Maturity onset diabetes of the young

Maturity onset diabetes of the young (Monogenic Diabetes)
Classification and external resources
OMIM	606391
DiseasesDB	8330
MeSH	D003924

Maturity onset diabetes of the young (MODY)^[1] refers to any of several hereditary forms of diabetes caused by mutations in an autosomal dominant gene^[2] (sex independent, i.e. inherited from any of the parents) disrupting insulin production. MODY is often referred to as "monogenic diabetes" to distinguish it from the more common types of diabetes (especially type 1 and type 2), which involve more complex combinations of causes involving multiple genes (i.e., "polygenic") and environmental factors. MODY 2 and MODY 3 are the most common forms. The severity of the different types varies considerably, but most commonly MODY acts like a very mild version of type 1 diabetes, with continued partial insulin production and normal insulin sensitivity. MODY is not type 2 diabetes in a young person, as might erroneously be inferred from the name.

History of the concept and treatment of MODY

The term MODY dates back to 1964, when diabetes mellitus was considered to have two main forms: juvenile-onset and maturity-onset, which roughly corresponded to what we now call type 1 and type 2. MODY was originally applied to any child or young adult who had persistent, asymptomatic hyperglycemia without progression to diabetic ketosis or ketoacidosis. In retrospect we can now recognize that this category covered a heterogeneous collection of disorders which included cases of dominantly inherited diabetes (the topic of this article, still called MODY today), as well as cases of what we would now call type 2 diabetes occurring in childhood or adolescence, and a few even rarer types of hyperglycemia (e.g., mitochondrial diabetes or mutant insulin). Many of these patients were treated with sulfonylureas with varying degrees of success.

The current usage of the term MODY dates from a case report published in 1974.^[3] This milder form of diabetes had been recognised in the pre insulin period. This was forgotton posibly because of Joslin's dictum that all young people with diabetes should be treated with insulin. With the introduction of sulphonylureas in the 1950s it was found that tolbutamide could improve or normalize carbohydrate tolerance in some young non-obese mildly diabetic patients. The geentic basis was over looked because it was thought that diabetes was a homogeneous disease with young and old patients forming part of the same continuum. In 1973 Fajans had shown that the carbohydrate intolerance of 45 patients diagnosed under age 25 had not progressed after up to 16 years on sulphonylureas and that 43 out of 45 of these subjects had a first degree relative with diabetes. In the same year Lestradet also described a non-insulin-dependent form of childhood diabetes which was later established to be dominantly inherited. In 1974 Tattersall described three families in which diabetes, although diagnosed in adolescence, could be treated with sulphonylureas over 40 years later and was dominantly inherited. Also in 1974 Tattersall and Fajans coined the acronym MODY which was defined as 'fasting hyperglycaemia diagnosed under age 25 which could be treated without insulin for more than two years'.

By the 1990s, as the understanding of the pathophysiology of diabetes has improved, the concept and usage of "MODY" have become refined and narrower. It is now used as a synonym for dominantly inherited, monogenic defects of insulin secretion occurring at any age, and no longer includes any forms of type 2 diabetes.

Signs, symptoms and differential diagnosis

Currently MODY is the final diagnosis in 1-2% people initially diagnosed with diabetes. It prevelance is 70 - 110 per million population. 50% of first degree relatives will inherit the same mutation giving them a >95% lifetime risk of developing MODY themselves. For this reason correct diagnosis of this condition is important. Typically patients present with a strong family history of diabetes (any type) and the onset of symptoms is in the second to fifth decade.

There are two general types of clinical presentation.

• Some forms of MODY produce significant hyperglycemia and the typical signs and symptoms of diabetes: increased thirst and urination (polydipsia and polyuria).
• In contrast, however, many people with MODY have no signs or symptoms and are diagnosed either by accident, when a high glucose is discovered during testing for other reasons, or screening of relatives of a person discovered to have diabetes. Discovery of mild hyperglycemia during a routine glucose tolerance test for pregnancy is particularly characteristic.

MODY cases may make up as many as 5% of presumed type 1 and type 2 diabetes cases in a large clinic population. While the goals of diabetes management are the same no matter what type, there are two primary advantages of confirming a diagnosis of MODY.

• Firstly, insulin may not be necessary and it may be possible to switch a person from insulin injections to oral agents without loss of glycemic control.
• Secondly, it may prompt screening of relatives and so help identify other cases in family members.

As it occurs infrequently, many cases of MODY are initially assumed to be more common forms of diabetes: type 1 if the patient is young and not overweight, type 2 if the patient is overweight, or gestational diabetes if the patient is pregnant. Standard diabetes treatments (insulin for type 1 and gestational diabetes, and oral hypoglycemic agents for type 2) are often initiated before the doctor suspects a more unusual form of diabetes.

Treatment

In some forms of MODY, standard treatment is appropriate, though exceptions occur:

• In MODY2, oral agents are relatively ineffective and insulin is unnecessary.
• In MODY1 and MODY3, insulin may be more effective than drugs to increase insulin sensitivity.
• Sulfonylureas are effective in the K_ATP channel forms of neonatal-onset diabetes.

Presentation of MODY

The following characteristics suggest the possibility of a diagnosis of MODY in hyperglycemic and diabetic patients:

• Mild to moderate hyperglycemia (typically 130–250 mg/dl, or 7-14 mM/L) discovered before 30 years of age. However, anyone under 50 can develop MODY.^[4]
• A first-degree relative with a similar degree of diabetes.
• Absence of positive antibodies or other autoimmunity (e.g., thyroiditis) in patient and family.
• Persistence of a low insulin requirement (e.g., less than 0.5 u/kg/day) past the usual "honeymoon" period.
• Absence of obesity (although overweight or obese people can get MODY), or other problems associated with type 2 diabetes or metabolic syndrome (e.g. hypertension, hyperlipidemia, polycystic ovary syndrome).^[5]
• Insulin resistance very rarely happens.^[6]
• Cystic kidney disease in patient or close relatives.
• Non-transient neonatal diabetes, or apparent type 1 diabetes with onset before 6 months of age.
• Liver adenoma or hepatocellular carcinoma in MODY type 3^[7]
• Renal cysts, rudimentary or bicornuate uterus, vaginal aplasia, absence of the vas deferens, epidymal cysts in MODY type 5^[8]

The diagnosis of MODY is confirmed by specific gene testing, now available through several commercial laboratories.

Pathophysiology

The recognised forms of MODY are all due to ineffective insulin production or release by pancreatic β-cells. Several of the defects are mutations of transcription factor genes. One form is due to mutations of the glucokinase gene. For each form of MODY, multiple specific mutations involving different amino acid substitutions have been discovered. In some cases, there are significant differences in the activity of the mutant gene product that contribute to variations in the clinical features of the diabetes (such as degree of insulin deficiency or age of onset).

Genetics

Some sources make a distinction between two different forms of monogenetic diabetes: MODY and neonatal diabetes.^[9] However, they have much in common, and are often studied together.

Heterozygous

MODY is inherited in an autosomal dominant fashion, and most patients therefore have other members of the family with diabetes; penetrance differs between the types (from 40% to 90%).

Type	OMIM	Gene/protein	Description
MODY 1	125850	hepatocyte nuclear factor 4α	Due to a loss-of-function mutation in the HNF4α gene. 5 - 10% cases.
MODY 2	125851	glucokinase	Due to any of several mutations in the GCK gene. 30 - 70% cases. Mild fasting hyperglycaemia throughout life. Small rise on glucose loading.
MODY 3	600496	hepatocyte nuclear factor 1α	Mutations of the HNF1α gene (a homeobox gene). 30 - 70% cases. Tend to be responsive to sulfonylureas. Low renal threshold for glucose.
MODY 4	606392	insulin promoter factor-1	Mutations of the IPF1 homeobox (Pdx1) gene. < 1% cases. Associated with pancreatic agensis in homozygotes and occasionally in heterozygotes.
MODY 5	137920	hepatocyte nuclear factor 1β	One of the less common forms of MODY, with some distinctive clinical features, including atrophy of the pancreas and several forms of renal disease. Defect in HNF-1 beta gene. 5 - 10% cases.
MODY 6	606394	neurogenic differentiation 1	Mutations of the gene for the transcription factor referred to as neurogenic differentiation 1. Very rare - 5 families reported to date.
MODY 7	610508	Kruppel-like factor 11	KLF11 has been associated with a form of diabetes[10] that has been characterized as "MODY7" by OMIM.[11]
MODY 8	609812	Bile salt dependent lipase	CEL has been associated with a form of diabetes[12] that has been characterized as "MODY8" by OMIM.[13] Very rare - 5 families reported to date. Associated with exocrine pancreatic dysfunction.
MODY 9	612225	PAX4
MODY 10	613370	INS	Mutations in the insulin gene. Usually associated with neonatal diabetes. Rare < 1% cases.
Permanent neonatal diabetes mellitus	606176	KCNJ11 and ABCC8	A newly identified and potentially treatable form of monogenic diabetes is the neonatal diabetes caused by activating mutations of the ABCC8 or KCNJ11 genes which encode subunits of the KATP channel. < 1% cases. Tend to respond to sulfonylureas.
Transient neonatal diabetes mellitus	601410 610374 610582	ABCC8	Some forms of neonatal-onset diabetes are not permanent. < 1% cases. Tend to respond to sulfonylureas.

Homozygous

By definition, the forms of MODY are autosomal dominant, requiring only one abnormal gene to produce the disease; the severity of the disease is moderated by the presence of a second, normal allele which presumably functions normally. However, conditions involving people carrying two abnormal alleles have been identified.^[14] Unsurprisingly, combined (homozygous) defects of these genes are both much rarer and much more severe in their effects.

• MODY2: Homozygous glucokinase deficiency causes severe congenital insulin deficiency resulting in persistent neonatal diabetes mellitus. About 6 cases have been reported worldwide. All have required insulin treatment from shortly after birth. The condition does not seem to improve with age.

• MODY4: Homozygous IPF1 results in failure of the pancreas to form. Congenital absence of the pancreas, termed pancreatic agenesis, involves deficiency of both endocrine and exocrine functions of the pancreas.

Homozygous mutations in the other forms have not yet been described. Those mutations for which a homozygous form has not been described may be extremely rare, or may result in clinical problems not yet recognized as connected to the monogenic disorder, or may be lethal for a fetus and not result in a viable child.

Management

Unfortunately, chronic hyperglycemia of any cause can eventually cause blood vessel damage and the microvascular complications of diabetes. The principal treatment goals for people with MODY — keeping the blood sugars as close to normal as possible ("good glycemic control"), while minimizing other vascular risk factors — are the same for all known forms of diabetes.

Tools available for management are also those available for all forms of diabetes: blood testing, changes in diet, physical exercise, oral hypoglycemic agents, and insulin injections. In many cases these goals can be achieved more easily with MODY than with ordinary types 1 and 2 diabetes. Some people with MODY may require insulin injections to achieve the same glycemic control that another person may attain with careful eating or an oral medication.

When oral hypoglycemic agents are used in MODY, the sulfonylureas remain the oral medication of first resort. When compared to patients with type 2 diabetes, MODY patients are often more sensitive to sulphonylureas, such that a lower dose should be used to initiate treatment to avoid hypoglycaemia. Patients with MODY less often suffer from obesity and insulin resistance than those with ordinary type 2 diabetes (for whom insulin sensitizers like metformin or the thiazolidinediones are often preferred over the sulfonylureas).

Incidence

According to data from Saxony, Germany, MODY was responsible for 2.4% of diabetes incidence in children aged less than 15 years.^[15]

References

1. ^ "What is maturity-onset diabetes of the young (MODY)?". National Diabetes Information Clearinghouse (NDIC) (National Institute of Diabetes and Digestive and Kidney Diseases, NIH). http://www.diabetes.niddk.nih.gov/dm/pubs/mody/#3. Retrieved 2008-07-29. 
2. ^ Barry J. Goldstein; Dirk Müller-Wieland (2008). Type 2 diabetes: principles and practice. CRC Press. pp. 529–. ISBN 9780849379574. http://books.google.com/?id=1NHv7Iwx5AcC&pg=PA529. Retrieved 12 June 2010. 
3. ^ Tattersall RB (1974) Mild familial diabetes with dominant inheritance. Q J Med 43(170):339-357
4. ^ MODY (Report). http://www.phlaunt.com/diabetes/14047009.php. Retrieved Jan 25, 2010. 
5. ^ Maturity Onset Diabetes, SparkPeople, http://www.sparkpeople.com/resource/health_a-z_detail.asp?AZ=595, retrieved Jan 21 2010 
6. ^ MODY (Report). Harvard. http://harvardatoz.demo.staywellsolutionsonline.com/71,AZ_d0523. Retrieved January 23, 2010. 
7. ^ A missense TCF1 mutation in a patient with MODY-3 and liver adenomatosis (Report). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2972616/. Retrieved May 19, 2011. 
8. ^ Renal Cysts and Diabetes Syndrome (Report). http://www.omim.org/clinicalSynopsis/137920?search=(number:(137920%20189907)). Retrieved May 19, 2011. 
9. ^ Leonid Poretsky (December 2008). Principles of Diabetes Mellitus. Springer. pp. 221–. ISBN 9780387098401. http://books.google.com/?id=ffyJZLp4l9gC&pg=PA221. Retrieved 12 June 2010. 
10. ^ Neve B, Fernandez-Zapico ME, Ashkenazi-Katalan V, et al. (March 2005). "Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function". Proc. Natl. Acad. Sci. U.S.A. 102 (13): 4807–12. doi:10.1073/pnas.0409177102. PMC 554843. PMID 15774581. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15774581. 
11. ^ Online 'Mendelian Inheritance in Man' (OMIM) MATURITY-ONSET DIABETES OF THE YOUNG, TYPE VII; MODY7 -610508
12. ^ Raeder H, Johansson S, Holm PI, et al. (January 2006). "Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction". Nat. Genet. 38 (1): 54–62. doi:10.1038/ng1708. PMID 16369531. 
13. ^ Online 'Mendelian Inheritance in Man' (OMIM) MATURITY-ONSET DIABETES OF THE YOUNG, TYPE VIII, WITH EXOCRINE DYSFUNCTION; MODY8 -609812
14. ^ Dhavendra Kumar; D. J. Weatherall (2008). Genomics and clinical medicine. Oxford University Press US. pp. 184–. ISBN 9780195188134. http://books.google.com/?id=BbeWA-gbiiwC&pg=PA184. Retrieved 12 June 2010. 
15. ^ "Incidence of Childhood Diabetes in Children Aged Less than 15 Years and Its Clinical and Metabolic Characteristics at the Time of Diagnosis: Data from the Childhood Diabetes Registry of Saxony, Germany". http://content.karger.com/ProdukteDB/produkte.asp?doi=10.1159/000303141. Retrieved 2010-06-12.