Introduction 1 2 Why diagnose monogenic diabetes? 3 3 5 6 7 Normal insulin release and normal insulin sensitivity 1 2 Fig. 1 1 2 3 4 From centre to right: Ins ER Golgi From left to right down: GLUT2 GCK G6P Mito ATP + VDCC Ca 2+ From centre to right WCRS DIDMOAD TRMAS IPEX From left to right down: ADP ATP ATP  Fig. 2 P Y IRS1 PI3K GLUT4 TG FFA S  Abnormal insulin release and abnormal insulin sensitivity 1 3 8 1 1 1 2 2 9 2 9 11 12 13 When to consider a diagnosis of monogenic diabetes? Given the limited resources available it is vital that genetic tests are used in situations where they are likely to be positive and will alter clinical care. This will involve careful clinical selection and physiological tests like C peptide and autoantibody measurement as well as examination of other family members before doing molecular genetic tests. Monogenic diabetes should be considered in any diabetic patient who has features inconsistent with their current diagnosis and clinical features of specific subtypes of monogenic diabetes. No specified diagnosis or features inconsistent with current diagnosis 5 No specified diagnosis of neonatal diabetes or of diabetes diagnosed below the age of 6 months 3 14 15 1 Table 1 Features of diabetes diagnosed before 6 months of age in addition to undetectable to low C-peptide Protein (Chromosome/gene; Syndrome) Clinical picture Number of cases described Median birth weight ingrams SDS (standard deviation score) Median age at diagnosis in weeks (range) Family history reflected by inheritance Other clinical features Other tests Treatment (% in consanguineous or isolated populations) Pancreatic appearance (present/size) • ZAC/HYMAI (6q24 imprinting defect) TNDM ±150 (rare) 2,100 (−2.94) 0.5 (0–4)  - Macroglossia (23%) Normal Insulin/pump > relapse: diet > insulin • Kir6.2 (KCNJ11) TNDM10% PNDM90% ±100 (rare) 2,580 (−1.73) 6 (0–260) - Spontaneous - DKA (30%) Normal High dose sulfonylurea - Dominant(10%) - Developmentaldelay 20%) - Epilepsy (6%) • PTF1A(10p13-12) PNDM 3 (100%) 1,390 (−3.8)  Recessive - Severeneurological dysfunction Atrophy Insulin/pump       - Cerebellar hypoplasia   • IPF1 (13q12.1) PNDM 2 (50%) 2,140 (−2.97)  - Recessive  No pancreas Insulin/pump - Parents may have early onset diabetes as heterozygotes • HNF1β (179) TNDM Rare 1,900 (−3.21)  - Dominant (60%) - Renal development disorders Atrophy Insulin/pump - Spotaneous • EIF2AK3(2p;Wolcott-Rallison Syndrome) PNDM 30 (90%)  13 (6–65) - Recessive - Epiphyseal dysplasia (90%) Exocrine dysfunction Insulin/pump       - Developmental delay (80%)         - Acute liver failure (75%)         - Osteopenia (50%)         - Hypothyroidism (25%)   • FOXP3 (Xp11.23; IPEX Syndrome) PNDM 14 (rare) 2,860 (−1.2) 6 (0–30) X-linked Hence only boys affected - Chronic diarrhoea with villous atrophy (95%)  Insulin/pump       - Pancreatic and thyroid autoantibodies (75%)         - Eczena (50%)         - Anaemia (30%)         - Thyroiditis (20%)         - Often die in first year   • GLUT2 (3q; Fanconi Bickel Syndrome) TNDM    Recessive - Impaired utilisation of glucose and galactose  Insulin/pump - Hepatorenal glycogen accumulation - Proximal renal tubular dysfunction > glucosuria • Glucokinase (GCK11 homozygote) PNDM 6 (85%) 1,720 (−2.75)  - Recessive  Normal Insulin/pump - Parents have fasting hyperglycaemia as heterozygotes Clinical features that are unusual for type 1 diabetes 5 4 15 16 Endogenous insulin production after 3 years of diabetes (the honeymoon phase), indicated by detectable C-peptide (>200 nmol/l) in response to raised glucose (>8 mmol/l) (1–5%). 17 18 Clinical features that are unusual for type 2 diabetes 19 22 19 22 19 22 19 22 Clinical features of specific subtypes of monogenic diabetes and their treatment 1 2 2 3 4 Neonatal diabetes and diabetes diagnosed before the age of 6 months irrespective of current age 23 24 ZAC HYMAI 1 14 23 23 KCNJ11 3 25 27 25 3 26 ABCC8 ATP 28 KCNJ11 3 29 30 1 14 26 70 31 36 70 7 70 37 Familial diabetes with an affected parent Children and young adults with a strong family history of diabetes 2 38 Young onset diabetes that shows characteristics of not-being insulin dependent e.g., do not develop keto-acidosis in the absence of insulin, achieve good glycaemic control on a small dose of insulin. Detectable C-peptide is measured when on insulin with glucose >8 mmol/l after 3 years of diabetes (the honeymoon period). Family history of diabetes. This might be insulin treated and considered to be type 1 diabetes. This would typically be diagnosed at their 20s, 30s or 40s. There may also be an affected grandparent although often these are diagnosed after 45 years. 39 39 40 41 Table 2 Familial diabetes diagnosed, or undiagnosed due to mild hyperglycaemia Gene/protein Clinical picture Number of cases described Median age at diagnosis in weeks (range) Family history reflected by inheritance Other clinical features Other tests Treatment Glucose at presentation in mmol/l Median (range) OGTT Familial diabetes diagnosed HNF-1α MODY3 197 14 (4–18) Dominant Hyperglycaemia is rapidly progressive with age 17 (11–26) Large increment (0 h–2 h usually >5 mmol/l) Diet > low dose of sulfonylurea     Low renal threshold > glucosuria        Sensitive to sulfonylurea    HNF-4α MODY1 22 17 (5–18) Dominant Hyperglycaemia is rapidly progressive with age 15 (9–20) Large increment (0 h–2 h usually >5 mmol/l) Low dose of sulfonylurea     Normal renal threshold        Sensitive to sulfonylurea        Reduced levels of apoAIII, apoCIII, and triglycerides    Other unusual causes: IPF1 (MODY4), NeuroD1 (MODY6), CEL (MODY7) Familial diabetes undiagnosed due to mild fasting hyperglycaemia Glucokinase (GCK, heterozygous) MODY2 152 10 (0–18) Dominant Hyperglycaemia is mild (fasting 5.5–8 mmol/l) 11 (5.5–16) Small increment (0 h–2 h usually <3.5 mmol/l) No treatment     (The mild hyperglycaemia might not have been diagnosed in relatives/parents) Hyperglycaemia is only slowly progressive with age> usually diagnosis is by incidental finding         Normal renal threshold    42 43 41 40 44 45 46 47 46 48 49 50 51 52 52 Mild (5.5–8.5 mmol/l) fasting hyperglycaemia especially if young or familial 39 HbA1C is typically just below or just above the upper limit of normal (5.5 to 5.7%) 39 39 39 53 Genetic syndromes associated with diabetes http://www.ncbi.nlm.nih.gov/entrez/query.fcgi http://www.diabetesgenes.org 3 4 Table 3 Syndromic features in addition to the diabetes: insulin synthesis/secretion Gene/protein Clinical picture Number of cases described Median age at diagnosis in weeks (range) Family history reflected by inheritance Other clinical features Treatment HNF1β Rarely isolated PNDM or MODY 5    - Renal developmental disorders, especially renal cysts and dysplasia Insulin (+possibly treat exocrine deficiency?) HNF1β Renal cysts and diabetes syndrome (RCAD)    - Uterine and genitalia developmental anomalies       - Hyperuricaemia, gout       - Abnormal liver function tests  WSF1 Diabetes insipidus, diabetes mellitus, optic atrophy, deafness (DIDMOAD) syndrome/Wolfram syndrome (90% have mutations) Especially where consanguineous marriages are frequent 6 years(Most <16 years) Dominant - Diabetes insipidus- Optic atrophy - Bilateral sensorineural deafness- Dilated renal tracts- Truncal ataxia- Protean neurological signs 75% has the complete phenotype, increasing with increasing age Insulin SLC19A2(Thiaminetransporter protein) Thiamine responsiveMegaloblastic anaemia (TRMA) syndrome Roger’s syndrome Rare  Recessive - Thiamine responsive megaloblastic anaemia- Sensorineural deafness Thiamine > insulin           tRNA(leu(UUR)) gene (3243 A to G; tRNA) - Maternally inherited diabetes (MID)- Mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like syndrome (MELAS)    - Sensorineural deafness- Short stature- Subclinical exocrine deficiency- Heteroplasmy Insulin Table 4 Syndromic features in addition to the diabetes: insulin resistance Protein Clinical picture Median age at diagnosis in weeks (range) Family history reflected by inheritance Other clinical features Other features/tests Treatment Acanthosis nigricans Insulin levels Androgen excess and hypertrichosis Insulin receptor Type A Adolescence Recessive (usually) Insulin resistance in absence of obesity Yes—marked ↑↑↑ ↑↑↑/PCO (Metformin/glitazones) > insulin/pump Insulin receptor Rabson-Mendenhall Congenital Recessive (usually) - Abnormal dentition Yes—marked ↑↑↑ ↑↑/PCO (Metformin/glitazones) > insulin/pump - Extreme growth retardation Insulin receptor Leprechaunism (Donahue syndrome) Congenital Recessive (usually) - Abnormal facies Yes—marked ↑↑↑ ↑↑↑/PCO (Metformin/glitazones) > insulin/pump - SGA and growth retardation - Large genitalia - Rarely survive infancy Seipin&AGPAT2 Total lipodystrophy Adolescence or congenital Recessive - Total loss of subcutaneous fat Yes—may be marked ↑↑ ↑↑↑/PCO+/− Recombinant /insulin Lamin AC&PPARγ Partial lipodystrophy Dominant - Partial loss of subcutaneous fat    Metformin > insulin MODY-5 due to an HNF-1β mutation (renal cysts and diabetes syndrome 54 55 56 57 in utero 3 58 57 Wolfram or DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) 59 61 62 3 62 62 62 Roger’s or TRMA syndrome (thiamine responsive megaloblastic anaemia) 63 3 Mitochondrial diabetes 64 65 66 3 Insulin resistance syndromes 4 2 2 4 2 2 2 67 68 Testing for a molecular monogenic diagnosis How to test for monogenic diabetes? http://www.diabetesgenes.org http://www.diabetesgenes.org 69 What if a monogenic diagnosis cannot be made? Occasionally molecular genetic test results are negative, despite unusual clinical features or typical features for a certain monogenic subtype. The certainty of such a negative result increases if a specialised centre performed testing. Even then, some cases remain unsolved. These can be referred to the ISPAD rare cases registry (see website or contact a.t.hattersley@exeter.ac.uk) to allow pattern finding and closer investigation by experts if a novel idea evolves, hence increasing chances for new and future insights, novel diagnoses and improved patient care. Summary Molecular genetic testing can define a diagnosis in 1–2% of all diabetic patients with monogenic diabetes. Advances in this field have led to the identification of the genes associated with many clinically identified subgroups of diabetes and explained clinical heterogeneity in conditions defined by age of diagnosis e.g. neonatal diabetes and MODY. Molecular genetic tests are now available to help define the diagnosis, and importantly alter prognosis and optimise treatment of children, young adults and their families with diabetes. As these tests are expensive genetic testing should be limited to those who on clinical grounds are likely to be positive. Considering testing for monogenic diabetes is hence a challenge and should be guided by unusual features of the current diagnosis, specific features concordant with monogenic subtypes and by the possibility of a change in treatment. This article discussed the pathophysiology and clinical manifestations used to select eligible patients and guide genetic testing, and demonstrates its importance in the treatment of monogenic diabetes.