Lecture 30: Inborn errors of metabolism (IEMs) Flashcards
What are inborn errors of metabolism?
genetic conditions in which an individual lacks an enzyme that controls a specific metabolic pathway
What are the two general effects of an enzyme deficiency?
1) accumulation of substrate behind the block in the pathway
2) lack of substrate production ahead of the block in the pathway
How often do IEMs occur?
Approx 1:1-2,000 live births
What is the clinical significance of side reactions produced by an accumulation of substrates behind blocks in enzyme pathways?
the new compounds can be used to diagnose inborn errors of metabolism
What is the name given to non-protein ‘helper’ molecules that aid enzyme catalysed transformations?
Cofactors
Give the three mechanisms of disease associated with inborn errors of metabolism:
1) accumulation of a toxin
2) energy deficiency
3) deficient production of essential metabolites or structural components
True or false: hyperammonaemia is a medical emergency
True
What causes hyperammonaemia?
urea cycle defects
What is the role of the urea cycle?
to convert toxic ammonia formed from amino acid deamination to urea for excretion
What is the firm step in the urea cycle?
ammonia is combined with carbon dioxide to form carbamoyl phosphate
What effect does an upper pathway urea cycle enzyme deficiency have on the onset of hyperammonaemia?
faster onset
Give two upper pathway urea cycle enzymes:
1) CPS1
2) NAGS
Give two lower pathway urea cycle enzymes:
1) arginase
2) agiosuccinic synthase
What effect does a lower pathway urea cycle enzyme deficiency have on the onset of hyperammonaemia?
Slower onset
Give 8 clinical effects of acute hyperammonaemia:
1) lethargy
2) poor feeding
3) convulsions
4) vomiting
5) encephalopathy
6) tachypnoea
7) coma
8) death
The disruption of which metabolic pathway results in the accumulation of porphyrins?
haem production
What does the outcome of hyperammonaemia depend on?
- Extent of hyperammonaemia ( NH3 concentration)
- Duration of elevation
Give the 6 molecules produced at each stage of haem production metabolism:
1) ALA
2) PBG
3) uroporphyrin
4) coproporphyrin
5) protoporphyrin
6) haem
True or false: the build up of porphyrins has toxic effects
True
The build up of which two porphyrins causes acute porphyria?
1) ALA
2) PBG
Give 6 symptoms of acute porphyria:
1) abdominal pain
2) vomiting and diarrhoea
3) insomnia
4) seizures
5) palpitations
6) red/ brown urine
The accumulation of which three porphyrins causes photosensitive porphyria?
1) uroporphyrin
2) coproporphyrin
3) protoporphyrin
How does the accumulation of photosensitive porphyrins cause disease?
they are stimulated by light to produce heat
Give 5 symptoms of photosensitive porphyria:
1) sensitivity to the sun
2) increased hair growth
3) fragile skin
4) blisters that take weeks to heal
5) red/ brown urine
Describe the energy deficiency mechanism of inborn errors of metabolism:
where enzyme deficiencies cause disruptions to energy metabolism pathways which convert nutrients into ATP
When does our body switch to alternative fuels such as fats?
during fasting or infection
What are the two clinical results of defects of fatty acid oxidation?
1) hypoketotic hypoglycaemic coma
2) hepatic failure
Briefly describe the process of oxidation of fatty acids:
fatty acids derived from triglycerides form acetyl CoA which can be used to form ketones to form energy OR to join the Krebs cycle
Where does oxidation of fatty acids take place?
mitochondrial matrix
What causes androgen insensitivity syndrome?
defective androgen receptor (testosterone)
Give 4 clinical features of androgen sensitivity syndrome:
1) healthy female phenotype (normal breast development, absent pubic hair)
2) patient is a genetic male
3) primary amenorrhoea
4) infertility
Give the four steps used to diagnose inborn errors of metabolism:
1) clinical presentation and history from symptomatic individual
2) genetic testing (WES or WGS)
3) metabolite testing
4) enzyme analysis
What molecule is tested to diagnose amino acid disorders?
amino acids
What molecule is tested to diagnose organic acidurias?
organic acids
What is organic acidurias?
accumulation of organic acids and the subsequent excretion in urine
What molecule is tested to diagnose fat oxidation defects?
acylcarnitines
What molecule is tested to diagnose peroxisomal disorders:
very long chain fatty acids (VLCFA)
What molecule is tested to diagnose lysosomal storage disorders?
oligosaccharides
What molecule is tested to diagnose galactosemia?
Gal-1-PUT
What is galactosemia?
genetic disease where there is a deficiency in converting galactose to glucose
What HELLP syndrome?
a life threatening pregnancy syndrome characterised by haemolysis, elevated liver enzymes and low platelet count
What is LCHADD deficiency?
a disorder of fat metabolism whereby long chain fatty acids cannot be metabolised properly
What gene is LCHADD deficiency associated with?
HADA gene
Why not test genes first when diagnosing IEMs?
- Cost/time (traditionally expensive and time consuming)
- Does not completely exclude disorders: - not all mutations maybe covered (large deletions, allelic imbalance etc)
- significance of mutation not always known, often poor genotype/phenotype relationship
Is cost per human genome decreasing or increasing over the past 20 years?
Generally decreasing
What will urine metabolic screens in Leeds screen for?
- organic acids
- amino acids
- sugar chromatography
- spot tests
- mucopolysaccharides*
- oligosaccharides/sialic acids*
