CHEMPATH: Metabolic disorders and screening (1+2) Flashcards
What are the inheritance types of metabolic disorders? Which abide by Mendelian inheritance?
- Chormosomal
- Polygenic
- Monogenic
Polygenic and monogenic mainly abide by Mendelian inheritance
What does OMIM stand for and what is its use?
Online Mendelian Inheritance in Man (OMIM)
- Constantly updated catalogue of metabolic conditions
- Most are autosomal and typically present at a young age with non-specific symptoms
- X linked is the next most common, then Y linked and mitochondrial
What are the causes of deficient enzyme activity?
- Lack of enzyme
- Reduced enzyme activity due to defects of…
- Post-translational modification
- Assembly
- Transportation
- Defects of co-factor activation
What are some commonly seen biochemical hallmarks of metabolic disorders?
- Lack of end-product
- Build-up of precursors
- Abnormal, often toxic metabolites (due to large amounts of substrate that does not usually react with the enzymes, starts reacting and producing toxic metabolites)
What is the criteria for screening for a metabolic condition (Wilson &Junger, 1968)?
- 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
What is the use of OMIM numbers?
Should be used when referring to any metabolic conditions as they may have several names
What is the pathophysiology of phenylketonuria?
- Phenylalanine hydroxylase (PAH) deficiency
- PAH converts phenylalanine into tyrosine
- If the enzyme is deficient, you get:
- Build-up of phenylalanine (toxic)
- Abnormal metabolites:
- Phenylpyruvate
- Phenylacetic acid (detected in urine)
How common is PKU? What are the clinical features?
~1 in 10,000
IQ <50 but no other physical symptoms
What investigations are used for diagnosing PKU and what is the management?
- Blood test for presence of phenylalanine
- NB: no gene test is available as over 400 different genes may be implicated in PKU
Management: dietary supplementation but must be started within the first 6 weeks of life otherwise it will not be effective at preventing complications.
What is the sensitivity and specificity of this test using measurement of a metabolite?
Sensitivity = true positive/total disease present
- Talking about those in whom the disease in present.
- Therefore if 48/50 then 96% sensitivity
Specificity = true negative/total disease absent
- Concerns those in whom the disease is absent
- In this example: 100/100 = 100%
What is the positive and negative predictive value of this test?
PPV = True positive/total positive found
- Only refers to positive tests (tells you if someone has the disease or if you can rule it out)
- 48/48 = 100%
NPV = True negative/total negative found
- Negative predictive value only refers to negative tests
- In this example 100/102 = 98%
What are the advantages and disadvantages of a lower cut-off for this test?
- Advantage - high sensitivity/no false negatives so no one with the disease will be missed
- Disadvantage - more false positives, lower positive predictive value
Which factor can have a big impact on the predictive value of a test?
Prevalence of the disease - high false positive rates with lower prevalence of disease and so low PPV.
From example:
- If instead of 50 disease present to 100 disease absent you’d have:
- 50 disease present to 49,950 disease absent.
- Assuming the specificity remains the same at 95%, you’d have 2,500 false positive for every 50 disease present
- PV+ve goes down to 2%
What is the test used to investigate for metabolic disorders in the newborn? When is it done?
5-8 days of life
- Heel prick test/Guthrie test
- Capillary blood from the posterior medial third of the foot is spotted onto a card.
How is the newborn heel prick test analysed?
- Sent to one of 17 UK Newborn Screening Laboratories Network labs
- Bloodspot punched out and blood sample eluted to measure phenylalanie etc
- PPV for PKU is ~80%
What is the incidence of congenital hypothyroidism? What are the causes and reasons for investigation by heel prick?
- Inherited in only 15% of cases; usually due to dysgenesis/agenesis of the thyroid glands
- Not always clinically detected
- Based on high TSH (in UK), started in 1970
- PPV ~ 60-70%
What did the National Screening Committee do to the Wilson and Jugner criteria?
Extended it to include 29 criteria including… ‘evidence from RCTs that the proposed screening would be effective in reducing mortality or morbidity’
When was sickle cell disease (OMIM 603903) added to the UK screening programme? What about CF and MCADD?
SCD - 2006
CF - 2007
MCADD - 2009
How common is CF and why was it added?
1 in 2500
Evidence that early intervention improves outcome
How many types of CF exist? What is the pathophysiology of CF? Which organs are affected and how?
6 classes of defects (image)
Pathophysiology:
Failure of Cl- to move from inside the epithelial cell into the lumen –> increased reabsorption of Na+/H2O –> viscous secretions –> ductule blockage –>
- Lungs - recurrent infection
- Pancreas - malabsorption, steatorrhoea, diabetes
- Liver - cirrhosis
What is measured in neonate blood tests to diagnose CF?
high blood immune reactive trypsin (IRT) if it is >70ng/ml in 3 bloodspots then DNA mutation detection panel is used etc.
What is the advatage and disadvantage of mass spectrometry in testing for metabolic diseases?
Advantage - from a single sample, many abnormal metabolites can be picked up
Disadvatage - testing for all diseases is rarely done as it is expensive and there may be no treatment
What is MCADD?
Medium chain Acyl-CoA dehydrogenase = fatty acid oxidation disorder
Added to newborn screening in 2009
What is the pathophysiology of MCADD?
Pathophysiology:
- The carnitine shuttle allows you to get fat into the mitochondria so that it can be broken down
- Fatty acid oxidation is a process of sequentially breaking down a fatty acid into smaller and smaller chains
- If MCAD is missing, you are NOT going to produce acetyl-CoA from fatty acids
- Acetyl-CoA is necessary in the TCA cycle to produce ketones, which spares glucose
- You use fat when you’re fasting or between meals, in order to spare your glucose stores
What is a classical presentation of MCADD? How is it diagnosed in the screening test? What is the management?
- MCAD deficiency is a classic cause of cot death – If a baby can’t break down fats, when they are not feeding, they will get massively hypoglycaemic and die
- Screening = measuring C6-C10 Acylcarnitine using tandem mass spectromerty
- Treatment = make sure the child NEVER becomes hypoglycaemic, and hence never becomes reliant on fats for energy
What is the cause of homocystinuria? What are the clinical features? Is screening done in the UK?
Homocystinuria = failure of remethylating homocysteine
Clinical features:
- Lens dislocation
- Mental retardation
- Thromboembolism
Possible inclusions for the UK new-born screening programme:
- Homocystinuria (amino acid disorder)
- Isovaleric acidaemia (organic acid disorder)
- Glutaric aciduria type I (organic acid disorder)
- Maple syrup urine disease (organic acid disorder)
- Long chain acyl CoA dehydrogenase deficiency (fatty acid oxidation disorder)