The Genetics of Metabolic Diseases Flashcards Preview

MD1 Metabolism > The Genetics of Metabolic Diseases > Flashcards

Flashcards in The Genetics of Metabolic Diseases Deck (35):
1

What are the most common rare metabolic disorders in Australia?

PKU
Mitochondrial disorders
Lysosomal storage disorders
Haemochromatosis

2

What is haemochromatosis?

Inability to clear Fe from body > Fe overload

3

How do you treat PKU?

Limit Phe intake

4

How do you treat galactosaemia?

Limit lactos and galactose in diet

5

How do you treat urea cycle disease?

Limit protein
Medication to remove ammonia from blood

6

How do you treat lysosomal storage diseases?

Symptomatic treatment

7

What is maturity onset diabetes of the young (MODY)?

1% of diabetes cases
Monogenic - 11 known genes
Pancreatic cell dysfunction
Often misdiagnosed

8

What is gestational diabetes?

Developed whilst pregnant
Implications for future glucose regulation of mother and baby

9

What is the inheritance pattern of MODY?

Autosomal dominant

10

When is the typical onset of MODY?

6 months-35 years

11

Is there variation in the phenotype of MODY?

Yes - can be sub-symptomatic

12

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

13

What is the penetrance of MODY?

40-90%

14

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

15

What are the three most common genes affected in MODY?

HNF4a
GCK
HNF1a

16

What are HNF4a and HNF1a?

Transcription factors

17

What does HNF4a do?

Control expression of HNF1a

18

What does HNF1a do?

Control expression of genes in liver

19

What is the protein product of GCK?

Glucokinase

20

Where is glucokinase expressed?

Hepatocytes
Pancreatic beta cells

21

How does the enzyme activity of glucokinase change with glucose concentration?

Changes depending on amount of glucose = glucose sensor

22

How does glucokinase act as a glucose sensor in the beta pancreatic cell?

1. Glucose enters cell via GLUT2
2. Glucose used to make ATP
3. Increased ATP inhibits ATP-gated K channel
4. Membrane depolarises
5. Voltage-gated Ca channel opens > Ca influx
6. Secretion of insulin

23

What do heterozygotes for a GCK deficiency have?

Altered glucose sensing in pancreas
Long-term mild hyperglycaemia
- Often mild enough not to require treatment

24

Is insulin always the best treatment for MODY?

No, often oral agents may be better

25

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

26

What is the heritability of type 1 diabetes?

About 80%

27

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

28

What parts of the region are shown in genome wide association studies (GWAS)?

Only large regions

29

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

30

What are the two types of type 1 diabetes risk associated genes?

Pancreas related
Immune related

31

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

32

What are the environmental factors in type 2 diabetes?

Obesity
Sedentary lifestyle
Unhealthy eating
Hypertension

33

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

34

Susceptibility to what increases the risk of type 2 diabetes?

Peripheral insulin resistance

35

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