The Genetics of Metabolic Diseases Flashcards
What are the most common rare metabolic disorders in Australia?
PKU
Mitochondrial disorders
Lysosomal storage disorders
Haemochromatosis
What is haemochromatosis?
Inability to clear Fe from body > Fe overload
How do you treat PKU?
Limit Phe intake
How do you treat galactosaemia?
Limit lactos and galactose in diet
How do you treat urea cycle disease?
Limit protein
Medication to remove ammonia from blood
How do you treat lysosomal storage diseases?
Symptomatic treatment
What is maturity onset diabetes of the young (MODY)?
1% of diabetes cases
Monogenic - 11 known genes
Pancreatic cell dysfunction
Often misdiagnosed
What is gestational diabetes?
Developed whilst pregnant
Implications for future glucose regulation of mother and baby
What is the inheritance pattern of MODY?
Autosomal dominant
When is the typical onset of MODY?
6 months-35 years
Is there variation in the phenotype of MODY?
Yes - can be sub-symptomatic
What are the symptoms of MODY?
Hyperglycaemia
Polyuria
Polydipsia
OR no signs of symptoms but high glucose during screening
OR diagnosed through mild hyperglycaemia during testing in pregnancy
What is the penetrance of MODY?
40-90%
What do the genes affected in MODY do?
Control development and/or function of pancreas
Control expression of insulin gene
Involved in glucose metabolic pathways
What are the three most common genes affected in MODY?
HNF4a
GCK
HNF1a
What are HNF4a and HNF1a?
Transcription factors
What does HNF4a do?
Control expression of HNF1a
What does HNF1a do?
Control expression of genes in liver
What is the protein product of GCK?
Glucokinase
Where is glucokinase expressed?
Hepatocytes
Pancreatic beta cells
How does the enzyme activity of glucokinase change with glucose concentration?
Changes depending on amount of glucose = glucose sensor
How does glucokinase act as a glucose sensor in the beta pancreatic cell?
- Glucose enters cell via GLUT2
- Glucose used to make ATP
- Increased ATP inhibits ATP-gated K channel
- Membrane depolarises
- Voltage-gated Ca channel opens > Ca influx
- Secretion of insulin
What do heterozygotes for a GCK deficiency have?
Altered glucose sensing in pancreas
Long-term mild hyperglycaemia
- Often mild enough not to require treatment
Is insulin always the best treatment for MODY?
No, often oral agents may be better
How are people with MODY different to those who have type 1 or 2 diabetes?
No autoAbs
No obesity
No insulin resistance
Close relative with similar symptoms/cystic kidney disease
What is the heritability of type 1 diabetes?
About 80%
What is the purpose of large-scale genetic studies?
Discover common and rare variants contributing to disease
Asking whether variants disease-informative
Effect of variants
Can they guide preventative/therapeutic interventions
What parts of the region are shown in genome wide association studies (GWAS)?
Only large regions
Are some variants associated with type 1 diabetes also associated with other diseases?
Yes, some positively associated with other autoimmune diseases
Others protective against other diseases; eg: Crohn’s disease
What are the two types of type 1 diabetes risk associated genes?
Pancreas related
Immune related
How can insulin gene and HLA variants alter the risk of type 1 diabetes?
Altering presentation of insulin fragments during
- Central tolerance
- Development of disease
What are the environmental factors in type 2 diabetes?
Obesity
Sedentary lifestyle
Unhealthy eating
Hypertension
What do many type 2 diabetes risk associated genes act through?
Reduced beta cell function/mass
Most cases changes in gene in expression level/activity, not loss of function
Susceptibility to what increases the risk of type 2 diabetes?
Peripheral insulin resistance
Does transgenerational epigenetic inheritance have an effect in type 2 diabetes?
Yes, could affect metabolism, thus altering risk of developing type 2 diabetes, but difficult to prove in humans
