Fatty Acid oxidation Part 2

Dr. D. Nandini
Importance of fatty acid oxidation :
• Why is hypoglycaemia main feature of fatty acid oxidation
disorder.

• Ans: fasting for more than two hours the glycogen

reserves are depleted.
• hence ATP is needed for gluconeogenesis .
• fatty acid generates ATP that is required for
gluconeogenesis.
• In absence of fatty acid oxidation no gluconeogenesis
take place due to lack of ATP.
• Leads to hypoglycemia.
Why decrease in ketone levels:in FAO
disorder
Fatty acid oxidation
generates
Precursour of
Acetyl CoA ketone body
synthesis
Hence fatty acid oxidation disorder low
ketone body observed
FAO disorders are divided in two groups:
1. Defect in the entry of fatty acids into the
mitochondria due to defective transporter.

1. Carnitine deficiency
2. CPT-I deficiency
3. CPT-II deficiency
 • 2. Deficiency of enzymes catalysing intra
mitochondrial β oxidation

1. Medium chain acyl CoA dehydrogenase

deficiency.
2. Consumption of uncooked Akee fruit
resulting in Acyl CoA dehydrogenase
deficiency.
1. Carnitine deficiency:
• Defective carnitine synthesis
• Defective uptake
• Inadequate dietary supply of lysine and methionine.
• Clinical features: hypoglycaemia, cardiomyopathy,
muscle cramps and weakness.
• Treatment: oral supplementation of carnitine, frequent
feeding,and avoidance of fasting.
CPT I deficiency:
• Defect in transport of fatty acid in mitochondria.
• Hence no ATP.
• Impaired gluconeogenesis
• Insufficient supply of glucose.

Clinical features:
Presents in early childhood.
Hypoglycemia, liver dysfunction.
Treatment ( CPT I deficiency)
• Frequent feeding and avoidance of fasting
• Intake of high carb diet and supplementation with oral
carnitine.
• Fats containing medium chain fatty acids should be
given as the medium chain fatty acids enters the
mitochondria directly bypassing the carnitine
transporter.
CPT II deficiency:
• Both liver and skeletal muscle affected.
• Clinical features: Hypoglycaemia, exercise intolerance,
rhabdomyolysis induced by exercise, muscle weakness.
• Clinical features resembles glycogen storage disorders
McArdle's syndrome caused by deficiency of Muscle
glycogen phosphorylase.
• Avoiding fast
• Supplementation of medium chain fatty acids.
Oxidation enzyme deficiencies:
• Medium chain acyl Co-A dehydrogenase deficiency.
• Defect : defieciency of the first enzyme in the beta oxidation
of medium chain fatty acids of length less than C12.
• Clinical features:
• Fasting hypoglycaemia during childhood.
• Occurs due to poor feeding.
• This disorder causes grave risk to the infants as they have low
glycogen content in the liver.
• Leads to sudden death.
• Diagnosis:
• Acyl carnitine profile by mass spectrometry.
• Treatment:
• Frequent feeding and avoid prolonged
fasting.
• Acute hypoglycaemia episodes should be
managed with intravenous administration of
glucose.
Jamaican vomiting sickness : Ackee fruit
poisoning
• Name : due to Jamaican Island.
• Fruit has to be cooked and consumed.---n why
• Raw fruit contains a heat labile alkaloid hypoglycin.

Hypoglycin Acyl co A dehydrogenase

Can cause hypoglycemia, vomiting and seizures.

Untreated can lead to coma and death
Ackee fruit:
Alternative modes of fatty acid oxidation…
• Even chain, unbranched and with length of 12-20
carbon atoms oxidation of fatty acid take place in
mitochondria…
Odd chain branched chain and very long chain
fatty acid oxidation can’t be handled by
mitochondria until the characteristics substrate
for mitochondria arrives .
Alternative path way
1. 1 branched chain fatty acids ..by alpha
oxidation in cytosol.
2. Omega oxidation of medium chain fatty acids in
ER.
3. Very long chain fatty acid in peroxisomes.
4. Odd chain fatty acids: beta oxidation followed
by metabolism of end product propionyl CoA
 Disorder of refsums disease: ( defect in alpha
oxidation.)
• Known as phytanic acid storage disease.
• Defect in alpha oxidation of phytanic acid.
• Clinical features:
1. Accumulation of phytanic substituted lipids in adipose
tissue store and in lipids of neuronal membranes.
2. Neurological disorder
3. Progressive peripheral neuropathy.
4. Muscle weakness.
5. Blindness.
Treatment:

• Diet low in green leafy vegetables,

• meat product
• ruminant milk.
Zellweger syndrome:defect in long chain fatty
acid oxidation.
• Known as Cerebro Hepato renal syndrome:
• Defect: peroxisomes lack enzyme
• Biochemical features:
• Accumulation of long chain fatty acids in tissue specially
in the brain , liver and kidney.

• Clinical feature:
• Dysmorphic facial features, poor feeding, muscle
hypotonia, hearing loss, blindness,
• Affected children do not survive beyond the first year of
life.

Diagnosis: increased VLCFA in blood.

Adrenoleukodystrophy
• Caused by defective transport of VLCFA into
peroxisomes leading to accumulation of fatty acid.
• These fatty acids are toxic to brain and adrenal gland.

Features:
Demyelination of neurons
Dysfunction of adrenal gland.
Disorders of odd chain fatty acid oxidation:
• Inborn error of metabolism
• Clinical features present with in 3 days of life.
• Poor feeding
• Vommiting
• Dehydration
• Seizers
• Lethargy
• If untreated infants die due to encephalopathy
2 types:

• Propionic acidemia:
• Deficiency of propionyl coA carboxylase.

• Methyl malonic aciduria:

• Deficiency of methyl malonyl co A mutase or
vitamin B12 .
• Methyl malonic is excreted in urine.
Case studies: 1

• An Indian tourist is brought to emergency ward in

Jamaican government hospital. He was disoriented.
His blood pressure was low and pulse rate was high.
He had complained uneasiness, nausea and
abdominal pain one hour after a night meal which had
akee fruit in salad. He had three episodes of vomiting
and collapsed. His blood sugar was determined and it
was 35mg/dl.
• What is the probable diagnosis? Explain the cause?
Ans:
• A. Jamaican vomiting sickness.
• B. the patient had consumed unripe ackee fruit, which
has a toxin,Hypoglycin inhibits beta oxidation. The
enzyme inhibited are short chain and medium chain
Acyl Co A dehydrogenases.
• The symptoms are reflective of hypoglycaemia.
Case 2:

• A 2 year old girl was brought to genetic

clinic with dysmorphic facial features and
developmental delay. Her diet consisted
more of dairy products. Her blood levels of
VLCFA and phytanic acid were elevated.
• What is the diagnosis? Explain the cause?
• Diagnosis: refsum disease.
• Inherited defect caused by the defect in alpha
oxidation of branched chain chain fatty acids
which affects the metabolism of phytanic acid.
• The phytanic acid is high in dairy product and
meat.
Case: 3
• A 20 year old college student presented with complaints
of recurrent muscle pain in the limbs and shoulder. He
was unable to move his arms and legs. He noticed dark
coloured urine after exercise in gym. His creatine kinase
levels was 100 time the upper limit of normal. His
plasma acyl carnitine and free carnitine levels were high.
• Possible diagnosis?
• Ans. CPT II deficiency.
Hypoglycaemic encephalopathy and lichi
fruit consumption by children.
• Hypoglycin in Ackee fruit

• MCPG ??methylene cyclo propyl glycine inhibit fatty acid oxidation.

• Fasting and eating lichi and Bihar death mystery of children. ?????
• Not only Akee fruit , even eating lichi in fasting state is also associated
with hypoglycemic encephalopathy in children .
• MCPG inhibits fatty acid oxidation thus inhibit gluconeogenesis.