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

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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 3

Unusual gait, stance, sitting posture High frequency of epilepsy Autosomal recessive Phenylalanine hydroxylase :Mixed function oxidase that uses cofactor (tetrahydrobiopterin ) and molecular oxygen 4

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. 5

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. 6

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. 7

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. 8

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

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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. 11

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. 12

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

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 14

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

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

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 18

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

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

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