L17: Inborn Errors Of Metabolism

Question 1

What are inborn errors of metabolism?

Answer 1

→Single gene defects resulting in disruption to metabolic pathways

Question 2

What are IEM effects due to?

Answer 2

→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

Question 3

What is alkaptonuria?

Answer 3

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

Question 4

What deficiency is seen in alkaptonuria?

Answer 4

→Homogentisic acid oxidase

Question 5

What is the genotype o alkaptonuria?

Answer 5

→Autosomal recessive disease

→congenital

Question 6

What are the symptoms of alkaptonuria?

Answer 6

→black urine

→Black ochrontic pigmentation of cartilage & collagenous tissue

Question 7

What is the one gene-one enzyme concept?

Answer 7

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

Question 8

What is the molecular disease concept?

Answer 8

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

Question 9

What are the mechanisms of inheritance?

Answer 9

→Autosomal recessive

→Autosomal dominant

→X-linked

→Mitochondrial

Question 10

What are examples of autosomal recessive disease?

Answer 10

→PKU,
→alkaptonuria,
→MCADD

Question 11

What are examples of autosomal dominant disease?

Answer 11

→Marfan’s,

→acute intermittent porphyria

Question 12

Are autosomal dominant diseases common or rare for IEMs?

Answer 12

→rare

Question 13

What is lyonisation?

Answer 13

→random inactivation of one of the X chromosomes

Question 14

What are examples of X-linked inheritance?

Answer 14

→Fabry’s disease,

→Ornithine carbamoyl transferase deficiency

Question 15

How are mitochondrial mutations inherited?

Answer 15

→Inherited exclusively from mother

→only the egg contributes mitochondria to the developing embryo

Question 16

Who does mitochondrial disease affect?

Answer 16

→both female and male

Question 17

What are some examples of mitochondrial disease?

Answer 17

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

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

Question 18

What is hetroplasmy?

Answer 18

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

Question 19

Which types of organs are most affected by mitochondrial diseases?

Answer 19

→high-energy

Question 20

What are the classification of IEM?

Answer 20

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

Question 21

What is toxic accumulation in IEM?

Answer 21

→protein metabolism

→carbohydrate intolerance

Question 22

What molecules are more likely to be accumulated?

Answer 22

→Amino acids e.g. PKU, tyrosinaemia

→Organic acids e.g. propionylacidaemia

→urea cycle disorders e.g. OTCD

Question 23

What are examples of disorders of complex molecules involving organelles?

Answer 23

→Lyososomal storage disorders e.g. Fabry’s

→Peroxisomal disorders e.g. Zellwegers

Question 24

What are examples of disorders in deficiency in energy production?

Answer 24

→Fatty acid oxidation e.g. MCADD

→Carbohydrate utilization/production e.g. GSDs

→Mitochondrial disorders e.g. MERFF

Question 25

What are the neonatal presentation of IEM?

Answer 25

→often acute

→Often caused by defects in carbohydrate intolerance and energy metabolism

Question 26

What are the late onset presentation of IEM due to?

Answer 26

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

Question 27

What are the clues for IEMS?

Answer 27

→Consanguinity

→FH of similar illness in siblings or unexplained deaths

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

Question 28

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

Answer 28

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

Question 29

What are examples of neonatal presentation of IEM?

Answer 29

→Poor feeding, lethargy, vomiting

→Epileptic encephalopathy

→Profound hypotonia –’floppy’ baby

→Organomegaly e.g. cardiomyopathy, hepatomegaly

→Dysmorphic features

→Sudden unexpected death in infancy (SUDI)

Question 30

What are the biochemical abnormalities of IEM in neonates?

Answer 30

→Hypoglycaemia

→Hyperammonaemia

→Unexplained metabolic acidosis / ketoacidosis

→Lactic acidosis

Question 31

What are routine lab investigations for IEMs?

Answer 31

→Blood gas analysis

→Blood glucose and lactate

→Plasma ammonia

Question 32

What are specialist investigations for IEMs?

Answer 32

→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

Question 33

What are confirmatory investigations of IEMs?

Answer 33

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

Question 34

What are the criteria for screening Wilson and Junger?

Answer 34

→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

Question 35

Describe newborn blood spot screening

Answer 35

→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

Question 36

What is one cause of raised plasma amino acids?

Answer 36

→Liver damage

→Gross elevations in tyrosine and methionine

Question 37

What are the causes of acute liver disease in neonate?

Answer 37

→Classical galactosaemia

→Hereditary fructose intolerance

→An organic acidaemia

→Tyrosinaemia type 1

Question 38

What is shown in tyrosinaemia type 1?

Answer 38

→Urine organic acid analysis showed increase in succinylacetone-

Question 39

How is tyrosinaemia type 1?

Answer 39

→nitisinone

Question 40

How does nitisinone work?

Answer 40

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

Question 41

What are the side effects of nitisinone?

Answer 41

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

Question 42

→What is tyrosinaemia type 1?

Answer 42

→Genetic deficiency in fumarylacetoacetase (FAH)

→Catalyzes the final step in tyrosine metabolism.

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

Question 43

What is ornithine transcarbamylase?

Answer 43

→urea cycle disorder
→converts carbamylphosphate to citrulline
→hyperammonemia

Question 44

What is the mode of inheritance in OTC disorders?

Answer 44

→X-linked

Question 45

What are the symptoms of OTC deficiency?

Answer 45

→Ataxia,
→seizures,
→hyperammmonaemic encephalopathy

Question 46

What factors can trigger a hyperammonaemic crisis?

Answer 46

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

→High protein intake