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Maturity onset diabetes of the young
(Monogenic Diabetes)
Classification and external resources
OMIM 606391 (http://omim.org/entry/606391)
DiseasesDB 8330
(http://www.diseasesdatabase.com/ddb8330.htm)
MeSH D003924
(http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?
field=uid&term=D003924)
Maturity onset diabetes of the young
From Wikipedia, the free encyclopedia
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.
Contents
1 History of the concept and treatment of MODY
2 Signs, symptoms and differential diagnosis
2.1 Treatment
2.2 Presentation
3 Pathophysiology
4 Genetics
4.1 Heterozygous
4.2 Homozygous
5 Management
6 Incidence
7 References
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
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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 genetic basis was overlooked 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 12% 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
(http://diabetesdirectory.org/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
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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
The following characteristics suggest the possibility of a diagnosis of MODY in hyperglycemic and diabetic patients:
Mild to moderate hyperglycemia (typically 130250 mg/dl, or 714 mmol/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 six 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 -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.
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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
(http://omim.org/entry/125850)
hepatocyte
nuclear factor
4
Due to a loss-of-function mutation in the HNF4
gene. 5 - 10% cases.
MODY 2
125851
(http://omim.org/entry/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
(http://omim.org/entry/600496)
hepatocyte
nuclear factor
1
Mutations of the HNF1 gene (a homeobox gene).
30 - 70% cases. Tend to be responsive to
sulfonylureas. Low renal threshold for glucose.
MODY 4
606392
(http://omim.org/entry/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
(http://omim.org/entry/137920)
hepatocyte
nuclear factor
1
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
(http://omim.org/entry/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
(http://omim.org/entry/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
(http://omim.org/entry/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
(http://omim.org/entry/612225)
PAX4
MODY
10
613370
(http://omim.org/entry/613370)
INS
Mutations in the insulin gene. Usually associated
with neonatal diabetes. Rare < 1% cases.
Permanent
neonatal
diabetes
606176
(http://omim.org/entry/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 K
ATP
channel.
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mellitus < 1% cases. Tend to respond to sulfonylureas.
Transient
neonatal
diabetes
mellitus
601410
(http://omim.org/entry/601410)
610374
(http://omim.org/entry/610374)
610582
(http://omim.org/entry/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).
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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)?"
(http://www.diabetes.niddk.nih.gov/dm/pubs/mody/#3) . 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 Mller-Wieland (2008). Type 2 diabetes: principles and practice
(http://books.google.com/?id=1NHv7Iwx5AcC&pg=PA529) . CRC Press. pp. 529. ISBN 978-0-8493-7957-4.
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 (http://www.phlaunt.com/diabetes/14047009.php) (Report).
http://www.phlaunt.com/diabetes/14047009.php. Retrieved Jan 25, 2010.
5. ^ Maturity Onset Diabetes (http://www.sparkpeople.com/resource/health_a-z_detail.asp?AZ=595) , SparkPeople,
http://www.sparkpeople.com/resource/health_a-z_detail.asp?AZ=595, retrieved Jan 21 2010
6. ^ MODY (http://harvardatoz.demo.staywellsolutionsonline.com/71,AZ_d0523) (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
(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2972616/) (Report).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2972616/. Retrieved May 19, 2011.
8. ^ Renal Cysts and Diabetes Syndrome (http://www.omim.org/clinicalSynopsis/137920?search=(number:
(137920%20189907))) (Report). http://www.omim.org/clinicalSynopsis/137920?search=(number:
(137920%20189907)). Retrieved May 19, 2011.
9. ^ Leonid Poretsky (December 2008). Principles of Diabetes Mellitus (http://books.google.com/?
id=ffyJZLp4l9gC&pg=PA221) . Springer. pp. 221. ISBN 978-0-387-09840-1. 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" (http://www.pnas.org/cgi/pmidlookup?
view=long&pmid=15774581) . Proc. Natl. Acad. Sci. U.S.A. 102 (13): 480712. doi:10.1073/pnas.0409177102
(http://dx.doi.org/10.1073%2Fpnas.0409177102) . PMC 554843
(//www.ncbi.nlm.nih.gov/pmc/articles/PMC554843/?tool=pmcentrez) . PMID 15774581
(//www.ncbi.nlm.nih.gov/pubmed/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 (http://omim.org/entry/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): 5462. doi:10.1038/ng1708
(http://dx.doi.org/10.1038%2Fng1708) . PMID 16369531 (//www.ncbi.nlm.nih.gov/pubmed/16369531) .
13. ^ Online 'Mendelian Inheritance in Man' (OMIM) MATURITY-ONSET DIABETES OF THE YOUNG, TYPE VIII,
WITH EXOCRINE DYSFUNCTION; MODY8 -609812 (http://omim.org/entry/609812)
14. ^ Dhavendra Kumar; D. J. Weatherall (2008). Genomics and clinical medicine (http://books.google.com/?
id=BbeWA-gbiiwC&pg=PA184) . Oxford University Press US. pp. 184. ISBN 978-0-19-518813-4.
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) .
http://content.karger.com/ProdukteDB/produkte.asp?doi=10.1159/000303141. Retrieved 2010-06-12.
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