ChemPath: Metabolic Disorders and Screening 2 ✔️ Flashcards

1
Q

Why is it difficult to get an ammonia sample?

A

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

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2
Q

What is the main role of the urea cycle?

A

Taking ammonia and producing urea

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3
Q

How many enzymes are there in the urea cycle?

A

7

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4
Q

Name three other diseases that count as urea cycle defects.

A
  • Lysinuric protein intolerance
  • Hyperornithaemia-hyperammonaemia-homocitrullinuria
  • Citrullinaemia type II
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5
Q

What do all urea cycle disorders result in?

A

High ammonia

NOTE: this is TOXIC

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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

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

A

Ornithine transcarbamylase deficiency (X-linked)

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8
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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9
Q

What is the treatment of urea cycle disorders?

A
  • Remove ammonia (using sodium benzoate, sodium phenylacetate or dialysis)
  • Reduce ammonia production (low protein diet)
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10
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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11
Q

List the key features of urea cycle disorders.

A
  • Vomiting without diarrhoea
  • Respiratory alkalosis
  • Hyperammonaemia
  • Encephalopathy
  • Avoidance or change in diet
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12
Q

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

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

NOTE: cheesy or sweaty smell

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13
Q

List three branched chain amino acids.

A
  • Leucine
  • Isoleucine
  • Valine
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14
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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15
Q

Describe the presenting features of organic acidurias in neonates.

A
  • Unusual odour
  • Lethargy
  • Feeding problems
  • Truncal hypotonia/limb hypertonia
  • Myoclonic jerks
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16
Q

Describe the chronic intermittent form of organic acidurias.

A
  • Recurrent episodes of ketoacidotic coma
  • Cerebral abnormalities
17
Q

What is Reye syndrome?

A

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

18
Q

Describe the features of Reye syndrome.

A
  • Vomiting
  • Lethargy
  • Increased confusion
  • Seizures
  • Decerebration
  • Respiratory arrest
19
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

20
Q

What do defects in mitochondrial fatty acid beta-oxidation cause (MCAD deficiency)?

A
  • Hypoketotic hypoglycaemia

NOTE: this means that you are unable to make ketones in between meals as an alternative energy source as unable to break down fat –> may result in hypoglycaemic episodes between meals and required a high carb diet

21
Q

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

A
  • Blood ketones
  • Urine organic acids
  • Blood spot acylcarnitine profile
22
Q

What is galactosaemia?

A

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

23
Q

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

A

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

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

24
Q

Describe the presentation of galactosaemia.

A
  • Vomiting
  • Diarrhoea
  • Conjugated hyperbilirubinaemia
  • Hepatomegaly
  • Hypoglycaemia
  • Sepsis (galactose-1-phosphate inhibits the immune response)
25
Q

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

A
  • Bilateral cataracts
  • High concentration of galactose-1-phosphate end up being a substrate for aldolase which is found in the lens of the eye
26
Q

List some investigations for galactosaemia.

A
  • Urine reducing substances (picks up high levels of galactose)
  • Red blood cell Galactose-1-phosphate uridyl transferase (Gal-1-PUT)
27
Q

What is the treatment for galactosaemia?

A

Avoid galactose (e.g. milk)

NOTE: galactose isn’t an essential nutrient

28
Q

Describe the pathophysiology of Glycogen storage disease type I (AKA Von Gierke’s).

A
  • Whenever glycogen is broken down, it produces glucose-1-phosphate and glucose-6-phosphate
  • Afterwards, the phosphate groups must then 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 as the phosphate is not removed
  • Thus the muscles and liver build up a lot of glycogen that cannot be liberated leading to hypoglycaemia
29
Q

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

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

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

A

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

31
Q

Which organs tend to be affected by mitochondrial disorders?

A

Defective ATP production leads to issue in organs with a high energy demand (e.g. brain, muscle, kidney, retina, endocrine organs)
NOTE: often patients have multi-system diseases

32
Q

List three examples of mitochondrial diseases and outline their manifestations.

A
  1. Barth syndrome - cardiomyopathy, neutropaenia and myopathy starting at birth
  2. MELAS - mitochondrial encephalopathy, lactic acidosis and stroke-like episodes presenting between 5-15 y/o
  3. Kearns-Sayre syndrome - chronic progressive external ophthalmoplegia, retinopathy, deafness and ataxia presenting between 12-30 y/o
33
Q

List some investigations for mitochondrial diseases.

A
  • 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 (NOTE: unexplained elevations of CK + lactate = think mitochondrial disorder)
  • Muscle biopsy
  • Mitochondrial DNA analysis (not so useful in children as mitochondrial disorders presenting in childhood are usually due to nuclear defects)
34
Q

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

A

Ragged red fibres

35
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, osteopenia and hepatomegaly

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