maturity onset diabetes of the young
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Maturity-onset diabetes of the young (MODY) refers to any of several
hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic inform ...
forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
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 and environmental factors.
MODY 2 MODY 2 is a form of maturity-onset diabetes of the young. It is due to any of several mutations in the ''GCK'' gene on human chromosome 7 for glucokinase. Glucokinase serves as the glucose sensor for the pancreatic beta cell. Normal glucokinase ...
and
MODY 3 MODY 3 (also HNF1A-MODY) is a form of maturity-onset diabetes of the young. It is caused by mutations of the HNF1-alpha gene, a homeobox gene on human chromosome 12. This is the most common type of MODY in populations with European ancestry, acco ...
are the most common forms. Robert Tattersall and Stefan Fajans initially identified the phenomenon known as maturity onset diabetes of the young in a classic study published in the journal '' Diabetes'' in 1975.


Signs and symptoms

MODY is the final diagnosis in 1%–2% of people initially diagnosed with diabetes. The prevalence is 70–110 per million people. 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 Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200  mg/dL), but symptoms may not start to become noticeable until even ...
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 Screening may refer to: * Screening cultures, a type a medical test that is done to find an infection * Screening (economics), a strategy of combating adverse selection (includes sorting resumes to select employees) * Screening (environmental), a ...
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.


Genetics

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


Heterozygous

MODY is inherited in an
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
fashion, and most patients therefore have other members of the family with diabetes; penetrance differs between the types (from 40% to 90%).


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. 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 Neonatal diabetes mellitus (NDM) is a disease that affects an infant and their body's ability to produce or use insulin. NDM is a monogenic (controlled by a single gene) form of diabetes that occurs in the first 6 months of life. Infants do not pr ...
. 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 The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an end ...
, 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.


Pathophysiology

The recognised forms of MODY are all due to ineffective insulin production or release by
pancreatic The pancreas is an Organ (anatomy), organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine ...
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).


Diagnosis

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 25 years of age. However, anyone under 50 can develop MODY. * 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 (GABA 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). * Persistence of a low insulin requirement (e.g., less than 0.5 u/kg/day) past the usual "
honeymoon A honeymoon is a vacation taken by newlyweds immediately after their wedding, to celebrate their marriage. Today, honeymoons are often celebrated in destinations considered exotic or romantic. In a similar context, it may also refer to the phase ...
" period. * Normal insulin levels (e.g. 2.6-24.9) * Absence of obesity (although overweight or obese people can get MODY) or other problems associated with type 2 diabetes or
metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Metabolic syndrome ...
(e.g.,
hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
, hyperlipidemia, polycystic ovary syndrome). *
Insulin resistance Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
very rarely happens. * Cystic kidney disease in patient or close relatives. * Non-transient
neonatal diabetes Neonatal diabetes mellitus (NDM) is a disease that affects an infant and their body's ability to produce or use insulin. NDM is a monogenic (controlled by a single gene) form of diabetes that occurs in the first 6 months of life. Infants do not pr ...
, or apparent type 1 diabetes with onset before six months of age. * Liver adenoma or hepatocellular carcinoma in MODY type 3 * Renal cysts, rudimentary or bicornuate uterus, vaginal aplasia, absence of the vas deferens, epidymal cysts in MODY type 5 The diagnosis of MODY is confirmed by specific gene testing available through commercial laboratories.


Classification

Common or well-established forms of MODY (1% of MODY or greater) - HNF1A-(MODY3), HNF4A-(MODY1) and GCK-(MODY2), HNF1B-(MODY5), ABCC8-(MODY12), KCNJ11-(MODY13), INS-(MODY10)
Rare forms of MODY (Few families described but reasonable generic evidence for causing MODY) - NEUROD1-(MODY6), IPF1/PDX1-(MODY4), CEL-(MODY8), WSF1 and RFX6
Genes reported as causal for MODY but evidence not compelling - BLK-(MODY11), PAX4-(MODY9) and KLF11-(MODY7), APPL1-(MODY14), NKX6-1


Treatment

In some forms of MODY, standard treatment is appropriate, though exceptions occur: * In MODY2, oral agents are relatively ineffective, however most patients are managed conservatively through diet and exercise. * In MODY1 and MODY3, sulfonylureas are usually very effective, delaying the need for insulin treatment. * Sulfonylureas are effective in the KATP 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. Chronic hyperglycemia due to any cause can eventually cause blood vessel damage and the
microvascular complications of diabetes Blood vessels are the structures of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away from t ...
. 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. The tools for management are similar for all forms of diabetes: blood testing, changes in diet, physical
exercise Exercise is a body activity that enhances or maintains physical fitness and overall health and wellness. It is performed for various reasons, to aid growth and improve strength, develop muscles and the cardiovascular system, hone athletic ...
, 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 Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
than those with ordinary type 2 diabetes (for whom insulin sensitizers like metformin or the
thiazolidinedione The thiazolidinediones , abbreviated as TZD, also known as glitazones after the prototypical drug ciglitazone, are a class of heterocyclic compounds consisting of a five-membered C3NS ring. The term usually refers to a family of drugs used in ...
s are often preferred over the sulfonylureas).


Epidemiology

According to data from Saxony, Germany, MODY was responsible for 2.4% of diabetes incidence in children younger than 15 years.


History

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 Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200  mg/dL), but symptoms may not start to become noticeable until even ...
without progression to
diabetic ketosis Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes mellitus. Signs and symptoms may include vomiting, abdominal pain, deep gasping breathing, increased urination, weakness, confusion and occasionally loss of ...
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 A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used th ...
or
mutant insulin In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It ...
). 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. Since 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.


Miscellaneous

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.


References


External links

{{Transcription factor/coregulator deficiencies Diabetes Congenital disorders