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Dysfunction > IEM > Flashcards

IEM Flashcards

1
Q

What are inborn errors of metabolism?

A

→Single gene defects resulting in disruption to metabolic pathways

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2
Q

What are IEM effects due to?

A

→Toxic accumulation of substrates
→Toxic accumulation of intermediates from alternative metabolic pathways

→Defects in energy production/use due to deficiency of products
→Combination of above

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3
Q

What is alkaptonuria?

A

→inherited disorder that prevents the body fully breaking down tyrosine and phenylalanine

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4
Q

What deficiency is seen in alkaptonuria?

A

→Homogentisic acid oxidase

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5
Q

What is the genotype o alkaptonuria?

A

→Autosomal recessive disease

→congenital

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6
Q

What are the symptoms of alkaptonuria?

A

→black urine

→Black ochrontic pigmentation of cartilage & collagenous tissue

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7
Q

What is the one gene-one enzyme concept?

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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8
Q

What is the molecular disease concept?

A

→Inborn errors of metabolism are caused by mutations in genes which then produce abnormal proteins whose functional activities are altered

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9
Q

What are the mechanisms of inheritance?

A

→Autosomal recessive

→Autosomal dominant

→X-linked

→Mitochondrial

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10
Q

What are examples of autosomal recessive disease?

A

→PKU,
→alkaptonuria,
→MCADD

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11
Q

What are examples of autosomal dominant disease?

A

→Marfan’s,

→acute intermittent porphyria

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12
Q

Are autosomal dominant diseases common or rare for IEMs?

A

→rare

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13
Q

What is lyonisation?

A

→random inactivation of one of the X chromosomes

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14
Q

What are examples of X-linked inheritance?

A

→Fabry’s disease,

→Ornithine carbamoyl transferase deficiency

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15
Q

How are mitochondrial mutations inherited?

A

→Inherited exclusively from mother

→only the egg contributes mitochondria to the developing embryo

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16
Q

Who does mitochondrial disease affect?

A

→both female and male

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17
Q

What are some examples of mitochondrial disease?

A

→MERFF -Myoclonic epilepsy and ragged red fibre disease: deafness, dementia, seizures

→MELAS – Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes

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18
Q

What is hetroplasmy?

A

→Cell contains varying amounts of normal mt DNA and also mutated mt DNA

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19
Q

Which types of organs are most affected by mitochondrial diseases?

A

→high-energy

20
Q

What are the classification of IEM?

A

→Toxic accumulation
→Deficiency in energy production/utilization
→Disorders of complex molecules involving organelles

21
Q

What is toxic accumulation in IEM?

A

→protein metabolism

→carbohydrate intolerance

22
Q

What molecules are more likely to be accumulated?

A

→Amino acids e.g. PKU, tyrosinaemia

→Organic acids e.g. propionylacidaemia

→urea cycle disorders e.g. OTCD

23
Q

What are examples of disorders of complex molecules involving organelles?

A

→Lyososomal storage disorders e.g. Fabry’s

→Peroxisomal disorders e.g. Zellwegers

24
Q

What are examples of disorders in deficiency in energy production?

A

→Fatty acid oxidation e.g. MCADD

→Carbohydrate utilization/production e.g. GSDs

→Mitochondrial disorders e.g. MERFF

25
Q

What are the neonatal presentation of IEM?

A

→often acute

→Often caused by defects in carbohydrate intolerance and energy metabolism

26
Q

What are the late onset presentation of IEM due to?

A

→Patients have residual enzyme activity allowing slower accumulation of toxins
→Present with organ failure, encepalopathy, seizures

27
Q

What are the clues for IEMS?

A

→Consanguinity

→FH of similar illness in siblings or unexplained deaths

→Infant who was well at birth but starts to deteriorate for no obvious reason

28
Q

What may bring on the onset of of IEMs in neonates?

A

→Change in diet, stopped night feeds- hypoglycemia and seizures

29
Q

What are examples of neonatal presentation of IEM?

A

→Poor feeding, lethargy, vomiting

→Epileptic encephalopathy

→Profound hypotonia –’floppy’ baby

→Organomegaly e.g. cardiomyopathy, hepatomegaly

→Dysmorphic features

→Sudden unexpected death in infancy (SUDI)

30
Q

What are the biochemical abnormalities of IEM in neonates?

A

→Hypoglycaemia

→Hyperammonaemia

→Unexplained metabolic acidosis / ketoacidosis

→Lactic acidosis

31
Q

What are routine lab investigations for IEMs?

A

→Blood gas analysis

→Blood glucose and lactate

→Plasma ammonia

32
Q

What are specialist investigations for IEMs?

A

→Plasma amino acids

→Urinary organic acids + orotic acid

→Blood acyl carnitines

→Urinary glycosaminoglycans

→Plasma very long chain fatty acids

→CSF tests e.g. CSF lactate/pyruvate, neurotransmitters- lumbar puncture

33
Q

What are confirmatory investigations of IEMs?

A 
→Enzymology
→Biopsy (muscle, liver, skin)
→Fibroblast studies
→Mutation analysis – whole genome sequencing
→Family history
34
Q

What are the criteria for screening Wilson and Junger?

A

→Condition should be an important health problem

→Must know incidence/prevelence in screening population

→Natural history of the condition should be understood

→Availability of a screening test that is easy to perform and interpret

→Availability of an accepted treatment for the condition

→Diagnosis and treatment of the condition should be cost-effective

35
Q

Describe newborn blood spot screening

A

→Samples should be taken on day 5 (day of birth is day 0).

→Taken from heel prick

→All four circles on ‘Guthrie’ card need to be completely filled with a single drop of blood which soaks through to the back of the card.

→Require good quality bloodspot for analysis.
→Demographics checked

36
Q

What is one cause of raised plasma amino acids?

A

→Liver damage

→Gross elevations in tyrosine and methionine

37
Q

What are the causes of acute liver disease in neonate?

A

→Classical galactosaemia

→Hereditary fructose intolerance

→An organic acidaemia

→Tyrosinaemia type 1

38
Q

What is shown in tyrosinaemia type 1?

A

→Urine organic acid analysis showed increase in succinylacetone-

39
Q

How is tyrosinaemia type 1?

A

→nitisinone

40
Q

How does nitisinone work?

A

→ inhibits an earlier step in the pathway to prevent accumulation of toxic metabolites
→prevents cirrhosis

41
Q

What are the side effects of nitisinone?

A

→accumulation of tyrosine,
→ requires dietary restriction of tyrosine
→precursor phenylalanine

42
Q

→What is tyrosinaemia type 1?

A

→Genetic deficiency in fumarylacetoacetase (FAH)

→Catalyzes the final step in tyrosine metabolism.

→Increased byproduct succinylacetone leads to significant organ toxicity (liver, kidney)

43
Q

What is ornithine transcarbamylase?

A

→urea cycle disorder
→converts carbamylphosphate to citrulline
→hyperammonemia

44
Q

What is the mode of inheritance in OTC disorders?

A

→X-linked

45
Q

What are the symptoms of OTC deficiency?

A

→Ataxia,
→seizures,
→hyperammmonaemic encephalopathy

46
Q

What factors can trigger a hyperammonaemic crisis?

A

→Increased endogenous protein catabolism e.g. infection, fasting, trauma, steroid administration

→High protein intake

Dysfunction (29 decks)

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