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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
Where are mitochondrial diseases inherited from?
Mother
26
Which gender do mitochondrial diseases affect?
Male and female offspring
27
Why are mitochondrial diseases exclusively inherited from the mother?
* Only the egg contributes mitochondria to the developing embryo
28
What are examples of mitochondrial diseases?
* MELAS * MERRF
29
What does MERRF stand for?
Myoclonic epilepsy and red ragged fibre disease
30
What does MERFF cause?
* Deafness * dementia * seizures
31
What does MELAS stand for?
Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes
32
What is heteroplasmy?
Heteroplasmy is when some mitochondria have the diseased gene and some have the healthy gene in the same cell
33
How do you establish the pattern of inheritance?
Accurate family history
34
What determines the presentation of mitochondrial inheritance?
Distribution of affected mitochondria
35
What are more frequently affected in mitochondrial inheritance?
High-energy requiring organs
36
What is the prevalence of IEM's?
* 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
What are IEM treated by?
Dietary control restriction and/or compound supplementation
38
What are the classifications of IEM?
* Toxic accumulation * Deficiency in energy production/utilisation * Disorders of complex molecules involving organelles
39
What are the types of toxic accumulation?
* Protein metabolism * Carbohydate intolerance
40
What are the categories of deficiency in energy production/utilisation IEMs?
* Fatty acid oxidation * Carbohydrate utilisation/production * Mitochondrial disorders
41
What is an example of a fatty acid oxidation deficiency IEM?
MCADD
42
What is an example of a deficiency of carbohydrate utilisation/production?
GSD
43
What are the deficiencies of mitochondria?
MERFF
44
What is an example of a lysosomal storage disorder?
Fabrys
45
What is an example of a peroxisomal disorder?
Zellwegers
46
How do IEM present?
* Depends on the severity of the metabolic defect * Neonatal presentation often acute – can be rapidly progressive and fatal
47
What are neonatal IEMs often caused by?
* Defects in carb intolerance and energy metabolism
48
What are late onset IEMs caused by?
Accumulation of toxic molecules
49
What do late onset IEMS present with?
* Organ failure * encephalopathy * seizures
50
When do IEM symptoms start to present in neonates?
First week of life when starting full milk feeds
51
What are the clues for IEM?
* 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
What are the clinical scenarios of neonate IEM presentation?
* Poor feeding, lethargy, vomiting * Epileptic encephalopathy * Profound hypotonia * Organomegaly * e.g.cardiomyopathy, hepatomegaly * Dysmorphic features * Sudden unexpected death in infancy
53
What are the biochemical abnormalities in neonate IEM presentation?
* Hypoglycaemia * Hyperammonia * Unexplained metabolic acidosis/ketoacidosis * Lactic acidosis
54
What are the routine tests for IEMs?
* Blood gas analysis * Blood glucose and lactate * Plasma ammonia
55
What are the specialist lab investigations for IEMs?
* Plasma amino acids * Urinary organic and orotic acid * Blood acyl carnitines * Urinary glycosaminoglycans * Plasma very long chain fatty acids * CSF tests
56
What are the confirmatory investigations that you can do for IEM?
* Enzymology * Biopsy * Fibroblasts studies * Mutation analysis (WGS)
57
What are the wilson and junger criteria for screening?
* 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
What conditions are tested for in newborn blood spot screening?
* PKU * congenital hypothyroidism * Sickle cell disease * Cystic fibrosis * MCADD
59
When are newborn blood spot screening samples taken?
* Day 5 (day of birth is day 0) from heel prick
60
What are the guidlines for a good quality bloodspot of newborn blood spot screening?
* 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
What is Tyrosinaemia type 1?
Genetic deficiency in fumarylacetoacetase
62
What is the function of fumarylacetoacetase?
Catalyses the final step in tyrosine metabolism
63
What is the treatment for tyrosinaemia type 1 and how does it work?
* Nitisinone (NTBC )inhibits an earlier step in the pathway to prevent accumulation of toxic metabolites * early treatment achieves around 90% survival rate
64
What is ornithine transcarbamylase deficiency?
* Urea cycle disorder * Rare
65
What are the symptoms of ornithine transcarbamylase deficiency?
* Ataxia, * seizures * Hyperammonaemic encephalopathy
66
What can trigger a hyperammonaemic crisis?
* Increased endogenous protein catabolism (infection, fasting, trauma, steroid administration) * High protein intake

MBD (23 decks)

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