syndromes associated with multisystem | ||||
dysfunction ( for example , Wolfram syndrome , where youth-onset | ||||
diabetes is associated with progressive optic atrophy ). 4 In most cases of MODY , only one copy of a | ||||
gene carries the mutation . This is | ||||
because two normal copies of these | ||||
particular genes are required for | ||||
healthy pancreatic function , like | ||||
two functional wheels on a bicycle | ||||
( see figure 2 ). This is known as | ||||
haploinsufficiency . | ||||
For haploinsufficient genes , like | ||||
most of those associated with MODY , | ||||
when one copy of a gene contains a loss-of-function mutation , the amount of normal product generated | ||||
by the single normal gene is insufficient | ||||
for healthy function , and so , | ||||
like losing one wheel on a bicycle , | ||||
mutation of a single allelic copy prevents | ||||
it from doing its normal job . | ||||
Mutations in different individual | ||||
genes have been demonstrated to be |
associated with MODY ( representing the 14 currently known MODY subtypes ). The most common causes of MODY are mutations in hepatocyte nuclear factor 1-alpha ( HNF1A ), HNF1B , HNF4A , and glucokinase ( GCK ) genes ( see table 1 ). 4 |
Figure 1 . Pregnant woman using lancing device for blood glucose monitoring . |
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Diabetes is always caused by the failure of insulin-dependent pathways to control blood glucose levels . |
over 1-4 weeks , associated with the classical symptomatic triad of poly |
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In MODY , diabetes is caused by a de novo or inherited loss-of-function mutation that impacts the ability |
dipsia , polyuria and unintentional weight loss . 4
In at least a quarter of cases ,
|
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of beta cells ( see figure 3 ) to gen |
ketoacidosis is the presenting fea |
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erate sufficient insulin to maintain healthy blood glucose levels . 4 Some of the known mutations that cause |
ture of type 1 diabetes , particularly in young patients . 19
In contrast , the symptomatic pres
|
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MODY impair the function of genes |
entation of diabetes in MODY is often |
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involved in beta cell development , |
mild and nonspecific ; ketoacidosis |
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maturation and endowment at birth . |
is uncommon as substantial beta cell |
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Some of these mutations reduce |
function is retained at diagnosis . As a |
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insulin production and secretion by |
result , the first presentation of diabe |
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beta cells ( see table 1 ). |
tes is more similar to that of a youth |
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For example , mutations in HNF1A |
onset of type 2 diabetes ( the ‘ maturity |
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gene ( the single most common |
onset diabetes ’ in MODY ). |
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cause of MODY in European popu |
In contrast to type 2 diabetes , |
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lations , also known as the MODY3 |
patients with MODY are often less |
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subtype ) cause diabetes by lowering |
overweight or obese than those pre |
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the amount of insulin made by the pancreas . 4 Other mutations interfere with the sensing of glucose lev |
senting with type 2 diabetes . However , the high prevalence of obesity in the general population , even at a young |
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els in the blood and the triggering |
age , reduces the discriminating power |
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of proportionate insulin release . Finally , some of the mutations that cause MODY result in cellular stress , |
of this clinical association . Moreover , youth-onset type 2 diabetes is also increasingly common , particularly in |
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accelerated senescence and apopto |
people from South Asia and the Mid |
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sis of beta cells . The genetic cause |
dle East , in whom pathogenic adipos |
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of MODY is unknown in approxi |
ity may be less obvious . 9 |
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mately one in five cases in Western |
Weight loss associated with chronic |
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populations . 4 |
glycosuria can also confound the clin |
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Despite the established link |
ical presentation of type 2 diabetes , |
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between a loss of function gene |
and MODY3 may independently exac |
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mutation and the onset of diabetes in |
erbate glycosuria ( see table 2 ). |
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MODY , it is now clear that not every |
It has been suggested that the |
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individual with a mutated copy develops diabetes . This is known as incomplete or reduced penetrance and is in part related to the specific |
Figure 2 . Haploinsufficiency : for some genes , two healthy copies are required for normal pancreatic function . |
absence of stigmata of insulin resistance ( for example , acanthosis nigricans [ see figure 4 ], excess skin tags ) may help discriminate MODY |
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gene affected and the position of this |
from type 2 diabetes , although many |
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mutation . For example , almost all |
the penetrance is much higher , |
suggests that up to one in five of all |
may first present with diabetes in |
patients with type 2 diabetes do not |
( 89 – 97 %) of individuals with MODY2 eventually have elevated blood glucose levels . |
reflecting the negative impact of other co-inherited genes and shared lifestyle factors . |
cases of type 2 diabetes in Greenland are linked to a single nucleotide mutation of HNF1A . 18 |
adulthood when over 35 . 12 However , there may be substantial variation in severity and age of |
have these signs . Another key feature is that many individuals with MODY have a strong |
In contrast , the penetrance of MODY3 in unselected individuals is less . 12 For example , in one survey , even in unrelated individuals |
It is also important to add that changes in the function of many of these same genes are also implicated in other forms of diabetes . For |
PRESENTATION
BOX 1 lists some of the clinical features that may raise suspicion of
|
onset ( known as variable expressivity ) depending on the specific gene ( see table 1 ) and the region of that gene that is mutated , as well as other |
family history of diabetes ( as MODY is usually inherited in an ‘ autosomal dominant ’ fashion ) across consecutive generations . Some guidelines use the |
with exactly the same mutation in |
example , some of the genes associ |
MODY in a youth or young adult diag |
factors including BMI , ethnicity , diet , |
presence of a positive family history |
the same MODY3 gene , at least half of the carriers remained diabetes free at 23 years , a third were diabe |
ated with monogenic diabetes are also linked to autoimmune type 1 diabetes . |
nosed with diabetes . Most people with MODY first present with diabetes at a young age ( the |
environment , lifestyle and genetics . The initial presentation of diabetes in patients with MODY is usu |
as an essential diagnostic criterion for MODY . 4 However , many people with type 1 diabetes or type 2 diabetes also |
tes free at 33 years , and 13 % were |
Equally , some variants of HNF1A |
‘ Y ’ in MODY ). The average age of |
ally much less acute than with type 1 |
have a family history of diabetes ( for |
diabetes free even at 50 years . 16 However , in patients with a family history of established or possible MODY ( that is , youth onset diabetes ), |