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Monogenic Diabetes Mellitus: Neonatal Diabetes and Maturity-Onset Diabetes of the Young
Introduction
Diabetes is a heterogeneous disorder with many different possible causes, both genetic and acquired. Risk for the most common causes, type 1 and type 2 diabetes, depends on many different gene loci with intermediate or low effects and are thus considered polygenic. However, approximately 1% to 5% of all diabetes is caused by abnormalities at a single gene or locus and as a group, these entities are termed monogenic diabetes. Over 30 genes have now been described as causing the various forms of monogenic diabetes, where they will typically fall into one or more of the three main overlapping phenotypic categories: neonatal diabetes, maturity-onset diabetes of the young (MODY), and syndromic diabetes. In this chapter, we describe several of the more common causes of neonatal diabetes in some detail, and also provide brief descriptions of some of the main forms of MODY and syndromic diabetes, with a focus on diagnosis and treatment.
Definition
Neonatal diabetes mellitus (NDM) was the initial term used to describe the presentation of diabetes within the first few days or weeks of life and was defined further in early reports as severe hyperglycemia occurring in the first month of life, lasting at least 2 weeks, and requiring insulin therapy to control blood glucose. These strict criteria have been progressively loosened as it became evident that the exact age at which the diabetes was diagnosed was more variable, even when an underlying cause, distinct from autoimmune type 1 diabetes mellitus (T1DM), was suspected, such as a genetic cause for pancreatic malformation, faulty insulin synthesis or secretion. Accumulated evidence has suggested an age under 6 months as being a particularly likely indication of NDM, because the majority of cases with an underlying monogenic cause will be diagnosed under 6 months, whereas autoimmune T1DM is highly unlikely during this window. Increasingly, however, it has become recognized that, for reasons that are poorly understood, several of the genetic forms can initially present with diabetes as late as 9 months to 1 year or even later. Indeed, pedigree analyses conclusively demonstrate that the same defect that causes permanent or transient NDM can be present in parents or other first-degree relatives with a phenotype consistent with MODY, but may have been misdiagnosed as T1DM or type 2 diabetes mellitus (T2DM) as subsequently detailed. Herein lies the importance of understanding the genetic basis of NDM, for although these entities are rare, they have taught us much about the genetic pathways involved in the formation of the exocrine and endocrine pancreas. For example, it has been shown that the specific combination of three transcription factors, Ngn3, Pdx1 , and Mafa , known to be implicated in the determination of cell lineage during pancreas formation, can reprogram adult mouse exocrine pancreatic cells into cells that closely resemble pancreatic beta cells. Such information is essential for the ultimate ability to generate beta cells and whole islets as potential therapies for any form of diabetes, including T1DM. Equally important is the demonstration that activating mutations in the pore-forming potassium inward rectifying channel, family 6 subtype2- KCNJ11 gene (Kir6.2) and its regulatory subunit sulfonylurea receptor 1- ABCC8 gene (SUR1) of the K ATP -regulated potassium channel, which keep the channel open and hence limit or preclude insulin secretion resulting in NDM ( Fig. 10.1 ), can be overcome by high-dose sulfonylurea therapy, which restores endogenous insulin secretion in response to feeding. Because of the restoration of endogenous insulin secretion that can be triggered by the incretin effect in response to feeding, this oral treatment provides better metabolic control than multiple daily injections of insulin or insulin pumps and with a better quality of life. Successful transfer to sulfonylureas is best predicted by in vitro response of specific mutation and diabetes duration. These findings emphasize the benefits of research for understanding pathophysiology and choosing appropriate treatment. Indeed, for those whose NDM is caused by mutations in the K ATP channel that respond to sulfonylureas, these treatments border on the miraculous.
Incidence
Early estimates placed the incidence of NDM at approximately one in 500,000, but as increased awareness has led to these entities being recognized more frequently, the reported incidence has risen considerably. In populations with high rates of consanguinity, some studies report an incidence of NDM as high as one in 21,000 births. A large representative database for pediatric diabetes reported that the incidence of NDM represented approximately one case in 89,000 live births in Germany, and a similar incidence occurred in Italy. In three other European countries, the incidence was reported to be one in 260,000 live births only for those with permanent NDM (PNDM) (suggesting a higher incidence if transient forms of NDM [TNDM] were also included). In the SEARCH for Diabetes in Youth Study involving 15,829 subjects aged under 20 years diagnosed with diabetes during the years 2001 to 2008, 39 were diagnosed before the age of 6 months. Among these 39 subjects with onset less than 6 months of age, 35 had permanent neonatal diabetes and an additional three had TNDM, leaving one subject whose status remained unknown. Hence, the total prevalence among children diagnosed with diabetes was approximately 0.246% or approximately 1 in 400. The majority were classified by their primary care providers as having T1DM and treated with insulin; only seven underwent mutational analysis for three of the most common genes ( KCNJ11, ABCC8 , and the insulin gene [ INS] ) and five of these seven had mutations in one of these three genes. The estimated population prevalence of PNDM in those aged less than 20 years in that study was one in 246,000 people.
Clinical presentation
Infants affected with diabetes may have diabetes in isolation, or the underlying genetic defect may also cause a variety of other clinical features ( Fig. 10.2 ). Infants with NDM are more likely to be born small for gestational age, and in many cases there may also have been concern for intrauterine growth retardation (IUGR) during their pregnancy, reflecting the in utero deficiency of insulin and emphasizing the role of insulin as a determinant of fetal growth. Their small size and low birth weight markedly contrasts with the large birth weight and size of infants with inactivating mutations in the same K ATP genes that instead of diabetes lead to hyperinsulinemic hypoglycemia (see Chapters 7 and 23 ). A disproportionate number of those with NDM are born prematurely at less than 37 weeks’ gestation, which in some cases may be associated with induction of the delivery because of their IUGR status. Hyperglycemia leads to osmotic diuresis and avid feeding from breast or bottle despite which the infants often fail to thrive. Delay in diagnosis from not considering the possibility of diabetes mellitus in a newborn may lead to severe dehydration and life-threatening diabetic ketoacidosis (DKA); in fact, a recent retrospective study of a large series of NDM cases in the United States showed that 66% of patients presented in DKA. Rare syndromic forms may have severe congenital malformations, such as intestinal and biliary atresia ( RFX6 ), congenital heart defects ( GATA6 or GATA4 ), or brain malformations ( PTF1A , NEUROD1 , IER3IP1, MNX1, NKX2.2 ), or alternatively may have other features, such as skeletal dysplasia ( EIF2AK3 ) that are difficult to recognize during the neonatal period. In addition to mutations in FOXP3 responsible for the IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked), several additional genes ( STAT1, STAT3 , LRBA , IL2RA ) have now been described to have mutations causing infancy-onset diabetes, along with other autoimmune disorders that result from dysfunction of immune regulation.
Patients with overexpression of genes at chromosome 6q24 present with TNDM and will often have more subtle features, such as macroglossia and umbilical hernia, reminiscent of Beckwith-Wiedemann syndrome. In addition, they rarely may have dysmorphic facies, as well as renal tract anomalies, such as hydronephrosis and vesicoureteral reflux, a variety of cardiac anomalies, hypothyroidism, or hand-finger anomalies. A coarse facial appearance together with epilepsy and later manifestations of developmental delay constitute the developmental delay, epilepsy, neonatal diabetes (DEND) syndrome associated with the most severe mutations of the KCNJ11 gene ; however, in most cases of KCNJ11 or ABCC8 mutations that maintain the K ATP channel in a variable open state and hence limit insulin secretion, there will not be any abnormal findings on physical examination. Even in those with the severe mutations causing significant neurodevelopmental dysfunction, the abnormalities may often not be recognized until patients are older. Clinical manifestations involving organs other than the pancreas may be part of the syndromes of a variety of genetic causes of NDM. These features in patients with NDM were previously incorporated in a retrospective categorization system to describe permanent, transient, and syndromic forms of NDM. However, now that the monogenic basis of NDM has been well established, genetic testing should be done immediately upon diagnosis of diabetes in the neonatal/infancy period, at which time it will be unclear whether the baby has a permanent or transient form of NDM (see Fig. 10.2 ). Furthermore, the extrapancreatic manifestations of genes causing syndromic NDM can be phenotypically quite variable and many of these features will often not be readily apparent during the neonatal period. Expert consensus has therefore shifted toward obtaining comprehensive genetic testing utilizing next-generation sequencing (NGS) panels (or a tiered approach) rather than iterative testing of fewer genes selected based on clinical features.
Transient neonatal diabetes mellitus
TNDM is so named because hyperglycemia resolves spontaneously within the first few months of life and no longer requires treatment, although it may reappear later in life. About 70% of these cases will have TNDM1 (6q24-related TNDM), whereas the majority of the remaining cases of TNDM will be caused by mildly activating mutations in the K ATP genes ABCC8 (SUR1) and KCNJ11 (Kir6.2), and only a small minority will be caused by recessive insulin gene mutations, mutations in the transcription factor HNF1B , or mutations in SLCA2A , the gene encoding the GLUT2 transporter.
6q24-Related Transient Neonatal Diabetes Mellitus (TNDM1)
TNDM1 (or 6q24-related TNDM) is caused by the overexpression of genes at the 6q24 chromosomal locus, including pleomorphic adenoma gene-like 1 ( PLAGL1 ), which is a proapoptotic zinc finger protein, and (hydatidiform mole-associated and imprinted transcript ( HYMAI ), encoding an untranslated messenger ribonucleic acid (mRNA). TNDM1 arises as a result of uniparental paternal disomy of the entire—or only a segment that includes 6q24—chromosome 6 (UPD6), a paternally inherited duplication of chromosome 6q24, or relaxation of imprinting of the maternally methylated genes on chromosome 6 ( Fig. 10.3 ). It is important to emphasize that these chromosomal changes cause altered expression of genes, rather than representing mutations. For example, PLAGL1 ( ZAC ) has antiproliferative properties and is thought to function as a tumor growth suppressor expressed only on the paternal allele ; overexpression in fetal life is believed to lead to underdevelopment of the pancreas. Although the precise mechanisms by which overexpression of PLAGL1 lead to TNDM1 are not known, overexpression of ZAC in a clonal pancreatic beta cell line impairs glucose-stimulated insulin translation and secretion. A transgenic mouse model expressing the human TNDM1 locus (6q24) is characterized by impaired glucose homeostasis with hyperglycemia in the neonatal period and impaired glucose tolerance with reduced insulin responses to intravenous (IV) glucose as adults. The pancreata of these animals display reduced expression of endocrine differentiation factors, notably PDX1, NGN3, and PAX6. There is also a reduction in the number of insulin staining cells and reduced insulin content or insulin secretion despite normal or elevated beta cell mass at all postnatal periods. Thus this model recapitulates TNDM1 and suggests that altered expression of ZAC/HYMAI cause impaired development of the endocrine pancreas, as well as impaired beta cell function. This mouse model also demonstrates resolution of abnormal insulin secretion with restoration of normal glucose tolerance during the “juvenile” phase of mouse development between 1.5 and 2 months of life, during which there is an approximate doubling of beta cell number that compensates for the reduced insulin synthesis and secretion of each cell. Also as in humans, the compensatory increase in beta cell mass is not sustained, resulting in a mild diabetes mellitus characterized by normal fasting glucose but hyperglycemia after glucose challenge. Overall, despite the recapitulation of the key features of the human disease, the mouse model displays milder features. One possible reason for this milder phenotype in mice is that pancreatic expression of the mouse ortholog Zac1 declines drastically during gestation and early postnatal growth in mice, whereas expression of the ZAC gene in human pancreas declines between the second trimester and adult life. More important, ZAC was specifically expressed only in the islets of the human fetus, whereas Zac1 was predominantly expressed in mesenchyme of the mouse embryo, which may explain the milder features in the mouse model of TNDM1.
In patients with TNDM1 resulting from hypomethylation of the maternal differentially methylated region (DMR) of chromosome 6q24, there may be hypomethylation of other maternally imprinted loci (HIL) throughout the genome. In cases displaying a more generalized HIL, the majority have a mutation in the transcription factor zinc finger protein 57 ( ZFP57 ). HIL also occurs in Beckwith-Wiedemann syndrome and this likely explains the macroglossia, umbilical hernia, and several congenital abnormalities described in TNDM1. In a large multinational cohort involving 163 patients with TNDM1, the authors describe IUGR with a mean birth weight of 2001 ± 417 g (mean ± standard deviation) and adjusted Z score for birth weight of − 2.5. The mean age of presentation was 8 ± 12 days with a median of 4 days and a mode of 1 day. Mean gestation was 37.8 ± 2.4 weeks and prematurity was significantly more common than in the general population. Remission occurred at a mean age of 4.5 ± 5.8 months with a median at 3 months. Age at presentation was positively correlated to gestational age, but age at remission was negatively correlated with adjusted birth weight. Thus the higher the birth weight, the earlier the remission and vice versa. This would be consistent with the effects of insulin on intrauterine growth, so that the larger infants would have the milder defect and therefore tend to enter remission sooner. Congenital anomalies were significantly more frequent in patients with UPD6 or HIL. Hypomethylation defects were overrepresented in patients born after assisted conception. Thus babies with TNDM1 generally present with diabetes mellitus within the first days of life, are small, and may have been born prematurely. The presence of one or more congenital anomalies suggests UPD or multiple HIL, and among the latter, almost one in seven had been conceived with assisted reproductive techniques. Macroglossia is present in about 50%, umbilical hernia in about 25%, and facial dysmorphism in about 20%. Cardiac and renal anomalies (~ 9%), hand abnormalities (~ 8%), and hypothyroidism (~ 4%) also may be present. Remission, when it occurs, is usually around 3 months and about half of these patients will revert to varying degrees of hyperglycemia in the teen years or later. An unusual manifestation following remission of diabetes in patients with 6q24 methylation defects is hypoglycemia with hyperinsulinemia, most often when the cause is UPD6. Modern molecular techniques permit diagnosis to be established which then influences treatment; however, many commercial sequencing panels for monogenic diabetes do not include testing that will reveal overexpression of genes at 6q24 as a cause of diabetes.
Patients with TNDM1 are sensitive to insulin and respond with excellent catch-up growth within several weeks of treatment. Progressive reduction of the insulin dose required to control blood glucose while avoiding hypoglycemia heralds the onset of remission. Although these patients do well with insulin treatment, some reports suggest a variable response to oral sulfonylurea treatment; though it is difficult to discern the extent to which the clinical improvement was caused by medical treatment versus spontaneous resolution of the condition in these observational studies. Of note, rare cases with 6q24-related TNDM will develop significant hypoglycemia within weeks or months after the remission of hyperglycemia. Most had evidence for hyperinsulinism as the cause of hypoglycemia and responded well to diazoxide treatment that was still required after several years in some cases. Even after resolution of diabetes during infancy, it is important that these patients understand that diabetes is highly likely to recur around the time of adolescence. Although a few papers report good response to other drugs besides insulin, the best approach to monitoring during remission, as well as to treatment after recurrence, remain uncertain. Because many questions remain about this condition, it is important that such cases be referred to research centers tracking long-term outcome, even if the diabetes has gone into remission.
K ATP Channel-Related Transient Neonatal Diabetes Mellitus (TNDM2)
TNDM2 is one classification given to diabetes that remits during infancy and may recur later in life but is caused by mutations in genes regulating insulin secretion rather than expression of imprinted genes. The majority of these entities are caused by activating mutations in the K ATP channel genes ABCC8 and KCNJ11 , which, respectively, code for the SUR 1 and Kir6.2 subunits of the K ATP channel (see Fig. 10.1 ). Recessive loss-of-function mutations in the INS itself may occasionally be responsible for TNDM2 ; the autosomal dominant insulin gene mutations are associated with PNDM. There are rare reports of HNF1B and SLC2A2 mutations also associated with TNDM.
The normal state of the K ATP channel is to remain open, setting the resting membrane potential of the beta cell. Insulin secretion occurs when the channel closes in response to an increase in adenosine triphosphate (ATP) generated from the metabolism of glucose or amino acids, thereby changing the ATP:adenosine diphosphate (ADP) ratio. Closure of the channel with intracellular retention of K + causes depolarization of the plasma membrane, opening of voltage-gated calcium channels, influx of calcium, and secretion of insulin. Activating mutations in ABCC8 or KCNJ11 alter the ability of the channel to respond to the change in the ATP:ADP, so that the channel remains open to some extent, efflux of K + from the beta cell continues, permitting the cell membrane to remain hyperpolarized and therefore resulting in various degrees of impaired insulin secretion. These same mechanisms are also responsible for the most common form of PNDM, as subsequently discussed. It remains unclear how or why remission occurs, but it has been shown in vitro that mutations causing TNDM have a less pronounced effect on channel function compared with mutations that cause PNDM. The ability of ATP to close the channel in vitro correlates with the severity of NDM, including the severe permanent form associated with the DEND syndrome, which demonstrates the greatest resistance to closure by ATP in vitro. Both resistance to closure caused by activating mutations, or resistance to opening of the channel because of inactivating mutations, segregate with certain mutations as illustrated in Fig. 10.4 . As shown in the figure, near the fulcrum of this spectrum, those with minor defects may be prone to either develop milder type 2 diabetes or may be resistant to the development of diabetes by virtue of enhanced insulin secretion (see Fig. 10.4 ).
In comparison with TNDM1, patients with TNDM2 generally have greater birth weight, present or are diagnosed with diabetes mellitus later, remit later, and recur earlier ( Table 10.1 ). Family members of patients with these forms of TNDM2 may have diabetes that was diagnosed in adulthood and was considered to be T1DM, T2DM, or MODY and yet harbor the same heterozygous mutations as the proband with NDM. This reflects the variable penetrance of these genes or upstream factors that may modify the expression of the gene in different individuals. Confirming the presence of an ABCC8 or KCNJ11 mutation in a case of NDM is important for management because most of these K ATP channel mutations respond to sulfonylurea treatment both at the time of initial diagnosis or later at the time of relapse. During their remission phase, these patients do not require therapy.
Table 10.1
Comparison of Clinical Characteristics of Patients With K ATP Channel Mutations to Patients With 6q24 TNDM (data given in median [range])
Modified from Flanagan SE, Patch AM, Mackay DJ, et al. Mutations in ATP-Sensitive K+ Channel Genes Cause Transient Neonatal Diabetes and Permanent Diabetes in Childhood or Adulthood. Diabetes Jul 2007, 56 (7) 1930–1937; Table 2. https://doi.org/10.2337/db07-0043 . Retrieved from: https://diabetes.diabetesjournals.org/content/56/7/1930.long .
| Characteristic (median) | ABCC8 / KCNJ11 (n = 25) | 6q24 * (n = 23) | P-Value |
|---|---|---|---|
| Age at diagnosis (weeks) | 4 (0–16) | 0 (0–4) | < .001 |
| Age at remission (weeks) | 35 (2–208) | 13 (5–60) | < .001 |
| Age at relapse (years) | 4.7 (3–15) | 16 (4–25) | .073 |
| Birth weight (g) | 2570 (1360–3570) | 1950 (1600–2670) | < .001 |
| Percentile birth weight | 12 (< 1st–89th) | < 1st (< 1st–21st) | < .001 |
* Data previously reported (Temple IK, Gardner RJ, Mackay DJ, Barber JC, Robinson DO, Shield JP: Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes. Diabetes 49: 1359–1366, 2000). Differences between groups were calculated using Mann-Whitney U and χ2 tests. Centile birth weights were calculated according to U.K. growth charts (Cole TJ, Freeman JV, Preece MA: British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Stat Med 17: 407–429, 1998) because the majority of patients were of U.K. white origin.
Recessive loss of function mutation in the INS gene has been reported in rare patients with TNDM. These patients appear to enter remission at a median age of 12 weeks and insulin was required before remission and after later relapse that was reported in some cases.
Patients with mutations in the transcription factor hepatocyte nuclear factor 1 beta ( HNF1B ) are known to have diabetes associated with renal cysts with onset at a median of 20 years. However, two reported patients had neonatal diabetes: one was diagnosed at age 15 days and required insulin, initially intermittently and then permanently; a second patient diagnosed at the age of 17 days had remission 2 weeks after diagnosis but relapsed at the age of 8 years. There have also been a few reported cases of mutations in SLC2A2 , which encodes the glucose transporter type 2 (GLUT2). Recessive inactivating mutations in this gene cause Fanconi-Bickel syndrome, characterized by glucosuria, galactosuria, aminoaciduria, proteinuria, and phosphaturia, as well as rickets, poor growth, and short stature with associated glucose and galactose intolerance and enlarged livers. Transient neonatal diabetes has been reported in these patients to occur in association with the classic Fanconi-Bickel syndrome.
Permanent neonatal diabetes mellitus
The majority of genes that cause NDM result in PNDM without any significant treatment remission. Approximately 80% to 85% of infants with diabetes diagnosed before 6 months of age will have an underlying monogenic cause that can be identified, and the remainder may carry as-yet uncharacterized defects. Although diabetes resulting from monogenic causes can also be diagnosed between 6 and 12 months of age or later, and genetic testing can be considered, the majority of diabetes cases in this age range will have autoimmune diabetes (T1D) that can be suggested by positive anti-beta cell autoantibody testing or type 1 diabetes genetic risk scores (routinely done in most NDM research centers). Except in certain populations with higher frequency of consanguineous births, the vast majority of PNDM is caused by mutations in three genes: the two K ATP channel genes KCNJ11 coding for the pore-forming protein Kir6.2 (50%) and ABCC8 coding for SUR1 (together account for 40%–45% of cases; see Figs. 10.1 and 10.2 ), and mutations in the gene encoding insulin itself ( INS ). Dominant mutations in GATA6 or GATA4 causing pancreatic hypoplasia are rarer than other dominant causes, as are X-linked mutations in FOXP3 causing the IPEX syndrome, or milder IPEX-like syndromes, whereas the remaining gene causes of PNDM are very rare recessive disorders that often include a variety of extrapancreatic syndromic features (see Fig. 10.2 ).
K ATP Mutations: KCNJ11 and ABCC8
Until the discovery of the genes responsible for the K ATP channel, patients with PNDM were considered to have insulin-dependent diabetes mellitus; now it is known that the majority of patients with K ATP mutations causing PNDM respond to oral therapy with sulfonylurea. Early genetic testing is imperative because those who are responsive to sulfonylurea treatment and have earlier initiation of treatment have been reported to have improved response to therapy and may help improve quality of life. Typically treated with high-dose sulfonylureas, a cohort with this treatment has shown mild and infrequent hypoglycemia. Patients with PNDM caused by mutations in the K ATP genes or the insulin gene usually present at 2 to 3 months of life, and sometimes later, and may be in severe DKA by the time of the diagnosis. Activating mutations in the Kir6.2 subunit of the K ATP channel were first reported in 2004, being found in 10 out of 29 subjects with PNDM. Whereas the insulin secretory response to IV glucagon and glucose was minimal, there was a better response to oral glucose. Patients did respond with insulin secretion to IV tolbutamide, clearly hinting at possible therapy by the administration of sulfonylurea and confirmed by a landmark study published 2 years later. Expression of the mutated Kir6.2 subunit together with a normal SUR1 subunit in Xenopus laevis oocytes revealed that the ability to enable channel closure by ATP was greatly impaired. This provided a means to correlate the degree of in vitro abnormality with the clinical severity of the diabetes. The affected patients predominantly had de novo mutations, with only 20% of the mutations inherited from a parent. It was also noted that 4 of 10 of the patients had severe developmental delay, muscle weakness, and epilepsy, as well as dysmorphic facial features, which was termed the DEND syndrome . The degree of muscle weakness was partially ameliorated by treatment with sulfonylurea, raising the possibility that the developmental delay and epilepsy may also be ameliorated, or perhaps prevented, by early recognition and treatment with sulfonylurea. Subsequently, it was demonstrated in mice that transgenic expression of an activating mutation in Kir6.2 in mouse pancreatic beta cells recapitulates neonatal diabetes and that the muscle dysfunction caused by a human K ATP channel mutation is neuronal and not muscular in origin. K ATP channels exist in other tissues and are known to modulate electric activity and neurotransmitter release at brain synapses in various regions of the brain. Moreover, K ATP channels in the ventromedial hypothalamic nucleus may be involved in the counterregulatory response to hypoglycemia ; in the arcuate nucleus neurons, K ATP channels may be involved in appetite regulation.
A spectrum of clinical disturbances occurs with different mutations ranging from the DEND syndrome, to relapsing diabetes, permanent diabetes appearing initially in childhood or later in adults. Mutations in adjacent locations may cause either neonatal diabetes or hyperinsulinism because they increase or decrease the open state of the channel. Likewise, mutations in the ABCC8 gene encoding SUR1 cause transient or permanent NDM, or permanent diabetes diagnosed beyond the newborn period in children, or in adults, and mutations at a similar site in the gene can result in either hyperinsulinism or neonatal diabetes.
Initial reports noted certain mutations (such as KCNJ11 V59M) are characterized by significant global developmental delay (often termed intermediate DEND syndrome , or iDEND ) in about 20% of cases, and anecdotal reports suggested improvement of neurological symptoms of weakness, dyscoordination, and visuomotor impairment after treatment with sulfonylureas (replacing insulin) was initiated. Several groups have since undertaken careful characterizations of large groups of patients using standardized measures that reveal a wide range of dysfunction, including behavioral difficulties and attention deficit hyperactivity disorder symptoms or diagnosis, lower educational attainment, and difficulties with executive functioning. In one study of 14 patients with mutations previously thought to cause diabetes in isolation, who did not have global developmental delay, IQ was found to be close to normal (91.1 ± 11.3) but significantly lower than 20 sibling controls (111.0 ± 8.3). Raising the importance of early proper diagnosis and treatment of these conditions, another study revealed better performance on a standardized measure of visuomotor functioning by the three patients who had been started on sulfonylurea treatment under a year, among eight patients with of V59M mutations in KCNJ11.
The safety and tolerability of high-dose sulfonylurea treatment, as well as its durability over more than 10 years of treatment, has also been reported in a few recent studies. A survey of 30 patients over a total of 166 patient years revealed no episodes of severe hypoglycemia, whereas mild to moderate hypoglycemia was unrelated to sulfonylurea dose. A recent follow-up study on 81 patients from a European cohort started on sulfonylureas before 2006 showed no episodes of severe hypoglycemia over 809 patient-years, with sustained excellent glycemic control on stable doses with infrequent mild side effects.
Insulin Gene Mutations
Insulin gene mutations as a cause of PNDM were first reported in 2007 and are now known to be the second most common mutations responsible for these entities. Inheritance was autosomal dominant in the familial cases, but the majority had de novo mutations. The mutations occurred in a critical region of the preproinsulin molecule, predicting misfolding and hence loss of normal trafficking of the proinsulin in the insulin secretory pathway. This misfolding was also proposed to induce the unfolded protein response, with degradation in the endoplasmic reticulum (ER), leading to severe ER stress and apoptosis of the beta cells, processes known to occur in mouse models of dominant insulin gene mutations. Clinically, the age at diagnosis averaged 13 weeks compared with 5 weeks for KCNJ11 and 7 weeks for ABCC8 mutations. With a normal range of gestational ages of 36 to 41 weeks, mean birth weight was also normal at 2846 g. Thus these abnormalities appear to disturb intrauterine growth less than in 6q24 TNDM or those with K ATP channel mutations. These dominant or de novo mutations are not usually associated with TNDM or remission, whereas recessive mutations of the insulin gene can result in a remitting type of NDM as described earlier. The initial suggestion of ER stress as a mechanism has been largely confirmed and the spectrum of disorders in the insulin gene extends to a MODY phenotype or onset in adulthood. Treatment of these patients is currently limited to insulin, whereby they can be managed very similarly to a patient with autoimmune T1DM. A few case series have demonstrated the effectiveness of insulin pumps and continuous glucose monitors in achieving good glycemic control as early as the neonatal period following diabetes diagnosis. One case study of two sisters suggested the theoretical benefit of early optimization of glycemic control to minimize the need for endogenous beta cells to respond to hyperglycemic excursions by producing mutated insulin that is toxic to beta cells. Limiting the toxic effects of protein production appeared to promote improved cell survival that might allow for at least low level production of insulin via the normal allele.
Other Genetic Forms of Permanent Neonatal Diabetes Mellitus
Two genes that cause MODY, the enzymatic metabolic gatekeeper glucokinase ( GCK ), and the islet formation transcription factor PDX1 (previously called IPF-1 ), cause monogenic forms of diabetes, respectively, known as MODY2 and MODY4 , when in the heterozygous state and can more rarely cause PNDM when in the homozygous or compound heterozygous state.
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