HEREDITARY DEFECTS AFFECTING
GENERAL METABOLISM OF CNS
(Phenylalanine and Tyrosine)
MARYAM JAMILAH BINTI ABDUL HAMID
08201...
Learning outcome
• Phenylketonuria (PKU)
• Alkaptonuria
• Albinism
• Hypertyrosinemias
1)Phenylketonuria (PKU)
Intro
• Genetic mutation;
– enzyme not synthesized
– enzyme non-functional
• 1 : 1 500 (WHO)
• Phe...
Phenylketonuria
Phenylalanine Tyrosine
Phenylalanine Hydroxylase
THB DHB
NADP+ NADPH
Dihydrobiopterin reductase
GTP
Biopterin
Types of PKU
Types Biochemical Abnormalities
I (Classical)
Total deficiency of phenylalanine
hydroxylase
II (Variant)
Part...
Clinical
Features
Phenylalanine
Tyrosine
Thyroid
hormone
-creatinism
-chubby Hypopigmentation-
Melanin
Serotonin
(THB;
try...
Diagnose
1) Blood phenylalanine
– Normal: 1mg/dL
– PKU: >20 mg/dL
– Chromatography or tandem mass method
2) Guthrie’s test...
3) Ferric chloride test
– Phenylketones about 500-3000 mg/day
(PKU’s urine)
– Add a drop of ferric chloride to the urine
–...
4) DNA Probes
• Defects in phenylalanine hydroxylase
and dihydrobiopterin reductase
Treatments
1) Dietary control of blood phenylalalnine
before conception
(Maternal hyperphenylalaninemia)
2)Alkaptonuria
• Also known as ‘black urine’
• Autosomal recessive condition
• 1: 250 000 births
• Deficiency of homogenti...
Alkaptone bodies polymerizeBlack
colour
Benzoquinone
acetic acid
normal alkaptonuria
Ochronosis (ear cartilage)
Ochronosis (intervertebral disc)
Albinism
• Autosomal recessive disease
• 1: 20 000 population
• Tyrosinase completely absent
– Defective synthesis of mela...
Tyrosine
DOPA
(dihydroxy phenylalanine)
NADPH
THB
+ O2
Indolequinone
Melanin
Tyrosinase
Tyrosinase
DOPA-quinone
Albino
Hypertyrosinemias
• Normal plasma tyrosine concentration:
30 to 120 micromol/L
• Hypertyrosinemia: >200 micromol/L
• Clini...
Hepatorenal
Tyrosinemia
• Tyrosinosis
• Autosomal recessive
• 1.5: 1000
• Defieciency fumaryl acetoacetate
hyrdrolase
• Sy...
• Mild mental retardation
• Tyrosine, para-hydroxyphenylpyruvic acid
(p-HPPA) & hydroxyphenyllactic acid
(Urine)
• Tyrosin...
Oculocutaneous
Tyrosinemia
• Deficiency of tyrosine amino transferase
• Mental retardation
• Keratosis of palmar surface
•...
Neonatal Tyrosinemia
• Absence of para-hydroxyphenlypyruvate
hydroxylase
• Transient hypertyrosinemia in new born
• Admini...
Hereditary p-HPPA Oxidase deficiency
• More aggressive
• Neurological abnormalities
• Excretion of tyrosine, p-HPPA,
hydro...
References
• DM Vasudevan, Biochemistry Textbooks
For Medical Students
Hereditary defects affecting general metabolism of CNS (Phenylalanine) (Tyrosine)
Hereditary defects affecting general metabolism of CNS (Phenylalanine) (Tyrosine)
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Hereditary defects affecting general metabolism of CNS (Phenylalanine) (Tyrosine)

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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

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Hereditary defects affecting general metabolism of CNS (Phenylalanine) (Tyrosine)

  1. 1. HEREDITARY DEFECTS AFFECTING GENERAL METABOLISM OF CNS (Phenylalanine and Tyrosine) MARYAM JAMILAH BINTI ABDUL HAMID 082013100002 IMS BANGALORE
  2. 2. Learning outcome • Phenylketonuria (PKU) • Alkaptonuria • Albinism • Hypertyrosinemias
  3. 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. 4. Phenylketonuria
  5. 5. Phenylalanine Tyrosine Phenylalanine Hydroxylase THB DHB NADP+ NADPH Dihydrobiopterin reductase GTP Biopterin
  6. 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. 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. 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. 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. 10. 4) DNA Probes • Defects in phenylalanine hydroxylase and dihydrobiopterin reductase
  11. 11. Treatments 1) Dietary control of blood phenylalalnine before conception (Maternal hyperphenylalaninemia)
  12. 12. 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
  13. 13. Alkaptone bodies polymerizeBlack colour Benzoquinone acetic acid
  14. 14. normal alkaptonuria Ochronosis (ear cartilage) Ochronosis (intervertebral disc)
  15. 15. 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
  16. 16. Tyrosine DOPA (dihydroxy phenylalanine) NADPH THB + O2 Indolequinone Melanin Tyrosinase Tyrosinase DOPA-quinone
  17. 17. Albino
  18. 18. 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
  19. 19. 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
  20. 20. • Mild mental retardation • Tyrosine, para-hydroxyphenylpyruvic acid (p-HPPA) & hydroxyphenyllactic acid (Urine) • Tyrosine in serum • Restricted diet on tyrosine & phenylalanine
  21. 21. 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
  22. 22. Neonatal Tyrosinemia • Absence of para-hydroxyphenlypyruvate hydroxylase • Transient hypertyrosinemia in new born • Administer ascorbic acid & restrict protein diet
  23. 23. Hereditary p-HPPA Oxidase deficiency • More aggressive • Neurological abnormalities • Excretion of tyrosine, p-HPPA, hydrocyphenyllactic & hydroxy phenylacetic acid in urine
  24. 24. References • DM Vasudevan, Biochemistry Textbooks For Medical Students
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