Metabolic Disease

Question 1

What are 3 key metabolic diseases ?

Answer 1

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

Question 2

Define Metabolism

Answer 2

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

Question 3

Define Metabolic Disease

Answer 3

genetic conditions that results in a defect in metabolism

Question 4

What are some causes for Metabolic Diseases ?

Answer 4

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

Question 5

When do metabolic diseases most commonly present ?

Answer 5

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

Question 6

What are some categories of metabolic disease ?

Answer 6

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

Question 7

Describe Phenylketonuria

Answer 7

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

Question 8

What occurs in 1/2% of phenylalanine patients ?

Answer 8

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

Question 9

What is BH4 ?

Answer 9

An essential cofactor for phenylalanine hydroxylase

Question 10

what is tyrosine a precursor to ?

Answer 10

dopamine

Question 11

Describe the clinical presentation of Phenylketonuria

Answer 11

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

Question 12

What are 2 pathophysiological factors of phenylketonuria ?

Answer 12

• low tyrosine levels
• high Phe levels

Question 13

Describe low tyrosine levels

Answer 13

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

Question 14

Describe the effects of high Phe levels

Answer 14

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

Question 15

Describe the transport of amino acids into the brain

Answer 15

• 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

Question 16

What are some examples of Large neutral amino acids?

Answer 16

• tyrosine, tryptophan , valine, isoleucine, leucine, threonine, methionine, histidine

Question 17

Describe Phe Toxicity

Answer 17

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

Question 18

Describe Oxidative Stress

Answer 18

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

Question 19

How does it appear that Phe causes oxidative stress?

Answer 19

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

Question 20

How many disorders are screened for in newborn screening?

Answer 20

9

Question 21

What are the 9 conditions screened for in newborn screening?

Answer 21

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

Question 22

What is needed for newborn screening to be diagnosed?

Answer 22

• 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

Question 23

Describe the process of marking a blood spot card

Answer 23

• 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

Question 24

Describe the Treatment of Phenylketonuria

Answer 24

• 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

Question 25

What is Medium Chain acyl-CoA dehydrogenase deficiency ?

Answer 25

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

Question 26

What happens when glucose reserves are depleted?

Answer 26

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

Question 27

Describe Medium chain acyl-CoA dehydrogenase deficiency

Answer 27

- 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

Question 28

Define Hypoketotic Hypoglycaemia

Answer 28

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

Question 29

How does MCADD present?

Answer 29

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

Question 30

Describe the treatment for MCADD

Answer 30

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

Question 31

What are safe fasting times for infants ?

Answer 31

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

Question 32

Describe Mitochondrial respiratory chain disorders

Answer 32

- 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

Question 33

Describe some symptoms you might find with mitochondrial respiratory chain disorders

Answer 33

- respiratory failure - liver failure - diabetes - thyroid disease - deafness - optic atrophy - seizures/developmental delay

Question 34

How are mitochondrial respiratory chain disorders diagnosed?

Answer 34

- no real biomarkers so it can't be diagnosed with newborn screening - main biochemical test that can be undertaken is a blood sample

Question 35

How can defects in the mitochondrial oxidative metabolism be diagnosed?

Answer 35

- elevated plasma lactate levels - glycolysis --> pyruvate --> lactate - ref range for plasma lactate = 0.5-1.65 mmol/L

Question 36

How is MRC disorder patients with 'normal' lactate levels?

Answer 36

- highest 'diagnostic yield' from enzymatic assessment of tissue - skeletal muscle biopsy - 50-100mg - MRC enzymes assayed by spectrophotometric assay using patient muscle homogenates

Question 37

Describe the treatment of Mitochondiral Respiratory Chain disorders

Answer 37

- no cure as of yet - treatments are aimed at improving MCR function or increasing mitochondrial biogenesis - supplementation of Coenzyme Q10

Question 38

Describe the Antioxidant function of CoQ10

Answer 38

- 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