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Monogenic Forms of Diabetes: Neonatal Diabetes Mellitus and Maturity-onset Diabetes of the Young

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The most common forms of diabetes, type 1 and type 2, are polygenic, meaning the risk of developing these forms of diabetes is related to multiple genes. Environmental factors, such as obesity in the case of type 2 diabetes, also play a part in the development of polygenic forms of diabetes. Polygenic forms of diabetes often run in families. Doctors diagnose polygenic forms of diabetes by testing blood glucose in individuals with risk factors or symptoms of diabetes.

Genes provide the instructions for making proteins within the cell. If a gene has a mutation, the protein may not function properly. Genetic mutations that cause diabetes affect proteins that play a role in the ability of the body to produce insulin or in the ability of insulin to lower blood glucose. People have two copies of most genes; one gene is inherited from each parent.

Monogenic Forms of Diabetes

Some rare forms of diabetes result from mutations in a single gene and are called monogenic. Monogenic forms of diabetes account for about 1 to 5 percent of all cases of diabetes in young people. In most cases of monogenic diabetes, the gene mutation is inherited; in the remaining cases the gene mutation develops spontaneously. Most mutations in monogenic diabetes reduce the body's ability to produce insulin, a protein produced in the pancreas that helps the body use glucose for energy. Neonatal diabetes mellitus (NDM) and maturity-onset diabetes of the young (MODY) are the two main forms of monogenic diabetes. MODY is much more common than NDM. NDM first occurs in newborns and young infants; MODY usually first occurs in children or adolescents but may be mild and not detected until adulthood.

Genetic testing can diagnose most forms of monogenic diabetes. If genetic testing is not performed, people with monogenic diabetes may appear to have one of the polygenic forms of diabetes. When hyperglycemia is first detected in adulthood, type 2 is often diagnosed instead of monogenic diabetes. Some monogenic forms of diabetes can be treated with oral diabetes medications while other forms require insulin injections. A correct diagnosis that allows the proper treatment to be selected should lead to better glucose control and improved health in the long term. Testing of other family members may also be indicated to determine whether they are at risk for diabetes.

Read more about diabetes in Your Guide to Diabetes: Type 1 and Type 2 at www.diabetes.niddk.nih.gov and in National Diabetes Statistics Report, 2014 at www.cdc.gov.

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What is neonatal diabetes mellitus (NDM)?

NDM is a monogenic form of diabetes that occurs in the first 6 months of life. It is a rare condition occurring in only one in 100,000 to 500,000 live births. Infants with NDM do not produce enough insulin, leading to an increase in blood glucose. NDM can be mistaken for the much more common type 1 diabetes, but type 1 diabetes usually occurs later than the first 6 months of life. In about half of those with NDM, the condition is lifelong and is called permanent neonatal diabetes mellitus (PNDM). In the rest of those with NDM, the condition is transient and disappears during infancy but can reappear later in life; this type of NDM is called transient neonatal diabetes mellitus (TNDM). Specific genes that can cause NDM have been identified. More information about each type of NDM is provided in the appendix.

This drawing shows a body cell with a nucleus in the center.  A close-up of the nucleus shows a pair of chromosomes.  A close-up of one chromosome shows a strand of DNA.  One section of the DNA strand is labeled as a gene.
Genes affect a person's risk of developing diabetes.

Symptoms of NDM include thirst, frequent urination, and dehydration. NDM can be diagnosed by finding elevated levels of glucose in blood or urine. In severe cases, the deficiency of insulin may cause the body to produce an excess of acid, resulting in a potentially life-threatening condition called ketoacidosis. Most fetuses with NDM do not grow well in the womb and newborns are much smaller than those of the same gestational age, a condition called intrauterine growth restriction. After birth, some infants fail to gain weight and grow as rapidly as other infants of the same age and sex. Appropriate therapy improves and may normalize growth and development.

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What is maturity-onset diabetes of the young (MODY)?

MODY is a monogenic form of diabetes that usually first occurs during adolescence or early adulthood. However, MODY sometimes remains undiagnosed until later in life. A number of different gene mutations have been shown to cause MODY, all of which limit the ability of the pancreas to produce insulin. This process leads to the high blood glucose levels characteristic of diabetes and, in time, may damage body tissues, particularly the eyes, kidneys, nerves, and blood vessels. MODY accounts for about 1 to 5 percent of all cases of diabetes in the United States. Family members of people with MODY are at greatly increased risk for the condition.

A drawing of a family tree shows a mother, father, and two daughters.  The mother and one daughter are shaded gray.  The father and the other daughter are a solid color.  Labels indicate that the mother and one daughter have MODY, while the father and the other daughter do not have MODY.
Each child of a parent with MODY has a 50 percent chance of inheriting the disease.

People with MODY may have only mild or no symptoms of diabetes and their hyperglycemia may only be discovered during routine blood tests. MODY may be confused with type 1 or type 2 diabetes. People with MODY are generally not overweight and do not have other risk factors for type 2 diabetes, such as high blood pressure or abnormal blood fat levels. While both type 2 diabetes and MODY can run in families, people with MODY typically have a family history of diabetes in multiple successive generations, meaning that MODY is present in a grandparent, a parent, and a child. Unlike people with type 1 diabetes who always require insulin, people with MODY can often be treated with oral diabetes medications. Treatment varies depending on the genetic mutation that has caused the MODY. More information about each type of MODY is provided in the appendix.

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What do I need to know about genetic testing and counseling?

Testing for monogenic diabetes involves providing a blood sample from which DNA is isolated. The DNA is analyzed for changes in the genes that cause monogenic diabetes. Abnormal results can determine the gene responsible for diabetes in a particular individual or show whether someone is likely to develop a monogenic form of diabetes in the future. Genetic testing can also be helpful in selecting the most appropriate treatment for individuals with monogenic diabetes. Prenatal testing can diagnose these conditions in unborn children.

Most forms of monogenic diabetes are caused by dominant mutations, meaning that the condition can be passed on to children when only one parent is affected. In contrast, if the mutation is a recessive mutation, a disease gene must be inherited from both parents for diabetes to occur. For recessive forms of monogenic diabetes, testing can indicate whether parents or siblings without disease are carriers for recessive genetic conditions that could be inherited by their children.

If you suspect that you or a member of your family may have a monogenic form of diabetes, you should seek help from health care professionals-physicians and genetic counselors-who have specialized knowledge and experience in this area. They can determine whether genetic testing is appropriate, select the genetic tests that should be performed, and provide information about the basic principles of genetics, genetic testing options, and confidentiality issues. They also can review the test results with the patient or parent after testing, make recommendations about how to proceed, and discuss testing options for other family members.

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Hope through Research

Researchers are studying the genetic causes of and metabolic processes related to diabetes. Discoveries about monogenic forms of diabetes may contribute to the search for the causes of and treatments for type 1 and type 2 diabetes. For information about clinical trials related to diabetes and genetics, see www.ClinicalTrials.gov.

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Points to Remember

  • Mutations in single genes can cause rare forms of diabetes.
  • Genetic testing can identify many forms of monogenic diabetes.
  • A physician evaluates whether genetic testing is appropriate.
  • A correct diagnosis aided by genetic testing can lead to optimal treatment.
  • Recent research results show that people with certain forms of monogenic diabetes can be treated with oral diabetes medications instead of insulin injections.

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For More Information

Information About Genetic Testing, Evaluation, and Counseling, Funded by the National Institutes of Health (NIH)

The GeneTests website provides information about medical genetics, an international directory of genetic testing laboratories, and an international directory of genetics clinics providing genetic evaluation and genetic counseling.

Information About Genetics

National Human Genome Research Institute
Genetic and Rare Diseases Information Center
P.O. Box 8126
Gaithersburg, MD 20898-8126
Phone: 1-888-205-2311
Fax: 240-632-9164
Email: gardinfo@nih.gov
Internet: www.genome.gov/health

The Genetics Home Reference website provides consumer-friendly information about genetic conditions. A service of the National Library of Medicine (NLM), NIH.

The Online Mendelian Inheritance in Man database is a catalog of human genes and genetic disorders with references and related links. A service of the National Center for Biotechnology Information, NLM, NIH.

Entrez Gene is a searchable database of genes with extensive information and related links. A service of the National Center for Biotechnology Information, NLM, NIH.

The Diabetes Research department and the Centre for Molecular Genetics at the Peninsula Medical School and Royal Devon and Exeter Hospital, Exeter, United Kingdom Exit Disclaimer image provides information for patients and health care professionals about genetic forms of diabetes.

The International Society for Pediatric and Adolescent Diabetes Exit Disclaimer image is an international society for health care professionals and others interested in childhood diabetes. They publish consensus guidelines; see the list of selected references.

Information About Diabetes

National Diabetes Information Clearinghouse
1 Information Way
Bethesda, MD 20892-3560
Phone: 1-800-860-8747
Fax: 703-738-4929
Email: ndic@info.niddk.nih.gov
Internet: www.diabetes.niddk.nih.gov

National Diabetes Education Program
1 Diabetes Way
Bethesda, MD 20892-3560
Phone: 1-800-438-5383
Fax: 703-738-4929
Email: ndep@mail.nih.gov
Internet: www.ndep.nih.gov

American Diabetes Association
National Call Center
1701 North Beauregard Street
Alexandria, VA 22311-1742
Phone: 1-800-DIABETES (342-2383)
Fax: 703-549-6995
Email: AskADA@diabetes.org
Internet: www.diabetes.org Exit Disclaimer image

Juvenile Diabetes Research Foundation International
26 Broadway, 14th Floor
New York, NY 10004
Phone: 1-800-533-CURE (2873)
Fax: 212-785-9595
Email: info@jdrf.org
Internet: www.jdrf.org Exit Disclaimer image

You may also find additional information about this topic by visiting MedlinePlus at www.medlineplus.gov.

This publication may contain information about medications. When prepared, this publication included the most current information available. For updates or for questions about any medications, contact the U.S. Food and Drug Administration toll-free at 1-888-INFO-FDA (1-888-463-6332) or visit www.fda.gov. Consult your doctor for more information.


The U.S. Government does not endorse or favor any specific commercial product or company. Trade, proprietary, or company names appearing in this document are used only because they are considered necessary in the context of the information provided. If a product is not mentioned, the omission does not mean or imply that the product is unsatisfactory.

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Appendix and Selected References

Appendix: Characteristics of Monogenic Forms of Diabetes

Type of Diabetes Gene or Syndrome* Affected Protein How Common Usual Age of Onset Type of Inheritance or Mutation** Causes Intrauterine Growth Restriction? Transient or Permanent?*** Treatment
Neonatal Diabetes Mellitus (NDM) Rare; occurs in about one of every 100,000 to 500,000 live births  
Permanent Neonatal Diabetes
Mellitus (PNDM)
50% of all cases of NDM  
PNDM KCNJ11 Kir6.2 Most common type of PNDM 3 to 6 months Autosomal dominant (10%)

Spontaneous
Yes Permanent (This gene also causes a transient form of NDM; see TNDM section) Treated with insulin in the past but often can be treated with oral sulfonylureas
PNDM ABCC8 SUR1-sulfonylurea receptor 1 Rare 1 to 3 months Autosomal dominant (12% of NDM)

Spontaneous
No Permanent (This gene also causes a transient form of NDM; see TNDM section) Treated with insulin in the past but often can be treated with oral sulfonylureas
PNDM GCK glucokinase Rare 1 week Autosomal recessive Yes Permanent Insulin
PNDM IPF1; also known as PDX1 insulin promoter factor 1 Rare 1 week Autosomal recessive Yes Permanent Treat to replace endocrine and exocrine pancreas functions
PNDM PTF1A pancreas transcription factor 1 A Rare At birth Autosomal recessive Yes Permanent Treat to replace endocrine and exocrine pancreas functions
PNDM FOXP3, IPEX syndrome forkhead box P3 Rare Sometimes present at birth X-linked Yes Permanent Insulin
PNDM EIF2AK3, Wolcott-Rallison syndrome eukaryotic translation initiation factor 2-alpha kinase 3 Rare 3 months Autosomal recessive Yes Permanent Insulin and treatment for associated conditions
Transient Neonatal Diabetes
Mellitus (TNDM)
50% of all cases of NDM  
TNDM ZAC/HYMAI ZAC: pleomorphic adenoma gene-like 1 or PLAG1

HYMAI: hydatiform mole-associated and imprinted transcript
Most common form of NDM Birth to 3 months Autosomal dominant

Spontaneous
Yes Transient Initially, treat with insulin; reduce dosage as needed; when diabetes recurs, treat with diet modification and physical activity; may also require insulin
TNDM ABCC8 SUR1-sulfonylurea receptor 1 Rare Birth to 6 months Autosomal dominant

Spontaneous
Varies Transient (This gene also causes a permanent form of NDM; see PNDM section) Oral sulfonylureas
TNDM KCNJ11 Kir6.2 Uncommon cause of TNDM but most common cause of PNDM Birth to 6 months Autosomal dominant

Spontaneous
Yes Transient (This gene also causes a permanent form of NDM; see PNDM section) Oral sulfonylureas
TNDM HNF1 β (beta); also known as HNF1B hepatocyte nuclear factor 1B Rare Birth to 6 months Autosomal dominant (60%)

Spontaneous
Yes Transient Insulin
Maturity-onset Diabetes of the
Young (MODY)
1 to 5% of all cases of diabetes in the United States  
MODY 1 HNF4A hepatocyte nuclear factor 4ɑ (alpha) Rare Adolescence or early adulthood Autosomal dominant No Permanent For most, oral sulfonylureas; some patients may need insulin
MODY 2 GCK glucokinase MODY 2 and MODY 3 account for about two-thirds of all cases of MODY

MODY 2 is the second-most common form of MODY
Mild hyperglycemia may be present at birth; otherwise, early childhood Autosomal dominant Lower than normal birth-weight can occur Permanent Diet modification and physical activity; medications usually not required; some patients do not require any treatment during childhood
MODY 3 TCF1 hepatic nuclear factor 1ɑ (alpha) or HNF1ɑ (alpha) or HNF1A MODY 3 is the most common form of MODY Adolescence or early adulthood Autosomal dominant No Permanent Initially, treat with diet modification; can be treated with oral sulfonylureas; some patients may need insulin
MODY 4 IPF1; also known as PDX1 insulin promoter factor 1 Rare Early adulthood; can present later Autosomal dominant No Permanent Oral sulfonylureas; some patients may need insulin
MODY 5 TCF2 hepatic nuclear factor 1β (beta) or HNF1B Rare Adolescence or early adulthood Autosomal dominant No Permanent Insulin; patients also may need treatment for related conditions such as kidney failure or cysts
MODY 6 NeuroD1, or BETA2 neurogenic differentiation factor 1 Rare In the fourth decade of life Autosomal dominant No Permanent Insulin

*Gene or Syndrome: the name of the gene with the mutation or the syndrome-a grouping of conditions that occur together and indicate a specific disease-caused by the mutated gene

**Type of Inheritance or Mutation:

  • Autosomal dominant. Normally, every cell has two copies of each gene-one that comes from the mother and one from the father. An autosomal dominant inheritance pattern means that a mutation happens in only one copy of the gene, and a parent with a mutation can pass on a copy of their working gene or a copy of their damaged gene. In autosomal dominant inheritance, a child who has a parent with a mutation has a 50% chance of inheriting that mutation.
  • Autosomal recessive. Normally, every cell has two copies of each gene-one that comes from the mother and one from the father. An autosomal recessive inheritance pattern means a mutation must be present in both copies of the gene in order for a person to be affected, and each parent must pass on a gene mutation for a child to be affected. If a person only has one copy of the gene mutation, that person is called a carrier. If both parents are carriers of a recessive gene mutation, each child has a 25% chance of being affected.
  • Spontaneous. A new mutation, or change, in a gene
  • X-linked. When a trait or a disease occurs in a person who has inherited a mutated gene on the X chromosome, one of the sex chromosomes

***Transient or Permanent: whether the form of diabetes goes away after some time, called transient, or is permanent

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Selected References

Babenko AP, Polak M, Cavé H, Busiah K, Czernichow P, Scharfmann R, Bryan J, Aguilar-Bryan L, Vaxillaire M, Froguel P. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. New England Journal of Medicine. 2006;355(5):456-466.

Colombo C, Delvecchio M, Zecchino C, Falenza MF, Cavallo L, Barbetti F. Transient neonatal diabetes mellitus is associated with a recurrent (R201H) KCNJ11 (Kir6.2) mutation. Diabetologia. 2005;48:2439-2441.

Craig ME, Hattersley A, Donaghue K. International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice Consensus Guidelines 2006-2007. Definition, epidemiology and classification. Pediatric Diabetes. 2006;7:343-351.

Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. New England Journal of Medicine. 2001;345(13):971-980.

Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njølstad PR, Ashcroft FM, Hattersley AT. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. New England Journal of Medicine. 2004;350(18):1838-1849.

Hattersley A, Bruining J, Shield J, Njølstad P, Donaghue K. International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice Consensus Guidelines 2006-2007. The diagnosis and management of monogenic diabetes in children. Pediatric Diabetes. 2006;7:352-360.

Hattersley AT. Beyond the beta cell in diabetes. Nature Genetics. 2006;38(1):12-13.

Hattersley AT, Ashcroft FM. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes. 2005;54:2503-2513.

Hattersley AT, Pearson, ER. Minireview: pharmacogenetics and beyond: the interaction of therapeutic response, beta-cell physiology, and genetics in diabetes. Endocrinology. 2006;147:2657-2663.

National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. The genetic landscape of diabetes. Available at: www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=diabetes.TOC&depth=2. Posted 2004. Accessed January 2, 2007.

Pearson ER, Flechtner I, Njølstad PR, Malecki MT, Flanagan SE, Larkin B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J, Robert JJ, Holst JJ, Clark PM, Ellard S, Søvik O, Polak M, Hattersley AT for the Neonatal Diabetes International Collaborative Group. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. New England Journal of Medicine. 2006;355(5):467-477.

Ræder H, Johansson S, Holm PI, Haldorsen IS, Mas E, Sbarra V, Nermoen I, Eide SA, Grevle L, Bjorkhaug L, Sagen JV, Aksnes L, Søvik O, Lombardo D, Molven A, Njølstad PR. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nature Genetics. 2006;38(1):54-62.

Sperling MA. ATP-sensitive potassium channels-neonatal diabetes mellitus and beyond. New England Journal of Medicine. 2006;355(5):507-510.

Sperling MA. Neonatal diabetes mellitus: from understudy to center stage. Current Opinion in Pediatrics. 2005;17:512-518.

Vaxillaire M, Froguel P. Genetic basis of maturity-onset diabetes of the young. Endocrinology and Metabolism Clinics of North America. 2006;35:371-384.

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National Diabetes Information Clearinghouse

1 Information Way
Bethesda, MD 20892–3560
Phone: 1–800–860–8747
TTY: 1–866–569–1162
Fax: 703–738–4929
Email: ndic@info.niddk.nih.gov
Internet: www.diabetes.niddk.nih.gov

The National Diabetes Information Clearinghouse (NDIC) is a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The NIDDK is part of the National Institutes of Health of the U.S. Department of Health and Human Services. Established in 1978, the Clearinghouse provides information about diabetes to people with diabetes and to their families, health care professionals, and the public. The NDIC answers inquiries, develops and distributes publications, and works closely with professional and patient organizations and Government agencies to coordinate resources about diabetes.

Publications produced by the Clearinghouse are carefully reviewed by both NIDDK scientists and outside experts. This publication was reviewed by Mark A. Sperling, M.D., Department of Pediatrics, Children's Hospital, University of Pittsburgh; Kenneth S. Polonsky, M.D., Department of Medicine, Washington University School of Medicine; and Concepcion R. Nierras, Ph.D., Juvenile Diabetes Research Foundation International.

This publication is not copyrighted. The Clearinghouse encourages users of this publication to duplicate and distribute as many copies as desired.


NIH Publication No. 07-6141
March 2007

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Page last updated August 27, 2014


The National Diabetes Information Clearinghouse is a service of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.

National Diabetes Information Clearinghouse
1 Information Way
Bethesda, MD 20892–3560
Phone: 1–800–860–8747
TTY: 1–866–569–1162
Fax: 703–738–4929
Email: ndic@info.niddk.nih.gov
Internet: www.diabetes.niddk.nih.gov

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