Hereditary defects affecting general metabolism of CNS (Phenylketonuria) (Tyrosine) -with some equations included. -Biochemistry MBBS 6 types of PKU Alkaptonuria Albinism -ocular albinism -ocular cutaneous albinism Hypertyrosinemias -Hepatorenal Tyrosinemia -Oculocutaneous Tyrosinemia -Neonatal Tyrosinemia

1. HEREDITARY DEFECTS AFFECTING
GENERAL METABOLISM OF CNS
(Phenylalanine and Tyrosine)
MARYAM JAMILAH BINTI ABDUL HAMID
082013100002
IMS BANGALORE

2. Learning outcome
• Phenylketonuria (PKU)
• Alkaptonuria
• Albinism
• Hypertyrosinemias

3. 1)Phenylketonuria (PKU)
Intro
• Genetic mutation;
– enzyme not synthesized
– enzyme non-functional
• 1 : 1 500 (WHO)
• Phenylalanine in serum
• Minor pathways are opened
• 5 types
Phenylalanine Tyrosine

4. Phenylketonuria

5. Phenylalanine Tyrosine
Phenylalanine Hydroxylase
THB DHB
NADP+ NADPH
Dihydrobiopterin reductase
GTP
Biopterin

6. Types of PKU
Types Biochemical Abnormalities
I (Classical)
Total deficiency of phenylalanine
hydroxylase
II (Variant)
Partial deficiency of phenylalanine
hydroxylase
III (Transient)
Delay maturation of phenylalanine
hydroxylase
IV
Deficiency of dihydrobiopterin reductase
deficiency
V
Defective in synthesizing of
dihydrobiopterin; dihydrobiopterin
synthase
Maternal
-genetic inborn error
-mother has hyperphenylalaninemia

7. Clinical
Features
Phenylalanine
Tyrosine
Thyroid
hormone
-creatinism
-chubby Hypopigmentation-
Melanin
Serotonin
(THB;
tryptophan)
CNS symptoms
-failure to grow,
walk, talk,
microcephaly,
convulsions,
mental
retardation &
low IQ
Phenylketones
(mousy and
musty odour of
urine and sweat)
Catecholamines
In serum

8. Diagnose
1) Blood phenylalanine
– Normal: 1mg/dL
– PKU: >20 mg/dL
– Chromatography or tandem mass method
2) Guthrie’s test
Baccillus subtilis needs Phenylalalnine to grow
– Normal urine + B. Subtilis = no growth
– PKU urine + B. Subtilis = growth of bacteria

9. 3) Ferric chloride test
– Phenylketones about 500-3000 mg/day
(PKU’s urine)
– Add a drop of ferric chloride to the urine
– Positive: transient blue-green colour
– Negative: no change
– Now, it’s not widely use anymore

10. 4) DNA Probes
• Defects in phenylalanine hydroxylase
and dihydrobiopterin reductase

11. Treatments
1) Dietary control of blood phenylalalnine
before conception
(Maternal hyperphenylalaninemia)

13. 2)Alkaptonuria
• Also known as ‘black urine’
• Autosomal recessive condition
• 1: 250 000 births
• Deficiency of homogentisate oxidase
• Living a normal life in early to middle ages

14. Alkaptone bodies polymerizeBlack
colour
Benzoquinone
acetic acid

15. normal alkaptonuria
Ochronosis (ear cartilage)
Ochronosis (intervertebral disc)

16. Albinism
• Autosomal recessive disease
• 1: 20 000 population
• Tyrosinase completely absent
– Defective synthesis of melanin
• Photophobia, nystagmus and decreased
visual acuity
• 2 types: ocular albinism
ocular cutaneous albinism

17. Tyrosine
DOPA
(dihydroxy phenylalanine)
NADPH
THB
+ O2
Indolequinone
Melanin
Tyrosinase
Tyrosinase
DOPA-quinone

18. Albino

19. Hypertyrosinemias
• Normal plasma tyrosine concentration:
30 to 120 micromol/L
• Hypertyrosinemia: >200 micromol/L
• Clinical manifestation: >500 micromol/L
• 3 types:-
–Hepatorenal Tyrosinemia
–Oculocutaneous Tyrosinemia
–Neonatal Tyrosinemia

20. Hepatorenal
Tyrosinemia
• Tyrosinosis
• Autosomal recessive
• 1.5: 1000
• Defieciency fumaryl acetoacetate
hyrdrolase
• Symptoms: first 6 months and death occur
rapidly
• Cabbage like odor, then hypoglycemia,
then liver failure

21. • Mild mental retardation
• Tyrosine, para-hydroxyphenylpyruvic acid
(p-HPPA) & hydroxyphenyllactic acid
(Urine)
• Tyrosine in serum
• Restricted diet on tyrosine &
phenylalanine

22. Oculocutaneous
Tyrosinemia
• Deficiency of tyrosine amino transferase
• Mental retardation
• Keratosis of palmar surface
• Painful corneal lesions
• Photophobia
• tyrosine and tyramine in urine
• Low protein diet

23. Neonatal Tyrosinemia
• Absence of para-hydroxyphenlypyruvate
hydroxylase
• Transient hypertyrosinemia in new born
• Administer ascorbic acid & restrict protein
diet

24. Hereditary p-HPPA Oxidase deficiency
• More aggressive
• Neurological abnormalities
• Excretion of tyrosine, p-HPPA,
hydrocyphenyllactic & hydroxy
phenylacetic acid in urine

25. References
• DM Vasudevan, Biochemistry Textbooks
For Medical Students