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.

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.

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.

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.

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.

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.

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.

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 provides information for patients and health care professionals about genetic forms of diabetes.

The International Society for Pediatric and Adolescent Diabetes 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

For more information about diabetes, see Diabetes Overview, which is available from the National Diabetes Information Clearinghouse, or contact

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

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

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