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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
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 currently known to be associated with nonsyndromic PNDM are KCNJ11 (30% of PNDM), ABCC8 (approximately 19%), INS (approximately 20%), GCK (4%), and PDX1 (<1%). Molecular genetic testing is available on a clinical basis for all genes.
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 and INS, autosomal dominant or autosomal recessive for mutations ABCC8, 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-MODY and PDX1-MODY, respectively. 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 MODY), and a 25% chance of being unaffected and not a carrier. Prenatal diagnosis for pregnancies at increased risk for KCNJ11- or INS-related PNDM is possible if the disease-causing mutations in the family are known. Although no laboratories offering molecular genetic testing for prenatal diagnosis for the other forms of PNDM are listed in the GeneTests Laboratory Directory, prenatal testing may be available through laboratories offering custom prenatal testing for pregnancies at increased risk in families in which the disease-causing mutation(s) have been identified.
Permanent neonatal diabetes mellitus (PNDM) was traditionally defined as diabetes mellitus beginning in the first three months of life; however, recent genetic findings suggest that the definition should be expanded to include diabetes mellitus beginning in the first six months of life.
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 such as glucosuria, ketonuria, and hyperketonemia may be present.
Pancreatic imaging. Imaging of the pancreas with ultrasound or CT is used to determine its presence and size.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genes. Five genes are currently known to be associated with nonsyndromic permanent neonatal diabetes:
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 [Stoy 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-MODY).
PDX1. Rarely, PNDM is attributed to inactivating mutations of PDX1 [Stoffers et al 1997a]. Carrier parents have mild, adult-onset diabetes mellitus (PDX1-MODY).
Note: Rare syndromic forms of neonatal diabetes can be caused by mutations in FOXP3, PTF1A, GLIS3, and EIF2AK3 (see Differential Diagnosis).
Clinical testing
Sequence analysis. Clinical testing by sequencing of coding regions of the following genes is available: KCNJ11, ABCC8, GCK, INS, and PDX1.
| Gene Symbol | Proportion of PNDM Attributed to Mutations in This Gene | Test Method | Mutation Detection Frequency by Gene and Test Method 1 | Test Availability |
|---|---|---|---|---|
| KCNJ11 | 30% | Sequence analysis | ~99% | Clinical
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| ABCC8 | 19% | ~99% | Clinical
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| INS | 20% | Unknown | Clinical
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| GCK | 4% | ~99% | Clinical
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| PDX1 | <% (estimate) | ~99% | Clinical
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1. Mutation detection frequencies given are estimates. Exonic or whole-gene deletions, which are not detected by sequence analysis, have not been reported to date; however, it is unclear whether mutational studies would have detected such deletions.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Confirming 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 these can be dominantly transmitted.
Individuals with neurologic findings suggestive of developmental delay, epilepsy, and neonatal diabetes mellitus (DEND) syndrome should first be tested for mutations in KCNJ11.
Individuals with two parents with diabetes mellitus should first be tested for mutations in GCK and PDX1, as carriers of these mutations can have mild diabetes mellitus (GCK-MODY and PDX1-MODY, 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.
Prognostication in an individual with the disorder
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 of exocrine pancreatic insufficiency.
Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Heterozygotes are asymptomatic.
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation(s) in the family.
KCNJ11, 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 diet or 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
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].
GCK. Dominant inactivating mutations of GCK are associated with a mild form of diabetes mellitus, maturity-onset diabetes of the young type 2 (GCK-MODY).
PDX1. Dominant inactivating mutations of PDX1 are associated with a mild form of diabetes mellitus (PDX1-MODY).
Permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of hyperglycemia within the first six months of life with a mean age of 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 as a result of 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 has been called the DEND syndrome [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 as a result of heterozygous INS mutations presents with diabetic ketoacidosis or marked hyperglycemia. Most newborns are small for gestational age [Stoy et al 2007, Polak et al 2008]. The median age at diagnosis is nine weeks, but some children present after age six months.
GCK. PNDM as a result of 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 as a result of 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 only 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 whereas others are associated with PNDM, p.Val252Ala and p.Arg201, however, 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 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, 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.
Reduced penetrance has been seen in PNDM caused by mutations in KCNJ11 and ABCC8 [Flanagan et al 2007].
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" should replace the designation "neonatal diabetes mellitus" [Massa et al 2005].
The estimated incidence of neonatal diabetes mellitus, both transient and permanent, is 1:400,000 births [Shield 2000].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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 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. The three mechanisms that cause TNDM in 90% of cases are:
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 the absence of the cerebellum as demonstrated by 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 the only gene currently known to be associated with 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 dysfunctional [Senee et al 2004]. The prognosis is poor. EIF2AK3, the gene encoding eukaryotic translation initiation factor 2-alpha kinase 3, is the only gene known to be associated with 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].
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.
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.
Initial treatment. Rehydration and intravenous insulin infusion should be started promptly after diagnosis.
Insulin therapy is crucial in permanent neonatal diabetes mellitus (PNDM) to establish appropriate weight gain as the majority of infants present with IUGR.
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 are available regarding the most appropriate insulin preparations for young infants.
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.
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) [Hattersley & Ashcroft 2005, Pearson et al 2006].
Long-term insulin therapy is required for all other causes of PNDM.
High caloric intake should be maintained to achieve weight gain.
Pancreatic enzyme replacement therapy is required in persons with exocrine pancreatic insufficiency.
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 and vulnerability to hypoglycemia in young children, the American Diabetes Association recommends the following:
Glycemic targets for children age <6 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]
Blood glucose concentrations should be monitored at least four times a day lifelong 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
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.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
The mode of inheritance of permanent neonatal diabetes mellitus (PNDM) varies by gene:
Autosomal dominant: KCNJ11 and INS
Autosomal dominant or autosomal recessive: ABCC8
Autosomal recessive: GCK and PDX1
Parents of a proband
Approximately 10% of individuals with autosomal dominant neonatal diabetes mellitus caused by mutations in KCNJ11 or INS have an affected parent. In contrast, no families have been described with dominantly inherited ABCC8-related PNDM [Patch et al 2007].
A proband with autosomal dominant neonatal diabetes mellitus may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations in KCNJ11 or INS is estimated to be 90%. De novo mutations account for approximately 57% of the cases of 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], but 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.
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].
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-MODY and PDX1-MODY, respectively).
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 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-MODY and PDX1-MODY, respectively).
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 testing for at-risk family members is available once the mutations have been identified in the family.
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. 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. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk for KCNJ11-related and INS-related neonatal diabetes mellitus is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele must be identified in the family before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
No laboratories offering molecular genetic testing for prenatal diagnosis for the other forms of PNDM are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available through laboratories offering custom prenatal testing for pregnancies at increased risk in families in which the disease-causing mutation(s) have been identified. See
.
Requests for prenatal testing for conditions such as PNDM that 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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|
| ABCC8 | 11p15.1 | ATP-binding cassette transporter sub-family C member 8 | ABCC8 | |
| KCNJ11 | 11p15.1 | ATP-sensitive inward rectifier potassium channel 11 | KCNJ11 | |
| GCK | 7p15-p13 | Glucokinase | Glucokinase (hexokinase 4) (GCK) @ LOVD | GCK |
| PDX1 | 13q12.1 | Pancreas/duodenum homeobox protein 1 | PDX1 | |
| INS | 11p15.5 | Insulin | INS |
| 138079 | GLUCOKINASE; GCK |
| 176730 | INSULIN; INS |
| 600509 | ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 8; ABCC8 |
| 600733 | INSULIN PROMOTER FACTOR 1; IPF1 |
| 600937 | POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 11; KCNJ11 |
| 606176 | DIABETES MELLITUS, PERMANENT NEONATAL; PNDM |
Normal allelic variants. KCNJ11 is located on chromosome 11p15.1, 4.5 kp telomeric to ABCC8. The gene spans approximately 3.4 kb of genomic DNA and has a single exon.
| Class of Variant Allele | DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences |
|---|---|---|---|
| Normal | c.67G>A | p.Glu23Lys 1 | NM_000525.3NP_000516.3 |
| Pathologic | c.103T>G | p.Phe35Val | |
| c.103T>C | p.Phe35Leu | ||
| c.124T>C | p.Cys42Arg | ||
| c.149G>C | p.Arg50Pro | ||
| c.155A>G | p.Gln52Arg | ||
| c.157G>C | p.Gly53Arg | ||
| c.157G>A | p.Gly53Ser | ||
| c.158G>A | p.Gly53Asp | ||
| c.175G>A | p.Val59Met | ||
| c.176T>G | p.Val59Gly | ||
| c.497G>T | p.Cys166Phe | ||
| c.497G>A | p.Cys166Tyr | ||
| c.499A>C | p.Ile167Leu | ||
| c.509A>G | p.Lys170Arg | ||
| c.510G>C | p.Lys170Asn | ||
| c.544A>G | p.Ile182Val | ||
| c.602G>A | p.Arg201His | ||
| c.601C>T | p.Arg201Cys | ||
| c.602G>T | p.Arg201Leu | ||
| c.755T>C | p.Val252Ala | ||
| c.886A>C | p.Ile296Leu | ||
| c.886A>G | p.Ile296Val | ||
| c.964G>A | p.Glu322Lys | ||
| c.989A>G | p.Tyr330Cys | ||
| c.997T>A | p.Phe333Ile | ||
| c.1001G>A | p.Gly334Asp |
See 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].
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.
| DNA Nucleotide Change | Protein Amino Acid Change | Reference | Reference Sequences |
|---|---|---|---|
| c.215A>G | p.Asn72Ser | Ellard et al [2007] | NM_000352.3NP_000343.2 |
| c.257T>C | p.Val86Ala | Ellard et al [2007] | |
| c.257T>G | p.Val86Gly | Ellard et al [2007] | |
| c.394T>G | p.Phe132Val | Ellard et al [2007] | |
| c.394T>C | p.Phe132Leu | Proks et al [2006] | |
| c.404T>C | p.Leu135Pro | Ellard et al [2007] | |
| c.627C>A | p.Asp209Glu | Ellard et al [2007], Flanagan et al [2007] | |
| c.631C>A | p.Gln211Lys | Ellard et al [2007] | |
| c.638T>G | p.Leu213Arg | Babenko et al [2006] | |
| c.674T>C | p.Leu225Phe | ||
| c.1144G>A | p.Glu382Lys | Ellard et al [2007] | |
| c.3554C>A | p.Ala1185Glu | Ellard et al [2007] | |
| c.4270A>G | p.Ile1424Val | Babenko 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).
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].
Normal allelic variants. GCK spans more than 45 kb of genomic DNA and is made up of ten exons.
| DNA Nucleotide Change (Alias 1 ) | Protein Amino Acid Change | Reference | Reference Sequences |
|---|---|---|---|
| c.629T>A | p.Met210Leu | Njolstad et al [2001] | NM_000162.2NP_000153.1 |
| c.683C>T | p.Thr228Met | ||
| c.790G>A | p.Gly264Ser | Njolstad et al [2003] | |
| 1133C>T | p.Ala378Val | ||
| c.1190G>T | p.Arg397Leu | Porter et al [2005] | |
| c.1505+2T>G (IVS8+2T>G) | -- | Njolstad 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).
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 gluocose 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.
Normal allelic variants. PDX1 has a transcript of 1527 bp and is made up of two exons.
Pathologic allelic variants. At least three 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]
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences |
|---|---|---|
| c.188_189delC | p.Pro63ArgfsX60 | NM_000209.2NP_000200.1 |
| c.492G>T | p.Glu164Asp | |
| c.532G>A | p.Glu178Lys |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
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 upon 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 such as 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.Pro63ArgfsX60) 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.
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.
| DNA Nucleotide Change | Protein Amino Acid Change | Reference | Reference Sequences |
|---|---|---|---|
| c.71C>A | p.Ala24Asp | Stoy et al [2007], Polak et al [2008] | NM_000207.2NP_000198.1 |
| c.94G>A | p.Gly32Ser | ||
| c.94G>C | p.Gly32Arg | ||
| c.127T>G | p.Cys43Gly | ||
| c.140 G>T | p.Gly47Val | ||
| c.143 T>G | p.Phe48Cys | ||
| c.265C>T | p.Arg89Cys | ||
| c.268 G>T | p.Gly90Cys | ||
| c.287G>A | p.Cys96Tyr | ||
| c.323 A>G | p.Tyr108Cys |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).
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. Some reported mutations disrupt normal disulfide bonds (p.Cys43Gly and p.Cys96Tyr) or add an additional upaired 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 [Stoy 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.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
The authors receive grant support from NIH grants K23-DK073663 (DDDL); and R01DK53012 and R01DK56268 (CAS).
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
