Inborn Errors of Metabolism Flashcards
Why are inborn metabolic diseases so clinically relevant?
Whilst they are individually rare, collectively they are a significant health problem
Approximately how many live births are affected by a rare metabolic disorder?
1 in 1,000-2,000 live births
Why are inborn metabolic disorders often missed?
They are often the last thing that doctors consider during diagnosis as they are so rare Often the symptoms will overlap with more common disorders
When do inborn metabolic disorders typically present?
Most (but not all of them) present during childhood
What are the most common type of metabolic disorders?
enzyme defects this affects biochemical reactions occurring within cells
What happens if a mutation occurs in the structural genes?
this affects how the protein is made the protein may fall apart and not be functional or it may only be affected slightly meaning enzyme reactions still occur, but more slowly
What happens if a mutation occurs in the regulatory regions of a gene?
This affects the amount of protein that is being produced There is either an overproduction or underproduction of protein
What is the main aim of the urea cycle?
ammonia is converted to non-toxic urea which can be excreted
there are many steps involved, which require many different enzymes
How can the urea cycle be affected by mutations?
a mutation could affect any stage in the process
Why do not all mutations produce a disorder in the urea cycle?
some genes are essential and a mutation within that gene is not compatible with life
What would happen if there was a genetic defect in enzyme c?
there would be a deficiency in the end product D
everything prior to the site of the block starts to accumulate
there is a larger accumulation of the intermediates that are close to the site of the block
If there is a mutation in enzyme c, how may clinical disease arise?
it may be due to not enough product being produced at the end
it could be due to accumulation of an intermediate going above a threshold value and becoming toxic
What may happen if molecules begin to accumulate prior to the block?
They may start forming new compounds (E&F)
These new products may be toxic, but act at useful biomarkers to identify a disease/condition
What is a cofactor?
How does it affect enzyme function?
Enzymes need cofactors to work properly
This is a vitamin or micronutrient that needs to be bound to the enzyme in order for it to function properly
What treatment may sometimes be given when an enzyme is not working properly, but this can be reversed?
a vitamin deficiency can often affect enzyme function, as vitamins act as cofactors
the cofactors can be given in high concentrations as a treatment to stimulate enzyme activity
What are the 3 mechanisms of disease resulting from an inborn error of metabolism?
- accumulation of a toxin
- energy deficiency
- deficient production of an essential metabolite/structural component
What is an ammonia accumulation?
What patients does it occur in and how urgent is it?
hyperammonaemia
it occurs in patients with urea cycle defects
it is a medical emergency and must be treated immediately
If a newborn child has a defect in the urea cycle, when will this present?
a few days after birth
it takes time for the metabolic pathways to kick in and accumulate enough metabolites to cause a clinical effect
If a patient has had hyperammonaemia, what major lifestyle factor is changed after treatment?
Diet - they need to have restricted amounts of protein in the diet to reduce the level of ammonia in the blood
What are the clinical effects of acute hyperammonaemia toxicity?
- lethargy
- poor feeding
- vomiting
- tachypnoea
- convulsions
- coma
- death
What are the key components in the urea cycle?
What condition does a reduction in the synthesis of haem l
Porphyrias
This is due to an accumulation of porphyrins
What compounds are involved in the pathway that leads to the synthesis of haem?
Why could there not be a complete block in the haem synthesis pathway?
This would lead to death as oxygen could not be carried in the blood
There are only partial defects in the enzymes, meaning that some haem is produced
In someone who has a partial defect in an enzyme involved in haem synthesis, when do they tend to present with symptoms?
When the pathway is put under stress, there is accumulation of porphyrins
There is usually a trigger - e.g. hormonal changes
What are the 2 different presentations of porphyrin accumulation?
What is the difference between the causes?
acute porphyria:
due to accumulation of ALA and PBG
photosensitive porphyria:
this is due to a block further down in the pathway
What are the possible signs of acute porphyria?
- severe abdominal pain
- palpitations
- pain in the chest, back or legs
- constipation or diarrhoea
- vomiting
- insomnia
- high blood pressure
- anxiety or restlessness
- seizures
- mental changes]
- breathing problems
- muscle pain/tingling/weakness/paralysis
- red or brown urine
Why is there excessive hair growth in photosensitive porphria?
the porphyrins generate heat when exposed to light
this leads to painful damaging skin lesions
excessive hair growth is a response to try and protect the skin from light damage
What are the possible signs of photosensitive porphyria?
- sensitivity to the sun/artificial light
- sudden painful erythema and oedema
- blisters that take weeks to heal
- itching
- fragile skin
- increased hair growth
- red or brown urine3
What are the 3 main sugars that are used for energy production and their component parts?
glucose - directly enters the glycolysis pathway (monosaccharide)
sucrose - made up from glucose and fructose
lactose - made up from galactose and glucose
How is energy stored in the body?
When is this required?
Energy is stored in the form of lipids (triglycerides)
When there is no glucose available, the triglycerides are broken down and used for energy generation
What is involved in fatty acid oxidation?
Fatty acids must be removed from glycerol and then transported into the mitochondria
the fatty acids are broken down to release ketons and acetyl CoA
ketones are used for energy in the brain and acetyl CoA enters the TCA cycle to produce energy
When will a defect of fatty acid oxidation become apparent?
during times of energy deficiency when there is insufficient glucose available
e.g. during fasting or infection
What happens if fatty acid oxidation is compromised?
the patient becomes hypoketotic and may enter a hypoglycaemic coma
this can lead to hepatic failure
What would a person with androgen insensitivity syndrome look like?
They would have a healthy female phenotype with normal breast development but absent pubic hair
They are genetically male
What is the background behind androgen insensitivity syndrome?
there is a mutation affecting a gene which codes for an androgen receptor
the patient produces testosterone, but it is unable to bind to the receptor and elicit an action in the cell
How do patients often initally present with androgen insensitivity syndrome?
- primary amenorrhoea
- infertility
What is meant by clinical heterogeneity?
there is often a poor genotype-phenotype correlation
many patients with the same condition present differently due to most disorders being multi-allelic
there may also be environmental involvement
By which 2 methods are inborn errors of metabolism diagnosed?
- pre-symptomatic screening
- investigation of symptomatic individuals
What is involved in pre-symptomatic screening?
You either look at whole populations or selected groups where a certain disorder is likely to be more common
A test is needed to determine whether a patient is healthy or has a disorder
In pre-symptomatic screening, why are there often false positives or negatives?
there is usually an overlap between affected and unaffected individuals and the symptoms that they present with
What are the 4 methods involved in investigation of symptomatic individuals?
- test body fluids for abnormal metabolites
- measure enzyme activities
- histochemical/immunochemical staining
- DNA analysis
What is the route that tends to be followed when investigating symptomatic patients?
- metabolite testing
- more complicated metabolite testing
- enzyme analysis/functional studies
- mutation/gene analysis
When investigating symptomatic patients, why are genes not analysed first even though the disorders are genetic?
- the significance of the mutation is not always known as there is often a poor genotype/phenotype relationship
- it is difficult to exclude disorders as not all mutations may be covered
What are the 6 things that are tested for in the basic urine metabolic screen?
- spot tests
- organic acids
- amino acids
- sugar chromatography
- oligosaccharides/sialic acids
- mucopolysaccharides
Why is an organic acid test usually performed?
small molecular weight organic acids are intermediates in most metabolic pathways
this allows many different disorders to be detected with just one test
What are the 3 classic organic acidaemias?
What causes them?
- propionic
- isovaleric
- methyl malonic
They are defects in branched chain amino acid catabolism
Why are organic acidaemias not detected by measuring amino acid levels?
the amino acids themselves are not always increased when there is a deficient catabolic enzyme
the further away the block is from the parent amino acid, the less likely it will be to accumulate
What are the 3 benefits to diagnosis of a inborn error of metabolism?
- treatment improves prognosis
- identify cause of clinical problem
- genetic counselling
