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Clinical Biochem > Metabolic Disease > Flashcards

Metabolic Disease Flashcards

1
Q

What are 3 key metabolic diseases ?

A
  1. Phenylketonuria
  2. Medium chain acly-CoA dehydrogenase deficiency
  3. mitochondrial respiratory chain disorders
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2
Q

Define Metabolism

A

the whole range of biochemical processes that occur within a living organism

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3
Q

Define Metabolic Disease

A

genetic conditions that results in a defect in metabolism

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4
Q

What are some causes for Metabolic Diseases ?

A

-defect;/mutation in single gene disrupting structure/function of an enzyme
- morbidity due to;
. toxic accumulation of substrates
. defects in energy production
.product deprivation

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5
Q

When do metabolic diseases most commonly present ?

A
  • usually neonatal/infant period but can occur at any time even into adulthood
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6
Q

What are some categories of metabolic disease ?

A
  • disordes that result in toxic accumulation of metabolites
  • disorders of energy productions/utilization
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7
Q

Describe Phenylketonuria

A
  • autosomal recessive
  • 1/10,000
  • results from deficiency in the liver enzyme phenylalanine hydroxylase
    -tyrosine deficiency
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8
Q

What occurs in 1/2% of phenylalanine patients ?

A
  • a defect in the synthetic pathway of BH4 or its regeneration
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9
Q

What is BH4 ?

A

An essential cofactor for phenylalanine hydroxylase

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10
Q

what is tyrosine a precursor to ?

A

dopamine

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11
Q

Describe the clinical presentation of Phenylketonuria

A
  • progressive developmental delay, intellectual impairment
  • seizures, severe behaviour disturbance
  • evidence of demyelination on MRI
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12
Q

What are 2 pathophysiological factors of phenylketonuria ?

A
  • low tyrosine levels
  • high Phe levels
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13
Q

Describe low tyrosine levels

A
  • impairs protein synthesis, especially in the brain
  • perturb dopamine synthesis - which is a neurotransmitter which regulates movement, attention, learning & emotional response
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14
Q

Describe the effects of high Phe levels

A
  • directly affects the transport of amino acids into the brain
  • Phe & its metabolites (phenlyketones) have a toxic effect
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15
Q

Describe the transport of amino acids into the brain

A
  • Phe is transported across the blood brain barrier & into the brain by the large neutral amino acid (LNAA) transporter
  • Phe competes with the 8 other LNAA’s
  • high plasma Phe concentrations increase Phe entry into the brain & restrict the entry of other LNAA’s
  • impairing cerebral protein synthesis
  • decreased entry of tyrosine & tryptophan into the brain –> impaired dopamine & serotonin synthesis
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16
Q

What are some examples of Large neutral amino acids?

A
  • tyrosine, tryptophan , valine, isoleucine, leucine, threonine, methionine, histidine
17
Q

Describe Phe Toxicity

A
  • Phe+ its metabolites act as neurotoxins in the brain
  • Phe- inhibits neurotransmitter synthesis
  • Phe+ its metabolites cause oxidative stress & impair cellular energy generation
18
Q

Describe Oxidative Stress

A

= imbalance between reactive oxygen species generation & antioxidant status
- PKU has been associated with evidence of oxidative stress

19
Q

How does it appear that Phe causes oxidative stress?

A
  • by decreasing the antioxidant status of patients
  • Phe+ and its metabolites decrease Coenzymes Q10 and GSH peroxidase activity
20
Q

How many disorders are screened for in newborn screening?

A

9

21
Q

What are the 9 conditions screened for in newborn screening?

A
  • phenylketonuria
  • Congenital hypothyroidism
  • sickle cell & Hb disorders
  • cystic fibrosis
  • MCADD
  • MSUD
  • IVA
    -homocystinuria
    -GA1
22
Q

What is needed for newborn screening to be diagnosed?

A
  • requirement for reliable diagnostic marker
  • this is typically provided by the accumulation of a particular metabolite/substrate in the blood that can be used as a diagnostic marker
  • must be stable & readily metabolised
23
Q

Describe the process of marking a blood spot card

A
  • clean the heel before taking a blood sample - contaminated sample = inaccurate result
  • fill the spots completely & allow to dry - incompletely filled spot = false negative
  • allow 1 drop of blood to fill each circle - layering of blood circles = false positives
24
Q

Describe the Treatment of Phenylketonuria

A
  • needs to be commenced in neonatal period to prevent irreversible brain damage
  • excellent prognosis if treated from birth
  • Phe treated diet
  • tyrosine supplementation
  • adjunct therapy of LNAAs
25
Q

What is Medium Chain acyl-CoA dehydrogenase deficiency ?

A

a condition were patients can’t metabolise medium chain fatty acids

26
Q

What happens when glucose reserves are depleted?

A
  • the body gets its energy from the break down of fatty acids by the process of acid beta-oxidation
27
Q

Describe Medium chain acyl-CoA dehydrogenase deficiency

A
  • MCADD is the most common disorder of fatty acid beta-oxidation
  • incidence of 1/10,000
  • treatable disorder if diagnosed early enough
  • responsible for sudden infant death syndrome
  • indicated by elevated C8 + C10 fatty acids
28
Q

Define Hypoketotic Hypoglycaemia

A

low levels of circulatory ketones together with a low level of blood glucose
- results in impaired ketogenesis

29
Q

How does MCADD present?

A
  • children can present with hypoketotic hypoglycaemia
  • vomiting, lethargy, siezures & liver dysfunction –> can progress to coma & death
    -sudden infant death syndrome
30
Q

Describe the treatment for MCADD

A
  • treatment if unwell = simple carbohydrates by mouth (glucose drinks)
  • important to avoid long periods without feeding for infants
31
Q

What are safe fasting times for infants ?

A

0-4 months = 6 hours
4-8 months = 8 hours
over a year = 12 hours

32
Q

Describe Mitochondrial respiratory chain disorders

A
  • most common group of metabolic disease
  • incidence = 1/5000
  • generally progressive & multi-systemic
  • typically affected organs are those with high energy demands –> neuromuscular & neurological presentations most common
  • complexity of genetics can lead to diverse symptoms
33
Q

Describe some symptoms you might find with mitochondrial respiratory chain disorders

A
  • respiratory failure
  • liver failure
  • diabetes
  • thyroid disease
  • deafness
  • optic atrophy
  • seizures/developmental delay
34
Q

How are mitochondrial respiratory chain disorders diagnosed?

A
  • no real biomarkers so it can’t be diagnosed with newborn screening
  • main biochemical test that can be undertaken is a blood sample
35
Q

How can defects in the mitochondrial oxidative metabolism be diagnosed?

A
  • elevated plasma lactate levels
  • glycolysis –> pyruvate –> lactate
  • ref range for plasma lactate = 0.5-1.65 mmol/L
36
Q

How is MRC disorder patients with ‘normal’ lactate levels?

A
  • highest ‘diagnostic yield’ from enzymatic assessment of tissue
  • skeletal muscle biopsy - 50-100mg
  • MRC enzymes assayed by spectrophotometric assay using patient muscle homogenates
37
Q

Describe the treatment of MRC disorders

A
  • no cure as of yet
  • treatments are aimed at improving MCR function or increasing mitochondrial biogenesis
  • supplementation of Coenzyme Q10
38
Q

Describe the Antioxidant function of CoQ10

A
  • neutralises ROS
    -CoQ10 inhibits the peroxidation of cell membrane lips & also lipoproteins in the circulation
  • improves the efficiency of electron transfer through the MRC - improve ATP synthesis
  • decreases oxidative stress by neutralising ROS

Clinical Biochem (14 decks)

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