CB - Inborn errors of metabolism (IEMs)

Question 1

What are the 4 main spontaneous causes of mutation?

Answer 1

1) Replication errors
2) Tautomerisation
3) Deamination
4) Depurination

Question 2

What are 7 induced causes of mutation?

Answer 2

1. Intercalating agents
2. Base analogues
3. Deaminating agents
4. Alkylating agents
5. Oxidising agents
6. Radiation
7. U/V

Question 3

How do replication errors lead to mutations?

Answer 3

• Wrong base introduced every 10¹⁰ base pairs (Can be repaired)
• Some repetitve regions cause slippage and insertion of more repeats Cannot be repaired)

Question 4

What are tautomeric shifts?

Answer 4

Where the bases of DNA are subject to spontaneuous structural alterations

Amino group (A or C) ↔ Imino group

Keto group (T or G) ↔ Enol group

Question 5

How can deamination lead to mutations? (3)

Answer 5

Loss of amino group can change base
e.g
* From Cysteine (pairs G) to Uracil (pairs A)
* From Adenine (pairs T) to Hypoxanthine (pairs C)
* From Guanine (pairs C) to Xanthine (pairs C less strongly)

Question 6

What is depurination?

Answer 6

Cleavage of base-sugar bond

Question 7

What is an example of an intercalating agent?

Answer 7

Ethidium bromide

Question 8

What are base analogues?

Answer 8

Compounds that are similar to bases
e.g Bromouracil (T analogue)

Question 9

What do alkylating agents do?

Answer 9

Add alkyl groups to nucleobases
e.g Nitrosamines, Methylbromide

• Can be repaired

Question 10

What are some examples of deaminating agents? (3)

Answer 10

1. Nitrous oxide
2. Nitrosamines
3. Nitrite

Question 11

What do oxidising agents do?

Answer 11

Alter nucleotides

Question 12

What are in born errors of metabolism?

Answer 12

A class of genetic disease involving altered metabolic function

Question 13

What are the 3 types of metabolic disorders?

Answer 13

Anabolic- Deficiency of product
Catabolic- Excess of reactant
Storage- Deposits of macromolecule (reactant),
Deficiency of monomer (product)

Question 14

What are 4 main examples of IEMs?

Answer 14

1. Phenylketonuria (PKU)- Amino acid
2. Glycogen storage diseases (GSD)- CHO
3. Familial hypercholesterolaemia (FH)- Cholestrol
4. Tay-Sachs disease- Lipid

Question 15

What causes PKU and what are the consequences?

Answer 15

Autosomal (12) recessive disorder in PAH gene

Phenylalanine Hydroxylase (PAH) affected
* Unable to metabolise Phenylalanine

Excess phenyl-ketones in urine
* Builds up in the blood

Consequences:
* Mental retardation
* Organ damage
* Unusual posture

Question 16

What causes GSD and what are the consequences?

Answer 16

Inability to convert glycogen → glucose
Autosomal recessive disease

Consequences
* Enlarged liver
* Hypoglycaemia

Question 17

What are the 4 enzymes involved in glycogen breakdown?

Answer 17

1) Glycogen Phosphorylase

• Glycogen → Glucose-1-Phosphate

2) Debranching enzyme

3) Phosphoglucomutase

• Glucose-1-Phosphate → Glucose-6-Phosphate

4) Glucose-6-phosphatase

• Glucose-6-Phosphate → Glucose

Question 18

What is the difference between von Gierke disease and McArdle disease?

Answer 18

von Gierke Disease
* Glycogen storage disease 1
* Glucose-6-phosphate is deficient
* Leads to severe hypoglycaemia

McArdle Disease
* Glycogen storage disease 5
* Muscle Glycogen phosphorlase is absent
* Leads to muscle weakness and cramps

Question 19

What causes FH and what are the consequences?

Answer 19

Build up in LDL (bad cholestrol) due to a defect in LDL-R gene

Autosomal dominant inheritance

Consequences

• Coronary atherosclerosis

Heterozygous- Double normal plasma LDL (250-500mg/L)
Homozygous- Excessive plasma LDL (>600mg/L)

Question 20

What can decrease the production of LDL cholestrol?

Answer 20

Statins