Chemical Pathology - Metabolic Disorders and Screening Flashcards
Deficiency of which enzyme causes phenylketouria?
what’s its function?
Phenylalanine hydroxylase (PAH) convert phenylalaine to tyrosine
What builds up in PKU that causes toxicity?
phenylalanine
What number must you use when requesting a metabolic screen?
OMIM number
Online Mendelian Inheritance in Man
What will be the result of not treating PKU shortly after birth?
IQ <50
How is PKU diagnosed?
Based on blood phenylalanine level, as >400 different mutations can cause PKU!
How quickly does PKU treatment need to be initiated in order to be effective?
First 6 weeks of life
What is the test for cystic fibrosis in the neonate?
immunoreactive trypsin test as part of guthrie heel prick test
What is MCADD?
medium-chain acyl-CoA dehydrogenase deficiency
AR condition preventing metabolism of fat into energy
prevents production of acetyl CoA and ketones, which permits glucose sparing
may die of hypoglycaemia - classic cause of cot death, as get hypo when not feeding and die
what metabolic defect can cause hyperammonaemia?
urea cycle defect
how can hyperammonaemia be treated?
remove ammonia w sodium benzoate or sodium phenyl acetate
reduce ammonia production (low protein diet)
what is the typical triad of biochemical findgings for organic aciduria?
Hyperammonaemia
Metabolic acidosis
High anion gap
What unusual odour might be smelt on a patient with isovaleric acidaemia?
Cheesy and sweaty
What are the typical neurological findings in organic acidurias?
truncal hypotonia and limb hypertonia
what condition causes chronic intermittent organic aciduria?
reye syndrome = liver and brain injury w hypoglyacaemia and hyperammonaemia
recall 3 drugs that can precipitate symptoms in Reye syndrome
Salicylates
Anti-emetics
Valporate
Which inherited metabolic disorder causes a hypoketotic hypoglycaemia?
MCADD
What is the most severe & common disorder of galactose metabolism?
Galactossaemia
Gal-1-put enzyme deficiency,
can’t convert galactose to glucose, so lots of gal-1-phosphate in blood
Galactose-1-phosphate uridyl transferase
How should Gal-1-Put be treated?
avoid galactose (milk - dairy and breast)
what ophthalmological sign may children with Gal-1-put deficiency have?
Bilateral cataracts
recall 3 biochemical findings of glycogen storage disease type 1
Hypoglycaemia
Neutropaenia
Lactic acidosis
How does Gal-1-Put present in neonates?
Diarrhoea & Vomiting
Conjugated hyperbilirubinaemia & hepatomegaly
sepsis (gal-1-phos inhibits the immune response)
When, and in which organ, do mitochondrial disorders present?
At any age in any organ!
Recall 3 mitochondrial DNA (mtDNA) disorders
BARTH syndrome - presents at birth
MELAS - at age 5-15
Kearns Sayre syndrome - at age 12-30
What abnormal blood results would be suggestive of a mitochondrial disorder?
Elevated lactate, even when fasted
Unexplained raised CK
What is the typical muscle biopsy histological finding in mitochondrial disorders?
ragged red fibres
what 9 diseases are screened for during neonatal heel prick (Guthrie) test?
SCD
CF
congenital hypothyroidism
metabolic
PKU
MCADD
homocystinuria
isovaleric academia
glutaric acuduria type , maple syrup disease
define sensitivity
true positives
correctly identify patients w a disease
= positve test/everyone who has actually the disease(true pos + false neg)
define specificity
true negatives
correctly identify people without the disease
= people who test neg/people whoa ctually dont have the disease (true neg + false pos)
A specific test helps rule a disease in when positive
what 2 specific metabolites accumulate in PKU?
phenylpyruvate
phenyl acetic acid (urine)
treatment of PKU?
diet that eliminated phenylalanine
may be breast fed
avoid protein
avoid aspartame
amino acid supplements
what are the symptoms of untreated PKU?
lighter skin and hair
musty smell to breath
learning disabilities
epilepsy
at birth may have microcephaly and LBW
define PPV and NPV
PPV = probability that following a positive test result, that individual will truly have that specific disease.
=true pos/ all postive (true and false)
NPV = negative predictive value is the probability that following a negative test result, that individual will truly not have that specific disease.
= true neg/all neg (true & false)
what do you measure as screening for MCADD?
C6-C10 Acylcarnitine using tandem mass spectrometry
define homocystinuria
AR disorder of the metabolism of the amino acid methionine due to a deficiency of methionine synthase
give 3 clinical features of homocystinuria
Lens dislocation
Mental retardation
Thromboembolism
give 4 clinical features of a urea cycle disorder?
hyperammonaemia w respiratory alkalosis
neurological encephaloptahy
vomiting without diarrhoea
avoidance of protein or change in diet
the urea acid cycle converts what to what?
ammonia to urea
in high levels of ammonia in the blood, what does the body convert it to?
attaches an ammonium group to glutamate to form glutamine
what biochemical findings suggest a urea cycle disorder (3)?
Serum glutamine is HIGH in hyperammonaemia
Serum amino acids in urea cycle will either be HIGH or ABSENT
Urine orotic acid
which urea acid cycle disorder is X linked?
OTC
Ornithine Transcarbamylase Deficiency
give 3 AR urea acid cycle diseases?
Lysinuric protein intolerance
Hyperornithinaemia-Hyperammonaemia-Homocitrullinuria (HHH)
Citrullinaemia type III
all cause high ammonia (toxic)
what may precipitate reye’s syndrome?
viral infection and aspirin use
what 3 biochemical changes are associated w reye’s syndrome?
hyperammonaemia
hypoglycaemia
prolonged prothrombin (PT) time
what does hyperketotic hypoglycaemia state indicate
starvation
what does hypoketotic hypoglycaemia state indicate
MCADD
what does hyperketotic hyperglycaemia state indicate
DKA
what does hypoketotic hyperglycaemia state indicate
HHS
what 2 investigations to diagnose gal-1-put deficiency?
- High galactose in urine
- absence of Gal-1-PUT activity in red cells
how do neonates with gal-1-put deficiency present(4)?
failure to thrive, jaundice, hepatomegaly and sepsis (e.coli)
what are the 3 features of Barth disease?
cardiomyopathy, myopathy, neutropenia)
what are the 3 features of MELAS?
mitochondrial encephalopathy, lactic acidosis and stroke-like episodes
what’s the most common enzyme deficiency worldwide? what’s the inheritance?
Glucose-6-phosphate dehydrogenase deficiency (G6PDD)
X-linked recessive = defective glucose-6-phosphate dehydrogenase enzyme
what’s the function of glucose-6-phosphate dehydrogenase?
glucose-6-phosphate dehydrogenase is an enzyme which protects red blood cells
defect causes haemolysis
what are 3 clinical features of G6PDD?
neonatal jaundice
kernicterus (bilirubin induced brain dysfunction)
haemoglobinuria (red or brown urine)
what’s favism?
Acute hemolytic anemia in G6PD-deficient people can develop after eating fava/broad beans.
define isovaleric acidaemia. what amino acid can’t be processed?
AR condition, deficiency in isovaleric acid-CoA dehydrogenase, meaning cant process leucine causing build up of isovaleric acid
it’s a type of organic aciduria/acidaemia
define glycogen storage disease type 1. aka?
liver being unable to properly break down stored glycogen
also know as von gierke disease
what are 2 carbohydrate disorders
galactosemia
glycogen storage disease type 1
define homocystinuria. what enzyme is deficient?
AR condition
inherited disorder of the metabolism of the amino acid methionine due to a deficiency of methionine synthase.
whats the treatment of homocystinuria?
low protein diet
pryroxidine (vitamin B6)
betaine later in life
what are 4 clincical feautures of kearns-sayre?
chronic progressive external ophthalmoplegia, retinopathy, deafness, ataxia
test & treatment for MCADD
blood acylcarnitine
regular carbohydrates
