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
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
