Phenylketonuria and Alkaptonuria

Abirin, Shareif Radzmier. Alberto, Dolly Camille. Aloya, Darlen Ann

Section G-Group 1
Objectives

Define Phenylketonuria and Alkaptonuria and discuss th

e metabolic pathway involved
Give the etiology of these diseases
Discuss the genetic involvement of the diseases
Present the cardinal manifestation of the diseases and
explain the molecular basis of each manifestation
Objectives

Enumerate the different types of Phenylketonuria

Enumerate the diagnostic procedures
Discuss the management and treatment of the diseases
Phenylketonuria

 Folling’s Disease
 Autosomal recessive
 Mutation in the PAH Gene at Chromosome 12
 Has two types: Classical or Non-classical
 Defective conversion of Phenylalanine to Tyrosine
 Urine Odor: Mousy
Types of Phenylketonuria
Classical Phenylketonuria

• Severe type
• Inborn
• Near complete to complete deficiency of Phenylalanine
hydroxylase
– Leads to toxic accumulation of Phenylalanine in the
blood and brain
Non-classical Phenylketonuria

Defect in the enzyme that catalyzes the regeneration of

tetrahydrobiopterin or may be due to a defect in the
synthesis of tetrahydrobiopterin
– GTP- Cyclohydrolase
• Converts GTP to dihydroneopterin triphosphate, a
nd 6-pyruvoyl tetrahydrobiopterin synthetase red
uces 6-pyruvoyl tetrahydrobiopterin to tetrahy
drobiopterin or sepiapterin
Non-classical Phenylketonuria

Required for the formation of L-Dopa and

5-Hydroxytryptophan - Precursors of the neurotransmitte
rs norepinephrine and serotonin, respectively.
Cardinal Manifestations
Phenylketonuria

1. Hypopigmentation

2. Mental Retardation

3. Mousey Odor Urine

Alkaptonuria

1. Dark Urine

2. Ochronosis

3. Large Joint Arthritis

Diagnostic Procedures
Diagnostic Procedures (PKU)
Guthrie’s Test (Guthrie Bacterial Inhibition Assay)

– Invented by Robert Guthrie in 1962

– He discovered that phenylalanine can reverse β-2-Thi

enylalanine's inhibition of Bacillus subtilis growth

– Recommended to be done between 24 hours to 7 da

ys after birth
Diagnostic Procedures (PKU)
Guthrie’s Test (Guthrie Bacterial Inhibition Assay)

– A spot of blood on a filter paper disc is placed on the

surface of an agar plate containing substance that inh
ibits growth of the bacteria

– Confirmed by the appearance of bacteria growing

around high concentrations of phenylalanine in the bl
ood spot
Diagnostic Procedures (PKU)
Mutation Analysis and Genotype Determination

– Subsequent diagnostic procedures that can identify

the specific types of PAH gene mutations inherited by
PKU infants.
Diagnostic Procedures (AKU)
Mutation Analysis and Genotype Determination

– Subsequent diagnostic procedures that can identify

the specific types of PAH gene mutations inherited by
PKU infants.
Diagnostic Procedures (PKU)
Urine test

– Ferric chloride is added to the urine

– (+) black color

Chromatography
– For detection of significant amount of homogentisic a
cid in the urine
Diagnostic Procedures (PKU)
DNA testing

– For detection of mutation in HGD gene (codes for

homogentistate 1,2 dioxygenase)

Suggestive findings
– Dark urine
– Ochronosis
– Arthritis
Treatment and Management
Treatment and Management (PKU)
Formulation for infants
– For detection of mutation in HGD gene (codes for
homogentistate 1,2 dioxygenase)

Formulation for older children and adults

– Not the same as the one used for infants but works o
n same principle
– Acts as nutritional substitute
– Continued for life
Treatment and Management (PKU)
Sapropterin (Kuvan)
– Helps lower phenylalanine levels
– Works by increasing phenylalanine tolerance
Treatment and Management (AKU)

• No preventive or curative treatment is available

• Dietary restriction of phenylalanine and tyrosine

• Vitamin C