Hereditary defects affecting general metabolism of CNS (Phenylalanine) (Tyrosine)
-
Upload
autumnpianist -
Category
Education
-
view
369 -
download
3
description
Transcript of Hereditary defects affecting general metabolism of CNS (Phenylalanine) (Tyrosine)
HEREDITARY DEFECTS AFFECTING GENERAL METABOLISM OF CNS
(Phenylalanine and Tyrosine)
MARYAM JAMILAH BINTI ABDUL HAMID082013100002
IMS BANGALORE
Learning outcome
• Phenylketonuria (PKU)
• Alkaptonuria
• Albinism
• Hypertyrosinemias
1)Phenylketonuria (PKU)
Intro• Genetic mutation;– enzyme not synthesized– enzyme non-functional
• 1 : 1 500 (WHO)• Phenylalanine in serum• Minor pathways are opened• 5 types
Phenylalanine Tyrosine
Phenylketonuria
PhenylalanineTyrosine
Phenylalanine Hydroxylase
THB DHB
NADP+ NADPH
Dihydrobiopterin reductase
GTP
Biopterin
Types of PKUTypes Biochemical Abnormalities
I (Classical) Total deficiency of phenylalanine hydroxylase
II (Variant) Partial deficiency of phenylalanine hydroxylase
III (Transient) Delay maturation of phenylalanine hydroxylase
IV Deficiency of dihydrobiopterin reductase deficiency
VDefective in synthesizing of dihydrobiopterin; dihydrobiopterin synthase
Maternal -genetic inborn error-mother has hyperphenylalaninemia
Clinical Features
Phenylalanine Tyrosine
Thyroid hormone
-creatinism-chubby Hypopigmentation-
Melanin
Serotonin(THB;
tryptophan)
CNS symptoms-failure to grow,
walk, talk, microcephaly, convulsions,
mental retardation &
low IQ
Phenylketones(mousy and
musty odour of urine and sweat)
Catecholamines
In serum
Diagnose1)Blood phenylalanine– Normal: 1mg/dL– PKU: >20 mg/dL– Chromatography or tandem mass
method
2)Guthrie’s testBaccillus subtilis needs Phenylalalnine to
grow– Normal urine + B. Subtilis = no growth– PKU urine + B. Subtilis = growth of
bacteria
3) Ferric chloride test
– Phenylketones about 500-3000
mg/day (PKU’s urine)
– Add a drop of ferric chloride to the
urine
– Positive: transient blue-green colour
– Negative: no change
– Now, it’s not widely use anymore
4) DNA Probes• Defects in phenylalanine hydroxylase and dihydrobiopterin reductase
Treatments1)Dietary control of blood
phenylalalnine before conception(Maternal hyperphenylalaninemia)
2)Alkaptonuria
• Also known as ‘black urine’
• Autosomal recessive condition
• 1: 250 000 births
• Deficiency of homogentisate
oxidase
• Living a normal life in early to middle
ages
Alkaptone bodies polymerizeBlack colour
Benzoquinone acetic acid
normal alkaptonuria
Ochronosis (ear cartilage)
Ochronosis (intervertebral disc)
Albinism• Autosomal recessive disease• 1: 20 000 population• Tyrosinase completely absent– Defective synthesis of melanin
• Photophobia, nystagmus and decreased visual acuity
• 2 types: ocular albinismocular cutaneous albinism
Tyrosine
DOPA(dihydroxy phenylalanine)
NADPHTHB
+ O2
Indolequinone
Melanin
Tyrosinase
TyrosinaseDOPA-quinone
Albino
Hypertyrosinemias• Normal plasma tyrosine concentration:
30 to 120 micromol/L
• Hypertyrosinemia: >200 micromol/L
• Clinical manifestation: >500 micromol/L
• 3 types:-
–Hepatorenal Tyrosinemia
–Oculocutaneous Tyrosinemia
–Neonatal Tyrosinemia
Hepatorenal Tyrosinemia
• Tyrosinosis• Autosomal recessive• 1.5: 1000• Defieciency fumaryl acetoacetate
hyrdrolase• Symptoms: first 6 months and death
occur rapidly• Cabbage like odor, then
hypoglycemia, then liver failure
• Mild mental retardation• Tyrosine, para-hydroxyphenylpyruvic
acid (p-HPPA) & hydroxyphenyllactic acid (Urine)
• Tyrosine in serum• Restricted diet on tyrosine &
phenylalanine
Oculocutaneous Tyrosinemia
• Deficiency of tyrosine amino transferase
• Mental retardation• Keratosis of palmar surface• Painful corneal lesions • Photophobia• tyrosine and tyramine in urine• Low protein diet
Neonatal Tyrosinemia
• Absence of para-
hydroxyphenlypyruvate hydroxylase
• Transient hypertyrosinemia in new born
• Administer ascorbic acid & restrict
protein diet
Hereditary p-HPPA Oxidase deficiency
• More aggressive
• Neurological abnormalities
• Excretion of tyrosine, p-HPPA,
hydrocyphenyllactic & hydroxy
phenylacetic acid in urine
References• DM Vasudevan, Biochemistry
Textbooks For Medical Students