Chem Path: Metabolic disorders and screening 2

Question 1

What are normal levels of ammonia?

Answer 1

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Question 2

What is the urea cycle?

Answer 2

Converts ammonia to urea

Question 3

What can go wrong in the urea cycle?

Answer 3

7 enzymes involved - Can have deficiency it any of them

Lysiniuric protein intolerance
HHH
Citrullinaemia type 2

Question 4

What happens when there is something wrong with the urea cycle?

Answer 4

Hyperammonaemia

Question 5

How are the urea cycle disorders inherited?

Answer 5

Recessive except for OTC deficiency which is x linked

Question 6

What happens in hyperammonaemia?

Answer 6

Glutamate is attached to it to make glutamine in an attempt to get rid of urea
So plasma glutamine rises

Question 7

What else can you measure to diagnose hyperammonaemia and urea cycle disorders

Answer 7

Urine orotic acid

Question 8

How is hyperammonaemia treated

Answer 8

Sodium benzoate or sodium phenylacetate or dialysis

Low protein diet

Question 9

How do hyperammonaemia and urea cycle disorders present

Answer 9

Respiratory alkalosis 
Vomiting without diarrhoea
Cerebral oedema 
Seizures 
Comatose

Question 10

What are associated with urea cycle disorders

Answer 10

ADHD/ Long standing mental illness
Methandrostenolone use
Creatinine supplement

Question 11

What happens in organic acidurias

Answer 11

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

Question 12

How does isovaleric acid smell

Answer 12

Cheesy/ Sweaty smell

Question 13

How do organic acidurias present?

Answer 13

Hyperammonaemia with METABOLIC ACIDOSIS and high anion gap

In neonates:

Unusual odour
Lethargy, feeding problems
Truncal hypotonia and limb hypertonia
Myoclonic jerks

Question 14

How does the chronic intermittent form of organic acidurias present in kids

Answer 14

Recurrent ketoacidotic comas
Cerebral abnormalities
Reye syndrome

Question 15

What is Reye syndrome

Answer 15

Rapidly progressing encephalopathy

Question 16

How does Reye syndrome present

Answer 16

Vomiting
Lethargy 
Confusion
Seizures 
Decerebration 
Respiratory arrest

Question 17

What can Reye syndrome be triggered by

Answer 17

Salicylates (aspirin), anti emetics, valporate

Question 18

How will you screen for Reye syndrome / Organic acidurea

Answer 18

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

Question 19

What happens in mitochondrial fatty acid beta oxidation defect

Answer 19

You cannot break down fatty acids so there is no ketone production

Question 20

Hoe does mitochondrial fatty acid beta oxidation defect present

Answer 20

Hypoketotic hypoglycaemia
Hepatomegaly
Cardiomyopathy

Question 21

How do you test for mitochondrial fatty acid beta oxidation defect

Answer 21

Blood ketones
Urine organic acids
Blood spot acylcarnitine profile

Question 22

What are the 2 carbohydrate break down disorders

Answer 22

Galactosaemia

Glycogen storage disease type 1 (Von Gierke disease)

Question 23

What is the most common deficiency in galactosaemia

Answer 23

Gal-1-PUT deficiency

Question 24

How does Gal-1-PUT deficiency present in neonates

Answer 24

Hepatomegaly
Hypoglycaemia 
D&V
Conjugated hyperbilirubinaemia 
Sepsis

Question 25

Why cant here be sepsis in mitochondrial fatty acid beta oxidation defect

Answer 25

Gal-1-PUT inhibits immune responses so babies can develop E Coli sepsis

Question 26

If not picked up at infancy, what can mitochondrial fatty acid beta oxidation defect cause in children

Answer 26

Bilateral cataracts as Gal-1-PUT can become a subtrate for aldolase

Question 27

How to investigate for mitochondrial fatty acid beta oxidation defect

Answer 27

Urine reducing substances | RBC Gal-1-PUT

Question 28

How tot treat mitochondrial fatty acid beta oxidation defect

Answer 28

Avoid milk (galactose)

Question 29

What happens in von Gierke disease

Answer 29

Lack of phosphatase enzyme to break down G6p and G1P. Leads to a buildup of glycogen in muscles, leading to hypoglycaemia

Question 30

How does von Gierke disease present

Answer 30

``` Hepatomegaly Nephromegaly Hypoglycaemia Lactic acidosis Neutropaenia ```

Question 31

What happens in mitochondrial disorders

Answer 31

Heteroplasmy of mtDNA - Develop symptoms after reaching a certain load of mtDNA Can present at any time, any age Defective ATP production

Question 32

What are some examples of mitochondrial disorders in terms of age of presentation

Answer 32

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)

Question 33

How would you investigate for mitochondrial disorders

Answer 33

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