Anna Reid Genetic Diabetes Nurse Nurse Consultant Guys and St Thomas NHSF Trust

1. Genetic diabetes: • Monogenic & Mitochondrial • Ensuring the correct diagnosis • Lambeth CCG Diabetes Learning Event • 4th October 2018 Anna Reid Genetic Diabetes Nurse Nurse Consultant Guys and St Thomas NHSF Trust

2. Monogenic diabetes • What is it • What's the incidence • Why does it matter • Case Studies • Referral

3. Monogenic diabetes – it depends on the Gene HNF1A HNF4A Glucokinase (GCK) HNF1B Neonatal

4. HNF1A & HNF4A – What are they? They are both genes that turn other genes on and off. Mutations in HNF1A & HNF4A cause diabetes by reducing insulin production, gradually reduces after childhood. Mutations in HNF1A account for 70% of Monogenic diabetes Mutations in HNF4A are rare Sensitive to Sulphonylureas, Gliclazide, Glipizide, Glibenclamide and Tolbutamide, likely need insulin over time. Children have 50% chance of inheriting the affected gene

5. Glucokinase (GCK) diabetes –What is it? The Glucokinase gene acts as a glucose sensor alerting the pancreas so insulin production increases. A mutation causes normal BG to be ‘reset’ at a higher rate, so that fasting are typically 5.5-8mmol/l. Asymptomatic, usually found in routine screening. Complication rare, usually no treatment required. Children have 50% chance of inheriting the affected gene Correct diagnosis will mean appropriate treatment & appropriate management during pregnancy.

6. HNF1B: What is it?Renal cysts and diabetes (RCAD) Renal involvement: Renal cysts frequent Renal abnormalities may be seen in utero Variable renal histology eg single / horseshoe kidney Renal function ranges from normal - dialysis Some patients have had renal transplants Diabetes: Typically develops after renal disease Age at diagnosis variable Beta cell dysfunction Usually require insulin Not all family members affected (50% of cases spontaneous mutations) Other features:uterine malformations and gout

7. Neonatal diabetes – what is it Commonest cause of neonatal diabetes is a mutation in Kir6.2 and SUR1 of the pancreatic K-ATP channel – the mutation keeps the channel open & stops insulin being produced. Diagnosed ≤ 6 months age Usually no family Hx (de-novo mutation). 20% have developmental delay, some cases epilepsy. Nil beta cell antibodies, often little C peptide. At least 300 people diagnosed type 1 diabetes have been identified and come off insulin. Most can be treated with sulphonylureas

8. Beta cell physiology- the KATP channel Ca2+ Voltage dependent Ca2+ channel Depolarisation Glucose GLUT2 glucose transporter Gloyn et al. NEJM 2004

9. What’s the incidence? Its rare – 2% of the diabetic population have monogenic diabetes = 40,000 individuals They are likely to be in your clinics

10. Monogenic Diabetes Diagnosis – Current Situation Referrals per million • Monogenic diabetes accounts for 2% of UK diabetes (40,000 cases) • >90% currently undiagnosed or initially misdiagnosed • Referrals for diagnostic testing for monogenic diabetes is sporadic Referrals per million Shields et al (2010) Diabetologia

11. Local services • Diabetes Genetic clinic - Guys • Three session Month – Genetic Diabetes Nurse • Monthly – Dr Anna Brackenridge • Pick up rate 30% of the referrals made

12. Why does it matter? • Getting the diagnosis right matters

13. Georgia - HNF1A monogenic diabetes Diagnosed at 11 yrs, presented ‘well with modest BG’ Presumed Type 1 diabetes Basal Bolus regime 0.6u/kg/day Referred to Exeter aged 14 yrs HbA1c 54mmol/mol (7.1%) Ht 1.6, Wt 50kg Mother, grandfather, great grandfather type 1 diabetes GAD and IA2 negative UCPCR 1.73 nmol/mmol (<0.2 nmol/mmol indicates insulin deficiency)

14. Georgia & her Mum ‘Type 1’ Mum, Emma, Dx 14 yrs Now 34 yrs, BMI 20 Presumed Type 1 insulin from diagnosis Basal bolus regime 1.3u/kg/day HbA1c 96 mmols/mol (10.9%) ‘Type 1’ Died 35yrs MI Dx 20yrs Basal bolus Insulin Dx 30yrs OHA Dx 14 yrs Insulin Dx 11 yrs Insulin GAD and IA2 negative UCPCR 3.75 nmol (20yrs post diagnosis) HNF1A monogenic diabetes confirmed

15. Impact of diagnosis Georgia: Stopped Insulin May 2012 on Gliclazide 20mg OD BG within target range Mum, Emma:Remained on Insulin as pregnant then transferred to Gliclazide. Mum’s siblings currently undergoing genetic testing also

16. Niona - Neonatal Diabetes • BW 6lbs, FT, ‘content’ baby • Admitted at 12 wks with suspected pneumonia • BG 36 mmol/l, DKA, Started insulin • HbA1c on Insulin 8.3-8.8% (67-73 mmol/mol) • No family history of diabetes • No detectable c-peptide & antibody negative • Attended main stream school but developmental delay, slow speech

17. Niona - Neonatal Diabetes • Kir6.2 mutation identified • After 33 years of insulin treatment Niona stopped insulin in May 2008, • HbA1c 5.4-6.3% (36-45mmol/mol) • Glibenclamide 10 mg bd Niona: ‘I feel great, I feel normal now’ Niona’s Mum: Niona is like a different person, she looks and feels better and her behaviour has improved’ DSN: ‘I noticed her speech had improved and she was more confident’

18. Neonatal diabetes ReferALLpatients diagnosed <6 months for genetic testing. (what ever their age now) Testing is FREE >90% of patients with KCNJ11 mutations successfully discontinued insulin (Pearson, NEJM, 2006) All improved HbA1c 8.1 - 6.4% (65-46mmol/mol) p<0.001 on high dose sulphonylureas (Pearson, NEJM, 2006)

19. Josef - GCK • Referred by GP Practice locally • 31 year old man diagnosed Type 1 diabetes age 16 years. BMI 23.7. Spanish - White • 10 units Glargine – HbA1c 6.1% / 43mM/M • No known complications • Family Hx Father, brother and sister all have diabetes. Paternal Grandfather Diabetes and AKA & poor vision • Diabetes antibodies: negative • c-peptide: 648 (nr370-1470) – BG 6.1mmol/l ‘The worse thing is I worry a lot about complications from diabetes’

20. Josef – Impact of Diagnosis • GCK MODY • Insulin reduced and then ceased • Hba1c stable • Father and sister underwent genetic testing both confirmed GCK and treatment ceased. ‘Our family had the best Christmas, we put it on face book and every one was so happy’

21. Josef – Family Tree Age 70 diabetes AKA Poor vision Diag type 2 diabetes on tablets – Positive GCK Not in contact Now age 26 Now age 31 Now age 16 Diabetes Diet controlled At Age ?12 Not yet tested for GCK Diagnosed Type 1 age 15 - insulin Positive GCK DiagType 1 age 16 Tested positive GCK Sept 2015

22. Monogenic diabetes – Summary • Monogenic Diabetes (MODY) It is caused by a change in a single gene. • Three key Features: • Early onset, diagnosed below 25yrs in at least one family member. • There is also an affected parent. • Non-insulin dependent (or could be if diagnosed). • Accounts for approx. 2% (40,000) of the diabetic population. • It is very likely that you will have individuals with undiagnosed Monogenic diabetes in your clinics.

23. Mitochondrial Diabetes – What is it? Mitochondria generate energy within the cells. All Mitochondria is inherited from our mothers. Mitochondrial diabetes is caused by a mutation in mitochondrial DNA.

24. Mitochondrial Diabetes – What is it? Mitochondria generate energy within the cells. All Mitochondria is inherited from our mothers. Mitochondrial diabetes is caused by a mutation in mitochondrial DNA. Affects 1% of all diabetes, often misdiagnosed, diabetes develops on average age 37 (11 - 68yrs). Usually insulin required within 2 years Significant variation in how an individual is affected, they may have 1 or 2 or no disease. For example Mitochondrial mutation (m.3243A>G) MIDD - Maternally inherited diabetes and deafness. An individual may have diabetes alone/ Deafness alone/both. Also Cardiac disease/renal disease/GI problems/Muscle weakness.

25. Mr RR - Mitochondrial Diabetes • Mr RR 50 yr old man from S. America • Diagnosed type 2 Diabetes age 35 treated with metformin & Gliclazide. • Developed hearing loss age 45, wears hearing aid. • Background Fibromyalgia, chronic migraines, stiff neck & muscular pains, Chronic fatigue,constipation, low mood. • Mother and 1 brother diabetes

26. Mr RR- Mitochondrial Diabetes • Appointments Over 7 years • ENT x 7 • Colo-rectal surgery clinic x 2 • Pain Management x 3 • Neurology x 7 • Oral Surgery x 3 • Pelvic floor clinic x 2 • Rheumatology x 1 • Physio x 7 • Diabetes x 2 Total 34 (visit 5-6 wks) • Plus community Psychology and appointments at KCH

27. Mr RR- Mitochondrial Diabetes • Referred to diabetes genetic clinic by DECS/eye clinic re: patchy pigmentary retinopathy ?in keeping with MIDD • Diagnosed m.3243A>G mutation: Maternally Inherited Deafness and Diabetes (MIDD) ‘Thank God there's a reason I thought I was going mad’

28. Diagnosis of diabetes before 25 years in at least 1 & ideally 2 family members Off insulin treatment or measurable C-peptide at least 3 (ideally 5) years after diagnosis Must be diabetes in one parent (2 generations) and ideally a grandparent or child (3 generations) Diagnostic criteria for Monogenic diabetes • Early-onset diabetes • Not insulin • dependent diabetes • Autosomal dominant • inheritance Caused by a single gene defect altering beta-cell function Tattersall (QJM 1974)

29. Online probability calculator can produce a probability of MODY based on clinical features www.diabetesgenes.org Shields et al (2012) Diabetologia Shields B et al (2012) Diabetologia

30. Where to refer • Diabetes Genetic clinic - Guys • Usual GSTT referral pathway for diabetes • anna.reid@gstt.nhs.uk

31. For more information on monogenic diabetes: www.diabetesgenes.org Training course - Exeter Monogenic Diabetes – right diagnosis, right treatment” Monday 1st and Tuesday 2nd July 2019