ChemPath: Metabolic Disorders and Screening 2

Question 1

What is the main role of the urea cycle?

Answer 1

Taking ammonia and producing urea

Question 2

What is the common underlying pathophysiology behind urea cycle disorders?

Answer 2

Enzyme deficiency resulting ammonia accumulation

Question 3

How many enzymes in the urea cycle?

Answer 3

5

Question 4

What is the most common urea cycle disorder? What is its inheritance pattern

Answer 4

Orthinine transcarbamylase (OTC) deficiency

X-linked recessive

Question 5

Name three other diseases that count as urea cycle defects.

Answer 5

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

Question 6

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

Answer 6

Autosomal recessive

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

• Reduce serum ammonia - sodium benzoate, sodium phenylacetate or dialysis
• Reduce ammonia production - strict low protein diet

Question 9

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

Answer 9

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

Question 10

List the key clinical features of urea cycle disorders.

Answer 10

• Vomiting without diarrhoea
• Respiratory alkalosis
• Hyperammonaemia
• Encephalopathy (without encephalitis)
• Avoidance or change in diet (patient will naturally reduce protein intake because will make them feel ill)

Question 11

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

Answer 11

Organic acidurias - abnormal amino acid metabolism (especially branched chain amino acids) which causes a build up of 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 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 (urine)
• 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

Encephalopathic symptoms

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

Hepatic symptoms

• Hepatomegaly

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
(following fasting)

Question 20

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

Answer 20

• Blood ketones (low)
• 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? Why is this?

Answer 22

• Classic galactosaemia - galactose-1-phosphate uridyltransferase (G1PUT) deficiency
• Results in accumulation of galactose-1-phosphate which is more toxic leading to liver and kidney disease

Question 23

What is the function of G1PUT?

Answer 23

Converts galactose-1-phosphate to UDP-galactose

Question 24

Describe the presentation of galactosaemia.

Answer 24

• Poor feeding and failure to thrive
• Vomiting, diarrhoea
• Conjugated hyperbilirubinaemia (jaundice)
• 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

* Cirrhosis and liver failure within weeks * Bilateral cataracts

Question 26

List some investigations for galactosaemia.

Answer 26

* Urine galactose (urine reducing substances) * Red cell GALT (measures activity of galactose-1-phosphate uridyltransferase in RBCs)

Question 27

What is the treatment for galactosaemia?

Answer 27

Complete avoidance of galactose and lactose-containing foods

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 * The phosphate groups must be removed because it cannot cross the cell membrane with those phosphate groups * **GSD1 is caused by glucose-6-phosphatase deficiency leading to defective glycogenolysis and gluconeogenesis** * 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 ## Footnote 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

How are mitochondrial diseases inherited?

Answer 30

Maternally

Question 31

What is the signifcance of heteroplasmy in mitochondria diorders?

Answer 31

Clinical manifestations only become evident above a certain threshold of abnormal mitochondrial DNA

Question 32

Which organs tend to be affected by mitochondrial disorders and why?

Answer 32

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

Question 33

List three examples of mitochondrial diseases and outline their manifestations.

Answer 33

* Barth syndrome - cardiomyopathy, neutropaenia and myopathy starting at **birth** * MELAS - mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (affects **5-15 year olds**) * Kearns-Sayre syndrome - ophthalmoplegia, retinitis pigmentosa, deafness and ataxia (affects **12-30 year olds**)

Question 34

List some investigations for mitochondrial diseases.

Answer 34

* **High lactate** - especially after periods of fasting *(normally should go down when fasting)* * **High CK** * **Muscle biopsy** - diagnostic * CSF lactate/pyruvate * CSF protein (elevated in Kearns-Sayre) * Mitochondrial DNA analysis

Question 35

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

Answer 35

Ragged red fibres

Question 36

What are congenital disorders of glycosylation? Give an example.

Answer 36

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 * Diagnosed with serum transferrin and glycoforms

Question 37

What are peroxisomal disorders? What are their symptoms? How do you investigate?

Answer 37

- They affect metabolism of very long chain fatty acids and biosynthesis of complex phospholipids (e.g. cant make bile acids) - Present in neonates with severe muscle hypotonia, seizures, hepatomegaly and mixed hyperbiliribinaemia, abnormal bone changes - Investigated with serum very long chain fatty acid profile

Question 38

What are lysosomal storage diseases? How do they present? How do you investigate them?

Answer 38

- These diseases result in intraorganelle accumulation of substrates - Very heterogenous presentation but generally results in dysmorphia - Very slow progressing - Neuroregression, hepatosplenomegaly, Cardiomyopathy - Investigate with urine mucopolysaccharides and oligosaccharides; leukocyte enzyme activity - Treatment involves BM transplant or exogenous enzyme replacement