PRINCIPLES IN BIOCHEMISTRY

SBK30132015/2016

CARNITINE DEFICIENCY

CASE :A teenage boy was brought to a hospital as he complaints that he always get too

tired when asked to participate in the any of school activities. The doctor found

muscle weakness in the boy’s arms and legs. From the muscle biopsy, the lab

pathologist found that greatly elevated amount of triglycerides esterified with

primary long fatty acid chain. They also found significant presence of lipid

vacuoles in the muscle biopsy. What causes this symptoms?

Focus of this case1.What is the effect of low carnitine?

2.How people with the disorder metabolize muscle glycogen aerobically?

Carnitine ?Carnitine is the quaternary ammonium compound biosynthesized from the amino acids lysine and methionine.

Carnitine produced by ?Liver and kidneys, but mostly located in thevoluntary muscle and cardiac muscles.

Carnitine deficiency?Do you know what is carnitine deficiency?

• A metabolic state in which carnitine concentrations in plasma and tissues are less than the levels required for normal function of the organism.

• This is a metabolic muscle disease that interferes with the processing of food such as fats for energy production.

• Carnitine deficiency results from inadequate intake of or inability to metabolize the long chain of amino acids.

Function of CarnitineThe amino acid carnitine is required for the transport of long-chain fatty acyl coenzyme A (CoA)

esters from the intermembraneous space in the mitochondria into mitochondrial matrix , where

they are oxidized for produce energy by breaking down the lipids.

Transports toxic or waste compounds out of cellular organelle to prevent accumulation.

Convert fat into energy - by transports of fatty acids into the mitochondria

Types of carnitine ?1. Primary carnitine deficiency : Genetic disorder of the cellular carnitinewhere the transport

system that usually with symptoms of cardiomyopathy, skeletal muscle weakness and hypoglycemia.

2. Secondary carnitine deficiency : Shows in the certain disorder such as chronic renal failure or under certain condition which using certain antibiotic. It can reduce the carnitine absorption and increase its excretion.

Primary Carnitine Deficiency:Prevent the body from using certain fats for energy .

Appear during infancy or early childhood:

- Brain disfunction

- Weak and enlarged heart (cardiomyopathy)

- Muscle weakness

- Low blood sugar (hypoglycemia)

* Some people are asymptomatic : does not show any signs or signals.

How primary carnitine occur ?• Low level of carnitine level in blood

• Gene mutation

• The gene provide information for making protein that transports carnitine into cells

• This mutation can affect carnitine transport by impairing maturation of transporters to the plasma membrane

• Result of mutation causes an absent/dysfunctional of the protein

• Shortage (deficiency) of carnitine within cells

• Without carnitine, fatty acids cannot enter mitochondria and be used to make energy

• Reduced energy production lead to muscle weakness and hypoglycemia(low blood sugar)

Gene Mutation ?Mutation :

- SLC22A5 gene : give instruction to make OCTN2 protein to transport the carnitine.

- Result of the mutation : an absent or dysfunction of OCTN2 proteins

- Create a premature stop signal in the instructions for making the OCTN2 protein, resulting in an abnormally short, nonfunctional protein. Other mutations change single protein building blocks (amino acids) in the OCTN2 protein.

http://ghr.nlm.nih.gov/gene/SLC22A5

Secondary Carnitine Deficiency:May present with crises consisting of hypoglycemia, ketoacidosis, and hyperammonemia.

Also may present with abnormal fatigability and lactic acidosis associated with exertion. These children also may present with encephalopathy and/or lipid storage myopathy and carnitine depletion.

Carnitine deficiency has been observed in children with urea cycle defects, and it may exacerbate episodes of hyperammonemia.

* excess of a particular protein building block (amino acid), called methionine, in the blood

Primary Carnitine vs Secondary CarnitinePRIMARY CARNITINE SECONDARY CARNITINE

Rare congenital deficiency Decreased carnitine synthesis due to liver disease

Carnitine palmitoly transferase system- Prevents renal absorption of carnitine- Faulty transporter prevents carnitine

uptake

Severely restricted vegetarian diet

Has very low levels of carnitine in blood due to a faulty carnitine transporter

During high metabolic requirement- Pregnancy- Severe infections- Trauma

Patient undergoing hemodialysis

What is the causes ?Inadequate intake of nutrition due to fad diet or long term TPN

*TPN is stand for “Total Parental Nutrition” which is a method of feeding that bypasses the gastrointestinal tract. It is used when a person cannot receive food or drink through his/her mouth.

Excess loss of carnitine due to diarrhea, diuresis and hemodialysis.

Decrease muscle carnitine level due to mitochondrial impairment (due to the use of zidovudine).

Inability to metabolize carnitine due to enzyme deficiency.(carnitine palmitoyltransferase disease)

use of valproate

Symptoms carnitine deficiency1. Severe brain dysfunction (encephalopathy)

2. Fatigue

3. Lipid storage myopathy

4. Hyperammonia (metabolic disturbance by excess of ammonia in blood)

5. Hypoglycemia (low blood sugar)

6. Vomitting

7. Fatty liver

8. Muscle weakness

9. Myoglobinuria (presence of myoglobin in urine)

10. Cardiomyopathy (weakened and enlarged heart)

TreatmentBetter diagnosis to allow for earlier identification of at-risk individuals and earlier

treatment

Continued examination of the role of exercise and diet in metabolic diseases

Development of enzyme replacement therapies

Development of gene therapies.

Avoidance of fasting and strenuous exercise

Dietary interventions, based on cause

1. L-carnitine

The main treatment for CTD is lifelong use of L-carnitine. This is a safe and natural substance that

helps body cells make energy. It also helps the body get rid of harmful wastes. L-carnitine can

reverse the heart problems and muscle weakness that happen in children with CTD.

Your doctor will decide whether or not your child needs L-carnitine. Unless you are advised

otherwise, use only L-carnitine prescribed by your doctor. Do not use L-carnitine without

checking with your doctor.

2. Avoid going a long time without food

Infants and young children with CTD need to eat frequently to prevent a

metabolic crisis. Your metabolic doctor will tell you how often your child

needs to be fed. In general, it is often suggested that infants be fed every

four to six hours. Some babies need to eat even more frequently than this.

It is important that infants be fed during the night. They may need to be

woken up to eat if they do not wake up on their own.

Your metabolic doctor and dietician will give you an appropriate feeding plan for your infant.

Your doctor will also give you a ‘sick day’ plan tailored to your child’s needs for you to follow

during illnesses or other times when your child will not eat.

Your metabolic doctor will continue to advise you on how often your child should eat as he or she

gets older. When they are well, many teens and adults with CTD can go without food for up to 12

hours without problems. The other treatments usually need to be continued throughout life.

3. Diet

Sometimes, in addition to L-carnitine treatment, a low-fat, high carbohydrate food plan is recommended. Any diet

changes should be made under the guidance of a dietitian familiar with CTD. Ask your doctor whether your child

needs to have any changes in his or her diet.

4. If your baby has CTD, call your doctor at the start of any illness

Always call your healthcare provider when your baby has any of the following:

poor appetite

low energy or excessive sleepiness

vomiting

diarrhea

an infection

a fever

persistent muscle pain or weakness

Are there health risks from too much carnitine? supposedly 3g/day

carnitine supplement can cause nausea, vomiting, abdominal cramps, diarrhea

rarer side effects include muscle weakness in uremic patients and seizures in those with seizure disorders

may increase the risk of cardiovascular disease

more pronounced effect to those people who likes meats than vegetarians

How people with the disorder metabolize muscle glycogen aerobically? ● Small energy demands do not initiate glycogenolysis

● Lightly loaded muscles manage to cover their energy needs through oxidation of circulating glucose and fatty acids.

● However, increasing work loads demands more powerful contractions and ATP utilization. This increases the rate of glycogen breakdown to cover these needs.

CONCLUSION FOR THE CASEFor our patient, we are sure that he suffered Primary Carnitine Deficiency.

From the muscle biopsy, the lab pathologist found that greatly elevated amount of triglycerides esterified with primary long fatty acid chain.

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. That’s why, a boy felt tiredness during activities.