Maturity onset diabetes of the young

Maturity onset diabetes of the young (monogenic diabetes)
Classification and external resources
Specialty	Endocrinology
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"^[3][4] 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. "^[5] MODY should not be confused with latent autoimmune diabetes of adults (LADA) — a form of type 1 DM, with slower progression to insulin dependence than child-onset type 1 DM, and which occurs later in life.

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.^[6][7]

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.^[8]

Signs, symptoms and differential diagnosis

Currently, MODY is the final diagnosis in 1%–2% of people initially diagnosed with diabetes. The prevalence is 70–110 per million population. 50% of first-degree relatives will inherit the same mutation, giving them a greater than 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, 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.

• 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.
• 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. The mouse model of MODY diabetes suggested that the reduced clearance of sulfonylureas stands behind their therapeutic success in human MODY patients, but Urbanova et al. found that human MODY patients respond differently to the mouse model and that there was no consistent decrease in the clearance of sulfonylureas in randomly selected HNF1A-MODY and HNF4A-MODY patients.^[9]

Presentation

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 mmol/l) discovered before 30 years of age. However, anyone under 50 can develop MODY.^[10]
• A first-degree relative with a similar degree of diabetes.
• Absence of positive antibodies or other autoimmunity (e.g., thyroiditis) in patient and family. However, Urbanova et al. found that about one quarter of Central European MODY patients are positive for islet cell autoantibodies (GADA and IA2A). Their expression is transient but highly prevalent. The autoantibodies were found in patients with delayed diabetes onset, and in times of insufficient diabetes control. The islet cell autoantibodies are absent in MODY in at least some populations (Japanese, Britons).^[11]
• 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).^[12]
• Insulin resistance very rarely happens.^[13]
• Cystic kidney disease in patient or close relatives.
• Non-transient neonatal diabetes, or apparent type 1 diabetes with onset before six months of age.
• Liver adenoma or hepatocellular carcinoma in MODY type 3^[14]
• Renal cysts, rudimentary or bicornuate uterus, vaginal aplasia, absence of the vas deferens, epidymal cysts in MODY type 5^[15]

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

Pathophysiology

The recognised forms of MODY are all due to ineffective insulin production or release by pancreatic beta 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 forms of monogenetic diabetes: MODY and neonatal diabetes.^[16] 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 hyperglycemia throughout life. Small rise on glucose loading. Patients do not tend to get diabetes complications and do not require treatment.[17]
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[18] that has been characterized as "MODY7" by OMIM.[19]
MODY 8	609812	Bile salt dependent lipase	CEL has been associated with a form of diabetes[20] that has been characterized as "MODY8" by OMIM.[21] It is very rare with five families reported to date. It is associated with exocrine pancreatic dysfunction.
MODY 9	612225	PAX4	Pax4 is a transcription factor. MODY 9 is a very rare medical condition.
MODY 10	613370	INS	Mutations in the insulin gene. Usually associated with neonatal diabetes. Rare < 1% cases.
MODY 11	613375	BLK	Mutated B-lymphocyte tyrosin kinase, which is also present in pancreatic islet cells. Very rare.
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.^[22] Unsurprisingly, combined (homozygous) defects of these genes are 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, 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 for management are those 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 younger than 15 years.^[23]

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). Retrieved 2008-07-29.
2. Barry J. Goldstein; Dirk Müller-Wieland (2008). Type 2 diabetes: principles and practice. CRC Press. pp. 529–. ISBN 978-0-8493-7957-4. Retrieved 12 June 2010.
3. Yorifuji, T; Kurokawa, K; Mamada, M; Imai, T; Kawai, M; Nishi, Y; Shishido, S; Hasegawa, Y; Nakahata, T (June 2004). "Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: Phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1beta gene due to germline mosaicism.". The Journal of Clinical Endocrinology and Metabolism 89 (6): 2905–8. doi:10.1210/jc.2003-031828. PMID 15181075.
4. Edghill, EL; Bingham, C; Slingerland, AS; Minton, JA; Noordam, C; Ellard, S; Hattersley, AT (December 2006). "Hepatocyte nuclear factor-1 beta mutations cause neonatal diabetes and intrauterine growth retardation: support for a critical role of HNF-1beta in human pancreatic development". Diabetic medicine : a journal of the British Diabetic Association 23 (12): 1301–6. doi:10.1111/j.1464-5491.2006.01999.x. PMID 17116179.
5. This page has previously claimed that MODY is equivalent to type 1 DM; however, the Oxford Handbook of Clinical Medicine states the above.
6. Tattersall RB (1974). "Mild familial diabetes with dominant inheritance". Q J Med 43 (170): 339–357. PMID 4212169.
7. Tattersall, R (1998). "Maturity-onset diabetes of the young: A clinical history". Diabetic medicine : a journal of the British Diabetic Association 15 (1): 11–4. doi:10.1002/(SICI)1096-9136(199801)15:1<11::AID-DIA561>3.0.CO;2-0. PMID 9472858.
8. "Diagnosis and Classification of Diabetes Mellitus". Retrieved 2014-12-04.
9. Urbanova, J.; et al. (2015). "Half-Life of Sulfonylureas in HNF1A and HNF4A Human MODY Patients is not Prolonged as Suggested by the Mouse Hnf1a-/- Model". Current Pharmaceutical Design 21: 5736–5748. doi:10.2174/1381612821666151008124036.
10. MODY (Report). Retrieved Jan 25, 2010.
11. Urbanova J, Rypackova B, Prochazkova Z, Kucera P, Cerna M, Andel M, Heneberg P (2014). "Positivity for islet cell autoantibodies in patients with monogenic diabetes is associated with later diabetes onset and higher HbA1c level". Diabetic Medicine 31 (4): 466–71. doi:10.1111/dme.12314. PMID 24102923.
12. Maturity Onset Diabetes, SparkPeople, retrieved Jan 21, 2010
13. MODY (Report). Harvard. Retrieved January 23, 2010.
14. A missense TCF1 mutation in a patient with MODY-3 and liver adenomatosis (Report). Retrieved May 19, 2011.
15. Renal Cysts and Diabetes Syndrome (Report). Retrieved May 19, 2011.
16. Leonid Poretsky (December 2008). Principles of Diabetes Mellitus. Springer. pp. 221–. ISBN 978-0-387-09840-1. Retrieved 12 June 2010.
17. Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT. (2014). "Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia.". JAMA 311 (3): 279–86. doi:10.1001/jama.2013.283980. PMID 24430320.
18. 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.
19. Online 'Mendelian Inheritance in Man' (OMIM) MATURITY-ONSET DIABETES OF THE YOUNG, TYPE VII; MODY7 -610508
20. 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.
21. Online 'Mendelian Inheritance in Man' (OMIM) MATURITY-ONSET DIABETES OF THE YOUNG, TYPE VIII, WITH EXOCRINE DYSFUNCTION; MODY8 -609812
22. Dhavendra Kumar; D. J. Weatherall (2008). Genomics and clinical medicine. Oxford University Press US. pp. 184–. ISBN 978-0-19-518813-4. Retrieved 12 June 2010.
23. Galler, Angela; Stange, Thoralf; Müller, Gabriele; Näke, Andrea; Vogel, Christian; Kapellen, Thomas; Bartelt, Heike; Kunath, Hildebrand; Koch, Rainer; Kiess, Wieland; Rothe, Ulrike (2010). "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". Hormone Research in Paediatrics 74 (4): 285–91. doi:10.1159/000303141. PMID 20516654. Retrieved 2010-06-12.