Chem Path - metabolic disorders and screening 2 Flashcards
What is the urea acid cycle?
A cycle that produces urea from ammonia (which is toxic). Happens in the liver.
Disorder in cycle leads to toxic build up of ammonia.
Leads to a toxic build-up of ammonia
Levels >300mmol/L lead to a hyperammonaemic coma, and probable death
The body tries to get rid of this ammonia by converting it to glutamine, the levels of which can also be detected
Also measure plasma amino acids and urine orotic acid
What genetic inheritance are most urea cycle disorders and when do they usually present?
Autosomal recessive (minus OTC deficiency which is X linked)
What are the clinical signs of urea cycle disorders?
Acute
Respiratory alkalosis (think: trying to breathe out the ammonia) Confusion/Delerium, low GCS, coma (think: same presentation as decomp liver disease)
Chronic
Protein avoidance due to ammonia causing symptoms
Psych - psychosis, ADHD
What are the red flag signs? (urea cycle disorder)
Vomiting without diarrhoea
Resp alkalosis with hyperammonaemia (very high)
Encephalopathy
Protein avoidance - diet change
What is the treatment?
Remove ammonia - sodium benzoate, or dialysis
Reduce ammonia production
What are organic acidureas?
A group of metabolic disorders that disrupt normal amino acid metabolism, causing a buildup of acid (hence acidurea).
What are the red flag signs? (organic acidurias)
Sweet or cheese smell urine - remember, cheese is very acidic so will smell similar
Developmental delay, diffiiculty feeding
Various neurological signs - Hypotonia, myoclonic jerks
What is the biggest distinction between urea cycle disorders and organic acidurias?
Organic aciduria picture =Metabolic acidosis + Hyperammonaemia
whilst urea cycle disorders give you a respiratory alkalosis.
If unclear, important to analyse the amino acids/organic acids in the urine to work out what’s in there.
There is large anion gap in organic acidurias as the anions are caused by amino acids
What are some odd incidental signs of organic acidurias?
Hypocalcaemia (due to more albumin binding due to the acidosis)
Thrombocytopenia
Neutropenia
Remember HTN (hypertension) - hypertension not actually related
An Indian mother is worried that her son, who has flu like symptoms, has rapidly deteriorated. He is severely dehydrated, with worsening neurological symptoms - trunk hypotonia, limb hypertonia, ataxia and seizures. She wonders if this has something to do with fenugreek, a spice which she says she can smell it in her son’s ear
Maple syrup urine disease
Disorder in metabolism of leucine, isoleucine and valine. These are branch chain amino acids.
Can be acute or chronic intermittent
Amish, mennonite, jew
What is another cause of organic aciduria?
Isovaleric acidaemia
Isoleucine is metabolised to isoveryl CoA and this is where the pathway is blocked.
Excreted in the urine as 3-OH-isovaleric acid - cheesy smell
How would chronic intermittent aciduria present?
Presents with recurrent episodes of ketoacidotic coma, cerebral abnormalities
Can present with a trigger and may present similarly to Reye syndrome - aspirin dose causing similar symptoms
How would you investigate a suspicion of organic aciduria?
Must collect samples during an acute episode (similar to porphyria or hypo)
Blood gas - acid=urea, organic, resp alk = urea
Plasma/blood ammonia - check for hyperammonaemia Plasma/blood amino acids - in both Urine organic acids analysis - differentiate Plasma/blood glucose and lactate - rule out other causes Blood spot carnitine profile: stays abnormal in remission
What is OTC deficiency?
Most common urea cycle disorder. X-linked, causes a rise in Orotic acid.
May have a megaloblastic anaemia that isn’t cured when given B12 or folic acid.
Triad
High orotic acid
high ammonia
low BUN (blood urea nitrogen)
What are the consequences of mitrochondrial disease?
Defective ATP production leads to multisystem disease, especially affecting organs with a high energy requirement such as brain, muscle, kidneys, retina and endocrine organs
Which mitochondrial disease presents at birth?
Barth Disease, X linked
Cardiomyopathy, neutropenia, myopathy
Which mitochondrial disease presents 5-15?
MELAS
Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes
Build up of lactic acid very common - acidosis
Which mitochondrial disease presents late (12-30) and has symptoms start in the eyes?
Kearns-Sayre
Chronic progressive external ophthalmoplegia, retinopathy, deafness, ataxia
Starts in the eyes (unilateral ptosis) then moves to other way then rest of face and works its way down
Investigations for mitochondrial disease
Raised fasting lactate, before and after meals - MELAS
CSF lactate/pyruvate
Has to be done by a metabolic doctor! Sometimes, the lactic acid levels in blood are normal but abnormal in CSF
CSF proteins (raised in Kearns-Sayre)
CK
Muscle biopsy
Mitochondrial DNA analysis
Child presents with failure to thrive, jaundice, diarrhoea and vomiting. Investigations show a high conjugated billirubin. The mother reported that her mother used to have an issue with processing carbs.
Galactosaemia - disorder of galactose metabolism
Deficiency in Galactose-1-phosphate uridylyltransferase, resulting in toxic buildup of Galactose-1-phosphate, which can cause hepatomegaly and kidney damage. Sepsis is another combination due to G1P inhibiting immune responses.
If not picked up as neonate, can give cateracts due to Galactitiol
How would you investigate Galactosaemia?
Urine Reducing Substances test - detects that carbs are in urine. If urine glucose is negative and reducing test is positive (which it will nearly always be), then consider Galactosaemia
Red Cell GAL-1-PUT activity
4 month old Pt presents with hypo. Has severe hepatomegaly, protruding at the abdomen. Severely lactic acidotic.
von Gierke’s Disease
Type 1 of glycogen storage disorder meaning glycogen cannot be converted to glucose.
Deficiency of glucose-6-phosphatase activity leads not only to excessive glycogen storage but also prevents glucose export from gluconeogenetic organs. Most common presentation is 3-6 months.
Hypoglycaemia with lactic acidosis.
Neutropenia.
Raised triglyceride, urate and transaminases.
Muscle biopsy for enzyme studies.
Lysosomal disease investigations
Lab investigations: Urine mucopolysaccharides and oligosaccharides, Leucocyte enzyme activity. Lysosomes are meant to clear out mucopolysaccharides et al. so these shouldn’t be in the urine.
Treatment: Bone Marrow transplant, exogenous enzymes
Peroxisomal disorders
Defect in peroxisomes - which are responsible to breaking down long chain fatty acids.
Neonate Profile:
Severe muscular hypotonia, seizures
Hepatic dysfunction – mixed hyperbilirubinaemia
Dysmorphic signs
Infant Profile:
Retinopathy (often leading to early blindness), sensorineural deafness, mental
deficiency
Hepatic dysfunction
Large fontanelle, osteopenia of long bones, calcified stippling
Neonatal signs are muscular (severe hypotonia) whilst infant signs are more sensory (seeing, hearing, thinking –> Retinopathy, deafness, LD)
