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EMS > Lecture 30: Inborn errors of metabolism (IEMs) > Flashcards

Lecture 30: Inborn errors of metabolism (IEMs) Flashcards

1
Q

What are inborn errors of metabolism?

A

genetic conditions in which an individual lacks an enzyme that controls a specific metabolic pathway

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2
Q

What are the two general effects of an enzyme deficiency?

A

1) accumulation of substrate behind the block in the pathway

2) lack of substrate production ahead of the block in the pathway

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3
Q

How often do IEMs occur?

A

Approx 1:1-2,000 live births

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4
Q

What is the clinical significance of side reactions produced by an accumulation of substrates behind blocks in enzyme pathways?

A

the new compounds can be used to diagnose inborn errors of metabolism

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5
Q

What is the name given to non-protein ‘helper’ molecules that aid enzyme catalysed transformations?

A

Cofactors

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6
Q

Give the three mechanisms of disease associated with inborn errors of metabolism:

A

1) accumulation of a toxin

2) energy deficiency

3) deficient production of essential metabolites or structural components

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7
Q

True or false: hyperammonaemia is a medical emergency

A

True

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8
Q

What causes hyperammonaemia?

A

urea cycle defects

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9
Q

What is the role of the urea cycle?

A

to convert toxic ammonia formed from amino acid deamination to urea for excretion

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10
Q

What is the firm step in the urea cycle?

A

ammonia is combined with carbon dioxide to form carbamoyl phosphate

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11
Q

What effect does an upper pathway urea cycle enzyme deficiency have on the onset of hyperammonaemia?

A

faster onset

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12
Q

Give two upper pathway urea cycle enzymes:

A

1) CPS1

2) NAGS

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13
Q

Give two lower pathway urea cycle enzymes:

A

1) arginase

2) agiosuccinic synthase

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14
Q

What effect does a lower pathway urea cycle enzyme deficiency have on the onset of hyperammonaemia?

A

Slower onset

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15
Q

Give 8 clinical effects of acute hyperammonaemia:

A

1) lethargy

2) poor feeding

3) convulsions

4) vomiting

5) encephalopathy

6) tachypnoea

7) coma

8) death

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16
Q

The disruption of which metabolic pathway results in the accumulation of porphyrins?

A

haem production

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17
Q

What does the outcome of hyperammonaemia depend on?

A
  • Extent of hyperammonaemia ( NH3 concentration)
  • Duration of elevation
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18
Q

Give the 6 molecules produced at each stage of haem production metabolism:

A

1) ALA

2) PBG

3) uroporphyrin

4) coproporphyrin

5) protoporphyrin

6) haem

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19
Q

True or false: the build up of porphyrins has toxic effects

A

True

20
Q

The build up of which two porphyrins causes acute porphyria?

A

1) ALA

2) PBG

21
Q

Give 6 symptoms of acute porphyria:

A

1) abdominal pain

2) vomiting and diarrhoea

3) insomnia

4) seizures

5) palpitations

6) red/ brown urine

22
Q

The accumulation of which three porphyrins causes photosensitive porphyria?

A

1) uroporphyrin

2) coproporphyrin

3) protoporphyrin

23
Q

How does the accumulation of photosensitive porphyrins cause disease?

A

they are stimulated by light to produce heat

24
Q

Give 5 symptoms of photosensitive porphyria:

A

1) sensitivity to the sun

2) increased hair growth

3) fragile skin

4) blisters that take weeks to heal

5) red/ brown urine

25
Q

Describe the energy deficiency mechanism of inborn errors of metabolism:

A

where enzyme deficiencies cause disruptions to energy metabolism pathways which convert nutrients into ATP

26
Q

When does our body switch to alternative fuels such as fats?

A

during fasting or infection

27
Q

What are the two clinical results of defects of fatty acid oxidation?

A

1) hypoketotic hypoglycaemic coma

2) hepatic failure

28
Q

Briefly describe the process of oxidation of fatty acids:

A

fatty acids derived from triglycerides form acetyl CoA which can be used to form ketones to form energy OR to join the Krebs cycle

29
Q

Where does oxidation of fatty acids take place?

A

mitochondrial matrix

30
Q

What causes androgen insensitivity syndrome?

A

defective androgen receptor (testosterone)

31
Q

Give 4 clinical features of androgen sensitivity syndrome:

A

1) healthy female phenotype (normal breast development, absent pubic hair)

2) patient is a genetic male

3) primary amenorrhoea

4) infertility

32
Q

Give the four steps used to diagnose inborn errors of metabolism:

A

1) clinical presentation and history from symptomatic individual

2) genetic testing (WES or WGS)

3) metabolite testing

4) enzyme analysis

33
Q

What molecule is tested to diagnose amino acid disorders?

A

amino acids

34
Q

What molecule is tested to diagnose organic acidurias?

A

organic acids

35
Q

What is organic acidurias?

A

accumulation of organic acids and the subsequent excretion in urine

36
Q

What molecule is tested to diagnose fat oxidation defects?

A

acylcarnitines

37
Q

What molecule is tested to diagnose peroxisomal disorders:

A

very long chain fatty acids (VLCFA)

38
Q

What molecule is tested to diagnose lysosomal storage disorders?

A

oligosaccharides

39
Q

What molecule is tested to diagnose galactosemia?

A

Gal-1-PUT

40
Q

What is galactosemia?

A

genetic disease where there is a deficiency in converting galactose to glucose

41
Q

What HELLP syndrome?

A

a life threatening pregnancy syndrome characterised by haemolysis, elevated liver enzymes and low platelet count

42
Q

What is LCHADD deficiency?

A

a disorder of fat metabolism whereby long chain fatty acids cannot be metabolised properly

43
Q

What gene is LCHADD deficiency associated with?

A

HADA gene

44
Q

Why not test genes first when diagnosing IEMs?

A
  1. Cost/time (traditionally expensive and time consuming)
  2. Does not completely exclude disorders: - not all mutations maybe covered (large deletions, allelic imbalance etc)
    - significance of mutation not always known, often poor genotype/phenotype relationship
45
Q

Is cost per human genome decreasing or increasing over the past 20 years?

A

Generally decreasing

46
Q

What will urine metabolic screens in Leeds screen for?

A
  • organic acids
  • amino acids
  • sugar chromatography
  • spot tests
  • mucopolysaccharides*
  • oligosaccharides/sialic acids*

EMS (54 decks)

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