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EMS MOD > inborn errors of metabolism > Flashcards

inborn errors of metabolism Flashcards

1
Q

what is the epidemiology of inborn errors of metabolism?

A

they are individually rare but collectively significant. They occur roughly 1 in 1-2000 live births and in Yorkshire alone there are around 25-50 cases p.a. Most will present in childhood but with advances in treatments and diagnostics and milder phenotypes there are some in adulthood.

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2
Q

why are they sometimes not diagnosed?

A

they are the last things that doctors think of as they are so rare and symptoms can overlap with common conditions

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3
Q

what are three products that glutamate can make?

A

glutamine, carbomyl P and glutamyl P

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4
Q

what is carbomyl P used for?

A

when with ornithine it can make citrulline which then makes arginino succinate, then arginine and then back to ornithine by giving off urea

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5
Q

other that citrulline, what else can ornithine make?

A

glutamine semialdehyde

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6
Q

what else can produce glutamine semialdehyde?

A

glutamyl P

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7
Q

on a gene, out of the operator repressor and structural regions, a mutation in which part will affect proteins?

A

in the structural part. The protein can then make enzymes, be used for structures or transport.

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8
Q

how is the urea cycle affected by mutation?

A

in the urea cycle ammonia is converted to non toxic urea. Mutations can affect any step of this cycle

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9
Q

what are disorders commonly a result of and how does this affect cells?

A

a lot are enzyme defects - affects the biochemical reactions occurring in cells

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10
Q

what can affect how transporters move substances across membranes?

A

a lysosomal storage disorder

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11
Q

what happens if a mutation in a protein coding gene is subtle?

A

will only slightly change the structure and therefore proteins are functional but a reaction may occur slowly

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12
Q

what affects how much of a protein is being produced?

A

where the mutation is located - if it is in the regulatory regions of the gene - this means that the protein can be under or overproduced

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13
Q

why may some mutations not be seen?

A

some mutations are in genes that are so essential that they are not compatible with life

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14
Q

how can accumulation lead to a disorder?

A

a substrate may be fine at low levels but become toxic once it has accumulated due to lack of enzyme converting it and therefore once it has crossed the threshold value is toxic

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15
Q

how can new toxic products be made from a deficiency in an enzyme further along a metabolic pathway?

A

there is accumulation of previous substrates which can then bind unspecifically and make new compounds which may be toxic

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16
Q

how can you identify the mutation or deficiency?

A

you can identify and measure the new compounds made to see what is accumulating

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17
Q

what is biochemical genetics?

A

it is the study or investigation of primarily genetic disorders that affects the metabolic pathways of cells

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18
Q

what is a cofactor?

A

it is a vitamin or micronutrient that is needed to be bound to an enzyme for it to work properly - enzymes need it to work properly

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19
Q

how can a vitamin deficiency result in pathway defects?

A

they can give a secondary defect

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20
Q

how can vitamins be used as treatments?

A

they will stimulate enzymatic activity

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21
Q

what are three mechanisms of disease?

A

accumulation of a toxin, energy deficiency or deficient production of essential metabolite/structural component

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22
Q

what results in urea cycle defects?

A

ammonia accumulation - hyperammonaemia toxicity

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23
Q

what are clinical features of hyperammonaemia?

A

lethargy, poor feeding, vomiting, tachypnoea, convulsions, coma, death

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24
Q

what is the main function of of the urea cycle?

A

to detoxify ammonia - too much is a medical emergency

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25
Q

why does it take a few days after birth for the hyperammonaemia to be recognised?

A

there is a latent period as it takes a few days for cycle to start working and then a few days for accumulation

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26
Q

what is the management of of hyperammonaemia?

A

can stop the catabolic pathways and make the patient anabolic - need to reduce the level of ammonia in the blood and protein restriction to keep levels of ammonia down

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27
Q

summarise the urea cycle?

A

HCO3 and NH3 combine to make carbamoyl phosphate. This then combines with ornithine to make citrullin and then eventually urea. Carbomyl P also make pyrimidines

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28
Q

what is porphyria?

A

it is a group of disorders that result from a build up of natural chemicals that make porphyrin which is essential for the function of Hb

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29
Q

what are the possible signs of acute porphyria?

A

abdo, chest, back or leg pain, insomnia, high blood pressure, diarrhoea and vomiting, palpitations, muscle weakness, tingling, paralysis or pain, seizures, red or brown urine, convulsions, mental changes, breathing problems and anxiety

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30
Q

what are signs of photosensitive porphyria?

A

sensitivity to sun or artificial light, blistering and ages to heal, sudden painful erythema and oedema, itching, fragile skin, increased hair growth, red brown urine

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31
Q

how does porphyrin make Hb?

A

ALA - PBG - UROPORPHRIN - CORPROPORPHRIN - PROTOPORPHRIN - HAEM

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32
Q

what increases in photosensitive porphyria?

A

protoporphrin, corproporphrin and uroporphrin

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33
Q

what increases in acute porphyria?

A

PBG and ALA

34
Q

why is there excessive hair growth in photosensitive?

A

the body is reacting to protect it from sensitivity to sunlight

35
Q

why are blisters so painful in photosensitive?

A

the porphyrins react to light and produce heat

36
Q

why does complete block lead to death?

A

porphyrin is involved in synthesis of haem and accumulation in Hb and therefore without oxygen cannot be transported around the body

37
Q

why is porphyria more common in adulthood?

A

pathway under stress due to changes and accumulation of porphyrins - changes in hormones etc

38
Q

what does energy deficiency cause?

A

crisis presentation in defects of fatty acid oxidation

39
Q

what happens in fasting or infection?

A

switch to alternative fuels for energy

40
Q

what happens if switching to alternative fuels is compromised?

A

hypokoetic coma or hypoglycaemic coma

41
Q

what is glucose?

A

it is a monosaccharide sugar that feeds into the glycolysis pathway for energy regeneration

42
Q

what is sucrose?

A

it is a disaccharide that is made of glucose and fructose - fructose must be converted to glucose and sucrose broken down before it can be used in glycolysis

43
Q

what is lactose?

A

it is a disaccharide that is made from galactose and glucose

44
Q

when does galactosaemia result?

A

when someone cannot metabolise galactose

45
Q

why is energy stored in the form of lipids?

A

this method is efficient

46
Q

what happens when there is no glucose available?

A

alternative pathways can lead to metabolism of fats and other molecules

47
Q

how can fatty acids be transported into the mitochondria?

A

they are removed from glycerol as they are stored as triglycerides

48
Q

what is FA oxidation?

A

it is a process of breaking down fats to release ketones which are used for energy in the brain or acetyl CoA that enters the TCA cycle

49
Q

what generates energy after glycolysis?

A

citric acid

50
Q

what generates ATP?

A

the electron transport chain

51
Q

what is good about fat metabolism?

A

it produces molecules that can enter the oxidative phosphorylation and generate AP

52
Q

what is the end product no matter the substrate?

A

ATP

53
Q

when it fat metabolism used?

A

when there is no glucose available - acute metabolic disorder when other energy stores are needed

54
Q

when is MCAD screened for?

A

newborn screening - the child often dies upon first presentation of hypoglycaemic coma

55
Q

what does defective receptors lead to?

A

androgen insensitivity syndrome

56
Q

what is the presentation of females?

A

normal breast development, no pubic hair, may be ambiguous genitalia, primary amenorrhoea, infertility

57
Q

what is the management of androgen insensitivity syndrome?

A

surgical resection of residual gonads

58
Q

what is the basis of androgen insensitivity syndrome?

A

problems with proteins meaning receptors are not functional, express testosterone as are genetically male, but present as female in appearance as androgens cannot bind to receptor so cannot produce action in cell

59
Q

what is clinical heterogeinity?

A

most disorders are multi allelic and most patients are compound heterozygotes meaning that there is variation of lesions due to other aspects, components of metabolism and environmrny

60
Q

why might different family members with the same mutation for AIS present differently?

A

there is a poor genotype/phenotype correlation

61
Q

how can IEM be screened?

A

through presymptomatic screening of a whole population or of a certain group or through investigation of symptomatic individuals through immunochemical staining, histochemical methods, DNA analysis, measuring enzymatic activities, testing bodily fluids for abnormal metabolites

62
Q

who do you look at in screening?

A

a whole population or those groups that have a high rate of disorder

63
Q

what does a test determine?

A

whether an individual has a disorder or not but there is overlap between unaffected and affected and therefore can be false negatives or positives

64
Q

when are genes tested first?

A

when there are no metabolites to measure

65
Q

there is a route that tends to be followed - why do genetic disorders not always get tested with genes first?

A

the cost or time, completely exclude disorders but not all mutations are covered, significance of mutation not always known as there is a weak phenotype genotype correlation

66
Q

what is the process of testing for IEM?

A

metabolite testing then more complicated metabolite testing then enzyme analysis or functional studies and then mutation or gene analysis

67
Q

what are the main basic urine metabolic screening tests?

A

organic acids and amino acids

68
Q

what does thin layer chromatography do?

A

old technique to look at amino acids in urine

69
Q

what are the basic urine metabolic tests?

A

spot tests, organic and amino acids, sugar chromatgraphy, oligosaccharides or sialic acids, mucopolysaccharides

70
Q

what are basic urine metabolic screen tests?

A

collection of tests that are easy to perform and can test for a lot of disorders

71
Q

what can you detect with automated amino acid analysis?

A

can detect many disorders with just one test - carbon based molecules which can be associated with and can accumulate in all different areas of metabolism - one of the main tests performed

72
Q

what are intermediates in most metabolic pathways?

A

small MW organic acids

73
Q

what can organic acids be made into?

A

neurotransmitters, carbohydrates, microorganisms, fatty acids, pyrimidines, purines, cholesterol, drugs, diet and amino acids

74
Q

where are classic organic acidaemias found?

A

defects in branches and chains of amino acid catabolism

75
Q

although amino acid metabolism is important why is it not always accurate?

A

the amino acids themselves are not always incrased in deficient catabolic enzymes - the further away from the parent AA the block is, the less likely it is to accumulate

76
Q

what are metabolic intermediates commonly?

A

they are anabolic and naturally organic

77
Q

what are classic organic acidaemias?

A

propionic, isovaleric and methyl malonic acidaemia

78
Q

how can acidaemias present?

A

with hyperammonaemia

79
Q

what is maple syrup urine disease?

A

defects in almost every step of the pathway

80
Q

what is benefits to diagnosis?

A

treatment, prognosis improvement, identify cause of clinical problems, genetic counselling, IEM acting as a model for other disorders, allows parents to decide whether to terminate a pregnancy when it is affected by a disorder

EMS MOD (28 decks)

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