Metabolic Disease Flashcards
What are 3 key metabolic diseases ?
- Phenylketonuria
- Medium chain acly-CoA dehydrogenase deficiency
- mitochondrial respiratory chain disorders
Define Metabolism
the whole range of biochemical processes that occur within a living organism
Define Metabolic Disease
genetic conditions that results in a defect in metabolism
What are some causes for Metabolic Diseases ?
-defect;/mutation in single gene disrupting structure/function of an enzyme
- morbidity due to;
. toxic accumulation of substrates
. defects in energy production
.product deprivation
When do metabolic diseases most commonly present ?
- usually neonatal/infant period but can occur at any time even into adulthood
What are some categories of metabolic disease ?
- disordes that result in toxic accumulation of metabolites
- disorders of energy productions/utilization
Describe Phenylketonuria
- autosomal recessive
- 1/10,000
- results from deficiency in the liver enzyme phenylalanine hydroxylase
-tyrosine deficiency
What occurs in 1/2% of phenylalanine patients ?
- a defect in the synthetic pathway of BH4 or its regeneration
What is BH4 ?
An essential cofactor for phenylalanine hydroxylase
what is tyrosine a precursor to ?
dopamine
Describe the clinical presentation of Phenylketonuria
- progressive developmental delay, intellectual impairment
- seizures, severe behaviour disturbance
- evidence of demyelination on MRI
What are 2 pathophysiological factors of phenylketonuria ?
- low tyrosine levels
- high Phe levels
Describe low tyrosine levels
- impairs protein synthesis, especially in the brain
- perturb dopamine synthesis - which is a neurotransmitter which regulates movement, attention, learning & emotional response
Describe the effects of high Phe levels
- directly affects the transport of amino acids into the brain
- Phe & its metabolites (phenlyketones) have a toxic effect
Describe the transport of amino acids into the brain
- 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
What are some examples of Large neutral amino acids?
- tyrosine, tryptophan , valine, isoleucine, leucine, threonine, methionine, histidine
Describe Phe Toxicity
- Phe+ its metabolites act as neurotoxins in the brain
- Phe- inhibits neurotransmitter synthesis
- Phe+ its metabolites cause oxidative stress & impair cellular energy generation
Describe Oxidative Stress
= imbalance between reactive oxygen species generation & antioxidant status
- PKU has been associated with evidence of oxidative stress
How does it appear that Phe causes oxidative stress?
- by decreasing the antioxidant status of patients
- Phe+ and its metabolites decrease Coenzymes Q10 and GSH peroxidase activity
How many disorders are screened for in newborn screening?
9
What are the 9 conditions screened for in newborn screening?
- phenylketonuria
- Congenital hypothyroidism
- sickle cell & Hb disorders
- cystic fibrosis
- MCADD
- MSUD
- IVA
-homocystinuria
-GA1
What is needed for newborn screening to be diagnosed?
- 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
Describe the process of marking a blood spot card
- 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
Describe the Treatment of Phenylketonuria
- 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
What is Medium Chain acyl-CoA dehydrogenase deficiency ?
a condition were patients can’t metabolise medium chain fatty acids
What happens when glucose reserves are depleted?
- the body gets its energy from the break down of fatty acids by the process of acid beta-oxidation
Describe Medium chain acyl-CoA dehydrogenase deficiency
- 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
Define Hypoketotic Hypoglycaemia
low levels of circulatory ketones together with a low level of blood glucose
- results in impaired ketogenesis
How does MCADD present?
- children can present with hypoketotic hypoglycaemia
- vomiting, lethargy, siezures & liver dysfunction –> can progress to coma & death
-sudden infant death syndrome
Describe the treatment for MCADD
- treatment if unwell = simple carbohydrates by mouth (glucose drinks)
- important to avoid long periods without feeding for infants
What are safe fasting times for infants ?
0-4 months = 6 hours
4-8 months = 8 hours
over a year = 12 hours
Describe Mitochondrial respiratory chain disorders
- 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
Describe some symptoms you might find with mitochondrial respiratory chain disorders
- respiratory failure
- liver failure
- diabetes
- thyroid disease
- deafness
- optic atrophy
- seizures/developmental delay
How are mitochondrial respiratory chain disorders diagnosed?
- no real biomarkers so it can’t be diagnosed with newborn screening
- main biochemical test that can be undertaken is a blood sample
How can defects in the mitochondrial oxidative metabolism be diagnosed?
- elevated plasma lactate levels
- glycolysis –> pyruvate –> lactate
- ref range for plasma lactate = 0.5-1.65 mmol/L
How is MRC disorder patients with ‘normal’ lactate levels?
- highest ‘diagnostic yield’ from enzymatic assessment of tissue
- skeletal muscle biopsy - 50-100mg
- MRC enzymes assayed by spectrophotometric assay using patient muscle homogenates
Describe the treatment of Mitochondiral Respiratory Chain disorders
- no cure as of yet
- treatments are aimed at improving MCR function or increasing mitochondrial biogenesis
- supplementation of Coenzyme Q10
Describe the Antioxidant function of CoQ10
- 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
