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