Chem Path: Metabolic disorders and screening 2 Flashcards
What are normal levels of ammonia?
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What is the urea cycle?
Converts ammonia to urea
What can go wrong in the urea cycle?
7 enzymes involved - Can have deficiency it any of them
Lysiniuric protein intolerance
HHH
Citrullinaemia type 2
What happens when there is something wrong with the urea cycle?
Hyperammonaemia
How are the urea cycle disorders inherited?
Recessive except for OTC deficiency which is x linked
What happens in hyperammonaemia?
Glutamate is attached to it to make glutamine in an attempt to get rid of urea
So plasma glutamine rises
What else can you measure to diagnose hyperammonaemia and urea cycle disorders
Urine orotic acid
How is hyperammonaemia treated
Sodium benzoate or sodium phenylacetate or dialysis
Low protein diet
How do hyperammonaemia and urea cycle disorders present
Respiratory alkalosis Vomiting without diarrhoea Cerebral oedema Seizures Comatose
What are associated with urea cycle disorders
ADHD/ Long standing mental illness
Methandrostenolone use
Creatinine supplement
What happens in organic acidurias
Defect in metabolism of leucine or isoleucine or valine
Isovaleryl CoA (a breakdown product of the amino acids) has to be broken down by isovaleryl CoA dehydrogenase. If this enzyme is deficient, you will have to excrete the compound as 3Oh isovaleric acid
How does isovaleric acid smell
Cheesy/ Sweaty smell
How do organic acidurias present?
Hyperammonaemia with METABOLIC ACIDOSIS and high anion gap
In neonates:
Unusual odour
Lethargy, feeding problems
Truncal hypotonia and limb hypertonia
Myoclonic jerks
How does the chronic intermittent form of organic acidurias present in kids
Recurrent ketoacidotic comas
Cerebral abnormalities
Reye syndrome
What is Reye syndrome
Rapidly progressing encephalopathy
How does Reye syndrome present
Vomiting Lethargy Confusion Seizures Decerebration Respiratory arrest
What can Reye syndrome be triggered by
Salicylates (aspirin), anti emetics, valporate
How will you screen for Reye syndrome / Organic acidurea
Plasma ammonia
Plasma/Urine amino acids
Urine organic acids
Plasma glucose and lactate
All of the 4 should be done during the acute episode
Blood spot carnitine profile can be done anytime
What happens in mitochondrial fatty acid beta oxidation defect
You cannot break down fatty acids so there is no ketone production
Hoe does mitochondrial fatty acid beta oxidation defect present
Hypoketotic hypoglycaemia
Hepatomegaly
Cardiomyopathy
How do you test for mitochondrial fatty acid beta oxidation defect
Blood ketones
Urine organic acids
Blood spot acylcarnitine profile
What are the 2 carbohydrate break down disorders
Galactosaemia
Glycogen storage disease type 1 (Von Gierke disease)
What is the most common deficiency in galactosaemia
Gal-1-PUT deficiency
How does Gal-1-PUT deficiency present in neonates
Hepatomegaly Hypoglycaemia D&V Conjugated hyperbilirubinaemia Sepsis
Why cant here be sepsis in mitochondrial fatty acid beta oxidation defect
Gal-1-PUT inhibits immune responses so babies can develop E Coli sepsis
If not picked up at infancy, what can mitochondrial fatty acid beta oxidation defect cause in children
Bilateral cataracts as Gal-1-PUT can become a subtrate for aldolase
How to investigate for mitochondrial fatty acid beta oxidation defect
Urine reducing substances
RBC Gal-1-PUT
How tot treat mitochondrial fatty acid beta oxidation defect
Avoid milk (galactose)
What happens in von Gierke disease
Lack of phosphatase enzyme to break down G6p and G1P. Leads to a buildup of glycogen in muscles, leading to hypoglycaemia
How does von Gierke disease present
Hepatomegaly Nephromegaly Hypoglycaemia Lactic acidosis Neutropaenia
What happens in mitochondrial disorders
Heteroplasmy of mtDNA - Develop symptoms after reaching a certain load of mtDNA
Can present at any time, any age
Defective ATP production
What are some examples of mitochondrial disorders in terms of age of presentation
Birth - Barth (Cardiomyopathy, neutropaenia, myopathy)
5-15 - MELAS (Mitochondrial encephalopathy, lactic acidosis and stroke like episodes)
12-30 - Kearns-Sayre (Chronic progressive external opthalmoplegia, retinopathy, deafness, ataxia)
How would you investigate for mitochondrial disorders
High lactate - especially after fasting or before and after meals - This would usually be LOW in normal people
CSF lactate / pyruvate
CSF protein - Raised in kearns-Sayre syndrome
High CK + High lactate
Ragged red fibres in muscle biopsy
