Inborn Errors of Metabolism (IEM)

Question 1

How many people are affected by inborn metabolic diseases?

Answer 1

1: 1-2000 live births.

- most present in childhood

Question 2

What causes inborn metabolic diseases?

Answer 2

Genetic defects of metabolic pathways.

Question 3

What type of genetics is concerned with genetic disorders that affect metabolic pathways?

Answer 3

Biochemical genetics.

Question 4

How can enzyme deficiencies be problematic? (2)

Answer 4

• Less metabolite produced (deficiency)

- Accumulation of substrate (toxic)

Question 5

What are the main mechanisms of metabolic diseases? (3)

Answer 5

• Accumulation of toxin
• Energy deficiency
• Deficient production of essential metabolite

Question 6

What substance accumulates in patients with urea cycle defects?

Answer 6

Ammonia.

-ammonia is not converted to urea sufficiently

Question 7

What are the main clinical effects of hyperammonaemia (^ammonia)?

Answer 7

• Lethargy
• Poor feeding
• Vomiting
• Tachypnoea
• Convulsions
• Death

Question 8

What substance accumulates in porphyrias?

Answer 8

Porphyrins.

Question 9

What pathway is blocked in porphyrias?

Answer 9

Blockage of haem production pathway.

Question 10

Outline the haem production pathway.

Answer 10

ALA
>>PBG
>> uroporphrin
>> coproporphrin
>> protoporphrin
>> haem.

Question 11

What are the main 2 types of porhyrias?

Answer 11

• Acute porphyria

- Photosensitive porphryia

Question 12

What substrates are in excess in acute porphyria? (2)

Answer 12

• ALA

- PBG

Question 13

What substrates are in excess in photosensitive porphyria? (3)

Answer 13

• Uroporphrin
• Coproporphrin
• Protoporphrin

Question 14

What are the possible signs of acute porphyrias?

Answer 14

• Severe abdominal pain
• Pain in chest//legs/back
• Constipation/diarrhoea
• Insomnia/anxiety
• Vomiting
• High BP
• Mental changes
• Seizures

Question 15

What are the possible signs of photosensitive porphyria?

Answer 15

• Sensitivity to light
• Sudden painful erythema/oedema
• Slow-healing blisters
• Fragile, itchy skin
• Increased hair growth

Question 16

What is a symptom present in both acute and photosensitive porphyria?

Answer 16

Red/brown urine.

Question 17

What is a major defect of energy deficiency?

Answer 17

Defects in fatty acid oxidation.

|&raquo_space; crisis presentations

Question 18

What is the general process of fatty acid oxidation?

Answer 18

Fatty acids
» fatty acid oxidation
» acetyl coA
»ketones (outside mitochondria) / TCA cycle

Question 19

Where does the majority of fatty acid oxidation take place?

Answer 19

Mitochondria.

Question 20

What is the effect of defects in fatty acid oxidation?

Answer 20

Decreased ketones.

Question 21

What can cause deficient production of essential metabolite/structural components?

Answer 21

Defective receptors.

Question 22

What can deficient production of essential metabolite/structural components lead to?

Answer 22

Androgen insensitivity syndrome.

-due to defective receptors

Question 23

What are androgens?

Answer 23

Males sex hormones.

-e.g. testosterone

Question 24

What is androgen insensitivity syndrome?

Answer 24

Genetically male persons is resistant to male hormones.

|&raquo_space; female phenotype, but the genetic makeup of a man

Question 25

How does androgen insensitivity syndrome usually present?

Answer 25

• Primary amenorrhoea
• Infertility
• Ambiguous genitalia

Question 26

What is the general genetic make up of most metabolic diseases?

Answer 26

• Multi-allelic

- Compound heterozygotes

Question 27

How are IEMs diagnosed?

Answer 27

• Pre-symptomatic screening

- Investigation of symptomatic individuals

Question 28

What tests are carried out on symptomatic individuals? (4)

Answer 28

• Body fluid for abnormal metabolites
• Measure enzyme activity
• Histochemical / immunochemical staining
• DNA analysis

Question 29

What is amino acid TLC?

Answer 29

Amino acid thin layer chromatography.

-separates different AAs

Question 30

Pre-natal screening; how are neural tube defects detected?

Answer 30

• Maternal serum

- Amniotic fluid

Question 31

Pre-natal screening; what are the tests for Down syndrome?

Answer 31

• 1st trimester; PAPA, HCG
• 2nd trimester; maternal serum, AFP, HCG, inhibin
• Free foetal DNA (ascent)

Question 32

What is homocystinuria?

Answer 32

An inherited disorder of the metabolism of the amino acid methionine.
» decreased production of cysteine

Question 33

What enzyme deficiency causes homocystinuria?

Answer 33

Cystathionine beta synthase.

Question 34

What are the clinical problems of homocystinuria? (5)

Answer 34

• Mental retardation
• Marfinoid habitus
• Ectopia lentis
• Osteoporosis
• Thromboembolism

Question 35

What is hyperhomocysteinemia?

Answer 35

An abnormally high level of homocysteine in the blood.

• above 15 µmol/L
• 5% of the population

Question 36

What conditions have an increased incidence of hyperhomocysteinemia? (3)

Answer 36

• Stroke
• Peripheral vascular disease
• Coronary artery disease

Question 37

What types of molecules are the intermediates in most metabolic pathways?

Answer 37

Low molecular weight organic acids.

-commonly anionic

Question 38

What are the defects in classic organic acidaemias?

Answer 38

Defects in branched chain AA catabolism.

-AAs are not always increased when deficient catabolic enzyme

Question 39

Name some classic organic acidaemias. (3)

Answer 39

• Propionic
• Isovaleric
• Methyl malonic