PNDM
PDMI diabetes mellitus, permanent neonatal, with neurologic features, included
developmental delay, epilepsy, and neonatal diabetes, included
DEND, included
Diabetes mellitus, permanent, of infancy
Permanent neonatal diabetes mellitus (PNDM) is characterised by the early onset of persistent hyperglycemia requiring lifelong treatment All cases of PNDM result from mutations affecting genes regulating pancreatic development, β‐cell function, apoptosis or the insulin molecule as such. Approximately half the cases of PNDM in the Caucasian population have been shown to involve defects in the genes transcribing the 2 subunits of K+ ATP channel Kir6.2 and SUR1, which regulate insulin release from the β‐cell. These subunit proteins are transcribed by KCNJ11 and ABCC8 genes respectively. Other genes implicated in PNDM include PTF‐1α, IPF‐1 (Pdx‐1), EIF‐2AK3, Glucokinase, FOXP3, insulin and GLIS3 (PMID:23869298).
Neonatal diabetes mellitus (NDM), defined as insulin-requiring hyperglycemia within the first 3 months of life, is a rare entity, with an estimated incidence of 1 in 400,000 neonates (Shield, 2000). In about half of the neonates, diabetes is ... Neonatal diabetes mellitus (NDM), defined as insulin-requiring hyperglycemia within the first 3 months of life, is a rare entity, with an estimated incidence of 1 in 400,000 neonates (Shield, 2000). In about half of the neonates, diabetes is transient (see 601410) and resolves at a median age of 3 months, whereas the rest have a permanent insulin-dependent form of diabetes (PNDM). In a significant number of patients with transient neonatal diabetes mellitus, type II diabetes (see 125853) appears later in life (Arthur et al., 1997). PNDM is distinct from childhood-onset autoimmune diabetes mellitus type I (IDDM; 222100). Massa et al. (2005) noted that the diagnostic time limit for PNDM has changed over the years, ranging from onset within 30 days of birth to 3 months of age. However, as patients with the clinical phenotype caused by mutation in the KCNJ11 gene have been identified with onset up to 6 months of age, Massa et al. (2005) suggested that the term 'permanent diabetes mellitus of infancy' (PDMI) replace PNDM as a more accurate description, and include those who present up to 6 months of age. The authors suggested that the new acronym be linked to the gene product (e.g., GCK-PDMI, KCNJ11-PDMI) to avoid confusion with patients with early-onset, autoimmune type I diabetes. Colombo et al. (2008) proposed that, because individuals with INS gene mutations may present with diabetes well beyond 6 months of age and cannot be distinguished from patients with type 1 diabetes except for the absence of type 1 diabetes autoantibodies, the term PNDM should be replaced with 'monogenic diabetes of infancy (MDI),' a broad definition including any form of diabetes, permanent or transient, with onset during the first years of life and caused by a single gene defect.
Permanent diabetes of infancy is primarily characterized by onset of hyperglycemia within the first 6 months of life. Among 12 patients with PNDI, Gloyn et al. (2004) reported a mean age of 7 weeks at diagnosis (range birth ... Permanent diabetes of infancy is primarily characterized by onset of hyperglycemia within the first 6 months of life. Among 12 patients with PNDI, Gloyn et al. (2004) reported a mean age of 7 weeks at diagnosis (range birth to 26 weeks). All affected patients had hyperglycemia (270 to 972 mg/dl), and 3 had ketoacidosis. None of the patients had pancreatic autoantibodies associated with IDDM. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. All patients had low birth weight. Three of 12 patients had similar neurologic abnormalities, including developmental delay, muscle weakness, and epilepsy. All 3 patients with neurologic abnormalities had dysmorphic features, including prominent metopic suture, a downturned mouth, bilateral ptosis, and limb contractures. Gloyn et al. (2006) reported 4 unrelated patients with developmental delay, epilepsy, and neonatal diabetes (DEND) associated with mutations in the KCNJ11 gene. All had infantile-onset of diabetes without pancreatic autoantibodies (diagnosed from day 1 of life to 3 months) with hyperglycemia, polydipsia, polyuria, and ketoacidosis in some. The most severely affected child had seizures with hypsarrhythmia, neurologic deterioration with social withdrawal, and mild dysmorphic features, including prominent metopic suture, downturned mouth, and bilateral ptosis. She died from aspiration pneumonia at age 6 months; genetic analysis revealed a novel mutation in the KCNJ11 gene (C166F; 600937.0015). Two other patients had developmental delay and axial hypotonia, but only 1 of these also had dysmorphic features and seizures. The fourth child, who had no dysmorphic or neurologic features, had a diabetic mother who also had no neurologic involvement. Gloyn et al. (2006) noted the phenotypic variability between patients, even between those with the same mutation.
Njolstad et al. (2001) described 2 patients in whom complete deficiency of glucokinase caused permanent neonatal-onset diabetes mellitus. Both patients showed total absence of basal insulin release, and both had homozygous missense ... - Mutation in GCK Njolstad et al. (2001) described 2 patients in whom complete deficiency of glucokinase caused permanent neonatal-onset diabetes mellitus. Both patients showed total absence of basal insulin release, and both had homozygous missense mutations in the GCK gene (138079.0010 and 138079.0011). Gloyn et al. (2002) concluded that complete glucokinase deficiency is not a common cause of permanent neonatal diabetes. - Mutation in KCNJ11 In 10 of 29 patients with permanent neonatal diabetes, Gloyn et al. (2004) identified 6 novel, heterozygous missense mutations in the KCNJ11 gene (see, e.g., 600937.0002-600937.0003). In 2 patients the diabetes was familial, and in 8 it arose from a spontaneous mutation. In 4 of the 10 families, the mutation was an arg201-to-his substitution (R201H; 600937.0002). When the most common mutation, R201H, was coexpressed with SUR in Xenopus oocytes, the ability of ATP to block mutant ATP-sensitive potassium channels was greatly reduced. Edghill et al. (2007) noted that the majority of KCNJ11 mutations resulting in neonatal diabetes mellitus occur de novo. They found that germline mosaicism was indicated by pedigree analysis in 2 of 18 families in which neither parent was affected and in 1 of 12 additional parents tested for somatic mosaicism. Edghill et al. (2007) concluded that de novo KCNJ11 mutations can arise during gametogenesis or embryogenesis, thus increasing the risk of neonatal diabetes for subsequent sibs. Mannikko et al. (2010) reported 2 novel mutations on the same haplotype (cis), F60Y (600937.0023) and V64L, in the slide helix of Kir6.2 (KCNJ11) in a patient with neonatal diabetes, developmental delay, and epilepsy. Functional analysis revealed that the F60Y mutation increased the intrinsic channel open probability, thereby indirectly producing a marked decrease in channel inhibition by ATP and an increase in whole-cell potassium-ATP currents. When expressed alone, the V64L mutation caused a small reduction in apparent ATP inhibition, by enhancing the ability of MgATP to stimulate channel activity. The V64L mutation also ameliorated the deleterious effects on the F60Y mutation when it was expressed on the same, but not a different, subunit. The authors concluded that F60Y is the pathogenic mutation and that interactions between slide helix residues may influence KATP channel gating. - Mutation in ABCC8 In a 27-year-old man who had permanent neonatal diabetes, severe developmental delay, and generalized epileptiform activity on EEG, Proks et al. (2006) identified heterozygosity for a de novo missense mutation (F132L; 600509.0016) in the ABCC8 gene. Functional studies showed that F132L markedly reduced the sensitivity of the K(ATP) channel to inhibition by MgATP, thereby increasing the whole-cell K(ATP) current; the authors noted that the functional consequence of the F132L mutation mirrors that of KCNJ11 mutations causing neonatal diabetes. From a group of 73 patients with neonatal diabetes, Babenko et al. (2006) screened the ABCC8 gene in 34 who did not have alterations in chromosome 6q or mutations in the KCNJ11 or GCK genes. In 2 PNDM patients, they identified heterozygosity for a mutation (600509.0017 and 600509.0018, respectively). They also identified heterozygosity for 5 different mutations (see, e.g., 600509.0019 and 600509.0020) in 7 patients with transient neonatal diabetes (TNDM2; 610374). Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had markedly higher activity than did wildtype channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia. The mutation-positive fathers of 5 of the probands with transient neonatal diabetes developed type II diabetes mellitus (125853) in adulthood; Babenko et al. (2006) proposed that mutations of the ABCC8 gene may give rise to a monogenic form of type II diabetes with variable expression and age at onset. The authors noted that dominant mutations in ABCC8 accounted for 12% of cases of neonatal diabetes in the study group. - Mutation in INS In affected members of a 3-generation family with autosomal dominant neonatal diabetes, who did not have mutations in the KCNJ11 and ABCC8 genes, Stoy et al. (2007) identified heterozygosity for a missense mutation in the INS gene (176730.0008). The authors then sequenced the INS gene in 83 probands with PNDM without a known genetic cause and identified 9 additional heterozygous missense mutations in the INS gene in 15 families (see, e.g., 176730.0009-176730.0011). PNDM patients with mutations in the INS gene presented at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, did not have beta-cell autoantibodies, and were treated from diagnosis with insulin. C-peptide values where measured were very low or undetectable, with all values less than 200 pmol/liter. Edghill et al. (2008) screened the INS gene in a series of 1,044 patients with permanent diabetes diagnosed during infancy, childhood, and adulthood and identified 16 different heterozygous INS mutations in 35 PNDM probands (see, e.g., 176730.0010-176730.0013), 12 of whom had been previously reported by Stoy et al. (2007). The median age at diagnosis for the INS mutation carriers was 11 weeks, and they presented with either symptomatic hyperglycemia (41%) or diabetic ketoacidosis (59%). All patients were treated with insulin replacement therapy. Autoantibodies, when measured, were not detected. Birth weights were reduced (median, 2.7 kg, corresponding to the sixth percentile), consistent with in utero growth retardation due to reduced insulin secretion. Polak et al. (2008) analyzed the INS gene in 38 patients with PNDM and 1 with nonautoimmune early-infancy diabetes who were negative for mutations in the GCK, KCNJ11, and ABCC8 genes, and identified heterozygosity for 3 different missense mutations in critical regions of the preproinsulin molecule (see 176730.0010-176730.0012) in 4 probands with marked variability in age of diagnosis and disease progression. The authors stated that in their cohort, INS mutations represented approximately 10% of all PNDM cases, and patients with INS mutations had a later presentation of diabetes and no associated symptoms, compared to patients with K(ATP) channel mutations. In 9 probands with PNDM who were known to be negative for mutations in the KCNJ11 gene (600937), Colombo et al. (2008) identified heterozygosity for 7 different mutations in the INS gene (see, e.g., 176730.0010). Expression of the mutant proinsulins in HEK93 cells demonstrated defects in insulin protein folding and secretion. The authors noted that 9 of 11 patients studied showed near-normal weight at birth, a finding clearly different from the low birth weight in patients with KCNJ11 mutations; they suggested that the beta-cell insufficiency in patients with INS mutations may occur primarily after birth, and noted that the observed postpartum decline in C-peptide was consistent with the hypothesis that a postnatal failure to maintain beta-cell mass due to proteotoxic proinsulin misfolding is a primary cause of PNDM in these patients. - Heterogeneity Of 31 Japanese patients with NDM, including 15 with PNDM and 16 with transient NDM (TNDM), Suzuki et al. (2007) identified a 6q24 abnormality (see 601410) in 11, a KCNJ11 mutation in 9, and an ABCC8 mutation in 2. Seven patients with a KCNJ11 mutation, including 2 with DEND and the 2 with an ABCC8 mutation, had PNDM. All of the patients with the 6q24 abnormality and 2 patients with a KCNJ11 mutation had TNDM. Suzuki et al. (2007) concluded that the 6q abnormality and KCNJ11 mutations are major causes of NDM in Japanese.
Permanent neonatal diabetes mellitus (PNDM) is defined as diabetes mellitus diagnosed in the first six months of life that does not resolve over time....
DiagnosisClinical DiagnosisPermanent neonatal diabetes mellitus (PNDM) is defined as diabetes mellitus diagnosed in the first six months of life that does not resolve over time.TestingLaboratory testing. Diagnosis of PNDM is based on evidence of persistent hyperglycemia (plasma glucose concentration >150-200 mg/dL) in infants younger than age six months. Other typical laboratory findings of diabetes mellitus (e.g., glucosuria, ketonuria, hyperketonemia) may be present.Pancreatic imaging. Imaging of the pancreas with ultrasound or CT is used to determine its presence and size. Molecular Genetic TestingGenes. The five genes in which mutations are currently known to cause nonsyndromic permanent neonatal diabetes are KCNJ11, ABCC8, INS, GCK, and PDX1.KCNJ11. Approximately 30% of PNDM is attributed to activating mutations of KCNJ11, the gene encoding one of the two components of the beta-cell plasma membrane ATP-dependent potassium channel [Ellard et al 2007]. ABCC8. Approximately 19% of PNDM is attributed to activating mutations of ABCC8, the gene encoding the second of the two components of the beta-cell plasma membrane ATP-dependent potassium channel [Babenko et al 2006]. INS. Approximately 20% of PNDM is attributed to mutations in INS, the gene encoding insulin [Støy et al 2007, Polak et al 2008]. GCK. Rarely, PNDM is attributed to inactivating mutations of GCK, the gene encoding glucokinase (hexokinase IV) [Njolstad et al 2001, Njolstad et al 2003]. Carrier parents have mild diabetes mellitus or glucose intolerance (GCK-familial monogenic diabetes, previously known as MODY2). PDX1. Rarely, PNDM is attributed to inactivating mutations of PDX1 [Stoffers et al 1997a]. Carrier parents have mild, adult-onset diabetes mellitus (PDX1-familial monogenic diabetes, previously known as MODY4). Note: Rare syndromic forms of neonatal diabetes can be caused by mutations in FOXP3, PTF1A, GLIS3, NEUROD1, RFX6, NEUROG3, and EIF2AK3 (see Differential Diagnosis).Clinical testing Sequence analysis of coding regions of the following genes: KCNJ11, ABCC8, GCK, INS, and PDX1Deletion/duplication analysis. The usefulness of deletion/duplication analysis has not been demonstrated, as no deletions or duplications involving ABCC8 or GCK as causative of permanent neonatal diabetes mellitus have been reported. Table 1. Summary of Molecular Genetic Testing Used in Permanent Neonatal Diabetes MellitusView in own windowGene SymbolEstimated Proportion of PNDM Attributed to Mutations in This GeneTest MethodMutations DetectedTest AvailabilityKCNJ11 30% 1Sequence analysis Sequence variants 2ClinicalABCC8 19% 3Sequence analysisSequence variants 2ClinicalDeletion / duplication analysis 4Exonic and whole-gene deletionsINS 20% 5Sequence analysisSequence variants 2ClinicalGCK 4% 6Sequence analysisSequence variants 2ClinicalDeletion / duplication analysis 4Exonic and whole-gene deletionsPDX1 7 Sequence analysisSequence variants 2Clinical1. Approximately 30% of PNDM is attributed to activating mutations of KCNJ11, the gene encoding one of the two components of the beta-cell plasma membrane ATP-dependent potassium channel [Ellard et al 2007]. 2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Approximately 19% of PNDM is attributed to activating mutations of ABCC8, the gene encoding the second of the two components of the beta-cell plasma membrane ATP-dependent potassium channel [Babenko et al 2006]. 4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment.5. Approximately 20% of PNDM is attributed to mutations in INS, the gene encoding insulin [Støy et al 2007, Polak et al 2008]. 6. Rarely, PNDM is attributed to inactivating mutations of GCK, the gene encoding glucokinase (hexokinase IV) [Njolstad et al 2001, Njolstad et al 2003]. Carrier parents have mild diabetes mellitus or glucose intolerance (GCK-familial monogenic diabetes, previously known as MODY2). 7. Rarely, PNDM is attributed to inactivating mutations of PDX1 [Stoffers et al 1997a]. Carrier parents have mild, adult-onset diabetes mellitus (PDX1-familial monogenic diabetes, previously known as MODY4). Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a proband Individuals with one parent with diabetes mellitus should first be tested for mutations in KCNJ11 and then ABCC8 and INS because heterozygotes can manifest diabetes mellitus. Individuals with neurologic findings suggestive of developmental delay, epilepsy, and neonatal diabetes mellitus (DEND) syndrome should first be tested for mutations in KCNJ11. Individuals whose parents both have diabetes mellitus should first be tested for mutations in GCK and PDX1, as individuals heterozygous for a mutation in these genes can have mild diabetes mellitus (GCK-familial monogenic diabetes and PDX1-familial monogenic diabetes, respectively) with onset in adolescence or early adulthood. Individuals with pancreatic insufficiency or agenesis should be tested for mutations in PDX1. For individuals with syndromic PNDM, the extrapancreatic characteristics should guide genetic testing. Individuals with PNDM and: Enteropathy and dermatitis should be tested for mutations in FOXP3 (IPEX syndrome); Cerebellar involvement should be tested for mutations in PTF1A; Congenital hypothyroidism should be tested for mutations in GLIS3; Cerebellar hypoplasia, sensorineural deafness, and visual impairment should be tested for mutations in NEUROD1;Pancreatic hypoplasia, intestinal atresia, and gall bladder hypoplasia should be tested for mutations in RFX6;Congenital malabsorptive diarrhea should be tested for mutations in NEUROG3.Molecular genetic testing to diagnose individuals with PNDM or transient neonatal diabetes mellitus (TNDM) as a result of mutations of KCNJ11 and ABCC8 can guide treatment as individuals with these mutations may respond to therapy with oral sulfonylureas. Oral sulfonylureas are associated with fewer episodes of hypoglycemia than traditional treatment with insulin and may, in addition to treating the diabetes, improve neurologic manifestations if present [Hattersley et al 2006, Pearson et al 2006, Slingerland et al 2006] (see Management). Molecular genetic testing to diagnose individuals with mutations of GCK, INS, and PDX1 can be used to confirm the diagnosis of NDM and for prognostication regarding need for treatment and risk for exocrine pancreatic insufficiency. For autosomal recessive PNDM,* carrier testing for relatives at risk of being carriers (i.e., heterozygous for a mutation that is not disease-causing) requires prior identification of the disease-causing mutations in the family. *The mode of inheritance of PNDM is autosomal recessive for mutations in GCK and PDX1 and can be either autosomal dominant or autosomal recessive for mutations in ABCC8 and INS.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies requires prior identification of the disease-causing mutation(s) in the family. Genetically Related (Allelic) DisordersKCNJ11, ABCC8, and GCK. Mutations in KCNJ11, ABCC8, and GCK are known to be associated with familial hyperinsulinism (FHI). FHI is characterized by hypoglycemia that ranges from severe difficult-to-manage neonatal-onset disease to childhood-onset disease with mild symptoms and difficult-to-diagnose hypoglycemia. Neonatal-onset disease manifests within hours to one to two days after birth; childhood-onset disease manifests during the first months or years of life. FHI-KATP, caused by mutations in either KCNJ11 or ABCC8, is most commonly inherited in an autosomal recessive manner and less commonly in an autosomal dominant manner.Infants with autosomal recessive FHI-KATP tend to be large for gestational age and usually present with severe refractory hypoglycemia in the first 48 hours of life; they usually respond only partially to medical management (i.e., diazoxide therapy) and thus may require pancreatic resection. The two distinct histologic forms of FHI-KATP- are diffuse hyperinsulinism and focal hyperinsulinism: In diffuse hyperinsulinism, beta cells throughout the pancreas are functionally abnormal; approximately 2%-5% of cells have characteristic enlarged nuclei [De León & Stanley 2007]. Focal hyperinsulinism accounts for approximately 40%-60% of all cases. In focal hyperinsulinism, a somatic reduction to homozygosity (or hemizygosity) of a paternally inherited mutation of KCNJ11 or ABCC8 and a specific loss of maternal alleles of the imprinted chromosome region 11p15 result in a focal lesion composed of hyperplastic islet cell clusters of clonal origin (focal adenomatosis) [De León & Stanley 2007]. Focal pancreatic lesions can be cured by surgical resection. FHI-GCK, caused by mutations in GCK is inherited in an autosomal dominant manner. Infants with FHI-GCK tend to be appropriate for gestational age at birth and present at about age one year (range: 2 days to 30 years).KCNJ11 and ABCC8 Normal variants in KCNJ11 and ABCC8, particularly the p.Glu23Lys polymorphism in KCNJ11, have been associated with type 2 diabetes mellitus [Hani et al 1998, Gloyn et al 2001, Hansen et al 2001, 't Hart et al 2002, Gloyn et al 2003, Nielsen et al 2003, Florez et al 2004]. Activating mutations in KCNJ11 and ABCC8 with less severe effects on channel function have been found to cause TNDM that is similar to the biphasic course seen in the 6q24 phenotype. Typically, infants with TNDM caused by KATP channel mutations present before age six months, then go into remission between ages six and 12 months and are likely to relapse during adolescence or early adulthood [Gloyn et al 2005, Flanagan et al 2007]. ABCC8. A dominant ABCC8 mutation is associated with hyperinsulinemic hypoglycemia in the neonatal period and diabetes mellitus later in life [Huopio et al 2003]. INS. Heterozygous mutations in INS have been reported in individuals with infancy-onset diabetes, type 1b diabetes, familial monogenic diabetes and early-onset type 2 diabetes [Støy et al 2010].GCK. Dominant inactivating mutations of GCK are associated with GCK-familial monogenic diabetes, a mild form of diabetes mellitus presenting later in life.PDX1. Dominant inactivating mutations of PDX1 are associated with PDX1-familial monogenic diabetes, a mild form of diabetes mellitus.
Permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of hyperglycemia within the first six months of life with a mean age at diagnosis of seven weeks (range: birth to 26 weeks) [Gloyn et al 2004b]....
Natural HistoryPermanent neonatal diabetes mellitus (PNDM) is characterized by the onset of hyperglycemia within the first six months of life with a mean age at diagnosis of seven weeks (range: birth to 26 weeks) [Gloyn et al 2004b].The diabetes mellitus is associated with partial or complete insulin deficiency.Clinical manifestations at diagnosis include intrauterine growth retardation (IUGR; a reflection of insulin deficiency in utero), hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and failure to thrive.Therapy with insulin corrects the hyperglycemia and results in dramatic catch-up growth.The course of PNDM is highly variable depending on the genotype.KCNJ11 and ABCC8. Most individuals with PNDM caused by mutations in KCNJ11 and ABCC8 are diagnosed before age three months, but a few present in childhood or early adult life. The majority of affected infants have low birth weight resulting from lower fetal insulin production. The typical presentation is symptomatic hyperglycemia, and in many cases ketoacidosis. Although most individuals with mutations in KCNJ11 have isolated diabetes, 20% have associated neurologic features, the most severe of which are generalized epilepsy, and marked delay of motor and social development [Hattersley et al 2006]. This syndrome is known as DEND (developmental delay, epilepsy, neonatal diabetes) [Gloyn et al 2004b]. A milder form, called intermediate DEND syndrome, presents with less severe developmental delay and without epilepsy. In individuals with KCNJ11 mutations, treatment with sulfonylureas corrects the hyperglycemia [Pearson et al 2006] and may reverse some of the neurologic manifestations [Hattersley & Ashcroft 2005, Slingerland et al 2006] (see Management).INS. PNDM caused by heterozygous INS mutations presents with diabetic ketoacidosis or marked hyperglycemia. Most newborns are small for gestational age [Støy et al 2007, Polak et al 2008]. The median age at diagnosis is nine weeks, but some children present after age six months [Edghill et al 2008]. GCK. PNDM caused by homozygous GCK mutations is characterized by IUGR, permanent insulin-requiring diabetes from the first day of life, and hyperglycemia in both parents. PDX1. Pancreatic hypoplasia caused by homozygous PDX1 mutations results in a more severe insulin deficiency than in KATP or GCK-related neonatal diabetes as shown by a lower birth weight and a younger age at diagnosis. In addition these individuals have exocrine pancreatic insufficiency.
Clear genotype-phenotype correlations exist for those forms of PNDM associated with KCNJ11 mutations....
Genotype-Phenotype CorrelationsClear genotype-phenotype correlations exist for those forms of PNDM associated with KCNJ11 mutations.Genotype-phenotype studies correlate KCNJ11 mutations and phenotype with the extent of reduction in KATP channel ATP sensitivity.Some KCNJ11 mutations are associated with TNDM; others are associated with PNDM; and two mutations, p.Val252Ala and p.Arg201His, are associated with both disorders [Colombo et al 2005, Girard et al 2006]. Furthermore, functional studies have shown some overlap between the magnitude of the KATP channel currents in TNDM- and PNDM-associated mutations [Girard et al 2006].The location of the mutation seems to predict the severity of the disease (isolated diabetes mellitus, intermediate DEND syndrome, DEND syndrome). Mutations in residues that lie within the putative ATP-binding site (Arg50, Ile192, Leu164, Arg201, Phe333) or are located at the interfaces between Kir6.2 subunits (Phe35, Cys42, and Gu332) or between Kir6.2 and SUR1 (Gly53) are associated with isolated diabetes mellitus. See Molecular Genetics, KCNJ11, Normal gene product for a discussion of Kir6.2 subunits.The severity of PNDM along the spectrum of isolated diabetes mellitus, intermediate DEND syndrome, and full DEND syndrome correlates with the genotype [Proks et al 2004]. Mutations that cause additional neurologic features occur at codons for amino acid residues that lie at some distance from the ATP-binding site (Gln52, Gly53, Val59, Cys166, and Ile296) [Hattersley & Ashcroft 2005].Of 24 individuals with mutations at the arginine residue, Arg201, all but three had isolated PNDM. The p.Val59Met mutation is associated with intermediate DEND syndrome. The following mutations associated with full DEND syndrome are not found in less severely affected individuals: p.Gln52Arg, p.Val59Gly, p.Ile296Val, p.Cys166Phe [Gloyn et al 2006], p.Gly334Asp [Masia et al 2007b], p.Ile167Leu [Shimomura et al 2007], p.Gly53Asp, p.Cys166Tyr, and p.Ile296Leu [Flanagan et al 2006] (see Table 2). Improvement of the neurologic features of DEND syndrome with sulfonylurea treatment also seems to be genotype dependent: children with the mutations p.Val59Met [Støy et al 2008, Mohamadi et al 2010] and p.Gly53Asp [Koster et al 2008] have been shown to respond to sulfonylureas (see Table 2).For neonatal diabetes caused by ABCC8 mutations, genotype-phenotype correlations are less distinct [Edghill et al 2010].The relationship between genotype and phenotype is beginning to emerge for NDM caused by mutations in INS. The diabetes mellitus in persons who are homozygous or compound heterozygous for mutations in INS can be permanent of transient. The mutations c.-366_343del, c.3G>A, c.3G>T, c.184C>T, c.-370-?186+?del and c.*59A>G appear to be associated with PNDM, whereas the mutations at c.-218A>C and c.-331C>A or C>G have been identified in persons with both PNDM and TNDM as well as persons with type 1b diabetes mellitus [Støy et al 2010] (see Table 6).
Permanent neonatal diabetes mellitus (PNDM) vs transient neonatal diabetes mellitus (TNDM). When diabetes mellitus is diagnosed in the neonatal period, it is difficult to determine if it is likely to be transient or permanent. ...
Differential DiagnosisPermanent neonatal diabetes mellitus (PNDM) vs transient neonatal diabetes mellitus (TNDM). When diabetes mellitus is diagnosed in the neonatal period, it is difficult to determine if it is likely to be transient or permanent. 6q24-related TNDM is defined as diabetes mellitus that begins in the first six weeks of life in a term infant and resolves by age 18 months. Diabetes tends to develop in the first week of life. The cardinal features are presence of severe IUGR, dehydration, and hyperglycemia and absence of ketoacidosis. Macroglossia and umbilical hernia are often present. Infants usually require insulin. Diabetes lasts from two weeks to over one year of age; the need for insulin gradually declines. Intermittent episodes of hyperglycemia may occur in childhood, particularly during intercurrent illnesses. Recurrence in adolescence is more akin to type 2 diabetes mellitus. Relapse in women during pregnancy is associated with gestational diabetes mellitus.6q24-related TNDM is caused by overexpression of two genes, PLAGL1 (ZAC) and HYMAI, found within an imprinted region on chromosome 6q24. Three mechanisms account for 90% of cases of TNDM:Paternal uniparental disomy (UPD) of chromosome 6 Duplication of 6q24 on the paternal allele 6q24 methylation defect The two most common causes of neonatal diabetes are 6q24-related TNDM and mutations in KCNJ11. In 50 children presenting with neonatal diabetes, Metz et al [2002] failed to demonstrate clear clinical indicators to differentiate 6q24-related TNDM from other causes.For infants presenting in the first two weeks of life, it is reasonable to test for 6q24-related aberrations first, followed by testing for KCNJ11 mutations. For infants presenting from the third week of life onward, it may be more appropriate to test for KCNJ11 mutations first, followed by testing for 6q24-related aberrations. For infants with associated features or consanguineous parents, other genetic analysis may be appropriate.Syndromic causes of permanent neonatal diabetes mellitus PTF1A-related PNDM. Homozygous inactivating mutations in PTF1A cause pancreatic agenesis leading to PNDM associated with cerebellar agenesis and severe neurologic dysfunction [Sellick et al 2004]. PTF1A encodes a basic helix-loop-helix protein of 48 kd. The protein plays a role in determining whether cells allocated to the pancreatic buds continue toward pancreatic organogenesis or revert back to duodenal fates [Kawaguchi et al 2002]. Infants with PTF1A-related PNDM present with severe IUGR, and very low circulating insulin and C-peptide in the presence of severe hyperglycemia. Neurologic features include flexion contractures of extremities and absence of the cerebellum demonstrated on brain imaging [Sellick et al 2004]. Exocrine pancreatic dysfunction may be present as well because the pancreas is absent. Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is characterized by the development of overwhelming systemic autoimmunity in the first year of life resulting in the commonly observed triad of watery diarrhea, eczematous dermatitis, and endocrinopathy seen most commonly as insulin-dependent diabetes mellitus. The majority of affected males have other autoimmune phenomena including Coombs-positive anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and tubular nephropathy. Typically, serum concentration of immunoglobulin E (IgE) is elevated. The majority of affected males die within the first year of life of either metabolic derangements or sepsis. FOXP3 is currently the only gene in which mutation is known to cause IPEX syndrome. Inheritance is X-linked. Wolcott-Rallison syndrome is characterized by infantile-onset diabetes mellitus and exocrine pancreatic dysfunction (25%) as well as the extra-pancreatic manifestations of epiphyseal dysplasia (90%), developmental delay (80%), acute liver failure (75%), osteopenia (50%), and hypothyroidism (25%). In addition, older individuals with Wolcott-Rallison syndrome may develop chronic kidney dysfunction [Senee et al 2004]. The prognosis is poor. EIF2AK3, the gene encoding eukaryotic translation initiation factor 2-alpha kinase 3, is the only gene in which mutations are known to cause Wolcott-Rallison syndrome. Durocher et al [2006] observed that the severity of the manifestations and age of presentation in individuals with the same mutation may vary and concluded that no simple relationship exists between the clinical manifestation and EIF2AK3 mutations in Wolcott-Rallison syndrome. Inheritance is autosomal recessive. A syndrome of neonatal diabetes mellitus with congenital hypothyroidism has been associated with mutations in GLIS3. GLIS3 encodes zinc finger protein GLIS3 (also known as GLI similar protein 3), a recently identified transcription factor expressed in the pancreas from early developmental stages. In addition to the neonatal diabetes and congenital hypothyroidism, the syndrome can present with congenital glaucoma, hepatic fibrosis, and polycystic kidneys [Senee et al 2006]. A syndrome of neonatal diabetes mellitus with pancreatic hypoplasia, intestinal atresia, and gall bladder hypoplasia has been associated with mutations in RFX6. RFX6 is a transcription factor required for the differentiation of four of the five islet cell types and for the production of insulin. RFX6 acts downstream of the pro-endocrine factor Neurog3 [Smith et al 2010]. A syndrome of neonatal diabetes, cerebellar hypoplasia, sensorineural deafness, and visual impairment has been associated with mutations in NEUROD1. NEUROD1 is a transcription factor that plays an important role in the development of the endocrine pancreas [Rubio-Cabezas et al 2010].A syndrome of congenital malabsorptive diarrhea and neonatal diabetes has been associated with mutations in NEUROG3. Neurogenin-3 is a basic helix loop helix transcription factor essential in the development of enteroendocrine, Paneth, goblet, and enterocyte cells in the intestine and pancreatic endocrine cells [Pinney et al 2011].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).KCNJ11-related PNDMINS-Related PNDMABCC8-related PNDM
To establish the extent of disease in an individual diagnosed with neonatal diabetes mellitus as a result of mutation in KCNJ11 or ABCC8, a complete neurologic evaluation should be performed....
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with neonatal diabetes mellitus as a result of mutation in KCNJ11 or ABCC8, a complete neurologic evaluation should be performed.To establish the extent of disease in an individual with suspected or confirmed mutations in PDX1, imaging of the pancreas and evaluation of pancreatic exocrine function should be performed.Treatment of ManifestationsInitial treatment. Rehydration and intravenous insulin infusion should be started promptly after diagnosis, particularly in infants with ketoacidosis. Long-term medical management. An appropriate regimen of subcutaneous insulin administration should be established when the infant is stable and tolerating oral feedings. Few data on the most appropriate insulin preparations for young infants are available. Intermediate-acting insulin preparations (neutral protamine Hagedorn [NPH]) tend to have a shorter duration of action in infants, possibly because of smaller dose size or higher subcutaneous blood flow. The newer, longer-acting preparations with no peak-of-action effect such as Lantus® (glargine) may work better in small infants. Some centers recommend the use of continuous subcutaneous insulin infusion for young infants [Polak & Cave 2007] as a safer, more physiologic, and more accurate way of administering insulin. Caution: In general, rapid-acting (lispro and aspart) and short-acting (regular) preparations (except when used as a continuous intravenous or subcutaneous infusion) should be avoided as they may cause severe hypoglycemic events. Extreme caution should be observed when using a diluted insulin preparation in order to avoid dose errors. Identification of a KCNJ11 or ABCC8 mutation is important for clinical management since most individuals with these mutations can be treated with oral sulfonylureas. Children with mutations in KCNJ11 or ABCC8 can be transitioned to therapy with oral sulfonylureas; high doses are usually required (0.4-1.0 mg/kg/day of glibenclamide). Treatment with sulfonylureas is associated with improved glycemic control [Hattersley & Ashcroft 2005, Pearson et al 2006]. Long-term insulin therapy is required for all other causes of PNDM, although mild beneficial effect of oral sulfonylureas in persons with GCK mutations has been reported [Turkkahraman et al 2008, Hussain 2010]. High caloric intake should be maintained to achieve weight gain.Pancreatic enzyme replacement therapy is required in persons with exocrine pancreatic insufficiency.Prevention of Primary Manifestations Several case reports have demonstrated measurable improvement in neurodevelopmental outcome in children with DEND syndrome treated with sulfonylureas. These reports raise the possibility that neurologic manifestations can be prevented by early treatment with these agents [Greeley et al 2010]. Prevention of Secondary ComplicationsAggressive treatment and frequent monitoring of blood glucose concentrations is essential to avoid acute complications such as diabetic ketoacidosis and hypoglycemia.Long-term complications of diabetes mellitus can be significantly reduced by maintaining blood glucose concentrations in the appropriate range. Given the increased risk and vulnerability to hypoglycemia in young children, the American Diabetes Association recommends the following:Glycemic targets for children younger than age six years: 100-180 mg/dL before meals 110-200 mg/dL at bedtime/overnight Hemoglobin A1c value between 7.5% and 8.5% [Silverstein et al 2005] SurveillanceLifelong monitoring (≥4x/day) of blood glucose concentrations is indicated to achieve the goals of therapy.Children with PNDM, particularly those with a mutation in KCNJ11 or ABCC8, should undergo periodic developmental evaluations.Yearly screening for chronic complications associated with diabetes mellitus should be started after age ten years and should include the following:Screening for microalbuminuria Ophthalmologic examination to screen for retinopathy Agents/Circumstances to AvoidIn general, rapid-acting insulin preparations (lispro and aspart) as well as short-acting (regular) insulin preparations should be avoided (except when used as a continuous intravenous or subcutaneous infusion) as they may cause severe hypoglycemic events in young children.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Permanent Neonatal Diabetes Mellitus: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDABCC811p15.1ATP-binding cassette transporter sub-family C member 8ABCC8 homepage - Mendelian genesABCC8KCNJ1111p15.1ATP-sensitive inward rectifier potassium channel 11KCNJ11 homepage - Mendelian genesKCNJ11GCK7p13GlucokinaseGlucokinase (hexokinase 4) (GCK) @ LOVDGCKPDX113q12.2Pancreas/duodenum homeobox protein 1PDX1 homepage - Mendelian genesPDX1INS11p15.5InsulinINS homepage - Mendelian genesINSData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Permanent Neonatal Diabetes Mellitus (View All in OMIM) View in own window 138079GLUCOKINASE; GCK 176730INSULIN; INS 600509ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 8; ABCC8 600733PANCREAS/DUODENUM HOMEOBOX PROTEIN 1; PDX1 600937POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 11; KCNJ11 606176DIABETES MELLITUS, PERMANENT NEONATAL; PNDMKCNJ11 Normal allelic variants. KCNJ11 is located on chromosome 11p15.1, 4.5 kb telomeric to ABCC8. The gene spans approximately 3.4 kb of genomic DNA and has a single exon. Pathologic allelic variants. At least 21 different mutations in KCNJ11 have been reported in association with neonatal diabetes mellitus (see Table 2). The two common hot spots for recurrent mutations are at amino acid residues Val59 and Arg201 [Hattersley & Ashcroft 2005]. (See Flanagan et al [2009] for mutations in KCNJ11 that cause both neonatal diabetes mellitus and persistent hyperinsulinemic hypoglycemia of infancy.)Table 2. Selected KCNJ11 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesNormal c.67G>Ap.Glu23Lys 1NM_000525.3 NP_000516.3 Pathologic c.103T>Gp.Phe35Val c.103T>Cp.Phe35Leuc.124T>Cp.Cys42Argc.149G>Cp.Arg50Proc.155A>Gp.Gln52Argc.157G>Cp.Gly53Argc.157G>Ap.Gly53Serc.158G>Ap.Gly53Aspc.175G>Ap.Val59Metc.176T>Gp.Val59Glyc.497G>Tp.Cys166Phec.497G>Ap.Cys166Tyrc.499A>Cp.Ile167Leuc.509A>Gp.Lys170Argc.510G>Cp.Lys170Asnc.544A>Gp.Ile182Valc.602G>Ap.Arg201Hisc.601C>Tp.Arg201Cysc.602G>Tp.Arg201Leuc.755T>Cp.Val252Alac.886A>Cp.Ile296Leuc.886A>Gp.Ile296Valc.964G>Ap.Glu322Lysc.989A>Gp.Tyr330Cysc.997T>Ap.Phe333Ilec.1001G>Ap.Gly334AspSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Associated with type 2 diabetes mellitus. See Genetically Related Disorders.Normal gene product. KCNJ11 and ABCC8 code for the proteins ATP-sensitive inward rectifier potassium channel 11 (Kir6.2) and ATP-binding cassette transporter sub-family C member 8 (SUR1), components of the beta-cell KATP channel. The KATP channel is a hetero-octameric complex with four Kir6.2 subunits forming the central pore, coupled to four SUR1 subunits. The KATP channels couple the energy state of the beta cell to membrane potential by sensing changes in intracellular phosphate potential (the ATP/ADP ratio). Following the uptake of glucose and its metabolism by glucokinase, there is an increase in the intracellular ATP/ADP ratio results in closure of the KATP channels, depolarization of the cell membrane, and subsequent opening of voltage-dependent Ca2+ channels. The resulting increase in cytosolic Ca2+ concentration triggers insulin release. Abnormal gene product. Mutations in either ABCC8 or KCNJ11 result in nonfunctional or dysfunctional KATP channels. In either case, channels do not close, and thus glucose-stimulated insulin secretion does not happen. All mutations in KCNJ11 studied to date produce marked decrease in the ability of ATP to inhibit the KATP channel when expressed in heterologous systems. This reduction in ATP sensitivity means the channel opens more fully at physiologically relevant concentrations of ATP, leading to an increase in the KATP current and hyperpolarization of the beta-cell plasma membrane with subsequent suppression of Ca2+ influx and insulin secretion [Hattersley & Ashcroft 2005]. ABCC8 Normal allelic variants. ABCC8 is located on chromosome 11p15.1, 4.5 kb centromeric to KCNJ11. The gene spans approximately 84 kb of genomic DNA and is made up of a 39 exons. Pathologic allelic variants. At least 24 different mutations have been associated with permanent neonatal diabetes (see Table 3). In addition, several other mutations in compound heterozygous have been associated with PNDM. (See Flanagan et al [2009] for mutations in ABCC8 that cause both neonatal diabetes mellitus and persistent hyperinsulinemic hypoglycemia of infancy.)Table 3. Selected ABCC8 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReferencesReference Sequencesc.215A>Gp.Asn72SerEllard et al [2007] NM_000352.3 NP_000343.2 c.257T>Cp.Val86AlaEllard et al [2007] c.257T>Gp.Val86GlyEllard et al [2007] c.394T>Gp.Phe132ValEllard et al [2007] c.394T>Cp.Phe132LeuProks et al [2006] c.404T>Cp.Leu135ProEllard et al [2007] c.627C>Ap.Asp209GluEllard et al [2007], Flanagan et al [2007] c.631C>Ap.Gln211LysEllard et al [2007] c.638T>Gp.Leu213ArgBabenko et al [2006] c.674T>C p.Leu225Phec.1144G>Ap.Glu382LysEllard et al [2007] c.3554C>Ap.Ala1185GluEllard et al [2007] c.4270A>Gp.Ile1424ValBabenko et al [2006], Masia et al [2007a]See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).For more information see Patch et al [2007], Figure 2 (click here for full text) and Edghill et al [2010], Figures 2 and 3 (click here for full text).Normal gene product. See KCNJ11, Normal gene product. Abnormal gene product. The increased activity of KATP channels resulting from mutations in ABCC8 is caused by an increase in the magnesium-dependent stimulatory action of SUR1 on the pore [Babenko et al 2006, Masia et al 2007a], or by alteration in the inhibitory action of ATP on a mutant SUR1 channel [Proks et al 2006]. GCK Normal allelic variants. GCK spans more than 45 kb of genomic DNA and is made up of ten exons. Pathologic allelic variants. At least ten mutations of GCK have been reported in association with PNDM (see Table 4). These mutations are nonsense, missense, or frameshift mutations and result in a deficiency of glucokinase activity.Table 4. Selected GCK Pathologic Allelic VariantsView in own windowDNA Nucleotide Change (Alias 1 )Protein Amino Acid ChangeReferencesReference Sequencesc.629T>Ap.Met210LeuNjolstad et al [2001] NM_000162.3 NP_000153.1 c.683C>Tp.Thr228Metc.790G>A p.Gly264SerNjolstad et al [2003] 1133C>Tp.Ala378Valc.1190G>T p.Arg397LeuPorter et al [2005] c.1505+2T>G (IVS8+2T>G)NANjolstad et al [2003] See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). NA= not applicable1. Variant designation that does not conform to current naming conventionsNormal gene product. The isoform expressed specifically in pancreatic islet beta cells has 465 amino acid residues. Glucokinase is a hexokinase that serves as the glucose sensor in pancreatic beta cells and seems to have a similar role in enteroendocrine cells, hepatocytes, and hypothalamic neurons. In beta cells, glucokinase controls the rate-limiting step of glucose metabolism and is responsible for glucose-stimulated insulin secretion [Matschinsky 2002]. Abnormal gene product. The reported missense mutations alter the kinetics of the enzyme: the glucose S0.5 is raised and the ATP Km is increased. The overall result for inactivating mutations is a decrease in the phosphorylating potential of the enzyme, which extrapolates to a marked reduction in beta-cell glucose usage and hyperglycemia. Splice-site mutations are predicted to lead to the synthesis of an inactive protein. PDX1 Normal allelic variants. PDX1 has a transcript of 1527 bp and is made up of two exons. Pathologic allelic variants. At least four PDX1 mutations have been described in association with pancreatic agenesis and PNDM: A homozygous single-nucleotide deletion c.188_189delC in one person [Stoffers et al 1997b] A homozygous missense mutation p.Glu178Gly in the PDX1 homeodomain associated with neonatal diabetes without exocrine insufficiency in two individuals [Nicolino et al 2010]Compound heterozygosity for p.Glu164Asp and p.Glu178Lys mutations within exon 2 of PDX1 [Schwitzgebel et al 2003]. See Table 5.Table 5. Selected PDX1 Pathologic Allelic VariantsView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.188_189delCp.Pro63Argfs*60NM_000209.3 NP_000200.1c.492G>Tp.Glu164Aspc.532G>Ap.Glu178LysSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).*= termination codonNormal gene product. The transcription factor insulin promoter factor 1 (PDX1) is a master regulator of pancreatic development as well as the differentiation of progenitor cells into the beta-cell phenotype. During embryogenesis in the mouse, pdx1 expression initiates on commitment of the foregut endoderm to a pancreatic fate. In the adult organism, pdx1 expression is limited to the beta cell and its importance in maintaining beta-cell phenotype is illustrated by multiple animal models. In mature beta cells, pdx1 regulates the expression of critical genes including insulin, glucokinase, and the glucose transporter Glut2 [Habener et al 2005].Abnormal gene product. The single nucleotide deletion mutation results in a truncated, inactive protein (p.Pro63Argfs*60) whereas the mutant proteins resulting from either the p.Glu164Asp or p.Glu178Lys mutations undergo increased degradation leading to a reduction in protein levels and ultimately to decreased transcriptional activity. The p.Glu178Gly mutation reduces PDX1 transactivation. INS Normal allelic variants. INS is located on chromosome 11p15.5. The gene is made up of three exons and two introns. Exon 2 encodes the signal peptide, the B chain, and part of the C peptide; exon 3 encodes the reminder of the C peptide and the A chain. Pathologic allelic variants. At least twenty-eight mutations have been described in association with PNDM [Støy et al 2007, Polak et al 2008, Støy et al 2010]. See Table 6 and Genotype-Phenotype Correlations.See Støy et al [2010] for mutations in INS that cause diabetes mellitus.Table 6. Selected INS Pathologic Allelic VariantsView in own windowDNA Nucleotide Change 1Protein Amino Acid ChangeReferencesReference Sequencesc.-366_343del 2, 3NAStøy et al [2007], Polak et al [2008] Støy et al [2010]NM_000207.2 11NP_000198.1 c.-370-?186+?del 2, 3, 4, 5c.-331C>A 2, 3, 6, 7c.-331C>G 2, 3, 6, 8c.-218A>C 2, 3, 6, 9c.3G>A 2p.0? 10c.3G>T 2p.0? 10c.71C>Ap.Ala24Aspc.94G>Ap.Gly32Serc.94G>Cp.Gly32Argc.127T>Gp.Cys43Glyc.140 G>Tp.Gly47Valc.143T>Gp.Phe48Cysc.184C>T 2p.Gln62*c.265C>Tp.Arg89Cysc.268G>Tp.Gly90Cysc.287G>Ap.Cys96Tyrc.323A>Gp.Tyr108Cysc.*59A>G 2, 12NASee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).NA = not applicable1. Negative number indicates the number of base pairs preceding the A of the ATG start codon. An asterisk indicates a position in the 3’UTR; the number is the position relative to the first base past the stop codon.2. See Genotype-Phenotype Correlations.3. Garin et al [2010]4. Denotes an exonic deletion starting at an unknown position in the promoter of coding DNA nucleotide -370 and ending at an unknown position in the intron 3’ of the coding DNA nucleotide 186 [Støy et al 2010].5. Raile et al [2011]6. Bonnefond et al [2011]7. -94 relative to transcription initiation site8. -93 relative to transcription initiation site9. A+20 relative to transcription initiation site10. p.0? = effect unknown; probably no protein is produced.11. Reference sequences of the insulin preprotein12. 59 nucleotides 3' of the termination codon (in the 3'UTR); * indicates termination codon.Normal gene product. Insulin is synthesized by the pancreatic beta cells and consists of two dissimilar polypeptide chains, A and B, which are linked by two disulfide bonds. Chains A and B are derived from a 1-chain precursor, proinsulin. Proinsulin is converted to insulin by enzymatic removal of a segment that connects the amino end of the A chain to the carboxyl end of the B chain. This segment is called the C peptide. Abnormal gene product. The diabetes-associated mutations lead to the synthesis of a structurally abnormal preproinsulin or proinsulin protein. The mutations associated with PNDM disrupt proinsulin folding and/or disulfide bond formation. Some reported mutations disrupt normal disulfide bonds (p.Cys43Gly and p.Cys96Tyr) or add an additional unpaired cysteine residue (p.Arg89Cys and p.Gly90Cys) at the A-chain C-peptide cleavage site. Mutation p.Tyr108Cys may cause mispairing of cysteines in a critical region close to a disulfide bond [Støy et al 2007]. All of the mutants are likely to act in a dominant manner to disrupt insulin biosynthesis and induce endoplasmic reticulum (ER) stress. The exact mechanism by which these unpaired cysteines disrupt ER function remains unclear [Izumi et al 2003]. Three other mutations (p.Gly32Ser, p.Gly32Arg, and p.Gly47Val) are located in a residue that is invariant in both insulin and the insulin-like growth factors and must play an important structural role. It is believed that these glycine mutations also act similarly to impair proinsulin folding and thereby induce ER stress via the unfolded protein response.