Chem Path - metabolic disorders and screening 2

Question 1

What is the urea acid cycle?

Answer 1

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

Question 2

What genetic inheritance are most urea cycle disorders and when do they usually present?

Answer 2

Autosomal recessive (minus OTC deficiency which is X linked)

Question 3

What are the clinical signs of urea cycle disorders?

Answer 3

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

Question 4

What are the red flag signs? (urea cycle disorder)

Answer 4

Vomiting without diarrhoea
Resp alkalosis with hyperammonaemia (very high)
Encephalopathy
Protein avoidance - diet change

Question 5

What is the treatment?

Answer 5

Remove ammonia - sodium benzoate, or dialysis

Reduce ammonia production

Question 6

What are organic acidureas?

Answer 6

A group of metabolic disorders that disrupt normal amino acid metabolism, causing a buildup of acid (hence acidurea).

Question 7

What are the red flag signs? (organic acidurias)

Answer 7

Sweet or cheese smell urine - remember, cheese is very acidic so will smell similar

Developmental delay, diffiiculty feeding

Various neurological signs - Hypotonia, myoclonic jerks

Question 8

What is the biggest distinction between urea cycle disorders and organic acidurias?

Answer 8

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

Question 9

What are some odd incidental signs of organic acidurias?

Answer 9

Hypocalcaemia (due to more albumin binding due to the acidosis)
Thrombocytopenia
Neutropenia

Remember HTN (hypertension) - hypertension not actually related

Question 10

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

Answer 10

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

Question 11

What is another cause of organic aciduria?

Answer 11

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

Question 12

How would chronic intermittent aciduria present?

Answer 12

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

Question 13

How would you investigate a suspicion of organic aciduria?

Answer 13

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

Question 14

What is OTC deficiency?

Answer 14

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)

Question 15

What are the consequences of mitrochondrial disease?

Answer 15

Defective ATP production leads to multisystem disease, especially affecting organs with a high energy requirement such as brain, muscle, kidneys, retina and endocrine organs

Question 16

Which mitochondrial disease presents at birth?

Answer 16

Barth Disease, X linked

Cardiomyopathy, neutropenia, myopathy

Question 17

Which mitochondrial disease presents 5-15?

Answer 17

MELAS

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes

Build up of lactic acid very common - acidosis

Question 18

Which mitochondrial disease presents late (12-30) and has symptoms start in the eyes?

Answer 18

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

Question 19

Investigations for mitochondrial disease

Answer 19

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

Question 20

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.

Answer 20

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

Question 21

How would you investigate Galactosaemia?

Answer 21

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

Question 22

4 month old Pt presents with hypo. Has severe hepatomegaly, protruding at the abdomen. Severely lactic acidotic.

Answer 22

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.

Question 23

Lysosomal disease investigations

Answer 23

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

Question 24

Peroxisomal disorders

Answer 24

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)