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review CP > ChemPath: Metabolic Disorders and Screening 2 > Flashcards

ChemPath: Metabolic Disorders and Screening 2 Flashcards

1
Q

What is the main role of the urea cycle?

A

Taking ammonia and producing urea

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2
Q

What is the common underlying pathophysiology behind urea cycle disorders?

A

Enzyme deficiency resulting ammonia accumulation

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3
Q

How many enzymes in the urea cycle?

A

5

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4
Q

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

A

Orthinine transcarbamylase (OTC) deficiency

X-linked recessive

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5
Q

Name three other diseases that count as urea cycle defects.

A
  • Lysinuric protein intolerance
  • Hyperornithaemia-hyperammonaemia-homocitrullinuria (HHH)
  • Citrullinaemia type II
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6
Q

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

A

Autosomal recessive

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7
Q

How does the body get rid of excess ammonia?

A
  • 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.

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8
Q

What is the treatment of urea cycle disorders?

A
  • Reduce serum ammonia - sodium benzoate, sodium phenylacetate or dialysis
  • Reduce ammonia production - strict low protein diet
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9
Q

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

A

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

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10
Q

List the key clinical features of urea cycle disorders.

A
  • 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)
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11
Q

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

A

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

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12
Q

List three branched chain amino acids.

A
  • Leucine
  • Isoleucine
  • Valine
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13
Q

Describe the breakdown of leucine.

A
  • 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
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14
Q

Describe the presenting features of organic acidurias in neonates.

A
  • Unusual odour (urine)
  • Lethargy
  • Feeding problems
  • Truncal hypotonia/limb hypertonia
  • Myoclonic jerks
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15
Q

Describe the chronic intermittent form of organic acidurias.

A
  • Recurrent episodes of ketoacidotic coma
  • Cerebral abnormalities
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16
Q

What is Reye syndrome?

A

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

17
Q

Describe the features of Reye syndrome.

A

Encephalopathic symptoms

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

Hepatic symptoms

  • Hepatomegaly
18
Q

What would constitute the metabolic screen for Reye syndrome?

A
  • 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

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

19
Q

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

A

Hypoketotic hypoglycaemia
(following fasting)

20
Q

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

A
  • Blood ketones
  • Urine organic acids
  • Blood spot acylcarnitine profile
21
Q

What is galactosaemia?

A

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

22
Q

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

A
  • 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
23
Q

What is the function of G1PUT?

A

Converts galactose-1-phosphate to UDP-galactose

24
Q

Describe the presentation of galactosaemia.

A
  • Poor feeding and failure to thrive
  • Vomiting, diarrhoea
  • Conjugated hyperbilirubinaemia (jaundice)
  • Hepatomegaly
  • Hypoglycaemia
  • Sepsis (galactose-1-phosphate inhibits the immune respose)
25
Q

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

A
  • Cirrhosis and liver failure within weeks
  • Bilateral cataracts
26
Q

List some investigations for galactosaemia.

A
  • Urine galactose (urine reducing substances)
  • Red cell GALT
27
Q

What is the treatment for galactosaemia?

A

Complete avoidance of galactose and lactose-containing foods

28
Q

Describe the pathophysiology of glycogen storage disease type I.

A
  • 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

NOTE: also known as von Gierke disease

29
Q

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

A
  • Hepatomegaly
  • Nephromegaly
  • Hypoglycaemia
  • Lactic acidosis
  • Neutropaenia
30
Q

How are mitochondrial diseases inherited?

A

Maternally

31
Q

What is the signifcance of heteroplasmy in mitochondria diorders?

A

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

32
Q

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

A

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

33
Q

List three examples of mitochondrial diseases and outline their manifestations.

A
  • 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)
34
Q

List some investigations for mitochondrial diseases.

A
  • High lactate - 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
35
Q

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

A

Ragged red fibres

36
Q

What are congenital disorders of glycosylation? Give an example.

A

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
37
Q

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

A
  • They affect metabolism of very long chain fatty acids and biosynthesis of complex phospholipids
  • Present in neonates with severe muscle hypotonia, seizures, hepatic dysfunction, abnormal bone changes
  • Investigated with serum very long chain fatty acid profile
38
Q

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

A
  • These diseases result in intraorganelle accumulation of substrates
  • Very heterogenous presentation but generally results in dysmorphia
  • Investigate with urine mucopolysaccharides and oligosaccharides; leukocyte enzyme activity

Treatment involves BM transplant or exogenous enzyme replacement

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