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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Permanent Neonatal Diabetes Mellitus

Synonym: Permanent Diabetes Mellitus of Infancy. Includes: ABCC8-Related Permanent Neonatal Diabetes Mellitus, GCK-Related Permanent Neonatal Diabetes Mellitus, INS-Related Permanent Neonatal Diabetes Mellitus, KCNJ11-Related Permanent Neonatal Diabetes Mellitus, PDX1-Related Permanent Neonatal Diabetes Mellitus,

, MD and , MD.

Author Information
, MD
Assistant Professor of Pediatrics
The Children's Hospital of Philadelphia
University of Pennsylvania
Philadelphia, Pennsylvania
, MD
Emeritus Professor of Pediatrics
The Children's Hospital of Philadelphia
University of Pennsylvania
Philadelphia, Pennsylvania

Initial Posting: ; Last Update: January 23, 2014.

Summary

Disease characteristics. Nonsyndromic permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of hyperglycemia within the first six months of life (mean age: 7 weeks; range: birth to 26 weeks) that does not resolve over time. Clinical manifestations at the time of diagnosis include intrauterine growth retardation (IUGR), hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and failure to thrive. Therapy with insulin corrects the hyperglycemia and allows for catch-up growth. The course of PNDM varies by genotype. Pancreatic agenesis/hypoplasia caused by homozygous mutations in PDX1 results in severe insulin deficiency and exocrine pancreatic insufficiency.

Diagnosis/testing. Persistent hyperglycemia (plasma glucose concentration >150-200 mg/dL) in infants younger than age six months establishes the diagnosis of PNDM. The five genes in which mutations are known to cause nonsyndromic PNDM are KCNJ11 (~30% of PNDM), ABCC8 (~19%), INS (~20%), GCK (~4%), and PDX1 (<1%).

Management. Treatment of manifestations: Start rehydration and intravenous insulin infusion promptly after diagnosis. When the infant is stable and tolerating oral feedings begin subcutaneous insulin therapy. Children with mutations in KCNJ11 or ABCC8 can be treated long term with oral sulfonylureas; all others require insulin long term. High caloric intake is necessary for appropriate weight gain. Pancreatic enzyme replacement therapy is required for those with exocrine pancreatic insufficiency.

Prevention of secondary complications: Aggressive treatment and frequent monitoring of blood glucose concentrations to avoid acute complications such as diabetic ketoacidosis and hypoglycemia.

Surveillance: Lifelong monitoring of blood glucose concentrations at least four times a day; periodic developmental evaluations. After age ten years, annual screening for chronic complications of diabetes mellitus including urinalysis for microalbuminuria and ophthalmologic examination for retinopathy.

Agents/circumstances to avoid: In general, avoid rapid-acting insulin preparations (lispro and aspart) as well as short-acting (regular) insulin preparations (except as a continuous intravenous or subcutaneous infusion) as they may cause severe hypoglycemia in young children.

Genetic counseling. The mode of inheritance of PNDM is autosomal dominant for mutations in KCNJ11, autosomal dominant or autosomal recessive for mutations in ABCC8 and INS, and autosomal recessive for mutations in GCK and PDX1.

Individuals with autosomal dominant PNDM may have an affected parent or may have a de novo mutation. Each child of an individual with PNDM inherited in an autosomal dominant manner has a 50% chance of inheriting the mutation.

The parents of a child with autosomal recessive PNDM are obligate heterozygotes and therefore carry one mutant allele. Heterozygotes (carriers) for mutations in GCK and PDX1 have a mild form of diabetes mellitus known as GCK-familial monogenic diabetes (formerly known as MODY2) and PDX1-familial monogenic diabetes (formerly known as MODY4). At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier (or of having familial monogenic diabetes), and a 25% chance of being unaffected and not a carrier.

Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation(s) in the family are known.

Diagnosis

Clinical Diagnosis

Nonsyndromic permanent neonatal diabetes mellitus (PNDM) is defined as diabetes mellitus diagnosed in the first six months of life that does not resolve over time.

Testing

Laboratory 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.

Note: Measurement of hemoglobin A1c is not suitable for diagnosing diabetes mellitus in infants younger than age six months because of the higher proportion of fetal hemoglobin compared to hemoglobin A.

Pancreatic imaging. Imaging of the pancreas with ultrasound, CT, or MRI is used to determine its presence and size.

Molecular Genetic Testing

Genes. The five genes in which mutations are known to cause nonsyndromic permanent neonatal diabetes are KCNJ11, ABCC8, INS, GCK, and PDX1.

Note: Syndromic forms of neonatal diabetes can be caused by mutations in FOXP3, PTF1A, GLIS3, NEUROD1, RFX6, NEUROG3, EIF2AK3, GATA6, SLC19A2, HNF1B, PAX6, and WFS1 (see Differential Diagnosis).

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Permanent Neonatal Diabetes Mellitus

Gene 1Estimated Proportion of PNDM Attributed to Mutations in This GeneTest MethodMutations Detected 2
KCNJ11 30% 3Sequence analysis Sequence variants 4
UnknownDeletion/duplication analysis 5Unknown, none expected 6
ABCC8 19% 7Sequence analysisSequence variants 4
Deletion/duplication analysis 5Unknown, none expected 6
INS 20% 8Sequence analysisSequence variants 4
Deletion/duplication analysis 5Exonic and whole-gene deletions 9
GCK 4% 10Sequence analysisSequence variants 4
UnknownDeletion/duplication analysis 5Unknown, none detected 6
PDX1 <1% 11Sequence analysisSequence variants 4
UnknownDeletion/duplication analysis 5Unknown, none detected 6

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Attributed to activating mutations of KCNJ11 [Ellard et al 2007]

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. No deletions or duplications involving KCNJ11, ABCC8, GCK or PDX1 have been reported to cause permanent neonatal diabetes mellitus. Note that these are activating mutations and therefore must be missense. Duplication/deletion analysis would be unrevealing for ABCC8 and KCNJ11 defects.

7. Attributed to activating mutations of ABCC8 [Babenko et al 2006]

8. Støy et al [2007], Polak et al [2008]

9. A 646-bp deletion in INS was reported in individuals with neonatal diabetes [Raile et al 2011].

10. [Njolstad et al 2001, Njolstad et al 2003]. Note: Carrier parents have mild diabetes mellitus or glucose intolerance (GCK-familial monogenic diabetes, previously known as MODY2.

11. Attributed to inactivating mutations [Stoffers et al 1997a]. Note: Carrier parents have mild, adult-onset diabetes mellitus (PDX1-familial monogenic diabetes, previously known as MODY4.

Testing Strategy

To 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, as heterozygotes can manifest diabetes mellitus.
  • 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 without extra-pancreatic abnormalities should be tested for mutations in PDX1.
  • For individuals with syndromic PNDM, the extrapancreatic characteristics should guide genetic testing (see Allelic Disorders and Differential Diagnosis).
  • Sequence analysis to diagnose individuals with PNDM or transient neonatal diabetes mellitus (TNDM) caused by mutation of KCNJ11 or 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).

Note: The usefulness of deletion/duplication analysis has not been demonstrated, as no deletions or duplications involving KCNJ11, ABCC8, GCK or PDX1 as causative of permanent neonatal diabetes mellitus have been reported.

Clinical Description

Natural History

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].

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] (see Genetically Related Disorders). In individuals with KCNJ11 mutations, treatment with sulfonylureas corrects the hyperglycemia [Pearson 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. These individuals also have exocrine pancreatic insufficiency.

Genotype-Phenotype Correlations

Clear 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 KCNJ11 mutation appears 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]. KCNJ11 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].

For neonatal diabetes caused by ABCC8 mutations, genotype-phenotype correlations are less distinct [Edghill et al 2010]. Children with neonatal diabetes associated with dominant ABCC8 mutations may have a parent with the same ABCC8 mutation and type 2 diabetes, suggesting that the severity of the phenotype and age of onset of diabetes is variable among individuals with ABCC8 mutations [Babenko et al 2006].

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 or 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.-331C>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).

Penetrance

Reduced penetrance has been seen in PNDM caused by mutations in KCNJ11 and ABCC8 [Flanagan et al 2007].

Nomenclature

As some cases of "neonatal" diabetes mellitus may not be recognized until age three to six months, it has been suggested that the term "diabetes mellitus of infancy" or “congenital diabetes” should replace the designation "neonatal diabetes mellitus" [Massa et al 2005, Greeley et al 2011].

Prevalence

The estimated incidence of permanent neonatal diabetes ranges from 1:215,000 to 1:260,000 live births [Stanik et al 2007, Slingerland et al 2009, Wiedermann et al 2010].

Differential Diagnosis

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.

6q24-related TNDM is defined as transient neonatal diabetes mellitus caused by genetic aberrations of the imprinted locus at 6q24. The cardinal features are: severe intrauterine growth retardation, hyperglycemia that begins in the neonatal period in a term infant and resolves by age 18 months, dehydration, and absence of ketoacidosis. Macroglossia and umbilical hernia are often present. Diabetes mellitus usually starts within the first week of life and lasts on average three months but can last over a year. Although insulin is usually required initially, the need for insulin gradually declines over time. 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 TNDM:

The two most common causes of transient 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.
  • In infants presenting between age six and 12 months or later who are antibody-negative or have a family history consistent with autosomal dominant inheritance, evaluation for mutations in INS should be considered first.

For infants with associated extra-pancreatic features or consanguineous parents, other genetic analysis may be appropriate.

Syndromic causes of permanent neonatal diabetes mellitus

  • GATA6-related PNDM. Heterozygous inactivating mutations in GATA6 are the most common cause of pancreatic agenesis [Lango Allen et al 2011]. Extrapancreatic features are common and include structural heart defects, biliary tract and gut anomalies, and other endocrine abnormalities. The diabetic phenotype in those with mutations in GATA6 is broad, ranging from PNDM with exocrine insufficiency to transient episodes of hyperglycemia. In the largest published series of GATA6-PNDM, the median age at diagnosis of diabetes was two days and the median birth weight was 1588 grams. Individuals with heterozygous mutation in GATA6 have also been diagnosed with diabetes at an older age [Lango Allen et al 2011, De Franco et al 2013]. Inheritance is autosomal dominant, but in most reported cases the mutations have arisen de novo.
  • 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. Inheritance is autosomal recessive.
  • 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. This is the most common cause of PNDM in consanguineous families [Rubio-Cabezas et al 2009]. 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. GLIS3 plays a role in the transcriptional regulation of neurogenin-3 and insulin [Kim et al 2012, Zeruth et al 2013]. In addition to neonatal diabetes and congenital hypothyroidism, the syndrome can present with congenital glaucoma, hepatic fibrosis, polycystic kidneys, and dysmorphic facial features [Senee et al 2006]. Inheritance is autosomal recessive and partial gene deletions are the most common type of mutations [Dimitri et al 2011].
  • 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 neurogenin-3. Pancreatic exocrine function is normal [Smith et al 2010]. Inheritance is autosomal recessive.
  • A syndrome of neonatal diabetes mellitus, 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. Pancreatic exocrine function is normal [Rubio-Cabezas et al 2010]. Inheritance is autosomal recessive.
  • A syndrome of congenital malabsorptive diarrhea and neonatal diabetes mellitus 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]. Diabetes may also present later in childhood [Wang et al 2006]. Pancreatic exocrine function may also be affected. Inheritance is autosomal recessive.
  • A syndrome of neonatal diabetes mellitus and renal abnormalities has been associated with mutations in HNF1B. HNF1 beta is a key regulator of a transcriptional network that controls the specification, growth and differentiation of the embryonic pancreas. The diabetes phenotype in individuals heterozygous for a single mutation in HNF1B manifests more frequently later in life (renal cysts and diabetes syndrome – RCAD, or MODY 5). The neonatal presentation due to biallelic mutations in HNF1B is characterized by evidence of severe insulin deficiency (low birth weight, diabetes ketoacidosis) and pancreatic exocrine insufficiency due to hypoplastic pancreas. The inheritance is autosomal recessive but penetrance is incomplete [Yorifuji et al 2004, Edghill et al 2006, Haldorsen et al 2008].
  • A syndrome of neonatal diabetes with brain malformations, microcephaly, and microphthalmia has been associated with mutations in PAX6. PAX6 is a transcription factor involved in eye and brain development that also plays a role in pituitary development and in ß-cell differentiation and function. In heterozygous individuals, diabetes presents later in life, however in individuals with biallelic mutations, the diabetes manifests in the neonatal period. The central nervous system (CNS) phenotype includes microcephaly and panhypopituitarism. The ocular phenotype includes aniridia, keratopathy, optic nerve defects, cataracts, microphthalmia and anophthalmia [Yasuda et al 2002, Solomon et al 2009].
  • Wolfram syndrome – Diabetes mellitus with optic atrophy, diabetes insipidus, and/or deafness. The affected gene, WFS1, encodes an endoplasmic reticulum (ER) membrane-embedded protein involved in regulating ER stress. The earliest and most consistent phenotypic characteristic in individuals with Wolfram syndrome is diabetes, which is usually diagnosed during childhood, but it can also present in the first year of life. The inheritance is autosomal recessive [Rigoli et al 2011, Rohayem et al 2011]. See WFS1-Related Disorders.
  • A syndrome of neonatal diabetes mellitus, deafness, and thiamine-responsive megaloblastic anemia caused by mutations in SLC19A2. SLC19A2 encodes a thiamine transporter. Also known as Rogers syndrome, this syndrome can also be associated with neurologic deficits, visual disturbances, and cardiac abnormalities. The diabetes phenotype can manifests in the first six months of life or later. The inheritance is autosomal recessive [Shaw-Smith et al 2012]. See Thiamine-Responsive Megaloblastic Anemia Syndrome.

Testing strategy for syndromic permanent neonatal diabetes mellitus. Individuals with PNDM and:

  • Pancreatic exocrine insufficiency or agenesis and cardiac abnormalities should be tested for mutations in GATA6;
  • 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;
  • Skeletal abnormalities and liver dysfunction should be tested for mutations in EIF2AK3 (WRS - Wolcott-Rallison syndrome);
  • Megaloblastic anemia and deafness should be tested for mutations in SLC19A2 (TRMA - thiamine-responsive megaloblastic anemia);
  • Renal and genital abnormalities should be tested for mutations in HNF1B;
  • Brain malformations, microcephaly and microphthalmia should be tested for mutations in PAX6;
  • Optic atrophy, diabetes insipidus and deafness should be tested for mutations in WFS1 (Wolfram syndrome).

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 (stool elastase, serum concentrations of fat-soluble vitamins) should be performed.

Medical genetic consultation should be obtained early in the evaluation of PNDM.

Treatment of Manifestations

Initial 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 longer-acting preparations with no significant peak-of-action effect such as Lantus® (glargine) or Levemir® (detemir) may work better in small infants.
  • In cases with very low insulin requirements, diluted insulin (5 or 10 U/mL) may be more appropriate if used with caution.
  • 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). Transfer protocols are available at www.diabetesgenes.org. 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 Secondary Complications

Aggressive 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 for 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]

Surveillance

Lifelong 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 Avoid

In 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 Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The management of pregnant women with PNDM should conform to the guidelines for treatment of other forms of diabetes during gestation [American Diabetes Association 2004]. Glycemic control during gestation is not only important to prevent complications in the mother, but also to prevent fetal overgrowth (due to fetal hyperinsulinemia triggered by the excess of maternal glucose crossing the placenta) and associated complications. Referral to a maternal-fetal medicine specialist should be considered. In addition, high resolution ultrasonography and fetal echocardiography should be offered during pregnancy to screen for congenital anomalies in the fetus.

Until recently, insulin was the mainstay of therapy of diabetes during pregnancy; however, emerging data support the safety and efficacy of glyburide in the treatment of diabetes during pregnancy [Moretti et al 2008]. Thus, in women with PNDM treated with glyburide before pregnancy, it is reasonable to continue this treatment if appropriate glycemic control can be achieved.

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The mode of inheritance of permanent neonatal diabetes mellitus (PNDM) varies by gene:

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Approximately 10% of individuals with autosomal dominant neonatal diabetes mellitus caused by mutations in KCNJ11 and 27% of individuals with autosomal dominant neonatal diabetes mellitus caused by INS have an affected parent.
  • A parent may have type 2 diabetes despite having the same ABCC8 mutation as their child with neonatal diabetes mellitus [Babenko et al 2006].
  • A proband with autosomal dominant neonatal diabetes mellitus may have the disorder as the result of a new mutation. The proportion of cases caused by de novo mutations in KCNJ11 and INS is estimated at 90% and 73%, respectively. De novo mutations account for most of the reported cases of heterozygous ABCC8-related PNDM [Patch et al 2007].
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Germline mosaicism for a mutation in KCNJ11 has been reported [Gloyn et al 2004a, Edghill et al 2007]; the overall incidence of germline mosaicism is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation in KCNJ11, ABCC8, or INS include molecular genetic testing and clinical testing for diabetes mellitus (oral glucose tolerance testing). Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although approximately 10% of individuals diagnosed with PNDM inherited in an autosomal dominant manner have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because germline mosaicism has been reported in this condition.

Offspring of a proband. Each child of an individual with PNDM inherited in an autosomal dominant manner has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members may be at risk.

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • In 43% of cases, ABCC8-related PNDM is inherited in an autosomal recessive manner from unaffected parents with heterozygous mutations [Patch et al 2007]. INS-related PNDM has also been reported to be inherited in an autosomal recessive manner from unaffected parents [Garin et al 2010].
  • The parents of a child with autosomal recessive PNDM are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) for mutations in GCK and PDX1 have a milder form of diabetes mellitus (GCK-familial monogenic diabetes and PDX1-familial monogenic diabetes, respectively). However, heterozygotes (carriers) for mutations in INS associated with recessively inherited NDM have normal glucose tolerance [Garin et al 2010].

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier (or having familial monogenic diabetes, previously known as MODY), and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) for mutations in GCK and PDX1 have a milder form of diabetes mellitus (GCK-familial monogenic diabetes, previously known as MODY2, and PDX1-familial monogenic diabetes, previously known as MODY4).

Offspring of a proband. The offspring of an individual with autosomal recessive neonatal diabetes mellitus are obligate heterozygotes (carriers) for a disease-causing mutation.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation(s) have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for the disease/gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like PNDM) do not affect intellect and have treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • DIABETESGENES.ORG
    Diabetesgenes.org aims to provide information for patients and professionals on research and clinical care in genetic types of diabetes.
    Peninsula Medical School
    Barrack Road
    Exeter EX2 5DW
    United Kingdom
  • International Society for Pediatric and Adolescent Diabetes (ISPAD)
    c/o KIT
    Kurfürstendamm 71
    Berlin 10709
    Germany
    Phone: +49 30 24603210
    Fax: +49 30 24603200
    Email: secretariat@ispad.org
  • American Diabetes Association (ADA)
    ATTN: Center for Information
    1701 North Beauregard Street
    Alexandria VA 22311
    Phone: 800-342-2383 (toll-free information/support); 703-549-1500
    Email: AskADA@diabetes.org
  • Diabetes UK
    Macleod House
    10 Parkway
    London NW1 7AA
    United Kingdom
    Phone: 020 7424 1000
    Fax: 020 7424 1001
    Email: info@diabetes.org.uk
  • US Neonatal Diabetes Mellitus Registry
    University of Chicago, Kovler Diabetes Center
    5841 South Maryland Avenue
    MC1027
    Chicago IL 60637
    Phone: 773-795-4454
    Email: neonataldiabetes@uchicago.edu

Molecular Genetics

Information 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 Databases

Data 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)

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; PNDM

KCNJ11

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic 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 variants in KCNJ11 that cause both neonatal diabetes mellitus and persistent hyperinsulinemic hypoglycemia of infancy.)

Table 2. Selected KCNJ11 Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Normal c.67G>Ap.Glu23Lys 1NM_000525​.3
NP_000516​.3
Pathogenic c.103T>Gp.Phe35Val
c.103T>Cp.Phe35Leu
c.124T>Cp.Cys42Arg
c.149G>Cp.Arg50Pro
c.155A>Gp.Gln52Arg
c.157G>Cp.Gly53Arg
c.157G>Ap.Gly53Ser
c.158G>Ap.Gly53Asp
c.175G>Ap.Val59Met
c.176T>Gp.Val59Gly
c.497G>Tp.Cys166Phe
c.497G>Ap.Cys166Tyr
c.499A>Cp.Ile167Leu
c.509A>Gp.Lys170Arg
c.510G>Cp.Lys170Asn
c.544A>Gp.Ile182Val
c.602G>Ap.Arg201His
c.601C>Tp.Arg201Cys
c.602G>Tp.Arg201Leu
c.755T>Cp.Val252Ala
c.886A>Cp.Ile296Leu
c.886A>Gp.Ile296Val
c.964G>Ap.Glu322Lys
c.989A>Gp.Tyr330Cys
c.997T>Ap.Phe333Ile
c.1001G>Ap.Gly334Asp

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. At least 24 different variants have been associated with permanent neonatal diabetes (see Table 3). In addition, several other variants in compound heterozygotes have been associated with PNDM. (See Flanagan et al [2009] for variants in ABCC8 that cause both neonatal diabetes mellitus and persistent hyperinsulinemic hypoglycemia of infancy.)

Table 3. Selected ABCC8 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReferencesReference Sequences
c.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.Leu225Phe
c.1144G>Ap.Glu382LysEllard et al [2007]
c.3554C>Ap.Ala1185GluEllard et al [2007]
c.4270A>Gp.Ile1424ValBabenko et al [2006], Masia et al [2007a]

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

For more information see Patch et al [2007], Figure 2 (full text) and Edghill et al [2010], Figures 2 and 3 (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

Gene structure. GCK spans more than 45 kb of genomic DNA and comprises ten exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. At least ten variants of GCK have been reported in association with PNDM (see Table 4). These are nonsense, missense, or frameshift mutations and result in a deficiency of glucokinase activity.

Table 4. Selected GCK Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReferencesReference Sequences
c.629T>Ap.Met210LeuNjolstad et al [2001] NM_000162​.3
NP_000153​.1
c.683C>Tp.Thr228Met
c.790G>A p.Gly264SerNjolstad et al [2003]
1133C>Tp.Ala378Val
c.1190G>T p.Arg397LeuPorter et al [2005]
c.1505+2T>G
(IVS8+2T>G)
NANjolstad et al [2003]

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

NA= not applicable

1. Variant designation that does not conform to current naming conventions

Normal 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

Gene structure. PDX1 has a transcript of 1527 bp and comprises two exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. At least four PDX1 variants have been described in association with pancreatic agenesis and PNDM:

Table 5. Selected PDX1 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.188_189delCp.Pro63ArgfsTer60NM_000209​.3
NP_000200​.1
c.492G>Tp.Glu164Asp
c.532G>Ap.Glu178Lys

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal 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.Pro63ArgfsTer60) 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

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. At least twenty-eight variants 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 variants in INS that cause diabetes mellitus.

Table 6. Selected INS Pathogenic Variants

DNA Nucleotide Change 1Protein Amino Acid ChangeReferencesReference Sequences
c.-366_343del 2, 3NAStøy et al [2007], Polak et al [2008], Støy et al [2010]NM_000207​.2 4
NP_000198​.1
c.-370-?186+?del 2, 3, 5, 6
c.-331C>A 2, 3, 7, 8
c.-331C>G 2, 3, 4, 9
c.-218A>C 2, 3, 7, 10
c.3G>A 2p.0? 11
c.3G>T 2p.0? 11
c.71C>Ap.Ala24Asp
c.94G>Ap.Gly32Ser
c.94G>Cp.Gly32Arg
c.127T>Gp.Cys43Gly
c.140 G>Tp.Gly47Val
c.143T>Gp.Phe48Cys
c.184C>T 2p.Gln62Ter
c.265C>Tp.Arg89Cys
c.268G>Tp.Gly90Cys
c.287G>Ap.Cys96Tyr
c.323A>Gp.Tyr108Cys
c.*59A>G 2, 12NA

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

NA = not applicable

1. 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. Reference sequences of the insulin preprotein

5. 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].

6. Raile et al [2011]

7. Bonnefond et al [2011]

8. -94 relative to transcription initiation site

9. -93 relative to transcription initiation site

10. A+20 relative to transcription initiation site

11. p.0? = effect unknown; probably no protein is produced.

12. 59 nucleotides 3' of the termination codon (in the 3'UTR)

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.

References

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Suggested Reading

  1. Greeley SA, John PM, Winn AN, Ornelas J, Lipton RB, Philipson LH, Bell GI, Huang ES. The cost-effectiveness of personalized genetic medicine: the case of genetic testing in neonatal diabetes. Diabetes Care. 2011;34:622–7. [PMC free article: PMC3041194] [PubMed: 21273495]
  2. Greeley SA, Tucker SE, Naylor RN, Bell GI, Philipson LH. Neonatal diabetes mellitus: a model for personalized medicine. Trends Endocrinol Metab. 2010;21:464–72. [PMC free article: PMC2914172] [PubMed: 20434356]
  3. Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab. 2008;4:200–13. [PubMed: 18301398]
  4. Rubio-Cabezas O, Ellard S. Diabetes mellitus in neonates and infants: genetic heterogeneity, clinical approach to diagnosis, and therapeutic options. Horm Res Paediatr. 2013;80:137–46. [PMC free article: PMC3884170] [PubMed: 24051999]
  5. Shield JP. Neonatal diabetes: new insights into aetiology and implications. Horm Res. 2000;53 Suppl 1:7–11. [PubMed: 10895036]

Chapter Notes

Acknowledgments

The authors receive grant support from NIH grants R01DK098517 and R01FD004095 (DDDL); and R37DK056268 (CAS).

Revision History

  • 23 January 2014 (me) Comprehensive update posted live
  • 5 July 2011 (me) Comprehensive update posted live
  • 4 March 2008 (cd) Revision: sequence analysis and prenatal diagnosis available for INS mutations
  • 8 February 2008 (me) Review posted to live Web site
  • 9 August 2007 (cas) Original submission
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