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

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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