- Phytanic acid is a branched-chain fatty acid found in dairy and ruminant products that is normally broken down via α-oxidation and β-oxidation pathways. - Refsum disease is caused by an inability to break down phytanic acid due to a deficiency in the enzyme phytanoyl-CoA hydroxylase, leading to its accumulation and neurological damage. - Symptoms include night blindness, loss of smell, deafness, skin problems, and loss of balance. Treatment focuses on severely restricting dietary sources of phytanic acid and plasma exchange may be used in severe cases.

1. PHYTANIC METABOLISM
PATHWAY AND REFSUM
DISEASE
Nguyen Tran Bao Chau
A1806014

2. Introduction
•Phytanic acid is know as
branched-chain fatty acid.
•It exists in small amounts of
dairy product, milk and tallow
of ruminant.
•Phytanic acid is biologically-
functional fatty acid can
prevent metabolic syndrome,
type 2 diabetes as well as
prevent breast, colon and other
cancers

3. 𝜶–oxidation𝜷–oxidation
𝜷–oxidation
• Because of the methyl group located at Carbon-3 so phytanic acid
cannot be degraded via β- oxidation like other fatty acids.
• In healthy people, degradation of phytanic acid starts by 𝜶–oxidation
step, follow by β- oxidation of pristanic acid.
• Small amounts of phytanic acid can be degraded via the alternative way
of ω-oxidation.
𝛚-oxidation
H2O and CO2
𝜔- and (𝜔-1)-
hydroxyphytanic
acids
𝜷–oxidation
H2O and CO2
Phytanic acid
Pristanic acid

4. • Phytanic acid
(C20H40O2)
• Pristanic acid
(C19H38O2)
Phytanic acid is degraded by 𝛼–oxidation
and produce pristanic acid
Accumulated too
much Phytanic acid
Neurological
damage
Rehsum disease
Lacking of enzyme
in 𝛼–oxidation

5. Phytanoyl-CoA hydroxylase
Phytanic acid
Pristanic acid
x
Lacking the enzyme
phytanoyl-CoA-hydroxylase
α-oxidation being blocked
Refsum disease
Neurological damage &
cardiac dysfunctions
which can even lead to death
Accumulation of phytanic acid

6. Classification
> 90% of patients
have deficiency of phytanoyl-CoA hydroxylase
encoded by the PHYH gene
< 10% of
patients
have a deficiency
of the PTS 2
receptor encoded
by PEX7 gene
Refsum disease patients

7. Phytanic acid ω-oxidation, an alternative
mechanism to degrade phytanic acid
Small amount of phytanic acid can be degrade by an
alternative way: 𝝎-oxidation.
Phytanic acid is hydroxylated and produce 𝜔- and (𝜔-1)-
hydroxyphytanic acid
𝜷–oxidation 𝜶–oxidation 𝛚-oxidation
𝜔- and (𝜔-1)-
hydroxyphytanic acids

8. ω-oxidation of phytanic acid
pH=7.7
(50 mM potassium
phosphate and 50 mM
pyrophosphate)
GC–MS chromatograms of extracts of
human and rat liver microsomes with or
without NADPH
The effect of pH on the formation of 𝜔-
hydroxyphytanic acid (𝜔-HPA)

9. The effect of the phytanic acid concentration on the formation of
𝜔-hydroxyphytanic acid (𝜔-HPA)
•
𝑚ethyl−𝛽−cyclodextrin
phytanic acid
is constant
• pH = 7.7
• NADPH = 1mM
ω-oxidation of phytanic acid

10. • Imidazole antimycotics effect on 𝜔-hydroxylation as inhibitors
• Imidazole derivatives: bifonazole, clotrimazole, ketoconazole, and
miconazole inhibit the 𝜔-hydroxylation.
Effect of different imidazole antimycotics on the 𝜔- and (𝜔-1)-
hydroxylation of phytanic acid.
𝜔-hydroxyphytanic acid (𝜔-1)-hydroxyphytanic acid

11. Symptoms of Refsum disease
Night blindness
Loss of the sense of smell
Weakness and pain in feet Dry, scaly skin
Deafness
Loss of balance

12. Loss of balance
Feet pain
Deafness
Loss of the sense
of smell
Night blindness
Dry, scaly skin

13. Refsum disease is inherited
in an autosomal recessive
manner
 25% chance of being
unaffected and not a
carrier
 50% chance of being an
asymptomatic carrier
 25% chance of being
affected

14. Treatment
Tolerance daily
intake of
phytanic acid is
≤ 10 mg/day
Follow the
restriction
diet
Restrict and avoid
consumption of
Ruminant animals and
certain fish, such as tuna,
cod, and haddock
Milk and dairy product
Certain vegetable, such
as red/yellow bell
pepper and rocket salad

15. Treatment Patients can require plasma exchange in which
blood is drawn, filtered, and reinfused back into
the body, to control phytanic acid.
For patients with
severe and rapidly
worsening condition
For patients with
failure of dietary
management

16. Medium chain fatty acids
H2O CO2
Phytanic
metabolism
pathway
Mitochondrial β-oxidation

17. Conclusion
• Phytanic acid is degraded by α-oxidation and 𝝎-oxidation.
• Refsum disease is a neurological disease that results in the over-
accumulation of phytanic acid in cells and tissues.
• Main reason is lacking the enzyme phytanoyl-CoA-hydroxylase
leads to α-oxidation being blocked induce Refsum disease.
• The disease usually begins in late childhood with increasing night
blindness, deafness, and other symptoms.
• Treatment for Refsum disease is to avoid foods that contain
phytanic acid, including dairy products; ruminant animals; fatty
fish and certain vegetables.
• Pharmacological up-regulation of the 𝝎-oxidation of phytanic acid
may form the basis of the new treatment strategy for Refsum
disease in the new future.

18. References
1. Krauß, S., et al. Phytyl fatty acid esters in vegetables pose a risk for
patients suffering from Refsum’s disease. PLOS One, 12, 1-11 (2017)
2. Horton Jr, A. M, et al. eds. The Encyclopedia of Neuropsychological
Disorders. Springer Publishing Company, (2011)
3. Baldwin, E. J., et al. The effectiveness of long-term dietary therapy in
the treatment of adult Refsum disease. Journal of Neurology,
Neurosurgery & Psychiatry 81, 954-957 (2010)
4. Wanders, R. J. A., Komen, J. C. Peroxisomes, Refsum's disease and the
α-and ω-oxidation of phytanic acid. Biochemical Society Transactions,
35, 865-869 (2007)
5. Komen, J.C., et al. Characterization of phytanic acid ω-hydroxylation in
human liver microsomes. Molecular Genetics and Metabolism, 85, 190-
195 (2005)
6. Van den Brink, D. M., et al. Identification of PEX7 as the second gene
involved in Refsum disease. The American Journal of Human
Genetics, 72, 471-477 (2003)
7. Wierzbicki, A. S., et al. Refsum's disease: a peroxisomal disorder
affecting phytanic acid α‐oxidation. Journal of Neurochemistry, 80, 727-
735 (2002)

19. Thank you for your attention