inborn errors of metabolism Flashcards
what is the epidemiology of inborn errors of metabolism?
they are individually rare but collectively significant. They occur roughly 1 in 1-2000 live births and in Yorkshire alone there are around 25-50 cases p.a. Most will present in childhood but with advances in treatments and diagnostics and milder phenotypes there are some in adulthood.
why are they sometimes not diagnosed?
they are the last things that doctors think of as they are so rare and symptoms can overlap with common conditions
what are three products that glutamate can make?
glutamine, carbomyl P and glutamyl P
what is carbomyl P used for?
when with ornithine it can make citrulline which then makes arginino succinate, then arginine and then back to ornithine by giving off urea
other that citrulline, what else can ornithine make?
glutamine semialdehyde
what else can produce glutamine semialdehyde?
glutamyl P
on a gene, out of the operator repressor and structural regions, a mutation in which part will affect proteins?
in the structural part. The protein can then make enzymes, be used for structures or transport.
how is the urea cycle affected by mutation?
in the urea cycle ammonia is converted to non toxic urea. Mutations can affect any step of this cycle
what are disorders commonly a result of and how does this affect cells?
a lot are enzyme defects - affects the biochemical reactions occurring in cells
what can affect how transporters move substances across membranes?
a lysosomal storage disorder
what happens if a mutation in a protein coding gene is subtle?
will only slightly change the structure and therefore proteins are functional but a reaction may occur slowly
what affects how much of a protein is being produced?
where the mutation is located - if it is in the regulatory regions of the gene - this means that the protein can be under or overproduced
why may some mutations not be seen?
some mutations are in genes that are so essential that they are not compatible with life
how can accumulation lead to a disorder?
a substrate may be fine at low levels but become toxic once it has accumulated due to lack of enzyme converting it and therefore once it has crossed the threshold value is toxic
how can new toxic products be made from a deficiency in an enzyme further along a metabolic pathway?
there is accumulation of previous substrates which can then bind unspecifically and make new compounds which may be toxic
how can you identify the mutation or deficiency?
you can identify and measure the new compounds made to see what is accumulating
what is biochemical genetics?
it is the study or investigation of primarily genetic disorders that affects the metabolic pathways of cells
what is a cofactor?
it is a vitamin or micronutrient that is needed to be bound to an enzyme for it to work properly - enzymes need it to work properly
how can a vitamin deficiency result in pathway defects?
they can give a secondary defect
how can vitamins be used as treatments?
they will stimulate enzymatic activity
what are three mechanisms of disease?
accumulation of a toxin, energy deficiency or deficient production of essential metabolite/structural component
what results in urea cycle defects?
ammonia accumulation - hyperammonaemia toxicity
what are clinical features of hyperammonaemia?
lethargy, poor feeding, vomiting, tachypnoea, convulsions, coma, death
what is the main function of of the urea cycle?
to detoxify ammonia - too much is a medical emergency
why does it take a few days after birth for the hyperammonaemia to be recognised?
there is a latent period as it takes a few days for cycle to start working and then a few days for accumulation
what is the management of of hyperammonaemia?
can stop the catabolic pathways and make the patient anabolic - need to reduce the level of ammonia in the blood and protein restriction to keep levels of ammonia down
summarise the urea cycle?
HCO3 and NH3 combine to make carbamoyl phosphate. This then combines with ornithine to make citrullin and then eventually urea. Carbomyl P also make pyrimidines
what is porphyria?
it is a group of disorders that result from a build up of natural chemicals that make porphyrin which is essential for the function of Hb
what are the possible signs of acute porphyria?
abdo, chest, back or leg pain, insomnia, high blood pressure, diarrhoea and vomiting, palpitations, muscle weakness, tingling, paralysis or pain, seizures, red or brown urine, convulsions, mental changes, breathing problems and anxiety
what are signs of photosensitive porphyria?
sensitivity to sun or artificial light, blistering and ages to heal, sudden painful erythema and oedema, itching, fragile skin, increased hair growth, red brown urine
how does porphyrin make Hb?
ALA - PBG - UROPORPHRIN - CORPROPORPHRIN - PROTOPORPHRIN - HAEM
what increases in photosensitive porphyria?
protoporphrin, corproporphrin and uroporphrin
what increases in acute porphyria?
PBG and ALA
why is there excessive hair growth in photosensitive?
the body is reacting to protect it from sensitivity to sunlight
why are blisters so painful in photosensitive?
the porphyrins react to light and produce heat
why does complete block lead to death?
porphyrin is involved in synthesis of haem and accumulation in Hb and therefore without oxygen cannot be transported around the body
why is porphyria more common in adulthood?
pathway under stress due to changes and accumulation of porphyrins - changes in hormones etc
what does energy deficiency cause?
crisis presentation in defects of fatty acid oxidation
what happens in fasting or infection?
switch to alternative fuels for energy
what happens if switching to alternative fuels is compromised?
hypokoetic coma or hypoglycaemic coma
what is glucose?
it is a monosaccharide sugar that feeds into the glycolysis pathway for energy regeneration
what is sucrose?
it is a disaccharide that is made of glucose and fructose - fructose must be converted to glucose and sucrose broken down before it can be used in glycolysis
what is lactose?
it is a disaccharide that is made from galactose and glucose
when does galactosaemia result?
when someone cannot metabolise galactose
why is energy stored in the form of lipids?
this method is efficient
what happens when there is no glucose available?
alternative pathways can lead to metabolism of fats and other molecules
how can fatty acids be transported into the mitochondria?
they are removed from glycerol as they are stored as triglycerides
what is FA oxidation?
it is a process of breaking down fats to release ketones which are used for energy in the brain or acetyl CoA that enters the TCA cycle
what generates energy after glycolysis?
citric acid
what generates ATP?
the electron transport chain
what is good about fat metabolism?
it produces molecules that can enter the oxidative phosphorylation and generate AP
what is the end product no matter the substrate?
ATP
when it fat metabolism used?
when there is no glucose available - acute metabolic disorder when other energy stores are needed
when is MCAD screened for?
newborn screening - the child often dies upon first presentation of hypoglycaemic coma
what does defective receptors lead to?
androgen insensitivity syndrome
what is the presentation of females?
normal breast development, no pubic hair, may be ambiguous genitalia, primary amenorrhoea, infertility
what is the management of androgen insensitivity syndrome?
surgical resection of residual gonads
what is the basis of androgen insensitivity syndrome?
problems with proteins meaning receptors are not functional, express testosterone as are genetically male, but present as female in appearance as androgens cannot bind to receptor so cannot produce action in cell
what is clinical heterogeinity?
most disorders are multi allelic and most patients are compound heterozygotes meaning that there is variation of lesions due to other aspects, components of metabolism and environmrny
why might different family members with the same mutation for AIS present differently?
there is a poor genotype/phenotype correlation
how can IEM be screened?
through presymptomatic screening of a whole population or of a certain group or through investigation of symptomatic individuals through immunochemical staining, histochemical methods, DNA analysis, measuring enzymatic activities, testing bodily fluids for abnormal metabolites
who do you look at in screening?
a whole population or those groups that have a high rate of disorder
what does a test determine?
whether an individual has a disorder or not but there is overlap between unaffected and affected and therefore can be false negatives or positives
when are genes tested first?
when there are no metabolites to measure
there is a route that tends to be followed - why do genetic disorders not always get tested with genes first?
the cost or time, completely exclude disorders but not all mutations are covered, significance of mutation not always known as there is a weak phenotype genotype correlation
what is the process of testing for IEM?
metabolite testing then more complicated metabolite testing then enzyme analysis or functional studies and then mutation or gene analysis
what are the main basic urine metabolic screening tests?
organic acids and amino acids
what does thin layer chromatography do?
old technique to look at amino acids in urine
what are the basic urine metabolic tests?
spot tests, organic and amino acids, sugar chromatgraphy, oligosaccharides or sialic acids, mucopolysaccharides
what are basic urine metabolic screen tests?
collection of tests that are easy to perform and can test for a lot of disorders
what can you detect with automated amino acid analysis?
can detect many disorders with just one test - carbon based molecules which can be associated with and can accumulate in all different areas of metabolism - one of the main tests performed
what are intermediates in most metabolic pathways?
small MW organic acids
what can organic acids be made into?
neurotransmitters, carbohydrates, microorganisms, fatty acids, pyrimidines, purines, cholesterol, drugs, diet and amino acids
where are classic organic acidaemias found?
defects in branches and chains of amino acid catabolism
although amino acid metabolism is important why is it not always accurate?
the amino acids themselves are not always incrased in deficient catabolic enzymes - the further away from the parent AA the block is, the less likely it is to accumulate
what are metabolic intermediates commonly?
they are anabolic and naturally organic
what are classic organic acidaemias?
propionic, isovaleric and methyl malonic acidaemia
how can acidaemias present?
with hyperammonaemia
what is maple syrup urine disease?
defects in almost every step of the pathway
what is benefits to diagnosis?
treatment, prognosis improvement, identify cause of clinical problems, genetic counselling, IEM acting as a model for other disorders, allows parents to decide whether to terminate a pregnancy when it is affected by a disorder
