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SUMMARY

Clinical implications of a molecular geneticclassification of monogenic -cell diabetesRinki Murphy, Sian Ellard and Andrew T Hattersley*

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medical education (CME) for this journal article,

allowing clinicians the opportunity to earn CME credit.

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Learning objectives

Upon completion of this activity, participants should be

able to:

1 List the 4 proposed clinical subtypes of monogenic

diabetes.

2 Describe the clinical features of glucokinase

hyperglycemia/diabetes.

3 Describe the criteria for testing to distinguish dia-

betes caused byhepatocyte nuclear factor-1alpha

(HNF-1alpha) mutations from type 1 and 2 diabetes.

4 Describe the clinical features of permanent and

transient neonatal diabetes.

Competing interests

The authors declared no competing interests. Dsire

Lie, the CME questions author, declared no relevant

financial relationships.

INTRODUCTION

Since 1992, numerous genetic subtypes of diabeteshave been described in which gene mutationsresult in diabetes primarily through -cell dysfunc-tion. This knowledge means that patients whowere previously categorized clinically as having

maturity-onset diabetes of the young (MODY),permanent neonatal diabetes mellitus (PNDM)or transient neonatal diabetes mellitus (TNDM)can now usually be classified by genetic subgroup.Definition of the genetic subgroup can result inappropriate treatment, genetic counseling andprognostic information.

In this article we describe the challenge ofidentifying the minority of patients who havemonogenic -cell diabetes (12% of all diabetescases) amongst the vast majority who have type 1

Monogenic diabetes resulting from mutations that primarily reduce

-cell function accounts for 12% of diabetes cases, although it is oftenmisdiagnosed as either type 1 or type 2 diabetes. Knowledge of the geneticetiology of diabetes enables more-appropriate treatment, better predictionof disease progression, screening of family members and genetic counseling.We propose that the old clinical classifications of maturity-onset diabetesof the young and neonatal diabetes are obsolete and that specific geneticetiologies should be sought in four broad clinical situations because of their

specific treatment implications. Firstly, diabetes diagnosed before 6 monthsof age frequently results from mutation of genes that encode Kir6.2 (ATP-sensitive inward rectifier potassium channel) or sulfonylurea receptor 1subunits of an ATP-sensitive potassium channel, and improved glycemiccontrol can be achieved by treatment with high-dose sulfonylureas ratherthan insulin. Secondly, patients with stable, mild fasting hyperglycemiadetected particularly when they are young could have a glucokinasemutation and might not require specific treatment. Thirdly, individuals

with familial, young-onset diabetes that does not fit with either type 1 ortype 2 diabetes might have mutations in the transcription factors HNF-1(hepatocyte nuclear factor 1-) or HNF-4, and can be treated with low-dose sulfonylureas. Finally, extrapancreatic features, such as renal disease(caused by mutations in HNF-1) or deafness (caused by a mitochondrialm.3243A>G mutation), usually require early treatment with insulin.

KEYWORDS genetics, glucokinase, maturity onset diabetes of the young,neonatal diabetes, transcription factor

R Murphy was a Clinical Research Fellow, S Ellard is Professor of HumanMolecular Genetics, and AT Hattersley is Professor of Molecular Medicine atthe Peninsula Medical School, Exeter, UK.

Correspondence*Peninsula Medical School, Barrack Road, Exeter, Devon EX2 5DW, UK

[email protected]

Received 29 October 2007 Accepted 14 December 2007 Published online 26 February 2008

www.nature.com/clinicalpractice

doi:10.1038/ncpendmet0778

REVIEW CRITERIAFor this Review we selected papers and abstracts listed in PubMed that reportedon the clinical features, genetics, prevalence, pathophysiology and treatmentof-cell monogenic diabetes. We concentrated on neonatal diabetes and thosetypes of diabetes previously classified as maturity-onset diabetes of the young.

SUMMARY

CME

200 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM APRIL 2008 VOL 4 NO 4

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APRIL 2008 VOL 4 NO 4 MURPHY ET AL. NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 201


or 2 diabetes. First, we discuss why we thinkthe term MODY might be outdated. Next,we describe how to differentiate monogenicdiabetes from other types of diabetes. We thenoutline the monogenic -cell forms of diabetesunder the following four main phenotypic cate-gories for clearer clinical identification: diabetesdiagnosed before 6 months of age (which is usuallyassociated with mutations in Kir6.2 or sulfonyl-urea receptor 1 [SUR1], or with abnormalities inchromosome 6q24); familial, mild fasting hyper-glycemia (associated with glucokinase muta-tion); familial, young-onset diabetes (associatedwith HNF1 homeobox A gene [HNF1A;previ-ously termed TCF1] or HNF4 homeoboxA gene[HNF4A]); and diabetes with extrapancreaticfeatures (associated with HNF1 homeobox Bgene [HNF1B; previously termed TCF2] ormitochondrial m.3243A>G mutation).

WHY THE TERM MODY IS DEAD

The confusing term maturity-onset diabetes of

the young originates from the time when theterms juvenile-onset and maturity-onset wereused to distinguish between type 1 (insulin-dependent) and type 2 (noninsulin-dependent)diabetes. MODY was used to describe a subgroupof autosomal-dominantly inherited diabetes thatdespite having a young age of onset (at least onefamily member diagnosed before 25 years ofage) was noninsulin-dependent (as patients hadmoderate but insufficient circulating C-peptidelevels 5 years after diagnosis).1

At least seven discrete genetic etiologies ofdiabetes24 have been described, and theseaccount for much of the clinical heterogeneityapparent among patients receiving a diagnosisof MODY on the basis of this clinical definition.The different genetic subtypes differ in age ofonset, pattern of hyperglycemia, response totreatment and associated extrapancreatic mani-festations, which suggests that it is inappropriateto lump them all into a single category. Thematurity-onset part of MODY implies a resem-blance to type 2 diabetes, but all the subtypesas well as differing from each otherare verydifferent from type 2 diabetes. Since the classifi-cation of diabetes was revised in 1998 to reflectetiology,5 we propose that the term MODY isnow obsolete and that the correct monogenicnames of the different forms of young-onsetdiabetes should be used when possible.

DIFFERENTIATION OF MONOGENIC FROM

OTHER TYPES OF DIABETES

Differentiation from apparent

type 1 diabetes

Patients with a clinical diagnosis of type 1diabetes who also have a two-generation orthree-generation family history of diabetes withevidence of noninsulin dependence should besuspected of having monogenic diabetes (Table 1).Absence of autoantibodies against pancreaticantigens and detection of measurable C-peptidein the presence of hyperglycemia outside thehoneymoon period (the period of up to 5 years

Table 1 Differentiation of -cell monogenic diabetes from type 1 and type 2 diabetes.

Features Type 1 diabetes Young-onsettype 2 diabetes

GCK DM TF DM KATP PNDM 3243 MIDD

Insulin dependence Yes No No No Yes Yes or no

Parent affected 24% Yes Yes Yes 15% Mother

Age of onset 6 months toyoung adulthood

Adolescence andyoung adulthood

Birth Teens to youngadulthood


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after diagnosis when there is some endogenousinsulin secretion) are atypical for type 1 diabetesand increase the probability that the patient hasmonogenic diabetes. We recommend genetictesting for HNF1A mutations (the most commontranscription factor mutations that cause mono-

genic diabetes) in any young adult with apparenttype 1 diabetes and a diabetic parent, and who isantibody-negative at diagnosis, especially if thereis preservation of C-peptide levels in both thechild and the parent.

Differentiation from apparent young-onset

type 2 diabetes

Monogenic forms of diabetes should be suspectedin cases of young-onset, apparent type 2 diabeteswhen obesity and features of insulin resistanceare absent (Table 1). In patients with young-

onset diabetes, lack of obesity, absence of acan-thosis nigricans or polycystic ovarian syndrome,and elevated or normal HDL-cholesterol andreduced or normal triglyceride levels68 are allfeatures that make presence of monogenic -cellforms of diabetes likely.

As mentioned above, when monogenicdiabetes is diagnosed it can be classified underfour phenotypic categories: diabetes diagnosedbefore 6 months of age; familial, mild fastinghyperglycemia; familial, young-onset diabetes(Figure 1); or diabetes with extrapancreaticfeatures (Figure 2). We now detail when each ofthese categories should be considered, and thefeatures of each.

DIABETES DIAGNOSED BEFORE

6 MONTHS OF AGE

Diabetes diagnosed before 6 months of ageis likely to be one of the monogenic forms ofneonatal diabetes and not autoimmune type 1diabetes.9,10 The diabetes resolves in approxi-mately half of all patients with neonatal diabetes,and the majority of cases of TNDM (~70%) arelinked to abnormalities in the chromosome 6q24

region.11 In individuals with PNDM, mutations inKCNJ11 (potassium inwardly rectifying channel,subfamily J, member 11 gene) orABCC8 (ATP-binding cassette, subfamily C, member 8 gene)which encode the Kir6.2 and SUR1 subunits,respectively, of the ATP-sensitive potassiumchannel (KATP channel)are found in half of thepatients.1217 It is important to identify patientswith these mutations becausedespite beinginsulin dependentoral sulfonylurea providesthe most effective therapy.18

Mutations in KCNJ11 or ABCC8 can alsocause TNDM.16,19 At the time of diagnosis, it isnot known whether the diabetes in an infant willbe transient or permanent. We therefore recom-mend testing for 6q24 abnormalities and KCNJ11mutations first, and for ABCC8 mutations

if these tests are negative (Figure 1).

Neonatal diabetes due to mutations in the

ATP-sensitive potassium channel

Clinical featuresThe majority of patients with Kir6.2 neonataldiabetes (i.e. neonatal diabetes caused byKir6.2 mutations) have isolated diabetes; mosthave PNDM rather than TNDM, but 20% haveneurological features (Table 2). These featuresoccasionally constitute a severe syndrome ofdevelopmental delay, epilepsy and neonatal

diabetes (DEND) or, more commonly, inter-mediate DEND, which is characterized bydiabetes and less-severe developmental delaywithout epilepsy.20 The diabetes typicallypresents from birth to 26 weeks of age (mean5 weeks), usually with marked hyperglycemiaand ketoacidosis.15 Low birth weight (mean2,500 g) is common because of fetal insulin defi-ciencyin utero, because insulin is a major fetalgrowth factor in the third trimester of preg-nancy.21 SUR1 neonatal diabetes has a similarphenotype, but TNDM is more common thanPNDM, and DEND syndrome is rare.

PathophysiologyFour Kir6.2 and four SUR1 subunits make up thepancreatic KATP channel; this channel regulatesinsulin secretion by linking intracellular ATPproduction to -cell membrane potential andinsulin secretion. Activating KCNJ11 orABCC8mutations mostly reduce the response of thechannel to ATP, which prevents channel closureand consequent insulin secretion. The specificmutation determines the phenotype,15,22 and forKir6.2 mutations there is a striking correlation

with the functional severity of the muta-tion (reviewed by Hattersley and Ashcroft20),although there are a few exceptions.23,24

TherapyThe identification of KATP channel mutations inpatients with PNDM has had a dramatic impacton their diabetes therapy. These patients have littleor no endogenous insulin secretion and C-peptideis usually undetectable,12 so they were previouslyassumed to require lifelong insulin treatment.

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Sulfonylureas do, however, bind to the SUR1

subunits of the KATP channel and close the channelin an ATP-independent manner. Approximately90% of patients with Kir6.2 neonatal diabetes cantransfer from insulin to sulfonylurea tablets andachieve improved glycemic control,18,23 and asimilar pattern is emerging for patients with SUR1neonatal diabetes.16,22

Most patients with KATP channel mutationsare treated with glibenclamide. The doses used areconsiderably higher than those used for thetreatment of type 2 diabetes,13,18 and these high

doses (typically 0.40.8 mg/kg/day) may cause

transitory diarrhea.25 Glibenclamide bindsnonspecifically to SUR subunits found in KATPchannels in nerve, muscle and brain, in addi-tion to cells, and hence enables some improve-ment of associated neurological symptoms aswell as the diabetes. Although many patientswith mild developmental delay and diabetes(intermediate DEND) treated with sulfonylureatherapy have been able to discontinue insulin,and have shown improved motor function,concentration and speech,26 others with the

Diabetes diagnosed

before 6 months of age

Familial, young-onset

diabetes

Familial, mild fasting

hyperglycemia (>5.5mmol/l)a

Test for heterozygous

GCKmutations

No treatment

Test for HNF1A and

if negative HNF4A

Oral sulfonylurea (low dose)

May require insulin in pregnancy

depending on fetal growth

Transient Permanent

Test forchromosome

6q24

abnormalities

and, if negative,for KCNJ11 and

ABCC8

If negative,

consider INS or

GCKmutationsor rare causes in

presence of

other features

(Table 2)

Test forKCNJ11 and,

if negative,

ABCC8

Transientinsulin

Oral

sulfonylurea

(high dose)

Observe for

relapse ofdiabetes in

teenage years

Use

glibenclamideif neurological

featurespresent

Onset in adolescence or

young childhood

Progressive hyperglycemiaOGTT: large increment

(>4.5mmol/l) between 0h and2h glucoseComplications frequent

Onset at birth

Stable hyperglycemia

OGTT: low increment(


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full DEND syndrome have not responded tosulfonylurea therapy. Since a sulfonylurea drugwould be used in a situation where it does nothave a license, we recommend liaison withcenters that have experience in transferringpatients from insulin to sulfonylureas to helpguide this process.

Genetic counselingFamilies with two or more generations affectedare rare (~15% of cases), and most children withKATP channel mutations are born to parents whodo not have diabetes. The majority of sporadiccases result from de novo heterozygous muta-tions, but around 40% of patients with PNDMas a result ofABCC8 mutations show recessiveinheritance.17 For parents of children with reces-sively inherited ABCC8 mutations the risk ofneonatal diabetes for each future child is 25%,

but the affected child is at very low risk of havingaffected offspring. Affected individuals witha heterozygous KATP channel mutation have a50% chance of passing the mutation to their chil-dren. Unaffected parents of a child with a de novomutation, however, should be counseled that therecurrence risk of a second child being affectedis not negligible because germline mosaicism (inwhich mutations may be present in the gonadsbut not detectable in blood) has been reportedin several families.27,28

Transient neonatal diabetes due

to disordered imprinting

Clinical featuresTNDM is usually diagnosed in the first week oflife (range 181 days). Affected children are typi-cally born with lower birth weight (mean 2,000 g)than those with PNDM, but require less insulinand doses can be tapered so that they are nolonger insulin-treated by a median of 12 weeks.29The relapse rate is 5060%, at an average age of14 years; diabetes at this stage results predomi-nantly from moderate -cell dysfunction.One-third of patients with TNDM have macro-glossia, and occasionally an umbilical herniais present.

PathophysiologyGene imprinting occurs when only the paternalor maternal allele of a gene is expressed. In 70%

of cases of TNDM11 there is an abnormality ofa region of chromosome 6q24 that results in theoverexpression of the paternally expressed genesPLAGL1 (pleiomorphic adenoma gene-like 1;also termed tumor repressor ZAC) and HYMAI(hydatidiform mole associated and imprintedgene).29 Three types of abnormality have beendescribed: paternal uniparental disomy, whichaccounts for 50% of sporadic TNDM cases;paternal duplication of 6q24, found in mostfamilial cases; and abnormal methylation of

Renal cysts

Exocrine pancreatic deficiency

Genitourinary abnormalities

Deafness

Short stature

Pigmentary retinopathy

Diabetes with

extrapancreatic features

Optic atrophy

Diabetes insipidus

DeafnessRenal tract abnormalitiesNeurological abnormalities

Megaloblastic anemia

Deafness

Cardiac abnormalitiesNeurological abnormalities

Test for RCAD syndrome:

HNF1B

Test for MIDD: mitochondrial

m.3243A>G mutation

Test for Wolfram syndrome:

WFS1

Test for TRMA syndrome:

SLC19A2

Early insulin Oral sulfonylurea initially,

but rapid insulin requirementInsulin Thiamine and/or sulfonylurea

and/or early insulin

Figure 2 Clinical subtypes and management of monogenic -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.

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the maternal copy of chromosome 6, foundin sporadic cases.29 Most of the remainder ofpatients with TNDM have KATP channel muta-tions,11,19 but there is virtually no overlap withthe mutations observed in PNDM cases.

TherapyTreatment during the neonatal phase is withinsulin; however, on relapse treatment mayinclude dietary modification, oral hypoglycemicagents and/or insulin.30

Genetic counseling

Genetic counseling of TNDM cases dependson the genetic etiology. Cases with uniparentaldisomy of chromosome 6 are sporadic and,therefore, have low recurrence risk in siblingsand offspring. In cases of familial paternalduplications of the 6q24 region, males have a50% chance of transmitting TNDM to theirchildren. If females pass on this duplica-tion, their children will not be affected butthe sons may pass on the risk of TNDM totheir children.

Other subtypes of neonatal diabetes

Heterozygous mutations in theinsulin gene (INS)have been identified and could account for 1520% of cases of PNDM.31 Patients with PNDMand an INS mutation have permanent diabeteswithout extrapancreatic features except a lowbirth weight, which is a feature of all subtypesof neonatal diabetes. The other known geneticcauses of neonatal diabetes are rare (Table 2).Clinical features, such as pancreatic aplasia orextrapancreatic features, and knowledge ofconsanguinity can be very helpful when decidingwhether to test for other genetic subtypes.

FAMILIAL, MILD FASTING HYPERGLYCEMIA

Patients who have mild fasting hyperglycemia(5.58.0 mmol/l; to convert to mg/dl, multiplyby 18.02) that shows little deterioration with agemight have heterozygous glucokinase gene (GCK)mutations that do not require any specific treat-ment. Although the mild hyperglycemia can bepresent from birth, patients are asymptomaticand most remain undiagnosed until later in life.The age at testing will determine the clinical

Table 2 Causes of neonatal diabetes mellitus.

Pancreaticpathophysiology

Protein, chromosomeor gene affected

Reported prevalence Inheritance Features in addition to neonatal diabetesand low birth weight

Reduced -cellfunction

KATP channel 50% of PNDM and 25%of TNDM

Autosomal dominantor recessive

Developmental delay and epilepsy

Chromosome 6q24 70% of TNDM Variable Macroglossia and umbilical hernia

GCK(recessivemutation)

6 cases of PNDM7779(6 families)

Autosomal recessive Both parents have heterozygous GCK-associated hyperglycemia

SLC2A2 1 case of PNDM80(1 family)

Autosomal dominant Hypergalactosemia, hepatic failure

GLIS3 6 cases of PNDM81,82(3 families)

Autosomal recessive Congenital hypothyroidism, glaucoma, liverfibrosis and cystic kidney disease

Reducedpancreas mass

PTF1A 5 cases of PNDM83(2 families)

Autosomal recessive Pancreatic and cerebellar agenesis

PDX1 2 cases of PNDM56,84(2 families)

Autosomal recessive Pancreatic agenesis

HNF1B 1 case of PNDM, 1 caseof TNDM10,65 (2 families)

Autosomal dominant Exocrine pancreas insufficiency andrenal cysts

Increased -celldestruction

EIF2AK3 25 cases of PNDM8587(15 families)

Autosomal recessive Spondyloepiphyseal dysplasia, renal failure,recurrent hepatitis and mental retardation

FOXP3 17 cases of PNDM8892(13 families)

X-linked Immune dysregulation, intractable diarrhea,eczematous skin rash and elevated IgE

INS 21 cases of PNDM31(16 families)

Autosomal dominant None

Abbreviations: EIF2AK3, eukaryotic translation initiation factor 2- kinase 3 gene; FOXP3, forkhead box P3 gene; GCK, glucokinase gene; GLIS3, GLIS family zincfinger 3 gene; HNF1B, HNF1 homeobox B gene; INS, insulin gene; KATP channel, ATP-sensitive potassium channel;PDX1, pancreatic and duodenal homeobox 1gene (previously termed IPF1); PNDM, permanent neonatal diabetes mellitus; PTF1A, pancreas specific transcription factor, 1a gene;SLC2A2, solute carrierfamily 2, member 2 gene (previously termed GLUT2); TNDM, transient neonatal diabetes mellitus.

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classification given to patients; individuals canbe diagnosed as having incidental hyperglycemiaor even type 1 diabetes (if detected during child-hood), gestational diabetes (if detected duringpregnancy) or well-controlled type 2 diabetes (ifdetected in adulthood). A diagnosis of incidental

hyperglycemia in a young child might triggerintensive monitoring for incipient type 1 diabetesand in some cases unnecessary treatment withinsulin.32 Making a genetic diagnosis of gluco-kinase hyperglycemia is, therefore, worthwhile.33Fasting hyperglycemia in a child is strongly sugges-tive of a GCKmutation and apparently unaffectedparents should be tested for asymptomatic fastinghyperglycemia (Figure 1).

Prevalence

No large-scale population studies to assess

the prevalence of GCK mutations have beenperformed. Approximately 2% of pregnant womenare diagnosed as having gestational diabetes,and of these approximately 25% have a GCKmutation,34 which would suggest a populationprevalence of 0.040.10%.

Pathophysiology

The glucokinase enzyme catalyzes the rate-limiting step of glucose phosphorylation and,therefore, enables the cell and hepatocyte torespond appropriately to the degree of glycemia.35The kinetics of the glucokinase enzyme mean thatheterozygous mutations cause an increased fastingglucose set point but that glucose metabolism isregulated to this new level. As a result, most indivi-duals with heterozygous GCK mutations havefasting plasma glucose levels between 5.5 and8.0 mmol/l. Patients with mutated GCKproduceadequate insulin responses, and most have asmall increment in plasma glucose (


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(HNF-1; encoded by HNF1A). An importantreason for making this genetic diagnosis is that,in many cases, treatment with low-dose oralsulfonylurea is highly effective (Figure 1).

Heterozygous mutations in the transcriptionfactor genes HNF1A, HNF4A, or HNF1B (effects

of mutations in this gene are detailed in thelater section on diabetes with extrapancreaticfeatures), and more rarely in PDX1 (pancre-atic and duodenal homeobox 1 gene; previ-ously termed IPF1) orNEUROD1 (neurogenicdifferentiation 1 gene), result in similar diabetesphenotypes. Patients with these mutations differfrom those with glucokinase diabetes by havingnormal glucose levels at birth and progressivedeterioration in glucose tolerance. As a conse-quence of their increasing hyperglycemia theyare at high risk of diabetic complications. In theearly stages of diabetes, fasting glucose remainsrelatively normal initially, but increases greatlyfollowing meals or a glucose load.36

HNF1A mutation carriers

Clinical featuresPatients with HNF1A mutations typically presentin their teens or early adult life with symptomaticdiabetes and have progressive -cell failure thatresults in increasing hyperglycemia throughoutlife. HNF1A mutation carriers often have fastingplasma glucose levels that remain normal initially,despite diabetes being indicated by elevated2 h plasma glucose concentrations duringOGTT,36 with a large increment value (typically>4.5 mmol/l). This test result occurs becauseinitially the insulin secretion rate in HNF1Amutation carriers is appropriate to their insulinsensitivity at glucose values below 8 mmol/l.42

The frequency of microvascular complicationsin patients with HNF1A diabetes is similar tothat in patients with type 1 and type 2 diabetes,and is related to poor glycemic control.43Althoughthe frequency of hypertension in patients withHNF1A diabetes is similar to that in patients

with type 1 diabetes, the frequency of coronaryheart disease seems to be greater in patients withHNF1A diabetes.43 Raised HDL-cholesterol levelsare observed in patients with HNF1A diabetes,in contrast to the reduced levels seen in patientswith type 2 diabetes and the normal levels seenin patients with type 1 diabetes.7 The elevatedHDL-cholesterol level does not, however, seemto be cardioprotective.

Glycosuria is a key feature ofHNF1A mutationcarriers before they develop diabetes.44 A

positive urine test for glycosuria after a largeunrefined carbohydrate meal could, therefore,suggest the need for a formal OGTT and genetictesting in young children from families with anHNF1A mutation.

PrevalenceMutations in the HNF1A gene are the commonestmonogenic form of transcription factor diabetes,with 193 different mutations reported; the mostcommon mutation is the insertion of a C nucleotide(Pro291fsinsC) in a polyC-tract mutation hotspot.45We estimate that patients with mutations in HNF1Aaccount for approximately 12% of patients withdiabetes, although most cases are not diagnosed.This prevalence level would result in a populationfrequency of approximately 0.020.04%.

PathophysiologyPatients with HNF1A mutations have a progres-sive -cell defect. HNF-1 is one of several tran-scription factors within a complex regulatorynetwork that includes HNF-4, PDX1 and HNF-1. This network is crucial for pancreatic -celldevelopment and functioning.

PenetranceHNF1A mutations have a high penetrance, with63% of carriers developing diabetes by 25 years ofage, 79% by 35 years and 96% by 55 years.46 Theage at diagnosis is determined in part by the loca-tion of the mutation: patients with mutations in theterminal exons (810) diagnosed on average 8 yearslater than those with mutations in exons 16.47Intrauterine exposure to maternal diabetesreduces the age of onset of this type of diabetes inthe offspring by approximately 12 years.48

ManagementThe importance of diagnosing patients who haveHNF1A diabetes is that this type of diabetes isvery sensitive to sulfonylurea therapy.49 Thetherapy is highly effective because the -cell

defects that result from reduced transcriptionfactor function are in glucose metabolism andare, therefore, bypassed by sulfonylureas, whichact on the KATP channel to stimulate insulinrelease.49 We recommend sulfonylurea therapyinitially in very low doses (e.g. 2040 mg glicla-zide daily) as the first-line pharmacological treat-ment in HNF1A diabetes, and that patients onother oral agents or insulin should have a trial ofsulfonylureas. Currently, insulin remains the mostcommon treatment during pregnancy for this

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patient group, but further studies are requiredto validate the safety and efficacy of sulfonylureassuch as glibenclamide (also known as glyburide)that have least permeability through the placentaand have been used in gestational diabetes.50

Genetic counselingA parent with HNF1A diabetes has a 50% chanceof passing on the mutation to each child. Predictivegenetic testing in unaffected family members maybe helpful but should be preceded by counseling toenable relatives to make an informed decision. Themain advantages of knowing this genetic informa-tion include reduction in uncertainty over the riskof diabetes and increased efficiency in monitoringfor early signs of diabetes.51

HNF4A mutation carriers

Clinical featuresThe diabetes ofHNF4A mutation carriers presentsin a very similar way to that ofHNF1A mutationcarriers. Unlike HNF1Amutation carriers, however,these carriers have reduced levels of lipoprotein A1,lipoprotein A2 and HDL cholesterol, whereasLDL-cholesterol levels tend to be increased; thus,the lipid patterns of HNF4A mutation carriersresemble those commonly seen in patients withtype 2 diabetes.8 Increased birth weight (by~800 g) and macrosomia are common features ofHNF4A mutation carriers, and transient neonatalhypoglycemia may precede the diabetes.52

PrevalenceThe prevalence of HNF4A diabetes is 2030%in patients thought to have transcription factordiabetes who do not have a mutation in HNF1A.8

PathophysiologySimilar to patients with HNF1A diabetes, patientswith HNF4A mutations have a progressive -celldysfunction. The mechanism that underlies thebiphasic pattern of hyperinsulinism in uterofollowed by diabetes in later life is unknown.52

PenetranceGenerally,HNF4A has a high penetrance, with themajority of carriers developing diabetes bythe age of 25 years; however, in some families theage of diagnosis is older.52

ManagementLong-term treatment with low-dose sulfonyl-ureas seems effective for HNF4A diabetes.8 Theclinical significance of reduced HDL-cholesterol

and increased LDL-cholesterol levels in thesepatients remains to be determined; at presentthe cholesterol levels of patients with HNF4Amutations should be managed in light of othercardiovascular risk factors, as for other patientswith diabetes. Genetic counseling is similar to

that for individuals with HNF1A mutations.

Other etiologies

Mutations in the transcription factor genes PDX1andNEUROD1 are extremely rare,5356 but fromthe limited data it seems that the diabetes pheno-type, penetrance and pathophysiology resemblethose in patients with mutations in the tran-scription factor HNF-1. Two different mutationsin the transcription factor gene PAX4 (pairedbox 4 gene) have been identified in Thai fami-lies with MODY.57 Two families with diabetes

and exocrine pancreatic dysfunction have beenfound who have mutations in the gene encodingthe enzyme carboxyl ester lipase (CEL).3

In at least 11% of families with autosomal-dominant -cell disease a genetic diagnosis cannotbe made, presumably because of the presence ofas-yet-undetermined gene mutations.4

DIABETES WITH EXTRAPANCREATIC

FEATURES

Very rare diabetes-related disorders (Figure 2), suchas Wolfram syndrome and thiamine-responsivemegaloblastic anemia, are fairly easy to recog-nize because of the presence of comorbidities;Wolfram syndrome (also known as DIDMOADbecause of the occurrence of diabetes insipidus,diabetes mellitus, optic atrophy and deaf-ness) is also characterized by progressive neuro-degeneration. Patients with thiamine-responsivemegaloblastic anemia in addition to hemato-logical manifestations might also have deafness,cardiac abnormalities and neurological abnormal-ities. Two diabetes subtypes with extrapancreaticfeatures that are frequently underdiagnosed atpresent, however, are the renal cysts and diabetes

syndrome resulting from mutations or dele-tions of the transcription factor gene HNF1B,and maternally inherited diabetes and deafness(MIDD) resulting from the mitochondrial pointmutation m.3243A>G.

Renal cysts and diabetes syndrome

Clinical featuresThe predominant phenotype of patients withHNF1B mutations is developmental renaldisease, which is characterized by renal cysts

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(the most common phenotype), renal dysplasia,renal-tract malformations and/or familial hypo-plastic glomerulocystic kidney disease.10 Femalegenital-tract malformations, gout and hyper-uricemia can also occur (Figure 3A).58,59 Birthweight is reduced by around 800 g as a resultof reduced insulin secretion in utero.60 Half ofall HNF1B mutation carriers have early-onsetdiabetes that presents in a similar fashion toHNF1A diabetes, but HNF1B mutation carriersare more insulin resistant.61 Common vari-ants in the HNF1B gene are associated with anincreased risk for prostate cancer but protectagainst type 2 diabetes.62

PrevalenceHNF1B mutations are less frequent than HNF1A

or HNF4A mutations in patients with diabetes,but they are common in patients with develop-mental renal disease.63 A family history of renaldisease (or diabetes) is not essential to prompt ascreen for this disorder, as spontaneous muta-tions and deletions of this gene are common(one-third to two-thirds of cases).63,64

PathophysiologyHNF-1 is a transcription factor that is expressedin early embryonic development of the kidney,

pancreas, liver and genital tract, which explains themultiple organ involvement seen (Figure 3A).

PenetranceThere is wide variation in phenotypes evenwithin a single pedigree, such that differentcombinations and severities of organ involve-ment are manifest among affected individualswho have identical mutations.58,59,63,65

ManagementThe coexisting pancreatic atrophy and associ-ated insulin resistance means that the diabetes ofHNF1B carriers is not sensitive to sulfonylureamedication, and early insulin therapy is required.

Maternally inherited diabetes and deafness

Clinical featuresMaternally inherited diabetes associated with

young-onset, bilateral sensorineural deafness shouldprompt genetic testing for the most common mito-chondrial point mutationm.3243A>G. Thismutation results in dysfunction of mitochondria(organelles whose main purpose is to generateenergy by producing ATP); as a result, the manifes-tations in patients with MIDD are within the organsthat are most metabolically active (Figure 3B).At the most severe end of the spectrum, the

Developmental

kidney disease

Gout

Urogenitalabnormalities

Diabetes

Pancreaticatrophy

AbnormalLFTs

Focalsegmental

glomerulosclerosis

Constipation

Deafness

Myopathy

Diabetes

Cardiomyopathy

Pigmentary

retinopathy

A B

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.

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m.3243A>G mutation can manifest in mito-chondrial myopathy, encephalopathy, lactic acidosisand stroke-like episodes syndrome.66

Diabetes in MIDD usually presents insidiouslyin a similar way to type 2 diabetes, but approxi-mately 20% of patients have an acute presenta-

tion that resembles that of type 1 diabetes, withketoacidosis occurring in 8%.6769 The mean ageat diagnosis of diabetes is 37 years, and rangesfrom 11 to 68 years.67

PrevalenceThe prevalence of MIDD due to the m.3243A>Gmutation in Japanese patients with diabetesis 1.5%, which seems to be higher than that inEuropeans and other ethnic groups (0.4%).70

Pathophysiology

The pathophysiology of diabetes in MIDDis related to the mitochondrial dysfunctionin the highly metabolically active pancreaticislets. This dysfunction causes abnormal -cellfunction, reduction in -cell mass71,72 andinsulin deficiency.73,74

PenetranceThe penetrance of diabetes in offspring withthe m.3243A>G mutation is age dependent, butis estimated to be more than 85% by the ageof 70 years.69,75

ManagementThe majority of patients with MIDD are initiallytreated with dietary modification or oral hypo-glycemic agents, but insulin is usually requiredby 2 years after diagnosis.6769 Metformin shouldprobably be avoided because of the theoreticalrisk of exacerbating lactic acidosis, as metforminis known to interfere with mitochondrial function(although no cases have been reported to date).

Genetic counselingAffected fathers should be reassured that they

will not transmit the disorder to their children.An affected mother transmits the m.3243A>Gmutation to all her children, even though somechildren may remain clinically unaffected.

CONCLUSIONS

With the advances in defining the monogenicetiology of diabetes, which accounts for approxi-mately 12% of all diabetes cases, we have learnedthat these genetic subtypes of diabetes requiredifferent treatments. Patients with Kir6.2 or SUR1

PNDM require high-dose sulfonylurea therapy,most cases of transcription factor diabetes requirelow-dose sulfonylurea therapy, and glucokinasediabetes requires no hypoglycemic treatment.

These therapies are different to those used totreat type 1 or type 2 diabetes, so it is impor-

tant that we identify individuals with a probablemonogenic cause for their diabetes. Moleculargenetic testing for a mutation in the KCNJ11orABCC8 genes that encode the KATP channelsubunits should be considered in all patientswith diabetes diagnosed before 6 months ofage. Individuals with familial, young-onsetdiabetes (diagnosed before 25 years of age)that does not fit with type 1 or type 2 diabetesshould be screened for mutations in the tran-scription factor gene HNF1A, and then for thosein HNF4A. Patients with familial, mild fasting

hyperglycemia that does not deteriorate with ageshould be tested for GCKmutations. Diagnosticmolecular genetic testing is now available inmany countries.76 This testing can improvethe management of these monogenic forms ofdiabetes, which are often underdiagnosed.

KEY POINTS

The old clinical classifications of maturity-

onset diabetes of the young (MODY) and

neonatal diabetes should now be replaced with

a molecular genetic diagnosis, as this offers a

more useful guide to clinical management

Monogenic -cell diabetes is often

misdiagnosed as type 1 or type 2 diabetes and

a correct diagnosis can improve treatment

Diabetes diagnosed before 6 months of age will

be monogenic diabetes and the underlying gene

mutations can be identified in 75% of cases

Most neonatal patients with mutations in the

potassium-sensitive ATP channel subunits

Kir6.2 and sulfonylurea receptor 1 will be best

treated with high-dose sulfonylureas rather

than insulin injections, despite seeming

insulin dependent

Patients with glucokinase mutations have stable,

mild, regulated hyperglycemia throughout life

and do not need pharmacological treatment

except possibly during pregnancy

Patients with mutations in HNF1A have

hyperglycemia that deteriorates with age and

that can be severe; these patients, like patients

with mutations in HNF4A, are sensitive to the

hypoglycemic effects of sulfonylureas

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AcknowledgmentsWe thank all our colleagues

in Exeter (past and present)

for their contributions to the

literature reviewed here. The

assistance of K Colclough

during the preparation of the

manuscript is appreciated.

Our research is supported

by the Wellcome Trust(AT Hattersley is a Wellcome

Trust Clinical Research

Leave Fellow) and the

Research and Development

Directorate at the Royal

Devon and Exeter NHS

Foundation Trust (S Ellard).

Dsire Lie, University

of California, Irvine, CA,

is the author of and is

solely responsible for the

content of the learning

objectives, questions and

answers of the Medscape-

accredited continuing

medical education activity

associated with this article.

Competing interestsThe authors declared no

competing interests.

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molecular genetic classification of DM