Monogenic diabetes: advances in diagnosis and treatment

FRACP MMed(ClinEpid)
Institute of Endocrinology
and Diabetes, The Children’s
Hospital at Westmead
Discipline of Paediatrics and
Child Health, University of
Sydney, Australia
School of Women’s and
Children’s Health, University
of New South Wales

Monogenic diabetes:
advances in diagnosis
and treatment


by M. E. Craig, Australia

Monogenic diabetes accounts for approximately 1% to 5% of diabetes cases in young people, and its incidence has increased in recent decades in parallel with greater awareness and wider availability of genetic testing. It results from one or more defects in a single gene, and has been linked to more than 20 different genes. The two major subtypes are neonatal diabetes mellitus (NDM) and maturity-onset diabetes of the young (MODY). Mutations in the hepatocyte nuclear factor 1 α (HNF1A) gene lead to the most common cause of familial autosomal dominant diabetes, while mutations in the glucokinase gene (GCK) are the most common cause of persistent, mild, asymptomatic hyperglycemia in the pediatric population. NDM, which typically presents before the age of 6 months, is most often caused by a mutation in one of three genes: KCNJ11, ABCC8, or INS. The diagnosis of monogenic diabetes should be suspected in patients with one or more of the following characteristics: (i) diabetes presenting before 6 months of age; (ii) strong family history of diabetes; (iii) negative islet autoantibodies; (iii) low or no insulin requirements 5 years after diagnosis; (iv) absence of clinical features of type 2 diabetes; (v) mild fasting nonprogressive hyperglycemia; (vi) diabetes associated with extrapancreatic features. The diagnosis of monogenic diabetes can significantly impact on the care of the affected individual, by enabling prediction of the clinical disease course and guiding appropriate management. Some forms of MODY are sensitive to sulfonylureas, while mild fasting hyperglycemia due to mutations in GCK is not progressive and does not require treatment.

Medicographia. 2016;38:98-107 (see French abstract on page 107)

The heterogeneity of diabetes is well established, with the description more than 40 years ago of a subgroup of individuals who have a mild, familial form of diabetes presenting during adolescence or early adulthood.1,2 Since the disease clinically resembled non-insulin dependent diabetes that typically presented in older adults, the subtype became known as “maturity-onset diabetes of the young” (MODY).2 The strong familial nature, with autosomal dominant inheritance, suggested a genetic basis for MODY, although it was some years before single-gene mutations that cause the various forms of monogenic diabetes were discovered.3-6 To date, more than 20 different genetic subtypes of monogenic diabetes have been identified, with variable phenotypes and patterns of inheritance. Within families, inheritance may be expressed as a dominant, recessive, or non-Mendelian trait or may present as a de novo mutation. The genetic diagnosis has important clinical implications, because it can significantly impact on management of the affected individual, enabling prediction of the disease course and guiding appropriate therapy.

Epidemiology of monogenic diabetes

Monogenic diabetes represents approximately 1% to 5% of pediatric diabetes cases,7-10 although case ascertainment depends on awareness of the potential diagnosis and availability of genetic testing. While most children with genetically proven monogenic diabetes were previously misdiagnosed as having type 1, or less frequently, type 2 diabetes,11 increased awareness and availability of genetic testing is likely to have improved diagnosis and, therefore, the accuracy of more recent prevalence estimates.8,12

Among adults, there is a relative paucity of data examining the epidemiology of monogenic diabetes. In a UK survey of young adults diagnosed with diabetes before the age of 45 years, the proportion with MODY (3%)13 was similar to pediatric studies. All had mutations in the hepatocyte nuclear factor 1 α (HNF1A) gene (HNF1A-MODY), suggesting a population prevalence of 84 cases per million (95% confidence interval [CI], 31-136). The authors extrapolated that there were at least 5000 cases of HNF1A-MODY in the UK, of whom 90% were undiagnosed. In women with gestational diabetes mellitus, the prevalence of mutations in glucokinase (GCK-MODY) is approximately 0.5% to 1%.14,15

When to consider monogenic diabetes

Most cases of monogenic diabetes present as isolated diabetes, and therefore are commonly misdiagnosed as either type 1 or type 2 diabetes. The diagnosis of monogenic diabetes should be considered in people with diabetes who have an atypical presentation, in particular, if one or more of the following characteristics are present:

(i) Diabetes presenting before 6 months of age (since type 1 diabetes is extremely rare in this age group);
(ii) Strong family history of diabetes (for example in one parent and other first-degree relatives);
(iii) Diabetes with negative autoantibodies (particularly if measured at diagnosis of diabetes);
(iv) Preserved β-cell function, with low insulin requirements and detectable c-peptide (either in blood or urine) 5 or more years after diagnosis;
(v) Absence of classical features of type 2 diabetes (obesity, insulin resistance/acanthosis nigricans, high-risk ethnic group);
(vi) Mild fasting, nonprogressive hyperglycemia;
(vii) Diabetes associated with extrapancreatic features (such as renal cysts or deafness)

These characteristics should be not be considered in isolation, since the clinical phenotype can vary within and between the various forms of MODY, and there may be overlap with features of type 1 and type 2 diabetes. In particular, while the majority of individuals with MODY are not obese, the presence of obesity does not preclude a diagnosis of MODY. Both obesity and hyperinsulinemia have been observed in people with various forms of MODY.16

Classification of monogenic diabetes

The two major forms of monogenic diabetes are neonatal diabetes mellitus (NDM) and maturity-onset diabetes of the young (MODY). The different forms of monogenic diabetes can also be classified according to their main pathogenic mechanisms: genetic defects of pancreatic development,β-cell function, insulin action, and β-cell destruction. The site of action of these mutations localizes to the nucleus, cell membrane, cytoplasm, lysosome, endoplasmic reticulum, or mitochondria.17 In addition, a variety of genetic syndromes are associated with diabetes or severe insulin resistance (IR). The common forms of monogenic diabetes that typically present during adolescence or adulthood are shown in Table I (page 100); subtypes that present during the neonatal period or infancy are shown in Table III (page 102), and IR syndromes in Table II (page 101). Due to the higher prevalence of MODY compared with NDM, the former will be addressed first.

Maturity-onset diabetes of the young

Three genes are responsible for the majority of MODY cases (GCK, HNF1A, and HNF4A) (Table I), while mutations in a diverse range of genes cause more rare forms of autosomal dominant diabetes. The major MODY subtypes differ by their typical age of onset, glycemic pattern, and treatment. Although most forms are inherited as a dominant trait, sporadic de novo mutations in a number of genes can cause monogenic diabetes.18

Glucokinase gene mutations (GCK-MODY, MODY2)
The enzyme glucokinase is the β-cell glucose sensor; it catalyzes glucose phosphorylation (the first step in glycolysis), and therefore has a key role in regulating glucose metabolism. Glucokinase is expressed in the liver and β cells; the rate of glucose metabolism in these tissues is a function of the enzyme’s activity. Heterozygous inactivating mutations in GCK lead to glucokinase deficiency, resulting in an increased glucose threshold for insulin secretion and mild nonprogressive hyperglycemia. Although present at birth, hyperglycemia is often first detected incidentally later in life. Affected individuals are asymptomatic because the mild hyperglycemia does not cause osmotic symptoms. It is not uncommon for a parent or relatives to be undiagnosed or misdiagnosed with type 2 diabetes.

Table I. Classification and clinical features of monogenic diabetes with onset in adolescence or adulthood.

Abbreviations: MODY, maturity onset diabetes of the young; RCAD, renal cysts and diabetes syndrome; Ref, reference.

GCK-MODY is the most common subtype of monogenic diabetes in the pediatric population.8 Fasting blood glucose is typically in the impaired fasting glucose range (5.6-6.9 mmol/ L), and there is usually a small incremental rise in blood glucose (19 Glycated hemoglobin (HbA1c) is mildly elevated but typically below 7.5%,while free fatty acids (FFAs) are reduced,20 which suggests that there is a compensatory mechanism of increased insulin sensitivity in the setting of hyperglycemia and reduced insulin secretion. This contrasts with type 2 diabetes, where FFAs are usually elevated. Measurement of fasting glucose in parents may provide further evidence for the diagnosis and support genetic testing.

Since the hyperglycemia is mild and not progressive, GCKMODY is rarely associated with clinically significant vascular complications of diabetes.21 Treatment is not required, except during pregnancy when insulin treatment is recommended if the fetus does not inherit the GCK mutation.22


Heterozygous mutations in HNF1A are the most common cause of familial symptomatic monogenic diabetes,9,10,18 while heterozygous HNF4A mutations are much less frequent. In both HNF1A– and HNF4A-MODY, impaired glucose tolerance typically manifests during adolescence or early adulthood. In the early stages of the disease, fasting blood glucose may be normal but there is a large incremental rise in blood glucose (>5 mmol/L) after meals or at 2 hours during an OGTT.19 As the disease progresses, patients become symptomatic (with polyuria, polydipsia) and develop fasting hyperglycemia, but ketosis is rare due to persistent residual insulin secretion. People harboring mutations in HNF1A are at high risk of developing MODY; 63% of heterozygotes will develop diabetes by age 25 years and the majority (96%) by 55 years.23

Heterozygous individuals with the R76W mutation in HNF4A can also develop an atypical form of Fanconi renotubular syndrome, with hypercalciuria and nephrocalcinosis.24 The risk of chronic complications of diabetes is high and related to glycemic control.25 The frequency of microvascular complications (retinopathy, nephropathy, neuropathy) is similar to that of patients with type 1 and type 2 diabetes and HNF1A mutations are associated with an increased risk of cardiovascular mortality.26 Patients with MODY due to HNF1A and HNF4A mutations can be treated with dietary modification initially although they will ultimately require pharmacological treatment as their glycemic control deteriorates over time. Sulfonylureas are the first-line treatment, because they can be commenced at a low dose (one-quarter of the normal starting dose in adults) to avoid hypoglycemia. Provided they do not develop significant hypoglycemia, patients can be maintained on low-dose sulfonylureas for decades.27 A recent randomized controlled trial comparing a glucagon-like peptide (GLP-1) agonist with a sulfonylurea demonstrated lower fasting glucose in those treated with the GLP-1 agonist.28

Table II
Table II. Classification of syndromes of severe insulin resistance (IR).

Abbreviations: FPLD2, familial partial lipodystrophy type 2; IR, insulin resistance; MDPL syndrome, mandibular hypoplasia, deafness, progeroid features, and lipodystrophy; Ref, reference; SHORT syndrome, short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay.
Adapted from reference 10: Rubio-Cabezas et al. Pediatr Diabetes. 2014;15(suppl 20):47-64. © 2014, John Wiley & Sons, Inc.


Genetic syndromes associated with diabetes

A range of genetic syndromes may be associated with insulin resistance and type 1 or type 2 diabetes, including Turner syndrome, Prader-Willi syndrome, Klinefelter syndrome, Down syndrome, and Friedreich’s ataxia.29 These conditions are not discussed further, while some of the rare monogenic disorders associated with complex syndromes are summarized in Table II. The syndromes may either present early as NDM or later in life. Although treatment with dietary modification and oral agents may be used initially, insulin will usually be required eventually for the majority of these disorders. While collectively these conditions represent a small proportion of diabetes overall, it is important to consider the possibility of a monogenic disorder when diabetes is associated with multisystem extrapancreatic features.

Mitochondrial diabetes

The most common form of mitochondrial diabetes is caused by the m.3243A>G mutation in mitochondrial DNA. Diabetes onset is usually insidious but approximately 20% of patients have an acute presentation, even in diabetic ketoacidosis.30 Diabetes typically presents in adulthood, although it may present during childhood and adolescence. Early-onset diabetes is associated with the m.3243A>G mutation, and may be a feature of multiorgan diseases such as Kearns-Sayre syndrome (ophthalmoplegia, degeneration of retinal pigmentation, cardiomyopathy, deafness), MELAS syndrome (myopathy, encephalopathy, lactic acidosis, and stroke), and Pearson marrow-pancreas syndrome. Penetrance is high, with the majority of mutation carriers developing diabetes by age 70 years. Affected females always transmit the mutation, but may be unaffected, while males do not. Initial therapy can be with diet or oral hypoglycemic agents, but insulin is generally required within months or years. Metformin should be avoided as it interferes with mitochondrial function and may trigger episodes of lactic acidosis.

Table III
Table III (above and right page). Classification and clinical features of monogenic diabetes with onset in neonates and early childhood.

Abbreviations: CNS, central nervous system; IPEX, immune dysfunction, polyendocrinopathy, enteropathy, X-linked; PNDM, permanent neonatal diabetes mellitusTNDM, transient neonatal diabetes mellitus; Ref, reference; T1D, type 1 diabetes


Neonatal diabetes

NDM is a monogenic form of diabetes that presents in the first 6 months, although it may be diagnosed between 6 and 12 months of age in a small number of cases.31 In contrast, autoimmune type 1 diabetes is extremely rare before age 6 months and when islet autoantibodies are present in this age group, mutations in FOXP3 or STAT3 account for most cases.32,33 NDM is rare, with an incidence of 1 in 100 000 to 500 000 live births (Table III). Approximately half of them have permanent diabetes (PNDM), requiring lifelong treatment. The remaining cases have transient neonatal diabetes mellitus (TNDM), with remission of diabetes after weeks or months (although it might relapse later in life). While most cases of NDM have isolated diabetes, a range of extrapancreatic clinical features may be present (Table III). Many are born small for gestational age, which reflects the negative effects of prenatal insulin deficiency on intrauterine growth. Approximately two thirds of TNDM cases are caused by abnormalities in an imprinted region on chromosome 6q24,34 while most of the remaining cases are caused by activating mutations in either of the genes encoding the two subunits of the ATP-sensitive potassium (KATP) channel of the β-cell membrane (KCNJ11 or ABCC8). A minority of cases of TNDM is caused by mutations in other genes (Table III). The most common causes of PNDM in nonconsanguineous populations are mutations in the KATP channel or INS gene, with Wolcott-Rallison syndrome or homozygous/compound heterozygous mutations in the GCK gene the most common etiologies in the setting of consanguinity.31 However, approximately 30% of cases of PDNM do not have a recognized genetic abnormality. If parents are related, Wolcott-Rallison syndrome or homozygous mutations in the GCK gene are the most common etiologies.31

Neonatal diabetes due to mutations in the KATP channel genes
ATP-sensitive potassium (KATP) channels are cell metabolic sensors that couple cellular metabolic status to electric activity. In pancreatic β cells, the KATP channels are octameric structures composed of four Kir6.2 subunits—encoded by the KCNJ11 gene—that form the channel pore, surrounded by four sulfonylurea receptors (SURs) encoded by the ABCC8 gene.35 They play an important role in glucose homeostasis, by modulating insulin secretion in response to fluctuations in plasma glucose levels. An increase in metabolic activity within the β cell increases the ATP/ADP ratio; this closes the KATP channels, leading to cell membrane depolarization, an influx of intracellular calcium and consequent insulin secretion. Activating mutations in KCNJ11 or ABCC8, which prevent KATP channel closure and therefore insulin secretion in response to glucose, are the most common cause of PNDM and the second most common cause of TNDM (Table III). Mutations in KCNJ11 are more commonly associated with PNDM versus TNDM (90% versus 10%), while mutations in ABCC8 more frequently cause TNDM (approximately 66%). Approximately 20% of patients with mutations in KCNJ11 may have associated neurological features, in keeping with the expression of KATP channels in neurons and muscle cells, while neurological abnormalities are less common and milder in those harboring ABCC8 mutations. The most severe neurological phenotype is known as DEND (developmental delay, epilepsy and neonatal diabetes) syndrome, with an intermediate form of DEND syndrome (iDEND) that is characterized by milder motor speech or cognitive delay and patients typically do not have epilepsy. There is also some evidence that all patients with KATP channel mutations have defects in developmental coordination (particularly visual-spatial dyspraxia) or attention deficits.36

Neonatal diabetes due to INS mutations
Heterozygous coding mutations in the preproinsulin gene (INS) are the second most common cause of PNDM after KATP channel mutations. The mutation usually results in a misfolded proinsulin molecule that is trapped and accumulates in the endoplasmic reticulum, leading to endoplasmic reticulum stress and β-cell apoptosis.37 Similar to infants with KATP channel mutations, intrauterine growth retardation is typical; however, diabetes presents at a slightly later age in those with INS mutations and they do not develop neurological features as a direct consequence of the mutation.

Neonatal diabetes due to GCK mutations
Mutations in GCK are responsible for approximately 2% to 3% of cases of PNDM overall.31 In contrast to the asymptomatic phenotype of CGK-MODY due to heterozygous GCK mutations, homozygous or compound heterozygous mutations prevent the β cells from secreting insulin in response to hyperglycemia. The diagnosis should be considered in neonates who develop diabetes within the first few days of life whose parents have asymptomatic mild hyperglycemia (and harbor heterozygous mutations in GCK). Unlike KCNJ11 and ABCC8 mutations, patients are not responsive to sulfonylurea therapy and lifelong insulin treatment is required.

Other causes of neonatal diabetes
The clinical characteristics of other causes of neonatal and infancy-onset diabetes are shown in Table III. Apart from KATP– channel NDM, all other causes need to be treated with subcutaneous insulin. Patients with pancreatic aplasia/hypoplasia also require exocrine pancreatic supplements.

Treatment of neonatal diabetes
Initial treatment of NDM involves metabolic stabilization (since many cases present with severe dehydration, failure to thrive, and diabetic ketoacidosis). Insulin therapy should be commenced initially and a sample sent for molecular genetic diagnosis as soon as possible. Many laboratories will provide a rapid result (within 1 to 2 weeks) as to whether the infant has a mutation in KCNJ11 or ABCC8, in which case high-dose sulfonylurea therapy should be initiated.

The majority (90%) of patients with KATP channel mutations can be transferred from insulin to sulfonylurea therapy. The doses required are high (based on mg/kg body weight) compared with adults with type 2 diabetes. The typical dose is 0.5-1.0 mg/kg/day of glibenclamide, although higher doses may be required. The main side effects are hypoglycemia, transient diarrhea, and staining of the teeth. Sulfonylurea drugs may penetrate the blood-brain barrier and there is some evidence that sulfonylurea therapy may partially improve the associated neurological symptoms38; for this reason the higher range of the dose scale is recommended for patients with DEND or iDEND syndrome. For TNDM a much lower starting dose of glibenclamide is recommended (0.05 mg/kg/day); tapering upward or downward is often needed and eventually therapy will be ceased as the TDNM resolves. Patients with NDM due to INS mutations do not respond to sulfonylurea therapy and therefore insulin therapy is required.

Monogenic insulin resistance syndromes

Rare monogenic forms of severe IR can also cause diabetes, although diabetes is less common than in monogenic disorders leading to β-cell failure, particular before the onset of puberty. Classified according to their pathophysiology, there are three broad groups of IR: primary insulin signaling defects, IR secondary to adipose tissue abnormalities, and IR as a feature of complex syndromes, including ciliopathy-related diabetes.39 The genetic, clinical, and biochemical features of disorders within these three groups are shown in Table II.

Characteristics of IR syndromes include moderate to severe acanthosis nigricans associated with markedly elevated serum insulin concentrations or high insulin requirements in those with diabetes, in the absence of significant obesity. Female patients often present during adolescence with ovarian hyperandrogenism, resulting in a gender bias in the diagnosis. Variable other clinical features may help to guide specific genetic testing (see Table II).

The mainstay of therapy for lipodystrophies includes dietary advice with a low-fat, sometimes hypocaloric diet, with the aim of ameliorating metabolic derangements. In partial lipodystrophy, insulin sensitizers such as metformin and glitazones may be effective. Recombinant leptin has been used to treat patients with severe congenital lipodystrophy.40

Investigation of monogenic diabetes – rationale

Molecular genetic testing is both sensitive and specific for diagnosing monogenic diabetes, and is now available in many countries globally, with many laboratories offering rapid turnaround times, particularly for NDM. Molecular genetic testing is recommended at the time of diagnosis of NDM, since this will enable definition of the subtype, which impacts on treatment decisions such as use of sulfonylureas. Genetic testing should be strongly considered in patients who are suspected to have other forms of monogenic diabetes. A family history of diabetes is not essential to prompt genetic testing, as de novo mutations may occur. For example, spontaneous mutations and deletions are found in up to two-thirds of cases of MODY due to HNF1B,41 90% of heterozygous activating mutations in KCNJ11 that cause NDM arise de novo, and the majority of heterozygous INS mutations are sporadic de novo mutations, with a family history of autosomal dominant NDM present in only approximately 20% of cases. Informed consent should be obtained prior to testing from the individuals tested and their legal guardian as appropriate. Referral to a specialist team (diabetes genetics or clinical genetics) is recommended, particularly when testing of asymptomatic individuals is requested.


Advances in molecular genetics have contributed to unraveling the heterogeneity of diabetes and identification of clinically distinct subgroups. Although our current understanding is that monogenic diabetes contributes to no more than 5% of diabetes cases overall, the clinical implications of the diagnosis for the individual and their family support the use of genetic testing in specific cases. In particular, the absence of classical features of type 1 or type 2 diabetes, early onset of disease before the age of 6 months, and presence of extrapancreatic features warrant consideration of a genetic form of diabetes. Careful characterization of the phenotype is important to guide testing of specific genes. ■

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Keywords: c-peptide; familial; glucokinase; hepatic nuclear factor; insulin; MODY; monogenic diabetes; neonatal diabetes; sulfonylurea