What is carnitine deficiency?

Carnitine deficiency is a condition that disallow the body from using certain fats for energy, particularly during periods without food.

What is carnitine?

It is a naturally occurring hydrophilic amino acid derivative, produced endogenously in the kidneys and liver and derived from meat and dairy products in the diet. It plays an essential role in the transfer of long-chain fatty acids into the mitochondria for beta-oxidation.

 

Biologic effects of low carnitine levels may not be clinically significant until they reach less than 10-20% of normal. Carnitine deficiency may be primary or secondary.

Synthesis of Carnitine:  

Fig. 2 Biosynthesis of L-carnitine

In both humans and other animals, carnitine is frequently obtained through diet or synthesized by the body itself. The precursor for this synthesis pathway is actually lysine that is methylated to form N-trimethyllisine. The end product of this pathway will be L-carnitine. In the overall biosynthetic pathway, at least four enzymes are involved:  

1. N^ε-trimethyllysine hydroxylase 
2. 3-hydroxy-N^ε-trimethyllysine aldolase 
3. 4-N-trimethylaminobutyraldehyde dehydrogenase  
4. γ-butyrobetaine hydroxylase.

Primary:

Carnitine is a natural substance taken mostly through diet and is used by cells to process fats and produce energy. A person with primary carnitine deficiency has very low levels of carnitine in the blood due to a faulty carnitine transporter which prevents carnitine from getting into the cells where it is needed.The primary form of the disorder can be classified as either "systemic carnitine deficiency", which affects many organ systems including the heart and the brain, or "muscle carnitine deficiency", which is restricted to voluntary muscles.

Secondary:

The secondary form of carnitine deficiency can arise secondary to metabolic disorders in the mitochondria.

Blockage of metabolic pathways in the mitochondria leads to a build-up of acyl compounds. These compounds then bind to carnitine and the bound complex is then excreted by the kidney, causing carnitine levels to drop.

Mechanism of fatty acid metabolism

1. Fatty acid oxidation takes place in the cytosole, where free fatty acids (FFA) are activated to acyl-coenzyme A (acyl-CoA).

2. In the presence of carnitine, an enzyme of the mitochondrial outer membrane—carnitine palmitoyl transferase (CPT-1)—synthesizes corresponding acyl-carnitine (acyl-C). (The carnitine transport mediated by CPT-1 is one of the rate-limiting steps in the pathway of FFA oxidation. As the amount of carnitine decreases, FFA is not allowed in the mitochondria where it's final oxidation takes place.) Accumulation of activated molecules such as acyl-CoA and acyl-C inhibits several enzymatic activities and directly damages cellular membranes by detergent-like action.

3. FFA oxidation pathway is completed by acylcarnitine transferase, which transports acyl-C through mitochondrial membranes. After that an enzyme CPT-2 carries out reaction opposite to CPT-1 reaction—that is, it exchanges carnitine to CoA. Thus acyl-CoA is formed, which enters β-oxidation reactions resulting in synthesis of the acetyl-CoA needed for the citric acid cycle.

 Here's a video for you all so that it's easier to understand! Enjoy! (:



What genes are related to primary carnitine deficiency?
 
Mutation in the SLC22A5 gene can cause primary carnitine deficiency. This gene instruct the cell to synthesize the protein OCTN2 that transports carnitine into cell. Without carnitine, the cells are unable to bring certain types of fatty acids into the mitochondria for metobolism. The lost in this activity will lead to the depletion of energy for the heart, muscles, liver and other tissues. Unable to metabolise the fatty acids, it builds up which damage the liver, heart, and muscles. Another gene known as the SLC22A5 gene result in an absent or dysfunctional OCTN2 protein.This abnormal buildup causes the other signs and symptoms of the disorder.

Signs and Symptoms:

Signs and symptoms usually appear during infancy or early childhood phase. These signs and symptoms include:

However. some of these individuals do not show any signs or symptoms. All individuals with this disorder are at risk for heart failure, liver problems, coma, and sudden death.

How do people inherit primary carnitine deficiency?

Primary carnitine deficiency is inherited in an autosomal recessive pattern, where both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive disorder are carriers, which means they each carry one copy of the mutated gene. Carriers of SLC22A5 gene mutations may have some signs and symptoms related to the condition.

How is it treated?

Carnitine transporter deficiency is a disease that is currently uncurable. However, there are many forms of treatments available for patients suffering from this disease. The 2 main types of treatment for this disease are either by taking carnitine supplements or going for therapy to restore the levels of Acetyl-CoA. 
 

 

Non-scientific article: 

Introduction: 


Carnitine is a found mainly in foods of animal origin and is largely stored in the skeleton muscle tissues. Therefore, scientists were spurred to conduct a research on vegetarians to determine the level of carnitine in their bodies. 
There were two hypothesis that were set up;
Null Hypothesis: Vegetarians retains and takes up more in muscles than non-vegetarians
Alternative Hypothesis: Vegetarians retains less carnitine in muscles than non-vegetarians.

Implications:
Due to the lack of consumption of foods of animal origin, vegetarians have a lower level of energy compared to non-vegetarians who actually eat red meat etc. This results in the individual feeling weak if starvation occurs.

Fig. 4 Structure of L-Carnitine

Findings:
There is actually an active stereoisomer of carnitine known as L-carnitine which can be very beneficial for vegetarians when consumed as a supplement, providing them with enough energy. 




Study:

1. Primary carnitine deficiency - Genetics Home Reference. 2012. Primary carnitine deficiency - Genetics Home Reference. [ONLINE] Available at: http://ghr.nlm.nih.gov/condition/primary-carnitine-deficiency. [Accessed 03 July 2012].

Available at: http://www.uic.edu/classes/phar/phar332/Clinical_Cases/vitamin%20cases/carnitine/carnitine%20deficiency%20intro.htm [Accessed 02 July 2012]

"There are two types of carnitine deficiency, primary and secondary. A person with primary carnitine deficiency has very low levels of carnitine in the blood due to a faulty carnitine transporter which prevents carnitine from getting into the cells where it is needed.The primary form of the disorder can be classified as either "systemic carnitine decificiency", which affects many organ systems including the heart and the brain, or "muscle carnitine deficiency", which is restricted to vouluntary muscles.
The secondary form of carntine deficiency can arise secondary to metalobic disorders in the mitochondria. Blockage of metabolic pathways in the mitochondria leads to a build-up of acyl compounds. These compounds then bind to carnitine and the bound complex is then excreted by the kidney, causing carnitine levels to drop. Some of these mitochondrial disorders include cytochrome c oxidase deficiency, mitochondrial ATPase deficiency, and fatty acyl-CoA dehydrogenase deficiencies. In both primary and secondary carnintine deficiencies, increased dietary intake and supplements of carnitine can be beneficial. Although the exact mechanism is unknown, it is thought that flooding the body with high concentrations of carnitine assures that some carnitine are able to get into the cells."

3. Carnitine Deficiency - Medscape Reference. April 2010. [ONLINE] Available at: http://emedicine.medscape.com/article/942233-overview#a0104 [Accessed 02 July 2012] 

"In secondary carnitine deficiency, which is caused by other metabolic disorders (eg, fatty acid.  oxidation disorders, organic acidemias), carnitine depletion may be secondary to the formation of acylcarnitine adducts and the inhibition of carnitine transport in renal cells by acylcarnitines."  

4. Carnitine Biosynthesis - Wikipedia. [ONLINE] Available at: http://en.wikipedia.org/wiki/Carnitine_biosynthesis [Accessed 20 July 2012]

"Carnitine biosynthesis is a method for the endogenous production of L-carnitine, a molecule that is essential for energy metabolism. In humans and many other animals, L-carnitine is obtained from both diet and by biosynthesis. The carnitine biosynthesis pathway is highly conserved among many eukaryotes and some prokaryotes.
L-Carnitine is biosynthesized from N^ε-trimethyllysine. At least four enzymes are involved in the overall biosynthetic pathway. They are N^ε-trimethyllysine hydroxylase, 3-hydroxy-N^ε-trimethyllysine aldolase, 4-N-trimethylaminobutyraldehyde dehydrogenase and γ-butyrobetaine hydroxylase."

5. Carnitine Deficiency Medication - MedScape Reference. April 2010. [ONLINE]. Available at: http://emedicine.medscape.com/article/942233-medication [Accessed 20 July 2012]. 

"Cardiomyopathy often responds well to carnitine supplementation. Carnitine supplementation in fatty acid oxidation disorders and other organic acidurias is to correct carnitine deficiency and to allow removal of toxic intermediates. The other goal of therapy is to restore CoA levels."

Image References:


Video References:

1. TheCarnitine. (2010). Fatty Acids Transport [Youtube video]. Available at: http://www.youtube.com/watch?v=CLaAPl-_rRM. [Accessed 20 July 2012].