Inborn Errors of Metabolism Flashcards
What are inborn errors of metabolism?
Rare genetic (inherited)disordersin which the body cannot properly turn food into energy. Thedisordersare usually caused by defects in specific proteins (enzymes) that help metabolise parts of food.
When does ammonia accummulate?
In patients with urea cycle defects
What are the clinical effects of hyperammonaemia?
- lethargy- poor feeding- vomiting- tachypnoea- convulsions- coma - death
This is a medical emergency
What is the urea cycle?
A cycle of biochemical reactions that produces urea from ammonia.
What is the purpose of the urea cycle?
Amino acid catabolism results in waste ammonia which is toxic
What are porphyrins? Whar are they essential for?
Porphyrins are important in the synthesis of haem, so are essential for the function of haemoglobin.
What is porphyria?
Porphyrias are disorders caused by defects in the biosynthetic pathway of haem leading to buiildup of porphyrins.
The type of porphyria depends on where in the haem synthesis pathway is defected.
What are the possible signs of acute porphyria?
- Severe abdominal pain
- Pain in your chest, legs or back
- Constipation or diarrhoea
- Vomiting
- Insomnia
- Heartbeat you can feel (palpitations)
- High blood pressure
- Anxiety or restlessness
- Seizures
- Mental changes
- Breathing problems
- Muscle pain/tingling/weakness/paralysis
- Red or brown urine
What porphyrins accumulate in acute porphyria?
ALA and PBG (blockage early on in pathway)
Describe the pathway from ALA –> Haem
ALA –> PBG –> Uroporphrin –> Coproporphrin –> Protoporphrin –> Haem
What porphyrins accumulate in photosensitive porphyria?
- Uroporphrin
- Coproporphrin
- Protoporphrin
What occurs in photosensitive porphyria?
When light shines on them, they generate heat –> painful skin lesions
What are the signs of photosensitive porphyria?
- Sensitivity to the sun/artificial light
- Sudden painful erythema and oedema
- Blisters that take weeks to heal
- Itching
- Fragile skin
- Increased hair growth
- Red or brown urine
Describe the pathway that converts triglycerides into energy
- Triglycerides are broken down into fatty acids and glycerol
- Fatty acids are oxidised into acetyl CoA
- Acetyl CoA enters TCA cycle which produces energy
OR
- Acetyl CoA is converted into ketone bodies by ketogenesis
Where does ketogenesis primarily occur?
Mitochondria of liver cells
What is androgen insensitivity syndrome?
Androgen insensitivity syndrome (AIS) is when a person who is genetically male (who has one X and one Y chromosome) is resistant to male hormones (called androgens). As a result, the person has some or all of the physical traits of a woman, but the genetic makeup of a man.
What causes AIS?
Defective androgen receptor
Describe the phenotype in AIS
Wide range - patients with AIS can have different presentations within the same family (with same mutations)
Can range from a healthy female phenotype to having partial defects resulting in ambiguous genitalia
What are typical presentations of AIS?
Primary amenorrhoea, infertility, usually need surgical resection of residual gonads
How are inborn errors of metabolism diagnosed?
- Pre-symptomatic screen
- Investigation of symptomatic individuals
How are symptomatic individuals investigated for inborn errors of metabolism?
- test body fluids for abnormal metabolites
- measure enzyme activities
- histochemical / immunochemical staining
- DNA analysis
What route tends to be followed in the investigation of IEM?
- Metabolite testing (most IEM labs)
- More complicated metabolite testing (some IEM labs)
- Enzyme analysis/functional studies (only a few IEM labs)
- Mutation/gene analysis (genetics labs)
Tests generally become more specific, complex and costly
If IEM disorders are genetic, why does gene analysis not occur first?
- Cost/time (but both rapidly reducing with NGS)
- Completely exclude disorders, not all mutations maybe covered (+large deletions etc)
- Significance of mutation not always known, often poor genotype phenotype relationship
What is metabolomics?
Metabolomics is the large-scale study of small molecules, commonly known as metabolites
