INHERİTED DİSEASES OF AMİNO ACİD METABOLİSM

1. INHERİTED DİSEASES OF AMİNO ACİD METABOLİSM Prof.Dr.Arzu SEVEN

3. PHENILKETONURIA(PKU) • Deficiency of phenylalanine hydroxylase or a defect in biosynthesis/reduction of tetrahidrobiopterin • Urinary excretion of phenlypruvate and phenyllactate • Defective neural development • Severe mental retardation • Very light skin pigmentation

4. Unusual gait, stance, sitting posture • High frequency of epilepsy • Autosomal recessive • Phenylalaninehydroxylase :Mixedfunctionoxidasethatusescofactor (tetrahydrobiopterin ) andmolecularoxygen

5. Therapy:Diet restricted in phenylalanine but • supplemented with tyrosine • Don't consume protein-rich foods • Natural proteins, such as casein of milk, must be first hydrolyzed and phenylalanine removed • Foods sweetened with aspartame should be avoided • . • .

6. In patients with PKU, • Phenylalanine undergoes transaminaton with pyruvate to yield phenyl pyruvate. • Phenylpyruvate is either decarboxylated to phenylacetate or reduced to phenylactate. • Phenylacetate imports a characteristic odor to urine.

7. When there is a defect in the enzyme that catalyzes the regeneration of tetrahydrobiopterin, diet must be supplemented with L-dopa and 5-hydroxytryptophan (precursors of neurotransmitters norepinephrine and serotonin respectively) • Supplementing diet with tetrahydrobiopterin is ineffective because it is unstable and does not cross the blood-brain barrier.

8. ALBİNİSM • Lack of tyrosinase • A marked lack of pigmentation • Sensitive to damage from sunlight and must take added precaution against UV radiation • Normal eyesight • No neurologic deficits.

9. Tyrosine hydroxylase and aromatic amino acid decarboxylase deficiencies:Inherited causes of impaired biogenic amine metabolism

11. Inherited disorder affecting the activity of tyrosine hydroxylase results in brain dopamine deficiency. • Progressive gait disorder and infantile parkinsonism • Treatment: L-Dopa administration • To prevent decarboxylation of L-Dopa to dopamine in the blood by peripheric AADC, an inhibitor ,which does not affect brain AADC activity ,is given together with L-Dopa.

12. Such inhibition optimizes the transport of L-Dopa across the blood-brain barrier. • Within the brain AADC can convert L-Dopa to Dopamine • AADC also catalyzes the conversion of 5-0H tryptophan to serotonin • Inborn error affecting AADC activity results in brain deficiency of both dopamine and serotonin.

13. Severe movement disorder +abnormal eye movement +neurologic impairment. • Treatment:Monoamino oxidase inhibitors dopamine agonists (pergoliode bromocryptine)

14. ALKAPTONURİA (Black urine disease) • Lack of homogentisate oxidase • Homogentisic acid accumulates and is excreted in the urine. • This compound oxidizes on standing or on treatment with alkali, gives the urine a dark color

16. Deposition of dark (ochre-colored)pigment in cartilage tissue severe arthritis connective tissue pigmentation(ochronis)

17. autosomal recessive • symptoms start in 3 rd/4 th decade • relatively benign in comparison to PKU

18. Maple Syrup Urine Disease (MSUD ) Defect in branched-chain α keto acid dehydrogenase, a multienzyme complex associated with inner membrance of mitochondrion Branched chain ketonuria

19. Accumulation of-keto acids and hydroxy acids (especially leucine ) in blood and urine. • Physical and mental retardation of new born • Distinct maple syrup odor

20. Therapy: • Low-protein or modified diet • Supplementation of high doses of thiamine pyrophosphate • Limit the intake of valine, leucine, isoleucine.