Only a few years ago, not many researchers involved in the genetic research in the field of diabetes expected that the issue of molecular testing would be relevant to the patients with a very early of diabetes diagnosis. Discoveries described earlier in this review have had important clinical consequences for the patients diagnosed in the first 6 months of life. Before these discoveries, they were misdiagnosed as suffering from a very early onset form of T1DM and treated with insulin. Now, we know that they constitute a group whose disease pathogenesis and clinical picture are distinct from those of autoimmune diabetes. Even more importantly, in patients with some forms of PNDM, SU may be used instead of insulin. This treatment not only provides a better quality of life but is also safer and more effective in achieving good glycemic control [36,42]. The awareness of PNDM’s distinctiveness is growing among diabetologists, endocrinologists, paediatricians and doctors of other specialties as well as among the patients and their families. One may expect that they will be referred for genetic consultations and eventually most of them will be tested. It is worthy to note that such a patient may be a newborn, an infant, a child or an adolescent, but also an adult person. It is important to define whom to test, what genes to screen and what are the consequences of the diagnosis.

The basic criterion to consider genetic testing for PNDM is the age at diagnosis, which should not exceed the 6th month of life. The rationale for such a threshold, as described earlier in this paper, is based on the analysis of the presence of T1DM-related autoantibodies, a description of HLA distribution and an analysis of clinical features, for example birthweight, in patients with early diabetes diagnosis. In addition, most, although not all [81], carriers of PNDM gene mutations were diagnosed with diabetes below this cut-off point.

If the criterion of the age of diagnosis is fulfilled, genetic testing is justified. What genes should be examined? In the first place, Kir6.2 subunit of the β-cell ATP-dependent potassium channel encoded by the KCNJ11 gene. There are a few arguments in favour of beginning the genetic investigation from this gene. First, between one-third and half of all PNDM cases are caused by its mutations [23,26]. Secondly, a diagnosis of Kir6.2-related PNDM brings important clinical consequences related to possible treatment change [36,42]. Additionally, as the KCNJ11 is a relatively small gene [26], the cost of this search is limited. Because in about one-third of the patients with this form of disease diabetes is accompanied by neurological abnormalities, their presence constitutes another argument in favour of beginning the testing from Kir6.2. As most cases of Kir6.2 PNDM are caused by spontaneous de novo mutations, a negative family history in a patient should not be a surprise [26]. Nevertheless, as a result of the improvement in diabetes care, women with KCNJ11 gene mutations reach adulthood in good health and they can plan to have offspring. As many of them have already undergone genetic testing, one may encounter a situation where the mother is already diagnosed with a specific mutation [43]. This allows predictive testing to be performed either prenatally or after delivery. For the proband with autosomal dominant PNDM, as in the case of the KCNJ11 gene mutations, the risk of disease inheritance for next siblings and offspring is 50%. It should be also remembered that sometimes de novo KCNJ11 gene mutations may be the result of germline mosaicism; the empiric recurrence risk for affected siblings because of parental germline mosaicism is about 3%. [82,83].

It is important to understand the consequences of the KCNJ11 gene-related PNDM presence in a patient sent for genetic counselling. First, one should inform the patient and/or their family that there exists a possibility of switching from insulin to oral hypoglycemic agents (SU). The mechanisms of SU efficacy have been described earlier in this review. The medical team performing the therapy change must be aware that the procedure may take from a few days to a few weeks. In some patients with DEND syndrome, insulin therapy cessation may not be possible [34]. On the other hand, in subjects with intermediate DEND (iDEND, a less severe condition in which neonatal diabetes is accompanied by muscle weakness and developmental delay but not epilepsy), in whom the transfer was possible, some improvement in neurological function may be expected [30,31,84]. Nevertheless, we argue that a geneticist or a diabetologist should be very careful during the counselling for patients with DEND and iDEND PNDM to avoid generating unjustified expectations.

The second most frequent cause of PNDM is mutations in the INS gene. As the underlying mechanism of INS gene mutations leads to irreversible β-cell destruction, an attempt to interrupt insulin treatment and to start oral hypoglycemic agents, for example SU, is not justified. This information should be given to the patient and/or the family.

The next gene that should be considered for automated sequencing is ABCC8. The frequency of SUR1-related PNDM cases is only slightly lower than that of those caused by INS gene mutations. The ABCC8 gene, however, is much larger, and thus its sequencing is laborious, time-consuming and costly. We recommend that this gene be screened after the KCNJ11 and INS genes are examined with negative results. We consider that this order can be reversed if neurological features are present as they are not part of INS gene-related PNDM. Another situation that may prioritise SUR1 gene testing is variability of phenotypes in the examined family [45,49], although this may also occur in the families with the Kir6.2 gene mutations [85]. This may include PNDM, TNDM, relapsing neonatal diabetes and permanent diabetes in childhood or adulthood. The attempt to switch from insulin to SU is justified, and in most SUR1-related PNDM cases it is successful [49,51,52]. One should also remember that the ABCC8 gene is highly polymorphic and there exists a variety of its sequence differences associated with PNDM [86]. Thus, it is important that the parents of the proband are available for testing to verify whether the suspected variant is de novo. Where both parents of a PNDM child are unaffected carriers of the autosomal recessive mutation of the gene, for example the ABCC8 or INS, there is 25% risk in every pregnancy that their child will inherit the defective gene copy from both parents and be affected by diabetes. Matings between an affected parent with autosomal recessive PNDM and an unaffected parent will usually yield all unaffected offspring; only in the very unlikely event of the unaffected parent being a heterozygote can affected children be produced.

While most of PNDM cases could be explained by mutation is the KCNJ11, INS and ABCC8 genes, there are very rare situations when the phenotype of very early diabetes is related to sequence differences in other genes. The list includes PDX1, GCK, EIF2AK3, FOXP3, SLC2A2, GLIS3, NEUROD1, RFX6 and SLC19A2 genes [60–69]. The referral of patients for genetic testing of these genes should be very careful because of the rarity of the specific syndromes that are summarised in Table 1. Importantly, one should take into account additional clinical features in the patient or family members (Table 1). No pharmacogenetics apply to these forms of PNDM, and patients suffering from them require insulin therapy. A scheme of PNDM genetic testing and its forms management is presented in Figure 2.


Figure 2.  Clinical subtypes of permanent neonatal diabetes mellitus and their management are shown. If the referred patient is a newborn or an infant, it is not yet known whether the diabetes will be transient or permanent. Therefore, we recommend testing in nonsyndromic diabetes for 6q24 abnormalities and KCNJ11 mutations first and for ABCC8 mutations if these tests are negative.

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Summary points

  1. Top of page
  2. Abstract
  3. Permanent diabetes during the first year of age
  4. Permanent neonatal diabetes mellitus – different genes, different phenotypes
  5. Genetic testing in PNDM
  6. Summary points
  7. Acknowledgements
  8. Address
  9. References
  •  Patients developing permanent diabetes before the age of 6 months usually have a disease pathogenetically and clinically different from T1DM. This form of disease is usually called permanent neonatal diabetes mellitus (PNDM), although other names have been suggested, for example ‘monogenic diabetes of infancy’ or ‘diabetes diagnosed before 6 months of age’.
  •  Most cases of PNDM may be explained by a monogenic defect. The most frequent cause of PNDM is mutations in the KCNJ11 gene, explaining almost half of all cases. The INS and ABCC8 genes are less frequent causes of PNDM.
  •  PNDM is a rare phenomenon, but its proper differential diagnosis is very important. Most of the patients with KCNJ11 and ABCC8 gene mutations can be switched from insulin to SU.
  •  Genetic testing should be advised in all patients with PNDM.


  1. Top of page
  2. Abstract
  3. Permanent diabetes during the first year of age
  4. Permanent neonatal diabetes mellitus – different genes, different phenotypes
  5. Genetic testing in PNDM
  6. Summary points
  7. Acknowledgements
  8. Address
  9. References

ORC was supported by an “Ayuda para contratos post-Formación Sanitaria Especializada” from the “Instituto de Salud Carlos III148;” (FIS CM06/00013). MTM and TK are supported by the European Community FP7 program CEED3 (HEALTH-F2-2008-223211) and funds from the Jagiellonian University, Medical College (Grant K/ZDS/000399). The authors are grateful to Aleksandra Malecka for her linguistic help in the preparation of this manuscript.


  1. Top of page
  2. Abstract
  3. Permanent diabetes during the first year of age
  4. Permanent neonatal diabetes mellitus – different genes, different phenotypes
  5. Genetic testing in PNDM
  6. Summary points
  7. Acknowledgements
  8. Address
  9. References

Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK (O. Rubio-Cabezas); Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain (O. Rubio-Cabezas); Department of Metabolic Diseases, Medical College, Jagiellonian University, Krakow, Poland (T. Klupa, M.T. Malecki); University Hospital, Krakow, Poland (T. Klupa, M.T. Malecki).


  1. Top of page
  2. Abstract
  3. Permanent diabetes during the first year of age
  4. Permanent neonatal diabetes mellitus – different genes, different phenotypes
  5. Genetic testing in PNDM
  6. Summary points
  7. Acknowledgements
  8. Address
  9. References
  • 1
    Rosenbauer J, Herzig P, von Kries R, Neu A, Giani G. Temporal, seasonal, and geographical incidence patterns of type I diabetes mellitus in children under 5 years of age in Germany. Diabetologia 1999;42:10559.
  • 2
    Iafusco D, Stazi MA, Cotichini R, Cotellessa M, Martinucci ME, Mazzella M et al. ; Early Onset Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetology. Permanent diabetes mellitus in the first year of life. Diabetologia 2002;45: 798804.
  • 3
    Gillespie KM. Type 1 diabetes: pathogenesis and prevention. CMAJ 2006;175:16570.
  • 4
    Porter JR, Barrett TG. Acquired non-type 1 diabetes in childhood: subtypes, diagnosis, and management. Arch Dis Child 2004;89: 113844.
  • 5
    Komulainen J, Kulmala P, Savola K, Lounamaa R, Ilonen J, Reijonen H et al. Clinical, autoimmune, and genetic characteristics of very young children with type 1 diabetes. Childhood Diabetes in Finland (DiMe) Study Group. Diabetes Care 1999;22:19505.
  • 6
    Lindberg B, Ivarsson SA, Landin-Olsson M, Sundkvist G, Svanberg L, Lernmark A. Islet autoantibodies in cord blood from children who developed type I (insulin-dependent) diabetes mellitus before 15 years of age. Diabetologia 1999;42:1817.
  • 7
    Achenbach P, Bonifacio E, Koczwara K, Ziegler AG. Natural history of type 1 diabetes. Diabetes 2005;54(Suppl. 2):S2531.
  • 8
    Hattersley A, Bruining J, Shield J, Njolstad P, Donaghue KC. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2009;10(Suppl. 12):3342.
  • 9
    Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA et al. ; The Type 1 Diabetes Genetics Consortium. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 2009;41:7037.
  • 10
    Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med 2009;360:164654.
  • 11
    Edghill EL, Dix RJ, Flanagan SE, Bingley PJ, Hattersley AT, Ellard S et al. HLA genotyping supports a nonautoimmune etiology in patients diagnosed with diabetes under the age of 6 months. Diabetes 2006;55:18958.
  • 12
    Schatz D, Krischer J, Horne G, Riley W, Spillar R, Silverstein J et al. Islet cell antibodies predict insulin-dependent diabetes in United States school age children as powerfully as in unaffected relatives. J Clin Invest 1994;93:24037.
  • 13
    Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A 2007;104:170405.
  • 14
    Hummel M, Bonifacio E, Schmid S, Walter M, Knopff A, Ziegler AG. Brief communication: early appearance of islet autoantibodies predicts childhood type 1 diabetes in offspring of diabetic parents. Ann Intern Med 2004;140:8826.
  • 15
    Rubio-Cabezas O, Minton JA, Caswell R, Shield JP, Deiss D, Sumnik Z et al. Clinical heterogeneity in patients with FOXP3 mutations presenting with permanent neonatal diabetes. Diabetes Care 2009;32:1116.
  • 16
    Gicquel C, Le Bouc Y. Hormonal regulation of fetal growth. Horm Res 2006;65(Suppl. 3):2833.
  • 17
    Edghill EL, Flanagan SE, Patch AM, Boustred C, Parrish A, Shields B et al. Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes 2008;57:103442.
  • 18
    von Mühlendahl KE, Herkenhoff H. Long-term course of neonatal diabetes. N Engl J Med 1995;333:7048.
  • 19
    Shield JP. Neonatal diabetes: new insights into aetiology and implications. Horm Res 2000;53(Suppl. 1):711.
  • 20
    Massa O, Iafusco D, D’Amato E, Gloyn AL, Hattersley AT, Pasquino B et al. ; Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology and Diabetology. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat 2005; 25: 227.
  • 21
    Polak M, Cavé H. Neonatal diabetes mellitus: a disease linked to multiple mechanisms. Orphanet J Rare Dis 2007;2:112.
  • 22
    Miki T, Iwanaga T, Nagashima K, Ihara Y, Seino S. Roles of ATP-sensitive K+ channels in cell survival and differentiation in the endocrine pancreas. Diabetes 2001;50(Suppl.1):S48S51.
  • 23
    Stanik J, Gasperikova D, Paskova M, Barak L, Javorkova J, Jancova E et al. Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers. J Clin Endocrinol Metab 2007;92:127682.
  • 24
    Slingerland AS, Shields BM, Flanagan SE, Bruining GJ, Noordam K, Gach A et al. 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. Diabetologia 2009;52:16835.
  • 25
    Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P, Pearson ER et al. Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet 2005;14:92534.
  • 26
    Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 2004;29:183849.
  • 27
    Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM. Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. Proc Natl Acad Sci USA 2004;14:1753944.
  • 28
    Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H et al. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes 2004;53:27138.
  • 29
    Vaxillaire M, Populaire C, Busiah K, Cavé H, Gloyn AL, Hattersley AT et al. Kir6.2 mutations are a common cause of permanent neonatal diabetes in a large cohort of French patients. Diabetes 2004;53:271922.
  • 30
    Mlynarski W, Tarasov AI, Gach A, Girard CA, Pietrzak I, Zubcevic L et al. Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11. Nat Clin Pract Neurol 2007;3:6405.
  • 31
    Slingerland AS, Nuboer R, Hadders-Algra M, Hattersley AT, Bruining GJ. Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene. Diabetologia 2006;49:255963.
  • 32
    Noffs MH, Belzunces E, Rahal MA, Moisés RS. Sulfonylrea treatment in permanent neonatal diabetes due to G53D mutation in the KCNJ11 gene: improvement in glycemic control and neurological function. Diabetes Care 2007;30:e108.
  • 33
    Clark RH, McTaggart JS, Webster R, Mannikko R, Iberl M, Sim XL. Muscle dysfunction caused by a KATP channel mutation in neonatal diabetes is neuronal in origin. Science 2010;329:45861.
  • 34
    Sakura H, Ammälä C, Smith PA, Gribble FM, Ashcroft FM. Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel subunit expressed in pancreatic beta-cells, brain, heart and skeletal muscle. FEBS Lett 1995;377:33844.
  • 35
    Proks P, Girard C, Baevre H, Njølstad PR, Ashcroft FM. Functional effects of mutations at F35 in the NH2-terminus of Kir6.2 (KCNJ11), causing neonatal diabetes, and response to sulfonylurea therapy. Diabetes 2006;55:17317.
  • 36
    Pearson ER, Flechtner I, Njølstad PR, Malecki MT, Flanagan SE, Larkin B et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med 2006;355:46777.
  • 37
    Tonini G, Bizzarri C, Bonfanti R, Vanelli M, Cerutti F, Faleschini E et al. Sulfonylurea treatment outweighs insulin therapy in short-term metabolic control of patients with permanent neonatal diabetes mellitus due to activating mutations of the KCNJ11 (KIR6.2) gene. Diabetologia 2006;49:22103.
  • 38
    Zung A, Glaser B, Nimri R, Zadik Z. Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. J Clin Endocrinol Metab 2004;89:55047.
  • 39
    Kumaraguru J, Flanagan SE, Greeley SA, Nuboer R, Støy J, Philipson LH et al. Tooth discoloration in patients with neonatal diabetes after transfer onto glibenclamide: a previously unreported side effect. Diabetes Care 2009;32:142830.
  • 40
    Malecki MT, Skupien J, Klupa T, Wanic K, Mlynarski W, Gach A et al. Transfer to sulphonylurea therapy of adult subjects with permanent neonatal diabetes due to KCNJ11 activating mutations: evidence for improvement in insulin sensitivity. Diabetes Care 2007;30:1479.
  • 41
    Klupa T, Edghill EL, Nazim J, Sieradzki J, Ellard S, Hattersley AT et al. The identification of a R201H mutation in KCNJ11, which encodes Kir6.2, and successful transfer to sustained-release sulphonylurea therapy in a subject with neonatal diabetes: evidence for heterogeneity of β-cell function among carriers of the R201H mutation. Diabetologia 2005;48:102931.
  • 42
    Klupa T, Skupien J, Mirkiewicz-Sieradzka B, Gach A, Noczynska A, Zubkiewicz-Kucharska A et al. Efficacy and safety of sulfonylurea use in permanent neonatal diabetes due to KCNJ11 gene mutations: 34-month median follow-up. Diabetes Technol Ther 2010;12:38791.
  • 43
    Klupa T, Kozek E, Nowak N, Cyganek K, Gach A, Milewicz T et al. The First Case Report of Sulfonylurea Use in a Woman with Permanent Neonatal Diabetes Mellitus due to KCNJ11 Mutation during a High-Risk Pregnancy. J Clin Endocrinol Metab 2010;95: 3599604.
  • 44
    Patch AM, Flanagan SE, Boustred C, Hattersley AT, Ellard S. Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period. Diabetes Obes Metab 2007;9(Suppl. 2):2839.
  • 45
    Vaxillaire M, Dechaume A, Busiah K, Cavé H, Pereira S, Scharfmann R et al. New ABCC8 mutations in relapsing neonatal diabetes and clinical features. Diabetes 2007;56:173741.
  • 46
    Proks P, Arnold AL, Bruining J, Girard C, Flanagan SE, Larkin B et al. A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum Mol Genet 2006;15:1793800.
  • 47
    Babenko AP, Polak M, Cavé H, Busiah K, Czernichow P, Scharfmann R et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med 2006;355:45666.
  • 48
    Ellard S, Flanagan SE, Girard CA, Patch AM, Harries LW, Parrish A et al. Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. Am J Hum Genet 2007;81:37582.
  • 49
    Klupa T, Kowalska I, Wyka K, Skupien J, Patch AM, Flanagan SE et al. Mutations in the ABCC8 (SUR1 subunit of the K(ATP) channel) gene are associated with a variable clinical phenotype. Clin Endocrinol (Oxf) 2009;71:35862.
  • 50
    Proks P, Shimomura K, Craig TJ, Girard CA, Ashcroft FM. Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome. Hum Mol Genet 2007;16:20119.
  • 51
    Rafiq M, Flanagan SE, Patch AM, Shields BM, Ellard S, Hattersley AT. Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations. Diabetes Care 2008;31:2049.
  • 52
    Stoy J, Edghill EL, Flanagan SE, Ye H, Paz VP, Pluzhnikov A et al. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci USA 2007;104:150404.
  • 53
    Izumi T, Yokota-Hashimoto H, Zhao S, Wang J, Halban PA, Takeuchi T. Dominant nagative pathogenesis by mutant proinsulin in the Akita diabetic mouse. Diabetes 2003;52:40916.
  • 54
    Garin I, Edghill EL, Akerman I, Rubio-Cabezas O, Rica I, Locke JM et al. Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis. Proc Natl Acad Sci USA 2010;107:310510.
  • 55
    Matschinsky FM. Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 1996;45:22341.
  • 56
    Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanné-Chantelot C, Ellard S et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat 2009;30:151226.
  • 57
    Njølstad PR, Søvik O, Cuesta-Muñoz A, Bjørkhaug L, Massa O, Barbetti F et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med 2001;344:158892.
  • 58
    Molven A, Ringdal M, Nordbø AM, Raeder H, Støy J, Lipkind GM et al. Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes 2008;57:11315.
  • 59
    Boesgaard TW, Pruhova S, Andersson EA, Cinek O, Obermannova B, Lauenborg J. Further evidence that mutations in INS can be a rare cause of Maturity-Onset Diabetes of the Young (MODY). BMC Med Genet 2010;11:426.
  • 60
    Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997;15:10610.
  • 61
    Nicolino M, Claiborn KC, Senée V, Boland A, Stoffers DA, Julier C. A novel hypomorphic PDX1 mutation responsible for permanent neonatal diabetes with subclinical exocrine deficiency. Diabetes 2010;59:73340.
  • 62
    Hoveyda N, Shield JP, Garrett C, Chong WK, Beardsall K, Bentsi-Enchill E. Neo-natal diabetes mellitus and cerebellar hypoplasia/ agenesis: report of a new recessive syndrome. J Med Genet 1999;36:7004.
  • 63
    Sellick GS, Barker KT, Stolte-Dijkstra I, Fleischmann C, Coleman RJ, Garrett C et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 2004;36:13015.
  • 64
    Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syn-drome. J Med Genet 2002;39:53745.
  • 65
    Delépine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott–Rallison syndrome. Nat Genet 2000;25:4069.
  • 66
    Malecki MT, Jhala US, Antonellis A, Fields L, Doria A, Orban T et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Gene 1999;23:3238.
  • 67
    Rubio-Cabezas O, Minton JA, Kantor I, Williams D, Ellard S, Hattersley AT. Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes 2010;59:232631.
  • 68
    Mitchell J, Punthakee Z, Lo B, Bernard C, Chong K, Newman C et al. Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome. Diabetologia 2004;47:21607.
  • 69
    Smith SB, Qu HQ, Taleb N, Kishimoto NY, Scheel DW, Lu Y et al. Rfx6 directs islet formation and insulin production in mice and humans. Nature 2010;463:77580.
  • 70
    Rubio-Cabezas O, Patch AM, Minton JA, Flanagan SE, Edghill EL, Hussain K et al. Wolcott–Rallison syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families. J Clin Endocrinol Metab 2009;94:416270.
  • 71
    Yoo HW, Shin YL, Seo EJ, Kim GH. Identification of a novel mutation in the GLUT2 gene in a patient with Fanconi-Bickel syndrome presenting with neonatal diabetes mellitus and galactosaemia. Eur J Pediatr 2002;161:3513.
  • 72
    Senée V, Chelala C, Duchatelet S, Feng D, Blanc H, Cossec JC. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet 2006;38: 6827.
  • 73
    Labay V, Raz T, Baron D, Mandel H, Williams H, Barrett T et al. Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness. Nat Genet 1999;22:3004.
  • 74
    Metz C, Cavé H, Bertrand AM, Deffert C, Gueguen-Giroux B, Czernichow P et al. Neonatal diabetes mellitus: chromosomal analysis in transient and permanent cases. J Pediatr 2002;141:4839.
  • 75
    McCarthy MI, Hattersley AT. Molecular diagnostics in monogenic and multifactorial forms of type 2 diabetes. Expert Rev Mol Diagn 2001;1:40312.
  • 76
    Kentrup H, Altmüller J, Pfäffle R, Heimann G. Neonatal diabetes mellitus with hypergalactosemia. Eur J Endocrinol 1999;141:37981.
  • 77
    Kang HS, Kim YS, ZeRuth G, Beak JY, Gerrish K, Kilic G et al. Transcription factor Glis3, a novel critical player in the regulation of pancreatic beta-cell development and insulin gene expression. Mol Cell Biol 2009;29:636679.
  • 78
    Fleming JC, Tartaglini E, Steinkamp MP, Schorderet DF, Cohen N, Neufeld EJ. The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter. Nat Genet 1999;22:3058.
  • 79
    Hattersley AT. Molecular genetics goes to the diabetes clinic. Clin Med 2005;5:47681.
  • 80
    Ellard S, Bellanné-Chantelot C, Hattersley AT; European Molecular Genetics Quality Network (EMQN) MODY group. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia 2008;51:54653.
  • 81
    Mohamadi A, Clark LM, Lipkin PH, Mahone EM, Wodka EL, Plotnick LP. Medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15-yr-old boy with neonatal diabetes mellitus and intermediate DEND syndrome: extending the age of KCNJ11 mutation testing in neonatal DM. Pediatr Diabetes 2010;11:2037.
  • 82
    Gloyn AL, Cummings EA, Edghill EL, Harries LW, Scott R, Costa T et al. Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 Gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel. J Clin Endocrinol Metab 2004;89:39325.
  • 83
    Edghill EL, Gloyn AL, Goriely A, Harries LW, Flanagan SE, Rankin J et al. Origin of de novo KCNJ11 mutations and risk of neonatal diabetes for subsequent siblings. J Clin Endocrinol Metab 2007;92:17737.
  • 84
    Slingerland AS, Hurkx W, Noordam K, Flanagan SE, Jukema JW, Meiners LC et al. Sulphonylurea therapy improves cognition in a patient with the V59M KCNJ11 mutation. Diabet Med 2008;25:27781.
  • 85
    Yorifuji T, Nagashima K, Kurokawa K, Kawai M, Oishi M, Akazawa Y et al. The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus. J Clin Endocrinol Metab 2005;90:31748.
  • 86
    Flanagan SE, Clauin S, Bellanné-Chantelot C, de Lonlay P, Harries LW, Gloyn AL et al. Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat 2009;30:17080.