Metabolic disorders Flashcards
How are metabolic disorders detected on newborn screening?
Guthrie blood spot test at 6 days age
What does the guthrie blood spot test testing for? (5)
- phenylketonuria
- congenital hypothyroidism
- cystic fibrosis
- sickle cell disease
- medium chain acylCoA deficiency
What is phenylketonuria?
Phenylanine hydroxylase deficiency
What is cystic fibrosis?
Mutation in CFTR (F508del most common)
viscous secretions causing ductal blockages
How to screen for cystic fibrosis?
Immune reactive trypsin
if positive -> DNA mutation detection
What is Medium chain AcylCoA dehydrogenase deficiency?
Fatty acid oxidation disorder
How to screen for Medium chain AcylCoA dehydrogenase deficiency?
Acylcarnitine levels by tanden mass spectrometry
When talking about specificity and sensitivity is this regarding the population or the test itself?
The population
When talking about positive and negative predictive values are we talking about the population or the test?
The test itself
What is specificity?
The probability that someone without the disease will correctly test negative
How to calculate specificity?
TN / (FP + TN)
e.g. 85 people without CF, 80 actually test negative.
-> 80/85 = 94%
What is sensitivity?
Probability that someone with the disease will correctly test positive
How to calculate sensitivity?
TP/ (TN+FN)
e.g. 100 people with CF and 90 test positive that have the disease
-> 90/100 = 90%
What is the positive predictive value?
How is it calculated
PPV is the probability that someone who tests positive actually has the disease
TP / (TP +FP)
e.g. 95 people tested positive of which 90 had the disease
-> 90/95 = 95%
What is the negative predictive value?
How is it calculated
NPV is the probability that someone who tests negative actually has the disease
TN / (TN +FN)
e.g. 90 people tested negative of which 90 didn’t have the disease
-> 80/90 = 89%
What group 1 (Accumulation of toxins) metabolic disorders exist?
Organic acidaemias ‘Acidurias)
Urea cycle disorders (10 total)
Phenylketonuria
Homocystinuria
Tyrosinaemia
What are organic acidaemias?
You see Hyperammoniaemia + metabolic acidosis + high AG + high ketones
Associated with unusual odour in urine
Causes toxic encephalopathy
What is the test for organic acidaemias?
Plasma ammonia, plasma amino acids,
There are two types of organic acidaemias to remember
What are they and a distinct feature of both
Isovaleric acidaemia = cheesy /sweaty urine smell
Maple syrup urine disease = sweet odour to urine, sweaty feet
What inheritance pattern do urea cycle disorders follow?
All are autosomal recessive
1 is X linked. (OTC deficiency)
What are the key features of urea cycle deficiency presentation?
Hyperammoniaemia = encephalopathy
In a child : hyperammonaemia state after party having eaten alot of meat
In a adult : Hx psychiatric illness / ADHD
How to manage urea cycle disorders?
Remove excess ammonia via dialysis / sodium benzoate
long term = low protein diet
How to test for urea cycle disorders?
Test = blood ammonia (from a free flowing sample, kept in ice and rushed to laboratory) = HIGH
○ Other tests = glutamine levels (HIGH), urine orotic acid (HIGH)
What causes phenylketonuria?
Deficiency of phenylalanine hydroxylase
= high levels of toxic phenylalanine -> build up on phenulpyruvate + phenylacetic
Key features and symptoms of phenylketonuria?
Fair hair, blue eyes, fair skin
Learning disability
Musty smell
How to manage phenylketonuria?
Exclude foods high in phenylalanine
How to test for phenylketonuria?
Blood test for phenylalanine levels
What is homocystinuria?
Deficiency of enzyme cystathionine synthetase
more common in irish children
Features and symptoms of homocystinuria?
Fair skim, brittle hair
thrombotic episodes at an early age
Lens dislocation
How to manage homocystinuria?
Vit B6 supplementation
Low methionine diet
What are the features of tyrosinemia?
Cabbage like odour
Bloody stools, jaundice, hepatomegaly, liver failure, mental retardation
What metabolic disorders are listed under Group 2 - reduced energy stores?
Glycogen storage disorders
Galactosaemia
MCAD deficiency
What two Glycogen storage disorders are there?
Type 1 and Type 5
Type 1: Von Gierke’s disease :
(sugar stuff)
Type 5: Mcardle’s disease :
(muscle stuff)
What are key features of Von Gierke’s disease?
Hypoglycaemia in infancy
Hepatomegaly
Enlarged kidneys
= failure to mobilise glucose from glycogen
- in Ashkanazi Jews
What deficit is in Von Gierke’s disease?
glucose - 6 - phosphate (in the liver)
so cannot turn glycogen to glucose
How is Von Gierke’s disease managed?
Frequent glucose feeds
NG tubes for overnight feeds
What deficiency causes Mcardle’s disease?
Mycophosphorylase (muscle)
Key symptoms of mcardle’s disease?
Stiffness and pain following exercise
rhabdomyolysis
What deficiency is seen in Galactosaemia?
GAL-2-PUT most common and most severe type
causes elevated GAL-1-phosphate
What are the symptoms of Galactosaemia and a important differential?
Infant vomiting after milk ingestion
poor feeding, jaundice, bilateral cataracts, hypoglycaemia
- hypoglycaemia infant differential
What metabolic disorders puts infants at a high risk of sepsis with E-coli?
Galactosaemia
What is the disorder in MCAD deficiency?
Fatty acid oxidation disorder
causes hypoketotic hypoglycaemia
What features are seen in MCAD deficiency?
Hypoketonic Hypoglycaemia
How to test for MCAD deficiency
Blood acylcarnitine via MS - blood spot
Which disorders come under Large molecule synthesis?
- Peroxisomal disorders
- Glycosylation
How do peroxisomal disorders present?
The baby wont be able to catabolise very long fatty acids or make bile acids
- seizures
- retinopathy
- hepatomegaly + mixed hyperbiliribnaemia
- hypotonia = floppy baby
How do glycosylation disorders present?
Retardation and nipple inversion
What group 4 : defects in large molecule metabolism are there?
Lysosomal disorders
Tay sachs disease (affects ashkenazi jews)
How do group 4 metabolic disorders present?
Very slow progressing
Neuroregression, hepatosplenomegaly
Cardiomyopathy
Test urine mucooligopolysaccharides and
WBC enzyme levels
Who gets affected by Tay sachs?
Ashkenazi Jewish
What group 5 mitochondrial metabolic diseases are there?
MELAS
Kearn’s Sayre
POEMS
How do Group 5 - mitochondrial metabolic diseases present?
Involve the CNS, muscle and heart
High lactate and CK myopathy
Muscle biopsy diagnostic
