1. Monogenic & Mitochondrial Ensuring the correct diagnosis
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
Genetic diabetes: monogenetic & mitochondrial Ensuring the correct diagnosis

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
MODY is caused by a change in a single gene. 6 genes have been identified that account for 87% of UK MODY:
HNF1A
Glucokinase
HNF1B (including Renal Cysts and Diabetes (RCAD))
HNF4A

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
The HNF1A & HNF4A gene acts as a switch gene, turns on and off other genes in the body.
sensitive to the blood glucose lowering effects of a group of drugs called sulphonylureas.

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.
Glucokinase is a gene which plays an important role in recognising how high the blood glucose is in the body. It acts as the “glucose sensor” for the pancreas, so that when the blood glucose rises, the amount of insulin produced also increases.

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
encoding the Kir6.2 and SUR1 subunits of the pancreatic K-ATP channel as the most common cause of neonatal diabetes which is typically diagnosed in the first six months of life (Gloyn et al. N Eng J Med 2004:350; ; These patients often have de-novo mutations and so do not have diabetic relatives. However, around 10% show generation to generation transmission with an autosomal dominant inheritance and about 20% of patients have neurological features, typically developmental delay and in some cases epilepsy (termed DEND syndrome). Beta-cell autoantibodies seen in Type 1 diabetes are not detected. Patients usually present with very high glucose values and occasionally ketoacidosis and often C peptide is not measurable even in response to either glucose or glucagon. Treatment with high dose sulphonylureas is successful for most patients and achieves improved glycaemic control.
(Proks et al, Hum Mol Genet 2006:15; ).

8. Beta cell physiology - the KATP channel
Ca2+
Voltage dependent Ca2+ channel
Depolarisation
Glucose
GLUT2
glucose
transporter
ATP-sensitive potassium (KATP) channels play a central role in glucose-stimulated insulin secretion from pancreatic beta cells: insulin secretion is initiated by closure of the channels and inhibited by their opening
Sulfonylureas stimulate insulin secretion in type 2 diabetes by binding to SUR1 and closing KATP channels by an ATP-independent mechanism
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
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
Referrals per million
It is estimated that currently over 80% of MODY cases are currently undiagnosed or misdiagnosed in the UK. There is great variability in the referrals for diagnostic testing throughout the UK, as shown by this map here, with 13 referrals per million in Wales, and 106 referrals per million in the South West.
The decisions on who to test are entirely down to local opinion and tend to focus on areas with a genetic diabetes nurse or specific clinician interest. The main issue though is that genetic testing is expensive, so it needs to be targeted to those who will benefit the most from it and deciding on who to test can be challenging.
Shields et al (2010) Diabetologia 12 12 12

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. HNF1A monogenic diabetes confirmed
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
Talk through family tree and autosomal dominant inheritance
UCPCR: (<0.2 nmol/mmol indicates insulin deficiency)
GAD and IA2 negative
UCPCR nmol (20yrs post diagnosis)
HNF1A monogenic diabetes confirmed 16

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 % (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 % (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’
Niona had KCNJ11 diabetes identified
40% of cases of permanent neonatal diabetes are caused by KCNJ11 (Kir6.2) mutations (Hattersley, Diabetes, 2005)

18. Neonatal diabetes
Refer ALL patients 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 % (65-46mmol/mol) p<0.001 on high dose sulphonylureas (Pearson, NEJM, 2006)
By transferring to high dose sulphonylureas 20

19. Josef - GCK Referred by GP Practice locally
31 year old man diagnosed Type 1 diabetes age 16 years. BMI 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 (nr ) – 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 Not in contact
Diag type 2 diabetes on tablets – Positive GCK
Now age 26
Now age 31
Now age 16
Mr GERON TOVARUELA X
Diabetes
Diet controlled
At Age ?12
Not yet tested for GCK
Diagnosed Type 1
age 15 - insulin
Positive GCK
Diag Type 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.
Monogenic meaning the diabetes is caused by a change in a single gene – IT IS NOT MODY, this is an outmoded term, we can test for specific gene mutations now so this ‘label’ is no longer helpful
It is autosomal dominant inheritance, so the gene is passed from an affected parent from one generation to the next.
Because individuals may be wrongly diagnosed as type 1 they may be on insulin, but if diagnosed as monogenic in the first place can be managed without insulin.
Although 2% seems a small number of the total diabetes population it accounts for 40,000 people. Individuals who if had a diagnosis of monogenic diabetes may have a change in treatment that would have a significant benefit to their management and outcomes

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.
Mitochondria is present in every human cell, (apart from red blood cells) these structures are sometimes described as "the powerhouse of the cell" because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy.
As all the mitochondria we inherit are inherited from our mothers the genetic change is passed down from an affected mother to all her children.
MIDD affects up to 1% of all diabetes but often goes unrecognised and is misdiagnosed as either Type 1 or Type 2 diabetes..
Those with MIDD are usually of normal body weight. MIDD leads to diabetes because it reduces the amount of insulin made by the beta cells in the pancreas.
The majority of people with MIDD can, at the start, be treated with dietary changes or tablets. However insulin therapy is usually needed within 2 years of diagnosis reflecting the reduced insulin secretion.

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 ( yrs). 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.
Mitochondria is present in every human cell, (apart from red blood cells) these structures are sometimes described as "the powerhouse of the cell" because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy.
As all the mitochondria we inherit are inherited from our mothers the genetic change is passed down from an affected mother to all her children.
MIDD affects up to 1% of all diabetes but often goes unrecognised and is misdiagnosed as either Type 1 or Type 2 diabetes..
Those with MIDD are usually of normal body weight. MIDD leads to diabetes because it reduces the amount of insulin made by the beta cells in the pancreas.
The majority of people with MIDD can, at the start, be treated with dietary changes or tablets. However insulin therapy is usually needed within 2 years of diagnosis reflecting the reduced insulin secretion.

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. Diagnostic criteria for Monogenic diabetes
Diagnosis of diabetes before 25 years in at least 1 & ideally 2 family members
Early-onset diabetes
Not insulin
dependent diabetes
Autosomal dominant
inheritance
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)
USE THIS SLIDE AT THE END OF THE TALK TO REINFORCE DIAGNOSTIC CRITERIA
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
Because of this, we looked at ways of improving the detection of MODY, and put together a clinical prediction model that works with probabiilties rather than absolute cutoffs by using a weighted combination of the clinical features. The calculator is now available on our website at diabetesgenes.org and you can add in the clinical features of your patient and obtain their probability of MODY.
Shields et al (2012) Diabetologia
Shields B et al (2012) Diabetologia 31 31

30. Where to refer Diabetes Genetic clinic - Guys
Usual GSTT referral pathway for diabetes

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