Complex Genetic Diseases: Diabetes

Question 1

What types of monogenic diabetes are?

Answer 1

• Maturity onset diabetes of the young (MODY)
• Permanent neonatal diabetes (PND)
• Mitochondrial diabetes

Question 2

What is MODY caused by and what is the treatment dependant on?

Answer 2

Single gene disorder.
Caused by a collection of autosomal dominant monogenic disorders affecting genes involved in beta-cell glucose sensing and insulin secretion.

-Treatment dependant on the affected gene

Question 3

What is the difference between polygenic and monogenic diabetes?

Answer 3

Monogenic diabetes means that the person will develop diabetes but with polygeneic diabetes is a compilation of genetic changes that increase predisposition to developing type1/type2 BUT there also has to be a second hit to develop diabetes e.g environmental/ lifestyle

Question 4

How is GWAS used to contribute to our understanding of diabetes

Answer 4

GWAS helps to see if a disease is statistically associated with single nucleotide polymorphisms (SNPs)

Question 5

What do Genomic copy number variation include and why is this relevant?

Answer 5

Copy number variations:

• Deletions
• Extra copies of certain regions (duplication and amplification)
• inversions and translocations

Can increase risk of polygenic disease. We all have GSVs: some have no known effect and others are associated with ill effects.

Question 6

Describe what happens in HNF1-a mutation

Answer 6

Hepatic nuclear factor 1 a:

• transcription factor normally stimulating production
• in absence, insulin production reduced, but this only shows in adulthood when beta-cell function starts to naturally decline.

Question 7

What is the best treatment with those with HNF-1 alpha and what patients with this at more risk of?

Answer 7

Sulphonylureas

Risk of:

• Micro ( retinopathy, nephropathy and neuropathy) vascular and macro ( ischaemic heart disease, peripheral vascular disease and cerebrovascular disease). vascular complications
• may eventually end up requiring insulin therapy

Question 8

What are the clinical features of HNF1 alpha

Answer 8

• sensitivity hypoglycemia to low dose sulphonylureas
• young age t onset
• generational family history
• non-insulin requiring
• this is atypical for type 1 or type 2

Question 9

What does a mutation in the glucokinase cause?

Answer 9

• Glucokinase converts glucose to glucose-6-phosphate.
• Beta-cell glucose sensing
• Mutation results in a higher set-point at which insulin secretion is triggered

Question 10

What are the clinical features with patients with glucokinase mutation

Answer 10

• Have stable, mild hyperglycemia
• have high fasting and low post-prandial plasma glucose( blood glucose after a meal)
• not associated with long-term complications
• non-progressive mild life-long hyperglycaemia

Question 11

What other mutations are there and describe their features?

Answer 11

HNF 4 alpha:

• clinically similar to HNF-1 alpha but rarer
• older age of onset
• low renal glucose threshold
• macrosomia (large baby)
• transient neonatal hypoglycemia

HNF-1 beta:

• renal cysts and diabetes
• genital tract mutations

Question 12

What are the key features of mitochondrial diabetes?

Answer 12

• maternal transmission
• diabetes:
• young onset, sensorineural deafness (lies in the root of the ear)
• lactate
• muscle aches
• short stature

Question 13

What is permanent neonatal diabetes?

Answer 13

It is diabetes in first 6 months of life

• genetic defect resulting from mutation in:
• KCNJ11
• ABCC8
• INS
• KCNJ11&INS

Question 14

How can precision diabetes help?

Answer 14

With treatment e.g. give sulphonylureas in HNF1A MODY & PND
- pharmacogenetics- SNPS can predict metformin side effects.