ChemPath 5S: Metabolic Disorders 1 Flashcards
What are the types of inherited disorders?
- Chromosomal
- Polygenic (by Mendelian inheritance)
- Monogenic (by Mendelian inheritance)
What is the most common mode of inheritance of inherited metabolic disorders?
Autosomal is most common
How do inherited metabolic disorders most commonly present?
Typically present at a young age with non-specific symptoms
What may be the causes of deficient enzyme activity?
- Lack of enzyme
- Reduced enzyme activity due to defects of…
- Post-translational modification
- Transportation
- Assembly
- Defects of co-factor activation
Deficient enzyme activity can lead to… BIOCHEMICAL HALLMARKS (of the metabolic disorder).
Name some of these…
- Lack of end-products
- Build-up of precursors
- Abnormal, often toxic, metabolites (due to large amount of substrate that does not usually react with the enzyme, start reacting → toxic metabolites)
What are the requirements of any screening scheme?
Important health problem
Accepted treatment
Facilities for diagnosis and treatment
Latent or early symptomatic stage
Suitable test or examination
Test should be acceptable for population
Natural history understood
Agreed policy on whom to treat as patients
Economically balanced
Continuing process
Name some inherited metabolic disorders
- Phenylketonuria (PKU)
- Cystic fibrosis
- MACD (Mitochondrial Fatty acid Beta-oxidation)
- Homocystinuria
What is the pathophysiology of PKU?
- Phenylalanine hydroxylase (PAH) deficiency
- PAH converts phenylalanine into tyrosine
- If the enzyme is deficient, you get:
- Build-up of phenylalanine (toxic)
- Abnormal metabolites:
- Phenylpyruvate
- Phenylaceticacid (detected in urine)
Summarise PKU
- IQ<50
- Test – check for serum phenylalanine
- 400 different gene mutations can cause PKU
- Tx: phenylalanine restriction
What is the pathophysiology of cystic fibrosis?
- Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) defect
- 6 classes of defect
- Failure of Cl- ion movement from inside epithelial cells into the lumen → increased reabsorption of Na+/water → viscous secretions → duct blockage
What are the different classes of CF?
Symptoms of CF?
- Lungs → recurrent infection
- Pancreas → malabsorption, steatorrhoea, diabetes
- Liver → cirrhosis
- Testicles → infertility
Screening test for CF?
- high immune reactive trypsin (IRT)
-
→ If the IRT is above the 99.5th centile in 3 bloodspots → do mutation detections
- There are >500 mutations that can cause cystic fibrosis, but 4 are very common → F508 is the most common
- If you get 2 mutations of these 4 common types → diagnose CF
- If you get 1 mutation out of 4 → extend the test to a panel of 28 mutations
- If you pick up 0 mutations out of 4 → do another IRT at 21-28 days
What can mass spectrometry be used to detect?
- up to 30 inherited metabolic disorders (abnormal metabolites)
- illegal in the UK - cannot afford to pick up and treat all these diseases
What is MCAD?
- MACD is a fatty acid oxidation disorder
- Incidence 1: 10,000
- MCADD = Medium Chain Acyl-CoA Dehydrogenase Deficiency