ChemPath: Metabolic Disorders and Screening 2

Question 1

Why is it difficult to get an ammonia sample?

Answer 1

You need a free flowing sample, which needs to be put in ice and rushed to the laboratory

Question 2

What is the main role of the urea cycle?

Answer 2

Taking ammonia and producing urea

Question 3

How many enzymes are there in the urea cycle?

Answer 3

7

Question 4

Name three other diseases that count as urea cycle defects.

Answer 4

• Lysinuric protein intolerance
• Hyperornithaemia-hyperammonaemia-homocitrullinuria (HHH)
• Citrullinaemia type II

Question 5

What do all urea cycle disorders result in?

Answer 5

High ammonia (respiratory alkalosis)

NOTE: this is toxic

Question 6

What is the mode of inheritance of all of these urea cycle defects?

Answer 6

Autosomal recessive

Question 7

What is an exception to the recessive mode of inheritance of Urea Cycle Disorders?

Answer 7

Ornithine transcarbamylase deficiency (X-linked)

Question 8

How does the body get rid of excess ammonia?

Answer 8

• An ammonium group is attached to glutamate to make glutamine
• So, plasma glutamine in hyperammonaemic conditions will be high

NOTE: the amino acids within the urea cycle will be high or absent. You can also measure urine orotic acid.

Question 9

What is the treatment of urea cycle disorders?

Answer 9

• Remove ammonia (using sodium benzoate, sodium phenylacetate or dialysis)
• Reduce ammonia production (low protein diet)

Question 10

Why might patients with urea cycle disorders have a slight build?

Answer 10

Patients may subconsciously avoid protein becuase they know it makes them feel ill

Question 11

List the key features of urea cycle disorders.

Answer 11

• Vomiting without diarrhoea
• Respiratory alkalosis
• Hyperammonaemia
• Encephalopathy
• Avoidance or change in diet

Question 12

What tends to cause hyperammonaemia with metabolic acidosis and a high anion gap?

Answer 12

• Organic acidurias
• Also caused by defects in the complex metabolism of branched chain amino acids

Question 13

List three branched chain amino acids.

Answer 13

• Leucine
• Isoleucine
• Valine

Question 14

Describe the breakdown of leucine.

Answer 14

• An ammonia group will be broken off by a transaminase and a high energy protein group will be added
• This produces a breakdown product called isovaleryl CoA
• This is then converted by isovaleryl CoA dehydrogenase
• Molecules with high energy groups cannot traverse the cell membrane, so they need to be converted to other molecules:
  
  • Export from cell as: isovaleryl carnitine
  • Excrete as: 3OH-isovaleric acid (cheesy smell) and isovaleryl glycine

Question 15

Describe the presenting features of organic acidurias in neonates.

Answer 15

• Unusual odour (esp in urine)
• Lethargy
• Feeding problems
• Truncal hypotonia/limb hypertonia
• Myoclonic jerks

Question 16

Describe the chronic intermittent form of organic acidurias.

Answer 16

• Recurrent episodes of ketoacidotic coma
• Cerebral abnormalities

Question 17

What is Reye syndrome?

Answer 17

Rapidly progressive encephalopathy that can be triggered by aspirin use in children (also triggered by antiemetics and valproate)

Question 18

Describe the features of Reye syndrome.

Answer 18

• Vomiting
• Lethargy
• Increased confusino
• Seizures
• Decerebration
• Respiratory arrest

Swelling of liver and brain

Question 19

What would constitute the metabolic screen for Reye syndrome?

Answer 19

• Plasma ammonia
• Plasma/urine amino acid
• Urine organic acids
• Plasma glucose and lactate
• Blood spot carnitine profile (stays abnormal in remission)

NOTE: the top 4 need to be measured during an acute episode because the abnormal metabolites will disappear after a few days

Question 20

What do defects in mitochondrial fatty acid beta-oxidation cause?

Answer 20

• Hypoketotic hypoglycaemia
  = hepato and cardiomegaly
  NOTE: this means that you are unable to make ketones in between meals as an alternative energy source

Question 21

Which investigations are useful for defects in mitochondrial fatty acid beta oxidation?

Answer 21

• Blood ketones
• Urine organic acids
• Blood spot acylcarnitine profile

Question 22

What is galactosaemia?

Answer 22

A disorder of galactose metabolism resulting in high levels of galactose in the blood (3 disorders in total)

Question 23

What is the most severe and most common form of galactosaemia?

Answer 23

Galactose-1-phosphate uridyl transferase (Gal-1-PUT) deficiency

NOTE: high galactose-1-phosphate results in liver and kidney disease

Question 24

Describe the presentation of galactosaemia.

Answer 24

• Vomiting
• Diarrhoea
• Conjugated hyperbilirubinaemia
• Hepatomegaly
• Hypoglycaemia
• Sepsis (galactose-1-phosphate inhibits the immune respose)

Question 25

What is a long-term complication of galactosaemia if it is not detected in the neonatal period?

Answer 25

• Bilateral cataracts
• High concentration of galactose-1-phosphate end up being a substrate for aldolase which is found in the lens of the eye

Question 26

List some investigations for galactosaemia.

Answer 26

• Urine reducing substances (high levels of galactose)
• Red cell Gal-1-PUT

Question 27

What is the treatment for galactosaemia?

Answer 27

Avoid galactose (e.g. milk)

Question 28

Describe the pathophysiology of Glycogen storage disease type I.

Answer 28

• Whenever glycogen is broken down, it produces glucose-1-phosphate and glucose-6-phosphate and then the phosphate groups must be removed because it cannot cross the cell membrane with those phosphate groups
• A lack of phosphatase means that G1P and G6P cannot be exported
• This means that your muscles and liver build up a lot of glycogen that cannot be liberated leading to hypoglycaemia

NOTE: also known as von Gierke disease

Question 29

What are the clinical features of Glycogen storage disease type I?

Answer 29

• Hepatomegaly
• Nephromegaly
• Hypoglycaemia
• Lactic acidosis
• Neutropaenia

Question 30

What does ‘heteroplasmy’ mean, with regards to mitochondrial DNA?

Answer 30

Once you reach a certain load of abnormal mitochondrial DNA you will start to develop symptoms

Question 31

Which organs tend to be affected by mitochondrial disorders?

Answer 31

Defective ATP production leads to issue in organs with a high energy demand (e.g. brain, muscle, kidney, retina, endocrine organs)

Question 32

List three examples of mitochondrial diseases and outline their manifestations.

Answer 32

• Barth syndrome - cardiomyopathy, neutropaenia and myopathy starting at birth
• MELAS - mitochondrial encephalopathy, lactic acidosis and stroke-like episodes
• Kearns-Sayre syndrome - chronic progressive external ophthalmoplegia, retinopathy, deafness and ataxia

Question 33

List some investigations for mitochondrial diseases.

Answer 33

• High lactate (alanine) - especially after periods of fasting (NOTE: in normal people, lactate should go down when fasting)
• CSF lactate/pyruvate
• CSF protein (elevated in Kearns-Sayre)
• CK
• Muscle biopsy
• Mitochondrial DNA analysis

Question 34

What is the characteristic appearance of mitochondrial myopathy on a muscle biopsy?

Answer 34

Ragged red fibres

Question 35

What are congenital disorders of glycosylation? Give an example.

Answer 35

• A defect of post-translational protein glycosylation
• It is a multisystem disorder associated with cardiomyopathy, osteopaenia and hepatomegaly

Example: CDG type 1a - abnormal subcutaneous adipose tissue distribution with fat pads and nipple retraction