Inborn Errors of Metabolism (IEM) Flashcards
How many people are affected by inborn metabolic diseases?
1: 1-2000 live births.
- most present in childhood
What causes inborn metabolic diseases?
Genetic defects of metabolic pathways.
What type of genetics is concerned with genetic disorders that affect metabolic pathways?
Biochemical genetics.
How can enzyme deficiencies be problematic? (2)
- Less metabolite produced (deficiency)
- Accumulation of substrate (toxic)
What are the main mechanisms of metabolic diseases? (3)
- Accumulation of toxin
- Energy deficiency
- Deficient production of essential metabolite
What substance accumulates in patients with urea cycle defects?
Ammonia.
-ammonia is not converted to urea sufficiently
What are the main clinical effects of hyperammonaemia (^ammonia)?
- Lethargy
- Poor feeding
- Vomiting
- Tachypnoea
- Convulsions
- Death
What substance accumulates in porphyrias?
Porphyrins.
What pathway is blocked in porphyrias?
Blockage of haem production pathway.
Outline the haem production pathway.
ALA >>PBG >> uroporphrin >> coproporphrin >> protoporphrin >> haem.
What are the main 2 types of porhyrias?
- Acute porphyria
- Photosensitive porphryia
What substrates are in excess in acute porphyria? (2)
- ALA
- PBG
What substrates are in excess in photosensitive porphyria? (3)
- Uroporphrin
- Coproporphrin
- Protoporphrin
What are the possible signs of acute porphyrias?
- Severe abdominal pain
- Pain in chest//legs/back
- Constipation/diarrhoea
- Insomnia/anxiety
- Vomiting
- High BP
- Mental changes
- Seizures
What are the possible signs of photosensitive porphyria?
- Sensitivity to light
- Sudden painful erythema/oedema
- Slow-healing blisters
- Fragile, itchy skin
- Increased hair growth
What is a symptom present in both acute and photosensitive porphyria?
Red/brown urine.
What is a major defect of energy deficiency?
Defects in fatty acid oxidation.
|»_space; crisis presentations
What is the general process of fatty acid oxidation?
Fatty acids
» fatty acid oxidation
» acetyl coA
»ketones (outside mitochondria) / TCA cycle
Where does the majority of fatty acid oxidation take place?
Mitochondria.
What is the effect of defects in fatty acid oxidation?
Decreased ketones.
What can cause deficient production of essential metabolite/structural components?
Defective receptors.
What can deficient production of essential metabolite/structural components lead to?
Androgen insensitivity syndrome.
-due to defective receptors
What are androgens?
Males sex hormones.
-e.g. testosterone
What is androgen insensitivity syndrome?
Genetically male persons is resistant to male hormones.
|»_space; female phenotype, but the genetic makeup of a man
How does androgen insensitivity syndrome usually present?
- Primary amenorrhoea
- Infertility
- Ambiguous genitalia
What is the general genetic make up of most metabolic diseases?
- Multi-allelic
- Compound heterozygotes
How are IEMs diagnosed?
- Pre-symptomatic screening
- Investigation of symptomatic individuals
What tests are carried out on symptomatic individuals? (4)
- Body fluid for abnormal metabolites
- Measure enzyme activity
- Histochemical / immunochemical staining
- DNA analysis
What is amino acid TLC?
Amino acid thin layer chromatography.
-separates different AAs
Pre-natal screening; how are neural tube defects detected?
- Maternal serum
- Amniotic fluid
Pre-natal screening; what are the tests for Down syndrome?
- 1st trimester; PAPA, HCG
- 2nd trimester; maternal serum, AFP, HCG, inhibin
- Free foetal DNA (ascent)
What is homocystinuria?
An inherited disorder of the metabolism of the amino acid methionine.
» decreased production of cysteine
What enzyme deficiency causes homocystinuria?
Cystathionine beta synthase.
What are the clinical problems of homocystinuria? (5)
- Mental retardation
- Marfinoid habitus
- Ectopia lentis
- Osteoporosis
- Thromboembolism
What is hyperhomocysteinemia?
An abnormally high level of homocysteine in the blood.
- above 15 µmol/L
- 5% of the population
What conditions have an increased incidence of hyperhomocysteinemia? (3)
- Stroke
- Peripheral vascular disease
- Coronary artery disease
What types of molecules are the intermediates in most metabolic pathways?
Low molecular weight organic acids.
-commonly anionic
What are the defects in classic organic acidaemias?
Defects in branched chain AA catabolism.
-AAs are not always increased when deficient catabolic enzyme
Name some classic organic acidaemias. (3)
- Propionic
- Isovaleric
- Methyl malonic
