5s: Metabolic Disorders Flashcards
3 types of inherited disorders:
Chromosomal
Polygenic (Mendelian)
Monogenic (Mendelian)
What is an autosome?
Autosome = non-sex chromosomes
most common type of inherited metabolic disorder
Deficiency enzyme activity may be due to (2)
lack of enzyme
reduced enzyme activity:
- post-translational modification
- transportation
- assembly
- defects of co-factor activation
What can deficiency enzyme activity lead to:
BIOCHEMICAL HALLMARKS (of the metabolic disorder)
- build-up of precursors
- abnormal, often toxic, metabolites (due to large amount of substrate that does not usually react with enzyme, start reacting → toxic metabolites)
- lack of end-product
What is the catalogue of metabolic disease?
OMIM
c. 600 are IMD
What is phenylketonuria? MoA
Phenylalanine hydroxyls (PAH) DFEFICIENCY
- CONVERTS PHENYLALANINE INTO TYROSINE
if PAH deficient:
- phenylalanine build up (toxic)
- abnormal metabolites (phenyl pyruvate, phenyl acetic acid → detected in urine)
Key features of PKU (1 in 10k)
IQ <50
test = check for serum phenylalanine
400 different gene mutations can cause PKU
Tx: phenylalanine restriction
Sensitivity, specificity, PPV, NPV
Lower-cut off → not miss any diagnoses but more false positives
Sensitivity = correctly identify those with disease (true positives/total number with the disease)
- prioritised in screening for IMDs as you do not want to miss a diagnosis
- a lot more false positives with very rare diseases → reduced PPV (dependent on disease prevalence)
Specificity = correctly identify those without the disease (true negatives/total number without the disease)
PPV = true positives/total number positive
NPV = true negatives/total number negative
- PPV and NPV determine test accuracy to get diagnosis right or wrong
- I.E. dsDNA is only found in SLE, but isn’t in every SLE case = highly specific (96%), not very sensitive (60%)
- So, if tested -ve, as the specificity is defined as “true negatives / total number without disease” (very high at 96% here) because the majority of people without dsDNA do not have SLE (as it is only found in SLE)
UK Specimen collection (Guthrie Test)
5-8 days of life = Heel Prick Capillary on posterior medial third of foot
Blood spotted onto Guthrie card (thick filter paper) → sent to lab (UK New-born Screening Laboratories network UKNSLN)
Bloodsports punched out and phenylalanine is measured
PPV +ve = 80%
What IMDs does the UK screen
PKU
SCD
Cystic Fibrosis
MCAD Deficiency
Congenital Hypothyroidism
- not true metabolic disorder
- dysgenesis of thyroid gland
- high TSH level
- PPV +ve = 60-70%
Cystic fibrosis is a defect of what?
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
- 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
symptoms of Cystic Fibrosis
- lungs → recurrent infection
- pancreas → malabsorption, steatorrhoea, diabetes
- liver → cirrhosis
- testicles → infertility
Ix of cystic fibrosis
high immune reactive trypsinogen in Guthrie blood spot test (heel prick)
Screening test = high immune reactive trypsin (IRT)
- If the IRT is above the 99.5th centile in 3 bloodspots, you move on 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, you can diagnose CF
- If you get 1 mutation out of 4, you extend the test to a panel of 28 mutations
- If you pick up 0 mutations out of 4, you do another IRT at 21-28 days
Mass Spectrometry (MS) and IMD
- If you take a molecule, ionise it and then fragment it in a controlled way, you will end up with bits of molecules that will separate in mass and charge (but the same kinetic energy)
- This means that each fragment will have a unique footprint
- The benefit of MS is that from a single sample you can pick up a lot of metabolites
- Up to 30 different metabolic diseases could be picked up using mass spectrometry
What is MCADD (mitochondrial fatty acid beta oxidation disorder)? pathophysiology
MCADD = medium chain acyl-coa dehydrogenase deficiency
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
MCADD and babies
classic cause of cot death
if baby can’t break down fats, when they are not feeding, they will get massively hypoglycaemic and die
How do we screen and treat for MCADD
- Screening = measuring C6-C10 Acylcarnitine using tandem MS
- Treatment = make sure the child NEVER becomes hypoglycaemic, and hence never becomes reliant on fats for energy
What is homocysteinuria (do we screen for this)
failure of remethylating homocysteine
- lens dislocation
- mental retardation
- thromboembolism
part of neonatal screening in Wales
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)
What is phenylketonuria? MoA
Phenylalanine hydroxyls (PAH) DFEFICIENCY
- CONVERTS PHENYLALANINE INTO TYROSINE
if PAH deficient:
- phenylalanine build up (toxic)
- abnormal metabolites (phenyl pyruvate, phenyl acetic acid → detected in urine)
Sensitivity and Specificity MedEd
