inherİted dİseases of amİno acİd metabolİsm
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INHERİTED DİSEASES OF AMİNO ACİD METABOLİSM
Prof.Dr.Arzu SEVEN
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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
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• Unusual gait, stance, sitting posture
• High frequency of epilepsy
• Autosomal recessive
• Phenylalanine hydroxylase :Mixed function oxidase that uses cofactor (tetrahydrobiopterin ) and molecular oxygen
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• 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
• .• .
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• 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.
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• 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.
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• 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
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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.
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• 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.
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• Severe movement disorder +abnormal eye movement +neurologic impairment.
• Treatment:Monoamino oxidase inhibitors dopamine agonists (pergoliode bromocryptine)
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• 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
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• Deposition of dark (ochre-colored)pigment in cartilage tissue
severe arthritis
connective tissue pigmentation(ochronis)
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• autosomal recessive
• symptoms start in 3 rd/4 th decade
• relatively benign in comparison to PKU
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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
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• Accumulation of-keto acids and hydroxy acids (especially leucine ) in blood and urine.
• Physical and mental retardation of new born
• Distinct maple syrup odor
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• Therapy:
• Low-protein or modified diet
• Supplementation of high doses of thiamine pyrophosphate
• Limit the intake of valine, leucine, isoleucine.
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