Transcript INHERİTED DİSEASES OF AMİNO ACİD METABOLİSM

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.
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• 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 LDopa to Dopamine
• AADC also catalyzes the conversion of 50H 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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