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MODY syndrome

Maturity onset diabetes of the young (MODY) refers to any of several rare hereditary forms of diabetes mellitus due to dominantly inherited defects of insulin secretion. As of 2004, six types have been enumerated, but more are likely to be added. 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. It is not type 2 diabetes in a young person, as might erroneously be inferred from the name. more...

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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 our understanding of the pathophysiology of the various forms of diabetes has increased, 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

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 (1) accident, when a high glucose is discovered during testing for other reasons, or (2) 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, the two primary advantages of confirming a diagnosis of MODY are that (1) 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, and (2) it may prompt screening of relatives and discovery of 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 KATP channel forms of MODYX.


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The new genetics in clinical practice - The New Genetics, part 1
From British Medical Journal, 2/21/98 by John Bell

Common diseases are currently defined by their clinical

appearance, with little reference to mechanism. Molecular

genetics may provide the tools necessary to define

diseases by their mechanisms. This is likely to have pro

found effects on clinical decisions such as choice of

treatment and on our ability to characterise more clearly

the course of disease and contributory environmental

factors. This information also raises the possibility that

new therapeutic interventions can be obtained rationally,

based on a clear understanding of pathogenesis. Most of

these genetic factors will act as "risk factors" and should

be managed ethically and practically, as would other risk

factors (in hypertension or hypercholesterolaemia, for

example). The rapid advances in human molecular genetics

seen over the past five years indicate that within the next

decade genetic testing will be used widely for predictive

testing in healthy people and for diagnosis and

management of patients.

Molecular genetics was originally used in medicine to

map and identify the major single gene disorders, such as

cystic fibrosis[1] and polycystic kidney disease.[2] The

excitement in the field has shifted to the elucidation of the

genetic basis of the common diseases. With the help of

very large, well characterised family collections, genetic

linkages for many of the major causes of morbidity and

mortality in Western populations have been identified.

The genes and DNA variants responsible for these

disorders are now being cloned at an ever increasing pace.

Large scale genotyping, increasingly integrated genetic and

expressed sequence maps,[3] and large scale sequencing

programmes[4] have all contributed to this remarkable

evolution in our understanding of how genes might modify

our susceptibility to disease.

Considering the current rapid acquisition of genetic

information relating to common disease and the dramatic

technological developments that continue to fuel the field,

it would be surprising if most of the major genetic factors

involved in human disease were not defined over the next

5-10 years. This information will form an important

template for redefining disease, clarifying biological

mechanisms responsible for disease, and developing new

treatment for most disorders.

The rapid developments in human molecular genetics

have often been underestimated, largely due to a failure to

recognise the power of new technologies being applied to

the problem. The use of information encoded within the

genome for clinical practice has previously been limited by

problems of scaling up accurate detection of DNA

variation for rapid and inexpensive analysis. The problem

will soon be resolved, perhaps by the use of

oligonucleotide array technology or "chips."[5] The ease

with which this can be accomplished will determine how

widespread DNA diagnostics will become, but there is

little doubt that the problem is likely to be solved,

technologically, in the near future.

The role of genes for susceptibility to disease has

been emphasised in clinical medicine; it is now clear

that this represents too narrow a perspective for the

genetics of the future. Although such genes will be critical

for redefining diseases and understanding their

pathogenesis, equally important will be loci that determine

disease progression, disease complications, and response

to treatment.

A new taxonomy of disease

Perhaps the most important single contribution of the new

genetics to health care is that it will create a biological

rather than a phenotypic framework with which to

categorise diseases. Clinical physiology and biochemistry

have provided many insights into the biological

disturbances that accompany disease, but it is genetics

that is able to identify the pathways that are

unambiguously involved in pathogenesis. Such genetic

information will eventually lead to the redefinition of

disease on the basis of biochemical events rather than

phenotype; on molecular events driving biological

processes rather than a correlation of clinical syndromes

and outcomes.

The ability to redefine common human disease, using

genetics to define the biochemical processes responsible

for disease, will allow the subdivision of heterogeneous

diseases such as hypertension or diabetes into discrete

entities. Such subdivision is likely to help explain the wide

variation of these diseases, including apparent differences

in physiology, clinical course, and response to treatment,

and it might also provide a basis for identifying

environmental factors that contribute only to certain

subtypes of disease. This has already begun in diabetes,

where definition of the involvement of HLA genes

suggested an immune mechanism in a subset of patients,

leading to the subdivision into type I and type II diabetes.[6]

More recently, type II diabetes has been subdivided

further on the basis of distinct mechanisms involving

glucose phosphorylation and insulin (glucokinase)

secretion, transcriptional regulation (HNF), and insulin receptor


Disease mechanisms have led to clear definitions of

infectious diseases. For example, our understanding of

hepatitis has progressed: it used to be viewed as a clinical

syndrome with a wide variety of outcomes, and is now

seen as a set of quite specific diseases defined by the

aetiological agent, each with its own clinical course,

prognosis, and (perhaps) response to treatment. An

understanding of the biological process underlying the

clinical phenotype has been of unquestionable benefit in

defining and managing disease, and doctors are unlikely to

attempt to manage a jaundiced patient with

hepatitis without attempting to define the specific viral

agent involved. Similarly, pharmaceutical companies are

unlikely to attempt to develop novel vaccines or therapies

without precise information about the disease type. Even

in a well defined disease such as viral hepatitis, aspects of

disease progression such as viral persistence will need to

await genetic clarification.

Understanding the biological events and pathways

identified by genetics as contributing to disease

lead to clear definition of disease. Such information may

become the starting point in the management of most


A new taxonomy of disease based on genetics is

already being developed. The first examples of disease

definition have come from the loci in common disease

that seem to resemble autosomally inherited traits in

families. Although these contribute to disease in only a

small proportion of affected people, they provide

consider-able insights into disease mechanisms. Breast

cancer (BRCA1, BRCA2),[7 8] colon cancer (FAP,

HNPCC),[9] and diabetes (MODY 1, 2 and 3)[10-12] all have

such highly penetrant loci, and their elucidation has

provided some of the first insights into disease

pathogenesis. The controversy over the potential role of

impaired insulin secretion versus insulin resistance has

been clarified by our understanding of mechanisms that

result in each type of pathophysiology (glucokinase

mutations versus insulin receptor mutations). Disease

genes that contribute a component of susceptibility but

require other genetic and environmental factors for disease

to occur are also now available for disease definition. Apo

E4 involvement in Alzheimer's disease is leading to

revelations about its pathogenesis,[13] while angiotensin

converting enzyme[14] and angiotensinogen[15] probably

contribute to different forms of cardiovascular disease in

more predictable ways. The result of these developments

is that we are beginning to move toward a refined

taxonomy in medicine that is based on biochemical

mechanisms and driven by genetics.

Genetic information in clinical practice

Early diagnosis, patient stratification, and improved management

With an increasing trend to focus healthcare resources so

that they are most efficiently used, to develop accurate

definition of disease to predict its clinical course, to target

other forms of screening, and to choose optimal treatment,

it is likely that genetic information win be an essential

part of future clinical practice. Already it is possible to

identify people at high risk of breast or colon cancer and to

focus screening (such as mammography or colonoscopy)

or early interventional treatment on these groups. In both

breast and colon cancer we understand the genetic basis for

about 5% of cases, a sufficiently large number of patients

to overwhelm the already stretched genetic screening

capacity in the United Kingdom. As we learn more about

the effect of individual mutations on phenotype and as we

identify more high frequency, low penetrance genes in

both of these diseases, the pressure for screening in

populations with and without symptoms will increase.

Similarly, in diabetes, both the aetiological mutations

(HNF, glucokinase)[10 11] and other loci (ACE)[16] contribute to

the course of the disease or the frequency of

complications; hence these and other genes will be

important prognostic indicators for those managing the

disease and will need to be tested for. Even relatively

simple management decisions regarding individuals at risk

of deep venous thrombosis (patients with total hip

replacement, or those taking the oral contraceptive pill)

may benefit from evaluation of their factor V Leiden

status.[17] Decisions about the best treatment (CETP alleles

and statins, 5'-lipooxygenase in asthma, or tacrine in

Alzheimer's disease) or the side effects of drugs

(cytochrome P-450 and flecanide) may rely on genetic

stratification.[18] These and many other indications for the

use of genetic screening in patients with disease are likely

to emerge in the coming years, and the pressure from

patients and doctors for such services is likely to increase


Discovery and development of drugs

One of the earliest applications of this genetic information

will be in the discovery and development of new drugs.

Genetics is now widely used to identify new targets for

drug designs, and it is increasingly recognised that defining

disease populations by genotype will probably correlate

with response to drug treatment The variety of

mechanisms that underlie complex disease may account for

the wide variations in response seen in clinical practice

and the difficulty often encountered in

drug development of showing consistent large benefits in

trial populations. Wise pharmaceutical companies are

already introducing genotyping in their trials to predict

response, and eventually this information will be needed to

protect individuals from receiving a drug if they are

unlikely to respond to it. Effort will also be focused on

defining more clearly the basis for severe side effects of

drugs and not giving them to people likely to experience

side effects. Disease definition and drug response will go

hand in hand, and lifelong treatment is unlikely unless an

accurate genetic diagnosis provides an indication of

response. Development of drugs along genetic guidelines

will be a major force driving implementation of genetic

screening by healthcare providers, as both response to

treatment and complications will have been defined

genetically for many new therapeutic agents.

Genes as risk factors

An indication of how important genetic information will

be in defining disease and predicting outcomes in complex

diseases can be gained from our knowledge of Apo E4 and

Alzheimer's disease. Homozygosity for this allele is

associated with a shift of about 20 years in the average age

of onset of Alzheimer's disease.[13] These effects are at least

as great as other more conventional risk factors in common

disease (such as hypertension in hypercholesterolaemia).

Although Current recommendations suggest that Apo E

genotyping be used as an adjunct to diagnosis in

cognitively impaired people, it is likely that genetic

stratification by Apo E genotype will define drug

response, and hence such genotyping may soon be applied

in clinical trials and eventually will be more relevant to

daily clinical practice.

Examples such as Apo E4 raise the question of

whether a genetic susceptibility factor might best be

treated as another "risk factor." Other risk factors (blood

pressure or cholesterol concentrations) show similar

patterns of incomplete penetrance and have been

considered for population screening. There is little reason

that risk factors based on DNA should not be treated in

the same way. Genetic factors that can be used to predict

the risk of a population rather than an individual should be

viewed in the same way as other risk factors, particularly

if safe treatment or environmental modification were


This raises the possibility of population screening to

detect important susceptibility loci when intervention

becomes available. The obvious requirement for such

screening would be validation by large scale trials

on the benefits of such early detection and treatment A

combination of conventional and genetic risk factors may

be optimal for identifying populations at risk. In

hypertension or hypercholesterolaemia, risks vary greatly.

Treating the extremes of variation has the most favourable

cost benefit ratio, but most "at risk" patients fall within

the normal range. Genetics could be used to identify those

who have additional genetic risks and in whom reduction

of these variables might be beneficial, even where such

variables might be in the "normal" range. There are some

trial data to support such an



The widespread redefinition of disease through genetics

will be accompanied by the use of genetics for prediction

and diagnosis and to optimise treatment in most common

diseases. This is likely to occur within the next decade.

Testing for genetic "risk factors," even in people without

symptoms, may develop (as it has for other risk factors),

and this information may he used to identify people at

increased risk, for early intervention. There is a

possibility, however, that DNA diagnostics and

pharmacogenomics will be used without proper

evaluation--especially as few resources are available for rigorous

evaluation and pressure continues to introduce this

information in routine clinical practice.

Funding: Wellcome Fund.

Conflict of interest: JB sits as a non-executive member on the

board of Oxagen, a genomic biotechnology company, but holds no equity.

[1] Riordan JR, Rommens JM, Kerem B-S, Alon N, Rozmahen R, Grzelcak Z, et al.

Identification of the cystic fibrosis gene: cloning and characterisation of

complementary DNA. Science 1989;245:1066-73.

[2] European Polycystic Kidney Disease Consortium. The polycystic kidney

disease 1 gene encodes a 14 kb transcript and lies within a duplicated

region on chromosome 16. Cell 1994;77:881-6.

[3] Schuler GD, Boguski MS, Stewart EA, Stein LD, Gyapay G, Rice K, et al. A

gene map of the human genome. Science 1996;274:540-6.

[4] Marshall E. Genome researchers take the pledge. Science 1996;272:477-8.

[5] To affinity ... and beyond [editorial]. Nature Genet 1996;14:367-70.

[6] Ludworth AG, Woodrow JC. HL-A antigens and diabetes mellitus. Lancet


[7] Miki Y, Swensen J, Shattuck-Eidens D, Fureal PA, Harshman K, Tavtigian S,

et al. A strong candidate for the breast and ovarian cancer susceptibility gene

BRACT. Science 1994;266:66-71.

[8] Wooster R, Bignell G, Lancester J, Swift S, Seal S, Mangion J, et al.

Identification of the breast cancer susceptibility gene BRCA2. Nature


[9] Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell


[10] Yamagata K, Hiroto F, Oda N, Kaisaka PJ, Menzel S, Cos NJ, et al.

Mutations in the hepatocyte nuclear factor-4a gene in maturity-onset diabetes

of the young (MODY1). Nature 1996;384:458-60.

[11] Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, et al.

Familial hyperglycemia due to mutations in glycokinase: definition of a subtype

of diabetes mellitus. N Engl J Med 1993;328:697-702.

[12] Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, et al.

Mutations in the hepatocyte nuclear factor-1a gene in maturity-onset

diabetes of the young (MODY3). Nature 1996;384:455-8.

[13] Roses A. Apolipoprotein E genotyping in the differential diagnosis, not

prediction, of Alzheimer's disease. Ann Neurol 1995;38-6-14.

[14] Cambien F, Porier O, Lecerf L, Evans A, Cambou JP, Arveiler D, et al.

Deletion polymorphism in the gene for angiotensin-converting enzyme is a

potent risk factor for myocardial infraction. Nature 1992;359:641-4.

[15] Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru

A, et al. Molecular basis of human hypertension: role of angiotensinogen. Cell


[16] Schmidt S, Schone N, Ritz E. Association of ACE gene polymorphism and

diabetic nephropathy? The Diabetic Nephropathy Study Group. Kidney but


[17] Ridker PM, Miletick JP, Stampfer MJ, Goldhaber SZ, Linkpainter K,

Hennekens CH. Factor V Leiden and risks of recurrent idiopathic venous

thromboembolism. Circulation 1995;92:2800-2.

[18] Nebert DW. Polymorphisms in drug-metabolising enzymes: what is their

clinical relevance and why do they exist? Am J Hum Genet 997;60:265-71.

[19] Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al.

The effects of Pravastatin on coronary events after myocardial infarction in

patients with average cholesterol levels. N Engl J Med 1996;335:1001-9.

Related Article: Summary points

Genetic information is likely to transform the

practice of clinical medicine

Genetics will provide a taxonomy of disease that is

based on biochemical mechanisms rather than


Genetic information will be used to identify

individuals who are likely to respond to or suffer

toxicity from drugs

Genetic variation will be another form of "risk

factor" and will permit early treatment and

directed screening

RELATED ARTICLE: A new taxonomy of disease: diabetes

Type I

Autoimmune (HLA,INS)

Type II

Insulin resistant (INS receptor)

Insulin secretion (glucokinase)

Insulin transcription (?) (HNF1[Alpha], HNF4[Alpha], IPF)

Relate Article: Clinical benefit accruing from genetic studies of disease

* A new taxonomy of disease based on mechanisms,

not phenotype

* New drugs developed rationally from our

understanding of pathogenesis

* Drug development and

utilisation focused on disease subtypes likely to respond

to treatment

* Adverse effects of drugs avoided by

genetic screening

* "Risk factor" analysis will facilitate

environmental modification, screening, and

therapeutic management of people before they

develop symptoms

This is the first

of four articles

discussing the


implications of

advances in


Nuffield Department

of Clinical Medicine,

University of Oxford,

John Radcliffe

Hospital, Oxford OX3 9DU

John Bell, Nuffield

professor of clinical



BMJ 1998;316:618-20

COPYRIGHT 1998 British Medical Association
COPYRIGHT 2000 Gale Group

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