15. Inborn Errors of Metabolism Flashcards
Why are a lot of disorders that occur not seen?
As they are not compatible with life
What sometimes happens when compounds accumulate?
They can spontaneously convert into compounds that you don’t normally see - these may be toxic
Which substances often act as cofactors?
Vitamins or trace elements
Why can deficiency of vitamins and trace elements cause problems?
Vitamins and trace elements are often cofactors - lack of cofactors can lead to lack of activation of important enzymes
Give 3 mechanisms of disease
- accumulation of a toxin
- energy deficiency
- deficient production of essential metabolite/structural component
Accumulation of a toxin can be a mechanism of disease. What accumulates in patients with urea cycle defects?
Ammonia (NH3) - very toxic
What are the clinical effects of acute hyperammonaemia toxicity?
- lethargy
- poor feeding
- vomiting
- tachypnoea
- convulsions
- coma
- death
What is porphyria?
Disease in which there is abnormal metabolism of haemoglobin
Get accumulation of porphyrins
What are the 2 types of porphyria?
- acute porphyria
- photosensitive porphyria
What are the steps in the pathway between ALA and HAEM?
ALA
PBG
Uroporphyrin
Coproporphyrin
Protoporphyrin
Haem
What are the signs of acute porphyria?
- severe abdominal pain
- pain in chest, legs, back
- constipation or diarrhoea
- vomiting
- insomnia
- palpitations
- hypertension
- anxiety or restlessness
- seizures
- mental changes
- breathing problem
- muscle pain/tingling/weakness/paralysis
- red or brown urine
What are the signs of photosensitive porphyria?
- sensitivity to light
- sudden painful erythema and oedema
- blisters taking weeks to heal
- itching
- fragile skin
- increased hair growth
- red or brown urine
Fatty acid oxidation results in what product?
Acetyl CoA
Goes on to make ketones or enter the TCA cycle
Fatty acid oxidation occurs in which organelle?
Mitochondria
What happens in androgen insensitivity syndrome?
Produces male hormones but lack the androgen receptor and so they therefore cannot use these male hormones and end up with a female phenotype
What are the characteristic of a genetic male with androgen insensitivity syndrome?
- healthy female phenotype (normal breast development, absent pubic hair etc)
- partial defect results in ambiguous genitalia
- present with primary amenorrhea and infertility
- usually need surgical resection of residual gonads
What does the basic urine metabolism screen consist of?
- spot tests
- organic acids
- amino acids
- sugar chromatography
- oligosaccharides/sialic acids
- mucopolysaccharides
How can amino acids be tested?
By amino acid TLC (thin layer chromatography)
- can identity argininosuccinic acid which is a product of urea cycle defects
What is homocystinuria?
A disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine and its metabolites in urine
What are the clinical problems of homocystinuria?
- mental retardation
- marfinoid habitus
- ectopia lentis
- osteoporosis
- thromboembolism
What is hyperhomocystinaemia?
Medical condition characterised by an abnormally high level of homocysteine in the blood, conventionally described as above 15 µmol/L
What percentage of the general population have hyperhomocystinaemia?
5%
There is increased incidence of hyperhomocystinaemia in patients with which diseases?
- stroke
- peripheral vascular disease
- coronary artery disease
What act as intermediates in most metabolic pathways?
Small molecular weight organic acids eg. amino acids, cholesterol, purines and pyrimidines, fatty acids, carbohydrates, neurotransmitters, drugs and diet, microorganisms
The classic acidaemias are defects in what?
Branched chain amino acid catabolism
What are the classic organic acidaemias?
- propionic acidaemia
- isovaleirc acidaemia
- methyl malonic acidameia
What are the benefits of diagnosis of IEMs?
- treatment, improve prognosis
- identify cause of clinical problem
- genetic counselling
- IEM act as models for other disorders
How are neural tube defects diagnosed?
- maternal serum and amniotic fluid AFP
- ultrasound scan at 16 weeks
How is down syndrome diagnosed?
1st trimester - PAPA, HCG and nuchal translucency
2nd trimester - maternal serum AFP, HCG, inhibin and estriol
Test on the ascent: free foetal DNA
