PRINCIPLES IN

BIOCHEMISTRY
SBK3013
2015/2016

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
boys 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 case

1.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 the
voluntary 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 Carnitine
The 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 Carnitine

PRIMARY 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
1. Severe brain dysfunction (encephalopathy)
deficiency
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)

Treatment
Better 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 Lcarnitine 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 childs 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
Small energy demands do not initiate glycogenolysis
aerobically?
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 CASE

For 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. Thats why, a boy felt tiredness during activities.