Chem Path 6 - 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

Name three other diseases that count as urea cycle defects.

Answer 3

Lysinuric protein intolerance

Hyperornithaemia-hyperammonaemia-homocitrullinuria

Citrullinaemia type II

Question 4

What do all urea cycle disorders result in?

Answer 4

High ammonia

NOTE: this is toxic

Question 5

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

Answer 5

Autosomal recessive

Question 6

What is an exception to this?

Answer 6

Ornithine transcarbamylase deficiency (X-linked)

Question 7

How does the body get rid of excess ammonia?

Answer 7

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 8

What is the treatment of urea cycle disorders?

Answer 8

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

Question 9

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

Answer 9

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

Question 10

List the key features of urea cycle disorders.

Answer 10

Vomiting without diarrhoea

Respiratory alkalosis

Hyperammonaemia

Encephalopathy

Avoidance or change in diet

Question 11

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

Answer 11

Organic acidurias

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

Question 12

List three branched chain amino acids

Answer 12

Leucine

Isoleucine

Valine

Question 13

Describe the breakdown of leucine.

Answer 13

An ammonia group will be broken off using 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 14

Describe the presenting features of organic acidurias in neonates.

Answer 14

Unusual odour

Lethargy

Feeding problems

Truncal hypotonia/limb hypertonia

Myoclonic jerks

Question 15

Describe the chronic intermittent form of organic acidurias.

Answer 15

Recurrent episodes of ketoacidotic coma

Cerebral abnormalities

Question 16

What is Reye syndrome?

Answer 16

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

Question 17

Describe the features of Reye syndrome.

Answer 17

Vomiting

Lethargy

Increased confusion

Seizures

Decerebration

Respiratory arrest

Question 18

What would constitute the metabolic screen for Reye syndrome?

Answer 18

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 19

What do defects in mitochondrial fatty acid beta oxidation cause?

Answer 19

Hypoketotic hypoglycaemia

Question 20

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

Answer 20

Blood ketones

Urine organic acids

Blood spot acylcarnitine profile

Question 21

What is galactosaemia?

Answer 21

A disorder of galactose metabolism resulting in high levels of galactose in the blood

Question 22

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

Answer 22

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

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

Question 23

Describe the presentation of galactosaemia.

Answer 23

Vomiting

Diarrhoea

Conjugated hyperbilirubinaemia

Hepatomegaly

Hypoglycaemia

Sepsis (galactose-1-phosphate inhibits the immune response)

Question 24

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

Answer 24

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 25

List some investigations for galactosaemia.

Answer 25

Urine reducing substances (high levels of galactose)

Red cell Gal-1-PUT

Question 26

What is the treatment for galactosaemia?

Answer 26

Avoid galactose (e.g. milk)

Question 27

Describe the pathophysiology of Glycogen storage disease type I.

Answer 27

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 28

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

Answer 28

Hepatomegaly

Nephromegaly

Hypoglycaemia

Lactic acidosis

Neutropaenia

Question 29

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

Answer 29

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

Question 30

Which organs tend to be affected by mitochondrial disorders?

Answer 30

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

Question 31

List three examples of mitochondrial diseases and outline their manifestations.

Answer 31

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 32

List some investigations for mitochondrial diseases.

Answer 32

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 33

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

Answer 33

Ragged red fibres

Question 34

What are congenital disorders of glycosylation? Give an example.

Answer 34

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