6. Complex genetic disorders Flashcards
Diabetes
chronic hyperglycaemic state
characterised by beta cell dysfunction and/or insulin resistance
polygenic or monogenic
Type 1 Diabetes
Autoimmune system destroys pancreatic beta cells
Diminished/absent endogenous beta cell function, no/ little production of insulin
Presents at any age
Treatment of Type 1 diabetes
Insulin replacement
Type 2 Diabetes
resistance to insulin action leads to increased production and ultimately pancreatic exhaustion
Presents at middle/old age, increasing in youth
Treatment of type 2 diabetes
Diet
Exercise
Oral hypoglycaemic agents
Eventually insulin
Monogenic diabetes
Single gene defect:
Maturity onset diabetes of the young (MODY)
Permanent neonatal diabetes (PND)
Maturity onset diabetes of the young (MODY)
Collection of autosomal dominant monogenic disorders affecting genes involved in beta-cell glucose sensing and insulin secretion.
Often mutation of HNF1-α or Glucokinase
Different from Type 1 & Type 2 diabetes
Heritability
Study of genetic contribution to increased risk of a disease
Difficult to disentangle genetic from non-genetic factors
Percentage of diabetes that is monogenic and polygenic
monogenic: 5%, born with it
polygenic: 95%, may develop it
Proportion of T1DM and T2DM that are polygenic
T1DM: 5%
T2DM: 95%
Monogenic diabetes
100% risk of developing diabetes
No environmental factors
100% heritable
Polygenic diabetes
T1/2
Not born with it but can have genetic predisposition
Compilation of genetic changes that increase predisposition
Not 100% risk
Affected by environment
What is the difference between monogenic and polygenic diabetes?
In polygenic there has to be a 2nd hit to develop diabetes:
Environmental
Lifestyle
What are genome wide association studies (GWAS)?
Hypothesis free approach to find common variants in common disease
Looking to identify SNPs statistically associated with disease
Genomic Copy Number Variation (CNVs)
Deletions/duplications/insertions in genome
Range from few base pairs to > 1Mb
Can increase risk of polygenic disease
Common in obesity
Most risk appears to be conferred through single nucleotide changes
What did GWAS show for Type 2 diabetes?
SNPs account for 6%
Shows environment is heavily influential
What is Hepatic nuclear factor 1-alpha (HNF1-alpha)?
Transcription factor that stimulates insulin production
What is the consequence of absence/ mutation of HNF-1 alpha?
Insulin production reduced
Only manifests in adulthood when beta- cell function starts to naturally decline
How are HNF1-alpha mutations best managed?
With sulphonylureas
What are those with HNF1-alpha mutations at risk of?
Micro- and microvascular complications
Clinical features of HNF1-alpha mutations
Hypoglycaemic response to low dose sulphonylureas Young onset Generational family history Non- insulin requiring Atypical for T1/T2
What is glucokinase?
Enzyme that converts glucose to glucose-6-phosphate
Triggered at certain beta-cell glucose levels
What do glucokinase mutations result in?
Higher set-point at which insulin secretion is triggered
What defect characterises MODY 2?
Glucokinase mutation
Features of MODY 2
High fasting and low post-prandial plasma glucose
Stable, mild hyperglycaemia
Often misdiagnosed as T2DM, IFG or GDM
Why are there not often complications to MODY 2?
Isolated risk factor
Hyperglycaemia is mild and under homeostatic regulation
Similar insulin resistance and obesity as general population
‘Normal’ lipid profile
Name 2 rarer types of HNF mutation
HNF-4 alpha
HNF-1 beta
Describe HNF-4 alpha mutation
Clinically similar to HNF-1 alpha but rarer Older age of onset Low renal glucose threshold Macrosomia Transient neonatal hypoglycaemia
What characterises HNF-1 beta mutation (RCAD)?
Renal cysts and diabetes
Genital tract mutations
What are the barriers to diagnosing monogenic diabetes?
Incomplete understanding regarding benefits of diagnosis
Clinical challenge: need to think of it to make diagnosis
Access to genetic testing and robust interpretation
Interpreting variants of unknown significance
Needle in haystack
Mitochondrial diabetes
Maternally inherited diabetes and deafness (MIDD)
Associated with MELAS
Features of MIDD
Diabetes Young-onset sensorineural deafness Lactate Muscle aches Short stature
Permanent neonatal diabetes features
Monogenic
Diabetes in 1st 6 months of life
Genetic defect resulting from mutations in
KCNJ11, ABCC8 and INS
Precision diabetes allows accurate diagnosis and treatment
SNPs predict metformin side effects
Use sulphonylureas in HNF1a MODY and PND
