A number of rare inborn errors of metabolism have been identified where
a defect in an enzyme prevents patient to metabolize fatty acid properly.
Many of these disorders affect muscle and are called metabolic myopathies.
Severe metabolic myopathies can cause death at a very early age.
less severe forms may not appear until adulthood,
causing progressive muscle weakness.
Cramps, exercise intolerance, and even heart failure.
In this video, we'll look at few of these metabolic diseases.
Let's start with carnitine deficiency.
What are the causes of this deficiency?
We know that carnitine is either made in the liver or
obtained from our diet, mostly from meat.
Genetic defects of OCTN2, the carnitine transporter,
prevent the transport of carnitine into several tissues,
including cardiac and skeletal muscles.
Another possible cause of the carnitine deficiency
is a low level of carnitine synthesis by the liver.
There are several consequences to these deficiencies.
Acylcarnitine for example, palmitoylcarnitine.
are not made and fatty acids for example,
palmitate cannot enter The mitochondria to be oxidized.
There is an increase of liquid storage in muscle and
liver due to the unbalance between storage and breakdown.
The increased liquid storage is a common feature Of metabolic myopathies.
How can we treat carnitine deficiency?
Patients have to take oral carnitine supplements for the rest of their life.
There is also a class of drugs called fibrates that can be administered.
So what's the action of fibrates?
Fibrates activate The production of a family of transcription
factors called PPA are these factors will trigger
the expression of genes implicated in beta oxidation.
Therefore we lead to an overall boost of fatty acid oxidation.
>> How can carnitine supplementation help a patient with a defective transporter?
>> Oftentimes mutated transporter are not completely non functional, but
rather less active than normal.
In these cases, oral supplements raise the plasma level of carnitine.
And the higher carnitine concentration compensates for
a lower level of transport.
Another fatty acid oxidation disorder there is a CPT2 deficiency.
The most common cause of this deficiency is a point mutation in CPT2.
One of the component of the acylcarnitine shuttle
found in the inner mitochondrial membrane.
During the symptoms for this deficiency,
exercise intolerance, cramps, muscle weakness.
It appears early in adult life and
can be brought on when the body's metabolism is challenged.
For example during fasting over exercising during an infection,
more severe cases can present in infancy resulting in hypoglycemia and
sudden death.
CPT2 deficiency prevents the conversion of acylcarnitine to acid consomme,
a in the mitochondrial matrix, long as in chain carnitine
molecules accumulate and can cause irregular heartbeats.
How is CPT2 deficiency treated?.
Patients should avoid triggering factors such as prolonged exercises or fasting.
You should also adopt a high carbohydrate diet,
which minimise the dependency on liquid catabolism.
Fibrates are also a treatment option Even with CPT2 point mutations,
boosting the expression of this mutant form
can sometimes boost the overall activity of the enzyme.
Finally, fatty acid oxidation disorders
can be due to defects In acyl CoA dehydrogenase.
These dehydrogenase catalyzes the first step in beta oxidation.
There are different types of acid coenzyme dehydrogenase for
different length fatty acids.
a defect in any of these different forms can lead to metabolic myopathies
defects in vl.
VLCAD dehydrogenase affects the oxidation of the very long chain fatty acid coenzyme
a and will lead to progressive disease that typically manifests in education.
Because this enzyme is just downstream of CPT2 the defect
in VLCAD leads to symptoms similar to those caused by CPT2 deficiencies.
A defect in the MCAD,
the dehydrogenase,affect the oxidation of the medium chain as silicones are made.
It is one of the most frequent form of disease linked to fatty acid oxidations.
This enzyme reacts with fatty acids that have been shortened to 10, or 8 carbons.
Defects in the SCAD dehydrogenase
affect the oxidation of short-chain acyl-CoA enzyme.
Preventing the final rounds of beta oxidation.
This defect is less severe than the other one because some molecules of
acetate CoA has been already released by earlier round of beta oxidation.
So which metabolites are altered by a deficiency in acyl-CoA dehydrogenase?
VLCAD deficiencies are diagnosed by increased the concentration
of the long chain acylcarnitine in the blood and urine.
MCAD deficiencies lead to an accumulation of medium length
acid carnitine molecules, which have a neurotoxic effects.
SCAD deficiencies are diagnosed by a high concentration of
4-carbon acylcarnitine a related
molecule called Methylmalonic acid is produced,
accumulates in urine causing Aciduria, which is a decrease in the urine pH.
So how are acyl-CoA dehydrogenase deficiencies treated?
Patients usually take frequent, carbohydrate rich meals and avoid fasting.
The goal is to maintain a high level of muscle and
liver glycogen to reduce the dependency on fatty acid oxidation.
Patients with VLCAD deficiencies can have a diet low in very long chain fatty acid.
And can supplement their diet with triheptanoin a triglyceride
containing medium length fatty acid chains with an odd number of carbon.
Triheptanoin serves two purposes.
The medium length fatty acid bypass the defective enzyme.
Fatty Acid chains with an odd number of carbon
provides both acetyl co-enzyme A and propionyl coenzyme A.
As you recall, propionyl coenzyme A is a precursor of oxaloacetate.
So the citric acid cycle can continue to operate.
When only fats and not carbohydrates are available.
This video illustrates the importance of fatty acid
metabolism by showing that perturbations of the fatty
acid dependent ATP production have dramatic Health impacts.