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How many live births are affected by inborn errors of metabolism?

1:1-2000 live births


Inborn errors of metabolism are caused by genetic defects that code for what 3 types of protein (in general)?

1) transport proteins
2) structural proteins
3) enzymes


Why, in inborn errors of metabolism, do you tend not to have complete blockage of a metabollic pathway?

A full blockage in a pathway is unlikely to be compatible with life
Inborn errors of metabolism tend to be caused by reduced function of an enzyme (/structural/transport protein) thus you have a range of severity in each disorder


What kind of genetic defect tends to occur in inborn errors of metabolism?

A mutation which leads to over expression or under expression of a gene, doing something too much or too little is what causes the problems


What is biochemical genetics?

The study/investigation of (primarily) genetic disorders that affect the metabolic pathways of cells


Why do enzymes catalysing reactions give you a degree of control of the rate of reaction?

Can be controlled by over or under expression of genes


In a metabolic pathway involving multiple enzymes, what are the 3 possible damaging consequences of a malfunctioning enzyme towards the end of the pathway?

1) Dont produce enough of the end-point product
2) Intermediates produced prior to that enzyme can accumulate and can themselves be toxic
3) Intermediates that build up prior to that enzyme could be converted to something else which is a toxic substance


How can you work out which enzyme is malfunctioning in a metabolic pathway?

By measuring levels of intermediates and end point products to work out where the blockage occurs


How can vitamin and nutrition deficiencies sometimes mimic inborn errors of metabolism symptoms?

Many enzymes require a co-factor to carry out their function, these are often vitamins, they can give you a biochemical and clinical phenotype similar to the genetic phenotype so you need to work out if there is an actual problem


How can vitamins be useful in treating inborn errors of metabolism?

There is usually some residual enzyme activity there, you can give a vitamin supplement thus providing excess of the cofactor and maximise what is actually there, - this can decrease the symptoms


Give the 3 broad mechanisms of disease of inborn errors of metabolism?

1) Accumulation of a toxin
2) Energy deficiency
3) Deficient production of essential metabolite / structural component


What substance accumulates in patients with urea cycle defects?



Give the 7 clinical effects of acute hyperammonaemia toxicity?

1) Lethargy
2) Poor feeding
3) Vomiting
4) Tachypnoea
5) Convulsions
6) Coma
7) Death


What is porphyria?

Accumulation of porphyrins in the haem synthesis pathway


What is the haem synthesis pathway?

ALA - BPG - Uroporphrin - Corpoporphrin - Protoporphrin - Haem


Where do defects occur in the haem synthesis pathway in acute porphyria (and what are the 13 possible signs)?

In the first 2 steps
1) Severe abdo pain
2) Pain in the chest, legs, or back
3) Constipation or diarrhoea
4) Vomiting
5) Insomnia
6) Palpitations
7) Hypertension
8) Anxiety or restlessness
9) Seizures
10) Mental changes
11) Breathing problems
12) Muscle pain/tingling/paralysis
13) Red or brown urine


Where do the defects in the haem synthesis pathway occur in photosensitive porphyria (and what are the 7 possible signs)?

In the last 3 steps
1) Sensitivity to sunlight or artificial light
2) Sudden painful erythema and oedema
3) Blisters that take weeks to heal
4) Itching
5) Fragile skin
6) Increased hair growth
7) Red or brown urine


In what disorders of metabolism does energy deficiency cause crisis presentations?

Defects of fatty oxidation
Pt can be very well and then be hit by infection and need to use their fats and present in a crisis of energy deficiency


Androgen insensitivity syndrome is caused by an enzyme defect leading to what?

Defective receptors


What is androgen insensitivity syndrome, how does it present and what surgery is usually required?

Genetic males with a healthy female phenotype, normal breast development, absent pubic hair. Partial defect results in ambiguous genitalia.
Presentation - primary amenorrhoea, infertility
Surgery - usually requires surgical resection of residual gonads


Why is their much clinical heterogeneity with inborn errors of metabolism? 3

1) genetic variability of lesions, most disorders are multi-alleic
2) Variability of other aspects/ components of metabolism
3) Environment
Often genotype phenotype correlation is poor


In which 2 broad ways are IEM diagnosed?

1) Pre-symptomatic screening
2) Investigation of symptomatic individuals


Is everyone in the population screened for IEM?

Some IEM are screened for in the whole population as part of routine screening
Some IEM are only screened for in selected groups


What 4 things can investigation of symptomatic individuals include in diagnosing IEM?

1) testing body fluids for abnormal metabolites
2) measuring enzyme activities
3) histochemical/ immunochemical staining
4) DNA analysis


IEM are usually bottom of the list for diagnosis give a key trigger about a babies progression which may indicate a diagnosis of IEM?

A baby who was well at birth and suddenly had problems (as they had become completely reliant on their own metabolism rather than their mothers)


In basic urine metabolic screening in Leeds which 6 things are carried out?

1) Spot tests
2) Organic acids
3) Amino acids
4) Sugar chromatography
5) Oligosaccharides/Sialic Acids
6) Mucopolysaccharides


How does amino acid TLC (test of the urine work)?

Basic test with chromatography and different amino acids run to different points


Instead of urine amino acid chromatography what more precise technique can be carried out?

Automated amino acid analysis
Gives you quantitative data


What is homocysteinuria?

Disorder of methionine metabolism leading to an accumulation of homocysteine and its metabolites in the blood and urine


What are the 5 clinical problems of homocysteinuria?

1) Mental retardation
2) Marfinoid habitus
3) Ectopia lentis
4) Osteroporosis
5) Thromboembolism