1. LIPID METABOLISM DISORDERS
RELATED TO CARNITINE
Sir. Stymass Kasty
SOKOINE UNIVERSITY OF AGRICULTURE
MOROGORO-TANZANIA
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2. CONTENTS
 INTRODUCTION.
 β-OXIDATION OF FATTY ACIDS.
 TRANSPORT OF FATTY ACIDS IN TO THE MITOCHONDRIA.
 CARNITINE SHUTTLE
 FATE OF ACYL-CARNITINE IN MITOCHONDRIA
 INHIBITOR OF THE CARNITINE SHUTTLE
 METABOLIC DISORDERS ASSOCIATED WITH CARNITINE
 EPIDEMIOLOGY
 DIAGNOSIS
 LABORATORY FINDING
 TREATMENT
 CONCLUSION
 REFFERENCES
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3. INTRODUCTION
CARNITINE Is a specialized carrier protein (Low
molecular weight compound), which transports the
long chain fatty acyl groups from the cytosol in to the
mitochondrial matrix.
SOURCES OF CARNITINE IN THE BODY
 From the diet, primarily in Meat products.
 Synthesis from amino acids, LYSINE and
METHIONINE by the enzymatic pathway found in
the liver and kidney.
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4. β-OXIDATION OF FATTY ACIDS
This is a mitochondrial pathway; a major
pathway of the Catabolism of fatty acids in which
two-carbon fragments are successively removed
from the carboxyl group or end of the fatty Acyl
CoA, producing Acety CoA, NADH and FADH2.
Example of fatty acyl CoA is shown below,
[CH3-(CH2)x-CH2-CH2-C=O-S-CoA]
The energy yield from the β-oxidation
pathway is high.
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5. TRANSPORT OF FATTY ACIDS IN TO THE
MITOCHONDRIA
Because β-oxidation occurs in the mitochondrial
matrics, the fatty acid must be transported across
the inner mitochondrial membrane that is
impermeable to Coenzme A (CoA).
After a long chain fatty acids enters a cell, they
are converted in the cytosol to its CoA
derivative by long-chain fatty acyl CoA
synthetase (thiokinase), an enzyme of the outer
mitochondrial membrane.
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6. TRANSPORT OF FATTY ACIDS IN TO THE
MITOCHONDRIA
Fatty acids shorter than 12 Carbons gets activated
to their CoA derivatives inside the mitochondria
by matrix enzymes, and are oxidized.
The entry of short and medium chain fatty acids
in to the mitochondria do not require the help of
membrane transporters.
Those fatty acids with 14-Carbon or more can not
pass directly through the mitochondria
membrane.
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7. TRANSPORT OF FATTY ACIDS IN TO THE
MITOCHONDRIA
The transport of long chain fatty acids (LCFA)
in to the mitochondria requires a specialized
carriers. These carriers are called CARNITINE.
This rate limiting transport process is called
CARNITINE SHUTTLE.
Carnitine deficiency leads to the occurance of
among of the LIPID METABOLISM DISORDERS.
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8. CARNITINE SHUTTLE
Three enzymatic reactions are involved.
1st Reaction; The acyl group is transferred
from CoA to carnitine by Carnitine
acyltransferase-I (CAT-I). This reaction forms
acylcarnitine and regenerate free CoA.
2nd Reaction; The Acylcarnitine is transported
in to the mitochondrial matrix in exchange for
free carnitine by carnitine-acylcarnitine
translocase (Facilitated diffusion).
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9. CARNITINE SHUTTLE
3rd Reaction; Carnitine acyltransferase-II an
enzyme of the inner mitochondrial membrane
catalyses the transfer of the acyl group from
carnitine to CoA in to the mitochondrial
matrix in which free Carnitine is regenerated.
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10. CARNITINE SHUTTLE
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11. FATE OF ACYL-CARNITINE IN
MITOCHONDRIA
Once in the mitochondrial matrix,acyl-
carnitine is converted to the acyl-CoA and
regenerating carnitine.
The enzyme involved is carnitine
acyltransferase II.
Then carnitine move from matrix to the
cytosol for transporting another LCFA.
The acyl-CoA enter the β-Oxidation.
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12. INHIBITOR OF THE CARNITINE
SHUTTLE
Malonyl CoA inhibits Carnitine
acyltransferase-I (CAT-I) thus preventing the
entry of Long chain acyl groups in to the
mitochondrial matrix.
Example; Newly made palmitate in the cytosol
can not be transferred in to the mitochondria
and dagraded in the presence of Malonyl CoA.
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13. METABOLIC DISORDERS
ASSOCIATED WITH CARNITINE
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14. CARNITINE DEFICIENCIES
These can be broadly classified in to two
groups;
Primary carnitine deficiencies and
Secondary carnitine deficienices.
These deficiencies result in a decreased
ability of the tissues to use long-chain fatty
acids (LCFA) as a metabolic fuel.
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15. PRIMARY CARNITINE DEFICIENCY
Congenital deficiencies in one of the
Carnitine-acyltransferase (CAT) system which is also
known as Carnitine palmitoyltransferase (CPT)
system or Mutations in the SLC22A5 gene (making
of OCTN2 protein-transport Carnitine in to cells)
Genetic Carnitine palmitoyl transferase I (or CAT-
1) deficiency which affects the liver. This result in
a decreased or inability of the liver to synthesize
glucose during a fast.
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16. PRIMARY CARNITINE DEFICIENCY
This can lead to;
i. Severe hypoglycemia
ii. Coma and
iii. Death
Genetic Carnitine palmitoyltransferase-II (or
CAT-II) deficiency which occur primarly in
Cardiac and Skeletal muscles.
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17. PRIMARY CARNITINE DEFICIENCY
There are three main forms of CAT-II based on tissue-
specific symptomology and age of onset.
1.MYOPATHIC FORM.
 Most common form of the disorder.
 Mild to severe adult form with the following
symptoms.
Rhabdomyolysis (release of myoglobin due to
breakdown of muscle fibers).
 Myalgia (muscle pain) and weakness.
Myoglobinuria (myoglobin in urine).
.
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18. PRIMARY CARNITINE DEFICIENCY
2.MULTISYSTEMIC FORM.
It is severe infantile form.
Involves multiple organ systems
Symptoms occur between 6 and 24 months of
age.
Characterized by the following symptoms.
Hypoketotic
Acute liver failure.
Hepatomegaly.
Cardiomyopathy.
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19. PRIMARY CARNITINE DEFICIENCY
3.NEONATAL FORM.
It is a lethal form in neonatal.
It is the least common clinical presentation of
this disorder.
Symptoms occur just hours after birth to
within 4 days of life
Symptoms are; Encephalopathy, confusion,
Hypoglycemia, liver failure, Cardiomyopathy
and muscle weakness.
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20. SECONDARY CARNITINE DEFICIENCY
This may occur in many situations, such as;
A patient with liver disease causing decreased
synthesis of Carnitine.
Individual suffering from malnutrition and those
on strictly vegetarian diets.
Those with an increased requirements for
carnitine as a result of, for instance, Pregnancy,
severe infection, burns or trauma
Those undergoing Haemodialysis, which removes
carnitine from the blood.
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21. EPIDEMIOLOGY
 Primary systemic carnitine deficiency was
estimated in Japan to occur in 1 per 40,000
births (1:40,000).
 In Australia, the incidence has been estimated to
be between 1:37,000 to 1:100,000 newborns
 The frequent of this condition is not known
 However, in UK the previous report identified 4
affected mothers in 62,004 infants screened, with
a frequency of 1 per 15,500 (1:15,500).
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22. DIAGNOSIS
In neonates, carnitine palmitoyltransferase
deficiency (CPT) is diagnosed using mass
spectrometry to screen blood.
Prenatal diagnosis may be possible using
amniotic villous cells.
In adults, the definitive diagnosis is based on
acylcarnitine levels in serum, urine, and
tissues(muscle and liver for systemic deficiency;
muscle only for myopathic deficiency).
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23. LABORATORY FINDING
Low plasma carnitine level
Low level of ketone bodies
Low blood sugar level
Mutations…!
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24. TREATMENT
Avoid prolonged fast
Adopting a diet high in carbohydrate
Adopting a diet low in Long-chain fatty acids
Supplements with medium chain fatty acids
and Carnitine. This is because their oxidation
is not dependent on CPT-I hence it is not
subject to inhibition by malonyl CoA.
Treated by giving L-carnitine 25mg/kg per 6
hours.
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25. PROGNOSIS
Infantile metabolic and childhood myopathic
forms of the conditions can be FATAL if
untreated.
Long-term prognosis is exellent with oral
Carnitine supplimentation.
If the disorder is not recognised for a long
time, death can occur due to Cardiac failure,
hypoglycemia and arrhythmias or sudden
death.
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26. CONCLUSION
Carnitine is thus considered as a
“conditionally essential nutrient” since
individuals requirements might exceed dietary
intake during specific disease states.
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27. REFERENCES
• Richard H & Denise F. (2011).Lippincott’s Illustrated
Reviews: Biochemistry, 5th ed.
• Ayman W El-Hattab. Systemic primary carnitine
deficiency. GeneReviews .November 3,2016;
• Carnitine transporter defficiency. Screening,
Technology and Research in Genetics
(STARG).2/20/2016;
• Agnetti A, Bitton L, Techana B, Raymond A and
Caranon. Primary carnitine deficiency dilated
cardiomyopathy:28 years follow-up. Jun 2 2012;
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28. THANK YOU…!!!
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29. Email. Stymass1@gmail.com
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