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Molecular Genetic Classification of DM
Molecular Genetic Classification of DM
Molecular Genetic Classification of DM
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Table 1 Differentiation of β-cell monogenic diabetes from type 1 and type 2 diabetes.
Features Type 1 diabetes Young-onset GCK DM TF DM KATP PNDM 3243 MIDD
type 2 diabetes
Insulin dependence Yes No No No Yes Yes or no
Parent affected 2–4% Yes Yes Yes 15% Mother
Age of onset 6 months to Adolescence and Birth Teens to young <6 months Young adulthood
young adulthood young adulthood adulthood
Obesitya Population Increased Population Population Population Rare
frequency frequency frequency frequency frequency
Acanthosis No Yes No No No No
nigricans
Glycemia High Variable Mild High High Variable
β-Cell autoantibodies Yes No No No No No
C-peptide (nmol/l) <0.33 0.5–>1 0.1–0.7 0.1–0.7 <0.2 0.1–0.7
aThe population frequency is the frequency of obesity that occurs in the general population. Abbreviations: 3243 MIDD, maternally inherited diabetes and
deafness associated with mitochondrial m.3243A>G mutation; GCK DM, diabetes mellitus associated with mutations in glucokinase; KATP PNDM, permanent
neonatal diabetes associated with mutations in the ATP-sensitive potassium channel; TF DM, diabetes mellitus associated with mutations in transcription factors
(e.g. hepatocyte nuclear factor 1-α [HNF1-α], HNF4-α, or HNF-1β).
or 2 diabetes. First, we discuss why we think At least seven discrete genetic etiologies of
the term MODY might be outdated. Next, diabetes2–4 have been described, and these
we describe how to differentiate monogenic account for much of the clinical heterogeneity
diabetes from other types of diabetes. We then apparent among patients receiving a diagnosis
outline the monogenic β-cell forms of diabetes of MODY on the basis of this clinical definition.
under the following four main phenotypic cate- The different genetic subtypes differ in age of
gories for clearer clinical identification: diabetes onset, pattern of hyperglycemia, response to
diagnosed before 6 months of age (which is usually treatment and associated extrapancreatic mani-
associated with mutations in Kir6.2 or sulfonyl- festations, which suggests that it is inappropriate
urea receptor 1 [SUR1], or with abnormalities in to lump them all into a single category. The
chromosome 6q24); familial, mild fasting hyper- ‘maturity-onset’ part of MODY implies a resem-
glycemia (associated with glucokinase muta- blance to type 2 diabetes, but all the subtypes—
tion); familial, young-onset diabetes (associated as well as differing from each other—are very
with HNF1 homeobox A gene [HNF1A; previ- different from type 2 diabetes. Since the classifi-
ously termed TCF1] or HNF4 homeobox A gene cation of diabetes was revised in 1998 to reflect
[HNF4A]); and diabetes with extrapancreatic etiology,5 we propose that the term MODY is
features (associated with HNF1 homeobox B now obsolete and that the correct monogenic
gene [HNF1B; previously termed TCF2] or names of the different forms of young-onset
mitochondrial m.3243A>G mutation). diabetes should be used when possible.
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after diagnosis when there is some endogenous Mutations in KCNJ11 or ABCC8 can also
insulin secretion) are atypical for type 1 diabetes cause TNDM.16,19 At the time of diagnosis, it is
and increase the probability that the patient has not known whether the diabetes in an infant will
monogenic diabetes. We recommend genetic be transient or permanent. We therefore recom-
testing for HNF1A mutations (the most common mend testing for 6q24 abnormalities and KCNJ11
transcription factor mutations that cause mono- mutations first, and for ABCC8 mutations
genic diabetes) in any young adult with apparent if these tests are negative (Figure 1).
type 1 diabetes and a diabetic parent, and who is
antibody-negative at diagnosis, especially if there Neonatal diabetes due to mutations in the
is preservation of C-peptide levels in both the ATP-sensitive potassium channel
child and the parent. Clinical features
The majority of patients with Kir6.2 neonatal
Differentiation from apparent young-onset diabetes (i.e. neonatal diabetes caused by
type 2 diabetes Kir6.2 mutations) have isolated diabetes; most
Monogenic forms of diabetes should be suspected have PNDM rather than TNDM, but 20% have
in cases of young-onset, apparent type 2 diabetes neurological features (Table 2). These features
when obesity and features of insulin resistance occasionally constitute a severe syndrome of
are absent (Table 1). In patients with young- developmental delay, epilepsy and neonatal
onset diabetes, lack of obesity, absence of acan- diabetes (DEND) or, more commonly, inter-
thosis nigricans or polycystic ovarian syndrome, mediate DEND, which is characterized by
and elevated or normal HDL-cholesterol and diabetes and less-severe developmental delay
reduced or normal triglyceride levels6–8 are all without epilepsy.20 The diabetes typically
features that make presence of monogenic β-cell presents from birth to 26 weeks of age (mean
forms of diabetes likely. 5 weeks), usually with marked hyperglycemia
As mentioned above, when monogenic and ketoacidosis.15 Low birth weight (mean
diabetes is diagnosed it can be classified under 2,500 g) is common because of fetal insulin defi-
four phenotypic categories: diabetes diagnosed ciency in utero, because insulin is a major fetal
before 6 months of age; familial, mild fasting growth factor in the third trimester of preg-
hyperglycemia; familial, young-onset diabetes nancy.21 SUR1 neonatal diabetes has a similar
(Figure 1); or diabetes with extrapancreatic phenotype, but TNDM is more common than
features (Figure 2). We now detail when each of PNDM, and DEND syndrome is rare.
these categories should be considered, and the
features of each. Pathophysiology
Four Kir6.2 and four SUR1 subunits make up the
DIABETES DIAGNOSED BEFORE pancreatic KATP channel; this channel regulates
6 MONTHS OF AGE insulin secretion by linking intracellular ATP
Diabetes diagnosed before 6 months of age production to β-cell membrane potential and
is likely to be one of the monogenic forms of insulin secretion. Activating KCNJ11 or ABCC8
neonatal diabetes and not autoimmune type 1 mutations mostly reduce the response of the
diabetes.9,10 The diabetes resolves in approxi- channel to ATP, which prevents channel closure
mately half of all patients with neonatal diabetes, and consequent insulin secretion. The specific
and the majority of cases of TNDM (~70%) are mutation determines the phenotype,15,22 and for
linked to abnormalities in the chromosome 6q24 Kir6.2 mutations there is a striking correlation
region.11 In individuals with PNDM, mutations in with the functional severity of the muta-
KCNJ11 (potassium inwardly rectifying channel, tion (reviewed by Hattersley and Ashcroft20),
subfamily J, member 11 gene) or ABCC8 (ATP- although there are a few exceptions.23,24
binding cassette, subfamily C, member 8 gene)—
which encode the Kir6.2 and SUR1 subunits, Therapy
respectively, of the ATP-sensitive potassium The identification of KATP channel mutations in
channel (KATP channel)—are found in half of the patients with PNDM has had a dramatic impact
patients.12–17 It is important to identify patients on their diabetes therapy. These patients have little
with these mutations because—despite being or no endogenous insulin secretion and C-peptide
insulin dependent—oral sulfonylurea provides is usually undetectable,12 so they were previously
the most effective therapy.18 assumed to require lifelong insulin treatment.
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Figure 1 Clinical subtypes and management of monogenic β-cell diabetes that does not have
extrapancreatic features. See Figure 2 for diabetes that has extrapancreatic features. To convert plasma
glucose measurements to mg/dl, multiply by 18.02. Abbreviations: ABCC8, ATP-binding cassette,
subfamily C, member 8 gene; GCK, glucokinase gene; HNF, hepatocyte nuclear factor; HNF1A, HNF1
homeobox A gene; HNF4A, HNF4 homeobox A gene; INS, insulin gene; KCNJ11, potassium inwardly
rectifying channel, subfamily J, member 11 gene; OGTT, oral glucose tolerance test.
Sulfonylureas do, however, bind to the SUR1 doses (typically 0.4–0.8 mg/kg/day) may cause
subunits of the KATP channel and close the channel transitory diarrhea.25 Glibenclamide binds
in an ATP-independent manner. Approximately nonspecifically to SUR subunits found in KATP
90% of patients with Kir6.2 neonatal diabetes can channels in nerve, muscle and brain, in addi-
transfer from insulin to sulfonylurea tablets and tion to β cells, and hence enables some improve-
achieve improved glycemic control,18,23 and a ment of associated neurological symptoms as
similar pattern is emerging for patients with SUR1 well as the diabetes. Although many patients
neonatal diabetes.16,22 with mild developmental delay and diabetes
Most patients with KATP channel mutations (intermediate DEND) treated with sulfonylurea
are treated with glibenclamide. The doses used are therapy have been able to discontinue insulin,
considerably higher than those used for the and have shown improved motor function,
treatment of type 2 diabetes,13,18 and these high concentration and speech,26 others with the
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Diabetes with
extrapancreatic features
Test for RCAD syndrome: Test for MIDD: mitochondrial Test for Wolfram syndrome: Test for TRMA syndrome:
HNF1B m.3243A>G mutation WFS1 SLC19A2
Figure 2 Clinical subtypes and management of monogenic β-cell diabetes that has extrapancreatic features. See Figure 1 for diabetes
without extrapancreatic features. Abbreviations: HNF1B, HNF1 homeobox B gene; MIDD, maternally inherited diabetes and deafness;
RCAD, renal cysts and diabetes; SLC19A2, solute carrier family 19, member 2 gene; TRMA, thiamine-responsive megaloblastic
anemia; WFS1, Wolfram syndrome 1 gene.
full DEND syndrome have not responded to Transient neonatal diabetes due
sulfonylurea therapy. Since a sulfonylurea drug to disordered imprinting
would be used in a situation where it does not Clinical features
have a license, we recommend liaison with TNDM is usually diagnosed in the first week of
centers that have experience in transferring life (range 1–81 days). Affected children are typi-
patients from insulin to sulfonylureas to help cally born with lower birth weight (mean 2,000 g)
guide this process. than those with PNDM, but require less insulin
and doses can be tapered so that they are no
Genetic counseling longer insulin-treated by a median of 12 weeks.29
Families with two or more generations affected The relapse rate is 50–60%, at an average age of
are rare (~15% of cases), and most children with 14 years; diabetes at this stage results predomi-
KATP channel mutations are born to parents who nantly from moderate β-cell dysfunction.
do not have diabetes. The majority of sporadic One-third of patients with TNDM have macro-
cases result from de novo heterozygous muta- glossia, and occasionally an umbilical hernia
tions, but around 40% of patients with PNDM is present.
as a result of ABCC8 mutations show recessive
inheritance.17 For parents of children with reces- Pathophysiology
sively inherited ABCC8 mutations the risk of Gene imprinting occurs when only the paternal
neonatal diabetes for each future child is 25%, or maternal allele of a gene is expressed. In 70%
but the affected child is at very low risk of having of cases of TNDM11 there is an abnormality of
affected offspring. Affected individuals with a region of chromosome 6q24 that results in the
a heterozygous KATP channel mutation have a overexpression of the paternally expressed genes
50% chance of passing the mutation to their chil- PLAGL1 (pleiomorphic adenoma gene-like 1;
dren. Unaffected parents of a child with a de novo also termed tumor repressor ZAC) and HYMAI
mutation, however, should be counseled that the (hydatidiform mole associated and imprinted
recurrence risk of a second child being affected gene).29 Three types of abnormality have been
is not negligible because germline mosaicism (in described: paternal uniparental disomy, which
which mutations may be present in the gonads accounts for 50% of sporadic TNDM cases;
but not detectable in blood) has been reported paternal duplication of 6q24, found in most
in several families.27,28 familial cases; and abnormal methylation of
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classification given to patients; individuals can furthermore, because of the preserved regula-
be diagnosed as having incidental hyperglycemia tion of glycemia, such medication has minimal
or even type 1 diabetes (if detected during child- effect. In 28 patients we observed identical hemo-
hood), gestational diabetes (if detected during globin A1c values (6.3%) before and after treatment
pregnancy) or well-controlled type 2 diabetes (if with insulin or other medication was discontinued
detected in adulthood). A diagnosis of incidental (O Gill-Carey et al., unpublished data).
hyperglycemia in a young child might trigger Pregnancy is the one exception in which hypo-
intensive monitoring for incipient type 1 diabetes glycemic medication might be appropriate, but
and in some cases unnecessary treatment with insulin is required only in cases in which there is
insulin.32 Making a genetic diagnosis of gluco- excess fetal growth.39 The fetus has a 50% chance
kinase hyperglycemia is, therefore, worthwhile.33 of inheriting the GCK mutation from its mother,
Fasting hyperglycemia in a child is strongly sugges- and the presence of the GCK mutation in the
tive of a GCK mutation and apparently unaffected fetus influences its sensing of maternal glycemia.
parents should be tested for asymptomatic fasting If the fetus does not inherit the GCK mutation
hyperglycemia (Figure 1). it will respond to maternal hyperglycemia by
excess insulin production and, therefore, excess
Prevalence growth; however, if the fetus does inherit the
No large-scale population studies to assess GCK mutation it will produce normal amounts
the prevalence of GCK mutations have been of insulin and grow normally.40,41 If increased
performed. Approximately 2% of pregnant women fetal growth is detected it will be hard to lower
are diagnosed as having gestational diabetes, the mother’s glucose level (which is regulated
and of these approximately 2–5% have a GCK at the raised level); thus, greater-than-replacement
mutation,34 which would suggest a population doses of insulin will be required.39 Early delivery
prevalence of 0.04–0.10%. is often the most helpful intervention.
Even though microvascular complications
Pathophysiology are rare in glucokinase diabetes, it is prudent
The glucokinase enzyme catalyzes the rate- to maintain regular retinopathy screening in
limiting step of glucose phosphorylation and, patients over 40 years of age. The inheritance
therefore, enables the β cell and hepatocyte to of a GCK mutation does not protect against
respond appropriately to the degree of glycemia.35 the concurrent development of type 2 diabetes,
The kinetics of the glucokinase enzyme mean that which occurs at a similar prevalence in those with
heterozygous mutations cause an increased fasting GCK mutations as in the general population.
glucose set point but that glucose metabolism is
regulated to this new level. As a result, most indivi- Genetic counseling
duals with heterozygous GCK mutations have Each child of a parent with glucokinase diabetes
fasting plasma glucose levels between 5.5 and has a 50% chance of inheriting the GCK muta-
8.0 mmol/l. Patients with mutated GCK produce tion. Predictive genetic testing of children is not
adequate insulin responses, and most have a advocated since measurement of fasting blood
small increment in plasma glucose (<3 mmol/l in glucose provides a simple diagnostic test—GCK
70% of patients) 2 h after an oral glucose load.36 mutation carriers have mild hyperglycemia from
This feature also explains why hemoglobin A1c birth. Molecular genetic analysis can then be used
levels rarely exceed 7.5% and why microvascular as a confirmatory test. In the rare circumstance
complications are rare.37 Approximately half of in which both parents have glucokinase diabetes
all patients with a GCK mutation are diagnosed (more likely in consanguineous couples), each
as diabetic based on an oral glucose tolerance child has a 25% chance of having PNDM caused
test (OGTT), with the majority being diagnosed by inheriting two GCK mutations.
according to fasting values rather than 2 h values.
Most of those without diabetes have impaired FAMILIAL, YOUNG-ONSET DIABETES
fasting glucose levels.36,38 Those patients in whom diabetes is diagnosed
before age 25 years and does not fit the phenotypes
Management of either type 1 or type 2 diabetes, and who also
Hypoglycemic medication is not appropriate have a strong family history of diabetes, need to be
for most patients with heterozygous glucokinase evaluated for mutations in transcription factors,
diabetes, as they have mild hyperglycemia; most commonly hepatocyte nuclear factor 1-α
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(HNF-1α; encoded by HNF1A). An important positive urine test for glycosuria after a large
reason for making this genetic diagnosis is that, unrefined carbohydrate meal could, therefore,
in many cases, treatment with low-dose oral suggest the need for a formal OGTT and genetic
sulfonylurea is highly effective (Figure 1). testing in young children from families with an
Heterozygous mutations in the transcription HNF1A mutation.
factor genes HNF1A, HNF4A, or HNF1B (effects
of mutations in this gene are detailed in the Prevalence
later section on diabetes with extrapancreatic Mutations in the HNF1A gene are the commonest
features), and more rarely in PDX1 (pancre- monogenic form of transcription factor diabetes,
atic and duodenal homeobox 1 gene; previ- with 193 different mutations reported; the most
ously termed IPF1) or NEUROD1 (neurogenic common mutation is the insertion of a C nucleotide
differentiation 1 gene), result in similar diabetes (Pro291fsinsC) in a polyC-tract mutation hotspot.45
phenotypes. Patients with these mutations differ We estimate that patients with mutations in HNF1A
from those with glucokinase diabetes by having account for approximately 1–2% of patients with
normal glucose levels at birth and progressive diabetes, although most cases are not diagnosed.
deterioration in glucose tolerance. As a conse- This prevalence level would result in a population
quence of their increasing hyperglycemia they frequency of approximately 0.02–0.04%.
are at high risk of diabetic complications. In the
early stages of diabetes, fasting glucose remains Pathophysiology
relatively normal initially, but increases greatly Patients with HNF1A mutations have a progres-
following meals or a glucose load.36 sive β-cell defect. HNF-1α is one of several tran-
scription factors within a complex regulatory
HNF1A mutation carriers network that includes HNF-4α, PDX1 and HNF-
Clinical features 1β. This network is crucial for pancreatic β-cell
Patients with HNF1A mutations typically present development and functioning.
in their teens or early adult life with symptomatic
diabetes and have progressive β-cell failure that Penetrance
results in increasing hyperglycemia throughout HNF1A mutations have a high penetrance, with
life. HNF1A mutation carriers often have fasting 63% of carriers developing diabetes by 25 years of
plasma glucose levels that remain normal initially, age, 79% by 35 years and 96% by 55 years.46 The
despite diabetes being indicated by elevated age at diagnosis is determined in part by the loca-
2 h plasma glucose concentrations during tion of the mutation: patients with mutations in the
OGTT,36 with a large increment value (typically terminal exons (8–10) diagnosed on average 8 years
>4.5 mmol/l). This test result occurs because later than those with mutations in exons 1–6.47
initially the insulin secretion rate in HNF1A Intrauterine exposure to maternal diabetes
mutation carriers is appropriate to their insulin reduces the age of onset of this type of diabetes in
sensitivity at glucose values below 8 mmol/l.42 the offspring by approximately 12 years.48
The frequency of microvascular complications
in patients with HNF1A diabetes is similar to Management
that in patients with type 1 and type 2 diabetes, The importance of diagnosing patients who have
and is related to poor glycemic control.43 Although HNF1A diabetes is that this type of diabetes is
the frequency of hypertension in patients with very sensitive to sulfonylurea therapy.49 The
HNF1A diabetes is similar to that in patients therapy is highly effective because the β-cell
with type 1 diabetes, the frequency of coronary defects that result from reduced transcription
heart disease seems to be greater in patients with factor function are in glucose metabolism and
HNF1A diabetes.43 Raised HDL-cholesterol levels are, therefore, bypassed by sulfonylureas, which
are observed in patients with HNF1A diabetes, act on the KATP channel to stimulate insulin
in contrast to the reduced levels seen in patients release.49 We recommend sulfonylurea therapy
with type 2 diabetes and the normal levels seen initially in very low doses (e.g. 20–40 mg glicla-
in patients with type 1 diabetes.7 The elevated zide daily) as the first-line pharmacological treat-
HDL-cholesterol level does not, however, seem ment in HNF1A diabetes, and that patients on
to be cardioprotective. other oral agents or insulin should have a trial of
Glycosuria is a key feature of HNF1A mutation sulfonylureas. Currently, insulin remains the most
carriers before they develop diabetes.44 A common treatment during pregnancy for this
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patient group, but further studies are required and increased LDL-cholesterol levels in these
to validate the safety and efficacy of sulfonylureas patients remains to be determined; at present
such as glibenclamide (also known as glyburide) the cholesterol levels of patients with HNF4A
that have least permeability through the placenta mutations should be managed in light of other
and have been used in gestational diabetes.50 cardiovascular risk factors, as for other patients
with diabetes. Genetic counseling is similar to
Genetic counseling that for individuals with HNF1A mutations.
A parent with HNF1A diabetes has a 50% chance
of passing on the mutation to each child. Predictive Other etiologies
genetic testing in unaffected family members may Mutations in the transcription factor genes PDX1
be helpful but should be preceded by counseling to and NEUROD1 are extremely rare,53–56 but from
enable relatives to make an informed decision. The the limited data it seems that the diabetes pheno-
main advantages of knowing this genetic informa- type, penetrance and pathophysiology resemble
tion include reduction in uncertainty over the risk those in patients with mutations in the tran-
of diabetes and increased efficiency in monitoring scription factor HNF-1α. Two different mutations
for early signs of diabetes.51 in the transcription factor gene PAX4 (paired
box 4 gene) have been identified in Thai fami-
HNF4A mutation carriers lies with MODY.57 Two families with diabetes
Clinical features and exocrine pancreatic dysfunction have been
The diabetes of HNF4A mutation carriers presents found who have mutations in the gene encoding
in a very similar way to that of HNF1A mutation the enzyme carboxyl ester lipase (CEL).3
carriers. Unlike HNF1A mutation carriers, however, In at least 11% of families with autosomal-
these carriers have reduced levels of lipoprotein A1, dominant β-cell disease a genetic diagnosis cannot
lipoprotein A2 and HDL cholesterol, whereas be made, presumably because of the presence of
LDL-cholesterol levels tend to be increased; thus, as-yet-undetermined gene mutations.4
the lipid patterns of HNF4A mutation carriers
resemble those commonly seen in patients with DIABETES WITH EXTRAPANCREATIC
type 2 diabetes.8 Increased birth weight (by FEATURES
~800 g) and macrosomia are common features of Very rare diabetes-related disorders (Figure 2), such
HNF4A mutation carriers, and transient neonatal as Wolfram syndrome and thiamine-responsive
hypoglycemia may precede the diabetes.52 megaloblastic anemia, are fairly easy to recog-
nize because of the presence of comorbidities;
Prevalence Wolfram syndrome (also known as DIDMOAD
The prevalence of HNF4A diabetes is 20–30% because of the occurrence of diabetes insipidus,
in patients thought to have transcription factor diabetes mellitus, optic atrophy and deaf-
diabetes who do not have a mutation in HNF1A.8 ness) is also characterized by progressive neuro-
degeneration. Patients with thiamine-responsive
Pathophysiology megaloblastic anemia in addition to hemato-
Similar to patients with HNF1A diabetes, patients logical manifestations might also have deafness,
with HNF4A mutations have a progressive β-cell cardiac abnormalities and neurological abnormal-
dysfunction. The mechanism that underlies the ities. Two diabetes subtypes with extrapancreatic
biphasic pattern of hyperinsulinism in utero features that are frequently underdiagnosed at
followed by diabetes in later life is unknown.52 present, however, are the renal cysts and diabetes
syndrome resulting from mutations or dele-
Penetrance tions of the transcription factor gene HNF1B,
Generally, HNF4A has a high penetrance, with the and maternally inherited diabetes and deafness
majority of carriers developing diabetes by (MIDD) resulting from the mitochondrial point
the age of 25 years; however, in some families the mutation m.3243A>G.
age of diagnosis is older.52
Renal cysts and diabetes syndrome
Management Clinical features
Long-term treatment with low-dose sulfonyl- The predominant phenotype of patients with
ureas seems effective for HNF4A diabetes.8 The HNF1B mutations is developmental renal
clinical significance of reduced HDL-cholesterol disease, which is characterized by renal cysts
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A B Pigmentary
retinopathy
Deafness
Cardiomyopathy
Abnormal Focal
LFTs segmental
glomerulosclerosis
Diabetes
Developmental
Pancreatic Diabetes
kidney disease
atrophy
Constipation
Urogenital
abnormalities Myopathy
Gout
Figure 3 Phenotypes seen in diabetes with extra-pancreatic features. (A) Renal cysts and diabetes
syndrome caused by mutation in HNF1 homeobox B gene (HNF1B). (B) Maternally inherited diabetes and
deafness caused by mitochondrial m.3243A>G mutation. Kidney manifestations of HNF1B mutations
include hypoplastic glomerulocystic kidney disease, cystic renal dysplasia, solitary functioning kidney,
horseshoe kidney and oligomeganephronia. Urogenital manifestations of HNF1B mutations include
bicornuate uterus, bilateral agenesis of vas deferens, large epididymal cysts and asthenospermia.
Abbreviation: LFTs, liver function tests.
(the most common phenotype), renal dysplasia, pancreas, liver and genital tract, which explains the
renal-tract malformations and/or familial hypo- multiple organ involvement seen (Figure 3A).
plastic glomerulocystic kidney disease.10 Female
genital-tract malformations, gout and hyper- Penetrance
uricemia can also occur (Figure 3A).58,59 Birth There is wide variation in phenotypes even
weight is reduced by around 800 g as a result within a single pedigree, such that different
of reduced insulin secretion in utero.60 Half of combinations and severities of organ involve-
all HNF1B mutation carriers have early-onset ment are manifest among affected individuals
diabetes that presents in a similar fashion to who have identical mutations.58,59,63,65
HNF1A diabetes, but HNF1B mutation carriers
are more insulin resistant.61 Common vari- Management
ants in the HNF1B gene are associated with an The coexisting pancreatic atrophy and associ-
increased risk for prostate cancer but protect ated insulin resistance means that the diabetes of
against type 2 diabetes.62 HNF1B carriers is not sensitive to sulfonylurea
medication, and early insulin therapy is required.
Prevalence
HNF1B mutations are less frequent than HNF1A Maternally inherited diabetes and deafness
or HNF4A mutations in patients with diabetes, Clinical features
but they are common in patients with develop- Maternally inherited diabetes associated with
mental renal disease.63 A family history of renal young-onset, bilateral sensorineural deafness should
disease (or diabetes) is not essential to prompt a prompt genetic testing for the most common mito-
screen for this disorder, as spontaneous muta- chondrial point mutation—m.3243A>G. This
tions and deletions of this gene are common mutation results in dysfunction of mitochondria
(one-third to two-thirds of cases).63,64 (organelles whose main purpose is to generate
energy by producing ATP); as a result, the manifes-
Pathophysiology tations in patients with MIDD are within the organs
HNF-1β is a transcription factor that is expressed that are most metabolically active (Figure 3B).
in early embryonic development of the kidney, At the most severe end of the spectrum, the
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m.3243A>G mutation can manifest in mito- PNDM require high-dose sulfonylurea therapy,
chondrial myopathy, encephalopathy, lactic acidosis most cases of transcription factor diabetes require
and stroke-like episodes syndrome.66 low-dose sulfonylurea therapy, and glucokinase
Diabetes in MIDD usually presents insidiously diabetes requires no hypoglycemic treatment.
in a similar way to type 2 diabetes, but approxi- These therapies are different to those used to
mately 20% of patients have an acute presenta- treat type 1 or type 2 diabetes, so it is impor-
tion that resembles that of type 1 diabetes, with tant that we identify individuals with a probable
ketoacidosis occurring in 8%.67–69 The mean age monogenic cause for their diabetes. Molecular
at diagnosis of diabetes is 37 years, and ranges genetic testing for a mutation in the KCNJ11
from 11 to 68 years.67 or ABCC8 genes that encode the KATP channel
subunits should be considered in all patients
Prevalence with diabetes diagnosed before 6 months of
The prevalence of MIDD due to the m.3243A>G age. Individuals with familial, young-onset
mutation in Japanese patients with diabetes diabetes (diagnosed before 25 years of age)
is 1.5%, which seems to be higher than that in that does not fit with type 1 or type 2 diabetes
Europeans and other ethnic groups (0.4%).70 should be screened for mutations in the tran-
scription factor gene HNF1A, and then for those
Pathophysiology in HNF4A. Patients with familial, mild fasting
The pathophysiology of diabetes in MIDD hyperglycemia that does not deteriorate with age
is related to the mitochondrial dysfunction should be tested for GCK mutations. Diagnostic
in the highly metabolically active pancreatic molecular genetic testing is now available in
islets. This dysfunction causes abnormal β-cell many countries.76 This testing can improve
function, reduction in β-cell mass71,72 and the management of these monogenic forms of
insulin deficiency.73,74 diabetes, which are often underdiagnosed.
Penetrance
The penetrance of diabetes in offspring with
KEY POINTS
the m.3243A>G mutation is age dependent, but
■ The old clinical classifications of maturity-
is estimated to be more than 85% by the age onset diabetes of the young (MODY) and
of 70 years.69,75 neonatal diabetes should now be replaced with
a molecular genetic diagnosis, as this offers a
Management more useful guide to clinical management
The majority of patients with MIDD are initially
■ Monogenic β-cell diabetes is often
treated with dietary modification or oral hypo- misdiagnosed as type 1 or type 2 diabetes and
glycemic agents, but insulin is usually required a correct diagnosis can improve treatment
by 2 years after diagnosis.67–69 Metformin should
■ Diabetes diagnosed before 6 months of age will
probably be avoided because of the theoretical
be monogenic diabetes and the underlying gene
risk of exacerbating lactic acidosis, as metformin mutations can be identified in 75% of cases
is known to interfere with mitochondrial function
(although no cases have been reported to date). ■ Most neonatal patients with mutations in the
potassium-sensitive ATP channel subunits
Kir6.2 and sulfonylurea receptor 1 will be best
Genetic counseling
treated with high-dose sulfonylureas rather
Affected fathers should be reassured that they than insulin injections, despite seeming
will not transmit the disorder to their children. insulin dependent
An affected mother transmits the m.3243A>G
■ Patients with glucokinase mutations have stable,
mutation to all her children, even though some
mild, regulated hyperglycemia throughout life
children may remain clinically unaffected.
and do not need pharmacological treatment
except possibly during pregnancy
CONCLUSIONS
With the advances in defining the monogenic ■ Patients with mutations in HNF1A have
hyperglycemia that deteriorates with age and
etiology of diabetes, which accounts for approxi-
that can be severe; these patients, like patients
mately 1–2% of all diabetes cases, we have learned
with mutations in HNF4A, are sensitive to the
that these genetic subtypes of diabetes require hypoglycemic effects of sulfonylureas
different treatments. Patients with Kir6.2 or SUR1
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75 Maassen JA (2002) Mitochondrial diabetes: 85 Delepine M et al. (2000) EIF2AK3, encoding translation Acknowledgments
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