Maturity onset diabetes of the young
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 (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.

Contents 1 History of the concept and treatment of MODY 2 Signs, symptoms and differential diagnosis 3 Pathophysiology 4 Genetics 5 Management 6 Related homozygous disorders 7 References 8 External links

[edit] 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.

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.

[edit] Signs, symptoms and differential diagnosis

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 by either 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. In some forms of MODY, standard treatment is appropriate, though exceptions occur. For example, in MODY2, oral agents are relatively ineffective and insulin is unnecessary, while 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 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) discovered before 30 years of age.
• 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 (though obese people can get MODY), or other problems associated with type 2 diabetes or metabolic syndrome (e.g. hypertension, hyperlipidemia, polycystic ovary syndrome).
• Cystic kidney disease in patient or close relatives.
• Non-transient neonatal diabetes, or apparent type 1 diabetes with onset before 6 months of age.

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

[edit] 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).

[edit] Genetics

They are 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	MODY 1 is due to a loss-of-function mutation in the HNF4A gene on chromosome 20.
MODY 2	125851	glucokinase	MODY 2 is due to any of several mutations in the GCK gene on chromosome 7 for glucokinase.
MODY 3	600496	hepatocyte nuclear factor 1α	MODY 3 is caused by mutations of the HNF1α gene, a homeobox gene on chromosome 12.
MODY 4	606392	insulin promoter factor-1	MODY 4 arises from mutations of the IPF1 homeobox (Pdx1) gene on chromosome 13.
MODY 5	137920	hepatocyte nuclear factor 1β	HNF1β-related MODY is one of the less common forms of MODY, with some distinctive clinical features, including atrophy of the pancreas and several forms of renal disease.
MODY 6	606394	neurogenic differentiation 1	MODY 6 arises from mutations of the gene for the transcription factor referred to as neurogenic differentiation 1.
MODY 7	610508	Kruppel-like factor 11	KLF11 has been associated with a form of diabetes[2] that has been characterized as "MODY7" by OMIM.[3]
MODY 8	609812	Bile salt dependent lipase	CEL has been associated with a form of diabetes[4] that has been characterized as "MODY8" by OMIM.[5]
MODY 9	612225	PAX4
Permanent neonatal diabetes mellitus	606176	KCNJ11	A newly identified and potentially treatable form of monogenic diabetes is the neonatal diabetes caused by activating mutations of the KCNJ11 gene.
Transient neonatal diabetes mellitus	601410 610374 610582	ABCC8	Some forms of neonatal-onset diabetes are not permanent.

[edit] 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. 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).

[edit] Related homozygous disorders

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, a small number of people carrying two abnormal alleles have been identified. Unsurprisingly, combined (homozygous) defects of these genes are both much rarer and much more severe in their effects.

• 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.

• 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 HNF4α, HNF1α, HNF1β, and NeuroD1 mutations 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.

[edit] References

[edit] External links

• Fajans SS (1990). "Scope and heterogeneous nature of MODY". Diabetes Care 13 (1): 49–64. doi:10.2337/diacare.13.1.49. PMID 2404717.  (For historical perspective, this review covers the concept just before the nature of the first of the specific molecular defects was discovered. It illustrates the significant change in the disease(s) referred to as MODY before and after 1990.)

• Fajans SS, Bell GI, Polonsky KS (2001). "Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young". N. Engl. J. Med. 345 (13): 971–80. doi:10.1056/NEJMra002168. PMID 11575290. http://content.nejm.org/cgi/content/extract/345/13/971?view=extractpmid=11575290.  (An excellent overview of the modern concept of the 6 types of MODY.)
• Dean L and McEntyre J, 2004. The Genetic Landscape of Diabetes. Bethesda:NCBI, 2004. This is an entire online textbook on the complex genetics of the forms of diabetes. The chapter on MODY provides an up-to-date and concise overview of the molecular defects. Little expansion of clinical knowledge of the 6 types since 2001 has occurred.
• Andrew Hattersley's Exeter and Oxford research groups
• Virtual Grand Rounds: "MODY" by William E. Winter

v • d • e Endocrine pathology: endocrine diseases (E00-35, 240-259) Pancreas/ glucose metabolism Hypofunction Diabetes mellitus types: (type 1, type 2, MODY 1 2 3 4 5 6) · complications (coma, angiopathy, ketoacidosis, nephropathy, neuropathy, retinopathy, cardiomyopathy) insulin receptor (Rabson-Mendenhall syndrome) · Insulin resistance Hyperfunction Hypoglycemia · beta cell (Hyperinsulinism) · G cell (Zollinger-Ellison syndrome) Hypothalamic/ pituitary axes Hypothalamus gonadotropin (Kallmann syndrome, Adiposogenital dystrophy) · CRH (Tertiary adrenal insufficiency) · vasopressin (Neurogenic diabetes insipidus) · general (Hypothalamic hamartoma) Pituitary Hyperpituitarism anterior (Acromegaly, Hyperprolactinaemia, Pituitary ACTH hypersecretion) · posterior (SIADH) · general (Nelson's syndrome) Hypopituitarism anterior (Kallmann syndrome, Growth hormone deficiency, ACTH deficiency/Secondary adrenal insufficiency) · posterior (Neurogenic diabetes insipidus) · general (Empty sella syndrome, Pituitary apoplexy, Sheehan's syndrome, Lymphocytic hypophysitis) Thyroid Hypothyroidism Iodine deficiency · Cretinism (Congenital hypothyroidism) · Myxedema · Euthyroid sick syndrome Hyperthyroidism Hyperthyroxinemia (Thyroid hormone resistance, Familial dysalbuminemic hyperthyroxinemia) · Hashitoxicosis · Thyrotoxicosis factitia · Graves' disease Thyroiditis Acute infectious · Subacute (De Quervain's, Subacute lymphocytic) · Autoimmune/chronic (Hashimoto's, Postpartum, Riedel's) Goitre Endemic goitre · Toxic nodular goitre · Toxic multinodular goitre Thyroid nodule Parathyroid Hypoparathyroidism Pseudohypoparathyroidism Hyperparathyroidism Primary · Secondary · Tertiary · Osteitis fibrosa cystica Adrenal Hyperfunction aldosterone: Hyperaldosteronism/Primary aldosteronism (Conn syndrome, Bartter syndrome, Glucocorticoid remediable aldosteronism) · AME · Liddle's syndrome · 17α CAH cortisol: Cushing's syndrome (Pseudo-Cushing's syndrome) sex hormones: 21α CAH · 11β CAH Hypofunction/ Adrenal insufficiency (Addison's, WF) aldosterone: Hypoaldosteronism (21α CAH, 11β CAH) cortisol: CAH (Lipoid, 3β, 11β, 17α, 21α) sex hormones: 17α CAH Gonads ovarian: Polycystic ovary syndrome · Premature ovarian failure testicular: enzymatic (5-alpha-reductase deficiency, 17-beta-hydroxysteroid dehydrogenase deficiency) · Androgen receptor (Androgen insensitivity syndrome) general: Hypogonadism (Delayed puberty) · Hypergonadism (Precocious puberty) Height Gigantism · Dwarfism/Short stature (Laron syndrome, Psychogenic dwarfism) Multiple Autoimmune polyendocrine syndrome (APS1, APS2) · Carcinoid syndrome · Multiple endocrine neoplasia (1, 2A, 2B) · Progeria · Woodhouse-Sakati syndrome endocrine navs: anat/physio/dev/hormones, noncongen/congen/neoplasia, symptoms+signs/eponymous, proc