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mbd > Inborn Errors Of Metabolism > Flashcards

Inborn Errors Of Metabolism Flashcards

1
Q

What are the Inborn Errors of Metabolism?

A

A group of rare genetic disorders that result from a block to an essential pathway in the metabolism

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2
Q

Name the 3 pathophysiological subgroups that we divide IEMs into

A
  • Toxic accumulation
  • Defects in energy production/ use due to deficiency of products
  • Disorders of complex molecules involving organelles
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3
Q

What things can accumulate toxically in inborn errors of metabolism?

A
  • Substrates
  • Intermediates from alternative metabolic pathways
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4
Q

What can inborn errors of metabolism vary in?

A

Age of onset and clinical severity

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5
Q

What are the 4 disorders studied by Garrod?

A
  • Alkaptonuria
  • Cystinuria
  • Albinism
  • Pentosuria
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6
Q

What is Alkaptonuria?

A
  • Urine turns black on standing (and alkalinisation)
  • Black ochrontic pigmentation of cartilage and collagenous tissue
  • Homogentisic acid oxidase deficiency
  • Autosomal recessive disease
  • Congenital
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7
Q

What did Archibold Garrod propose the disorders were?

A
  • Congenital
  • Inborn
  • Followed mendels laws of inheritance
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8
Q

Define congenital

A

present at birth

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9
Q

Define inborn

A

Transmitted through gametes

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10
Q

Who came up with the one gene- one enzyme concept?

A

Beadle and tatum

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11
Q

What does the one gene-one enzyme concept mean?

A

Mutation of a single gene results in an alteration in the ability of the cell to carry out a single primary chemical reaction

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12
Q

What is an example of molecular disease concept?

A

Gene mutations produce an alteration in the primary structure of proteins by hamoglobin in sickle cell diesase

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13
Q

What are the four mechanisms of inheritance?

A
  • Autosomal recessive
  • Autosomal dominant
  • X-linked
  • Mitochondrial
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14
Q

Who transfers autosomal recessive inheritance?

A

Both parents carry a mutation affecting the same gene

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15
Q

What is the risk size in each autosomal recessive pregnancy?

A

1 in 4

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16
Q

What increases the risk of autosomal recessive conditions?

A

Cosanguinity

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17
Q

What are some examples of autosomal recessive diseases?

A
  • PKu
  • alkaptonuria
  • McADD
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18
Q

Are autosomal dominant conditions rare or common in IEMs?

A

Rare

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19
Q

What are some examples of autosomal dominant diseases?

A
  • Marfans
  • acute intermittent porphyria
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20
Q

How are X-linked mutations passed down?

A

Maternal line

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21
Q

Where do X-linked diseases appear and where are they carried?

A
  • Appear in men
  • carried in women
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22
Q

What is lyonisation?

A

Random inactivation of one of the X chromosomes in women so X-linked conditions can manifest in female carriers

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23
Q

What are some examples of X-linked conditions?

A
  • Fabrys disease
  • ornithine carbamoyl transferase deficiency
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24
Q

What are mitochondrial diseases?

A

Mitochondrial diseases are chronic, genetic disorders that occur when mitochondria fail to produce enough energy for the body to function properly

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25
Q

Where are mitochondrial diseases inherited from?

A

Mother

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26
Q

Which gender do mitochondrial diseases affect?

A

Male and female offspring

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27
Q

Why are mitochondrial diseases exclusively inherited from the mother?

A
  • Only the egg contributes mitochondria to the developing embryo
28
Q

What are examples of mitochondrial diseases?

A
  • MELAS
  • MERRF
29
Q

What does MERRF stand for?

A

Myoclonic epilepsy and red ragged fibre disease

30
Q

What does MERFF cause?

A
  • Deafness
  • dementia
  • seizures
31
Q

What does MELAS stand for?

A

Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes

32
Q

What is heteroplasmy?

A

Heteroplasmy is when some mitochondria have the diseased gene and some have the healthy gene in the same cell

33
Q

How do you establish the pattern of inheritance?

A

Accurate family history

34
Q

What determines the presentation of mitochondrial inheritance?

A

Distribution of affected mitochondria

35
Q

What are more frequently affected in mitochondrial inheritance?

A

High-energy requiring organs

36
Q

What is the prevalence of IEM’s?

A
  • Individually rare (e.g PKU 1:10,000)
  • Collectively common (1:800 to 1:2500) – number of rare disorders are large so called collectively common
    • High mortality within the first year of life
    • Significant contribution to children of school age with physical handicap and severe learning difficulties
  • Important to recognise in sick neonate – global newborn screening programs
37
Q

What are IEM treated by?

A

Dietary control restriction and/or compound supplementation

38
Q

What are the classifications of IEM?

A
  • Toxic accumulation
  • Deficiency in energy production/utilisation
  • Disorders of complex molecules involving organelles
39
Q

What are the types of toxic accumulation?

A
  • Protein metabolism
  • Carbohydate intolerance
40
Q

What are the categories of deficiency in energy production/utilisation IEMs?

A
  • Fatty acid oxidation
  • Carbohydrate utilisation/production
  • Mitochondrial disorders
41
Q

What is an example of a fatty acid oxidation deficiency IEM?

A

MCADD

42
Q

What is an example of a deficiency of carbohydrate utilisation/production?

A

GSD

43
Q

What are the deficiencies of mitochondria?

A

MERFF

44
Q

What is an example of a lysosomal storage disorder?

A

Fabrys

45
Q

What is an example of a peroxisomal disorder?

A

Zellwegers

46
Q

How do IEM present?

A
  • Depends on the severity of the metabolic defect
  • Neonatal presentation often acute – can be rapidly progressive and fatal
47
Q

What are neonatal IEMs often caused by?

A
  • Defects in carb intolerance and energy metabolism
48
Q

What are late onset IEMs caused by?

A

Accumulation of toxic molecules

49
Q

What do late onset IEMS present with?

A
  • Organ failure
  • encephalopathy
  • seizures
50
Q

When do IEM symptoms start to present in neonates?

A

First week of life when starting full milk feeds

51
Q

What are the clues for IEM?

A
  • Cosanguinity
  • Family history of similar illness and siblings or unexplained deaths
  • Infants who was well at birth and starts to deteriorate for no obvious reason
52
Q

What are the clinical scenarios of neonate IEM presentation?

A
  • Poor feeding, lethargy, vomiting
  • Epileptic encephalopathy
  • Profound hypotonia
  • Organomegaly
    • e.g.cardiomyopathy, hepatomegaly
  • Dysmorphic features
  • Sudden unexpected death in infancy
53
Q

What are the biochemical abnormalities in neonate IEM presentation?

A
  • Hypoglycaemia
  • Hyperammonia
  • Unexplained metabolic acidosis/ketoacidosis
  • Lactic acidosis
54
Q

What are the routine tests for IEMs?

A
  • Blood gas analysis
  • Blood glucose and lactate
  • Plasma ammonia
55
Q

What are the specialist lab investigations for IEMs?

A
  • Plasma amino acids
  • Urinary organic and orotic acid
  • Blood acyl carnitines
  • Urinary glycosaminoglycans
  • Plasma very long chain fatty acids
  • CSF tests
56
Q

What are the confirmatory investigations that you can do for IEM?

A
  • Enzymology
  • Biopsy
  • Fibroblasts studies
  • Mutation analysis (WGS)
57
Q

What are the wilson and junger criteria for screening?

A
  • Condition should be an important health problem
  • Must know prevelence in screening population
  • History of condition understood
  • Easy and reliable screening test
  • Availibility of an accepted treatment
  • Diagnosis and treatment should be cost effective
58
Q

What conditions are tested for in newborn blood spot screening?

A
  • PKU
  • congenital hypothyroidism
  • Sickle cell disease
  • Cystic fibrosis
  • MCADD
59
Q

When are newborn blood spot screening samples taken?

A
  • Day 5 (day of birth is day 0) from heel prick
60
Q

What are the guidlines for a good quality bloodspot of newborn blood spot screening?

A
  • All four circles on ‘guthrie’ card need to be completely filled with a single drip of blood which soaks through to the back of the card
61
Q

What is Tyrosinaemia type 1?

A

Genetic deficiency in fumarylacetoacetase

62
Q

What is the function of fumarylacetoacetase?

A

Catalyses the final step in tyrosine metabolism

63
Q

What is the treatment for tyrosinaemia type 1 and how does it work?

A
  • Nitisinone (NTBC )inhibits an earlier step in the pathway to prevent accumulation of toxic metabolites
  • early treatment achieves around 90% survival rate
64
Q

What is ornithine transcarbamylase deficiency?

A
  • Urea cycle disorder
  • Rare
65
Q

What are the symptoms of ornithine transcarbamylase deficiency?

A
  • Ataxia,
  • seizures
  • Hyperammonaemic encephalopathy
66
Q

What can trigger a hyperammonaemic crisis?

A
  • Increased endogenous protein catabolism (infection, fasting, trauma, steroid administration)
  • High protein intake

mbd (23 decks)

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