T4: Inborn Errors of Metabolism

Question 1

How can enzyme cofactors be involved in disease?

Answer 1

Enzymes often need cofactors such a vitamins in order for them to work. This can give problems as a vitamin deficiency can lead to a secondary defect in the pathway . You then need to consider if it is a genetic disorder or deficiency in the vitamin. This can make it very confusing as the problem and disorder can arise in different places. The vitamins can be given in high concentrations, this can help to stimulate enzyme activity to mediate symptoms and be an effective treatment.

Question 2

How can ammonia accumulation lead to disease?

Answer 2

Blockages can occur at many points in the urea cycle. Hyperammonaemia is a medical emergency. Many of these occur in a neonatal state. There is often a couple days after birth as it takes time for the metabolites to accumulate and take effect. They will go of quickly. The clinical effects are non-specific:
	- Lethargy 
	- Poor feeding
	- Vomiting 
	- Tachypnoea
	- Convulsions
	- Coma 
	- Death 
Sometimes there is nothing you can do. You can try stop catabolic pathways, dilate them and give drugs. The critical factor is how long the ammonia has been in the blood. If they are catabolic, breaking down the products, once managed the ammonia, you can protein restrict the diet and manage the problem.

Question 3

What is an accumulation of porphyrins a sign of?

Answer 3

The an error in the metabolism of haem.

Porphyria is a part of the metabolic pathway of haem. A complete block in the pathway is incompatible in life. Porphyrias are strange disorder, different things can set them off e.g. stress, hormonal changes and medication. Depending in where the blockage is.
An inability to synthesise haem may lead to an accumulation of porphyrins.

ALA or PBG disorders and therefore accumulation can lead to acute porphyria. This can lead to :
	- Abdominal pain
	- Chest, leg back pain
	- Constipation or diarrhoea
	- Vomiting Insomnia 
	- Palpitations 
	- Anxiety 
	- Seizures
	- Hypertension
	- Psychosis  
An accumulation lower down in the pathway can lead to porphyrins. These react to light due to the ring structures and generate heat:
	- Sensitivity to light and artificial light
	- Skin lesions 
	- Increased hair growth (protective)
	- Itching 
	- Fragile skin
	- Blisters that take weeks to heal

In the middle are some disorders that overlap leading to both symptoms

Question 4

How can energy deficiencies causes crisis presentations?

Answer 4

Energy deficiency causes crisis presentations in defects of fatty acid oxidation.
we store fats as triglycerides and transport fatty acids into the mitochondria. We then go through oxidation where we break down the fats to release ketones for energy or acetyl CoA into the TCA cycle for energy. We only turn on fat metabolism when we need energy e.g.:
- Fasting/infection we switch to alternative fuels
- If compromised we then see the problems. We can see hypoketotic hypoglycaemic come, hepatic failure etc. Between times we may be normal.
The most common is NCAD. If you do not fast or not in in infection and are given sugar you are well. However if you are compromised and not treated with glucose. You cannot metabolise fats properly, you would then die due to hypoglycaemic. Now we get very few deaths due to management. A lot of inborn errors will present in this way, at a point of stress. Particularly in the new-born presentation, the clinical presentation is non-specific - it is often mistaken for sepsis.

Question 5

Using the example of androgens receptors, how can deficient production of essential metabolite/structural component cause disease?

Answer 5

Androgen insensitivity syndrome: Androgens require receptors to have an effect. Without it the testosterone will not work. The males are genetically males XY and produce androgens. These have no effect. They present with a female phenotype. They have normal breast development, absent pubic hair, ambiguous genitalia etc. They often present in the childhood with primary amenorrhea and infertility. Usually need surgical resection of residual gonads.

Question 6

What is clinical heterogenitity?

Answer 6

Patients with the same condition present in different ways.

There is quite often other factors that affect clinical presentation leading to clinical heterogeneity:
- Genetic variability of lesions, most disorders are multi-allelic
- There is variability of other aspects/components of metabolism
- Environments
It can therefore get very complex.

Question 7

How are IEM diagnosed?

Answer 7

1. Pre-symptomatic screening - whole populations (new-born - this includes well children) and selected groups (high risk)
   
   2. Investigation of symptomatic individuals - test body fluids for abnormal metabolites, measure enzyme activities, histochemical/immunological staining and DNA analysis

Question 8

What do we test for in basic urine metabolic screens?

Answer 8

It tests for a lot, but not all disorder. We test for:

- Spot tests 
- Organic acids
- Amino acids
- Sugar chromatography 
- Oligosaccharides/sialic acids 
- Mucopolysaccharides

Organic acids are one of the most common test. These are small organic acids that are mediators in most metabolic pathways. These acids can be associated with and accumulate in all areas of metabolism. You can detect many different compounds and so disorders with one test. This is done using mass spectrometry.

Question 9

What is tyrosinemia type 1?

Answer 9

Tyrosinemia Type I - there is a block in the pathway in the metabolism of tyrosine. This causes a new compound to be produced called succinyl acetone. This is very toxic to the liver so when it accumulates in then build it can lead to carcinoma of the liver. Succinyl acetone is only found here, you can use it as a biomarker. If you inhibit further up the pathway and prevent this product, you can reduce the chance of liver disease improving prognosis.