INBORN ERRORS OF METABOLISM, PKU, PHENYLKETONURIA, BY: MR. DINABANDHU BARAD, MSC TUTOR, SUM NURSING COLLEGE, SIKSHA O ANUSANDHAN DEEMED TO BE UNIVERSITY, BHUBANESWAR, ODISHA

1. PHENYL KETONURIA
PRESENTED BY:
MR. DINABANDHU BARAD
MSC TUTOR, SNC, SOA,DTU

2. METABOLIC DISORDER
• Metabolism is the aggregate of the chemical reactions that are
continuously occurring in the living organisms to keep them alive.
• The principal function of the metabolism are the production of energy,
elimination of the nitrogen wastes, making building blocks for
carbohydrate, protein and fat.

3. METABOLIC DISORDER
• Numerous chemical reactions are occurring at the subcellular level at the
same time that are controlled by specific proteins or enzymes.
• Any defect in these proteins or enzymes may lead to defect in the metabolic
process and in turn leads to the disorders.

4. METABOLIC DISORDER
• The metabolic disorders or the inborn errors of metabolism are the group of rare
genetic disorders most of which are autosomal recessive, some are x-linked
recessive and few are autosomal dominant.
• Although these are very rare kind of genetic defects till now more than 500 in
born errors of metabolism diseases are identified.

5. CLASSIFICATION
The common groups of in born errors of metabolism with example are listed below
AMINO ACID METABOLISM DEFECT
A) Defective metabolism
(Phenylketonuria, Maple Syrup Urine Disease (MSUD), alkaptonuria,
tyrosinemia, albinism)
B) Defective transport
(Cystinosis, Cysturia, Hartnup disease, Lysinuric protein intolerance)

6. CLASSIFICATION
CARBOHYDRATE METABOLISM DEFECT
A. Galactosemia
B. Glucose 6 phosphate dehydrogenase(G6PD) deficiency
C. Pyruvate dehydrogenase deficiency
D. Carbohydrate intolerance disorders (Lactose intolerance, Heriditary fructose
intolerance)
E. Fructosuria
F. Pentosuria
G. Mucopolysachharidosis and oligosacharidosis
H. Glycogen storage disorders
Type-I (Von Gierke’s disease), Type-II (Pompe’s disease), Type-III (Cori’s disease), Type-IV
(Anderson’s disease), Type-V (Mc Ardle’s disease), Type-VI (Her’s disease), Type-VII
(Tauri’s disease)

7. CLASSIFICATION
LIPID METABOLISM DEFECT
A. Fatty acid oxidation defects
(Zellweger’s syndrome, Carnitine deficiency, refsum’s disease)
B. Lipid storage defects
(Tay-Sachs disease, Gaucher’s disease, Niemann pick disease, farber’s
disease, fabry’s disease, Krabbe’s disease)
C. Lipoprotein metabolism defects
Hyperlipoproteinaemias, Hypolipoproteinaemias (Tangier’s disease, A-
beta Lipoproteinaemia)

8. CLASSIFICATION
MINERAL METABOLISM DEFECT
(Wilson disease, Menkes Kinky hair disease, hemochromatosis)
PURINE AND PYRIMIDINE METABOLISM DEFECT
(Lesch-Nyhan disease)
MITOCHONDRIAL DISEASES
(Leigh disease, myoclonic epilepsy ragged red fibers (MERRF), Leber
hereditary optic neuropathy)

9. PHENYLKETONURIA
• It is an autosomal recessive disorder caused by defective metabolism of the
amino acid phenylalanine.
• Normally phenylalanine converts to tyrosine by the enzyme called phenylalanine
hydroxylase.
• This enzyme is encoded by the gene PAH located in the q arm of chromosome 12
(Chr. 12q23.2).

10. PHENYLKETONURIA
• Therefore mutation in this locus causes the deficiency of the enzyme which leads
to failure of conversion and finally there is accumulation of phenylalanine in the
blood, CSF and other tissues.
• The severity of the hyperpheynylalaninemia depends on the degree of enzyme
deficiency which may differ from very high plasma concentrations >20mg/dl
(Classic PKU) to mild elevation 2-6mg/dl.

11. PHENYLKETONURIA
• The excess amount of phenylalanine is metabolized and converted to phenyl
ketones (phenyl pyruvate and phenyl acetate) that are excreted through urine
thus justifies the name Phenylketonuria.

12. H2O
O2
METABOLIC PATHWAY
OF
PHENYLALANINE

13. TYPES OF PKU
Based on the defect of the enzymes PKU can be classified as follows:
• TYPE-I (Classical) : complete deficiency of the enzyme
Phenylalanine hydroxylase (PAH)
• TYPE-II (Variant) : Partial deficiency of enzyme PAH
• TYPE-III (Transient): Delayed maturation of PAH
• TYPE-IV : Deficiency of Dihydrobiopterin reductase
• TYPE-V : Deficiency of Dihydrobiopterin synthetase lead
to defective biosynthesis Of Dihydrobiopterin

14. ETIOLOGY
• Approximately 97% of the cases are affected with the phenylalanine hydroxylase
deficient PKU in which the enzyme PAH is partially or completely deficient and in
few cases there is immature phenylalanine hydroxylase which has altered
function.
• The deficiency of PAH is due to the mutation in the gene PAH which provides
instructions to make the enzyme Phenylalanine hydroxylase.

15. ETIOLOGY
• PAH gene is located in the q arm of the chromosome 12 at the locus 12q23.2
between 102,836,889bp-102,958,410 bp.
• There are more than 500 mutations identified till now in the PAH gene which
leads to PKU.

16. ETIOLOGY
• Most of the mutations are the point mutation which replaces single codon on the
DNA sequence thereby change the corresponding amino acid.
• The most common point mutation is the replacement of the amino acid arginine
with tryptophan at the position 408 (written as Arg408Trp or R408W).

17. CLASSIC PHENYLKETONURIA
When severe hyperphenylalaninemia (>20mg/dl in plasma) remain untreated it
shows sign symptoms of classic PKU except rare cases.
Clinical Features:
• The infants affected with classic PKU do not show sign symptoms at birth but
gradually begin to develop neurological manifestations due to accumulation of
excess phenylalanine in the brain which causes destruction of myelin sheath.

18. CLASSIC PHENYLKETONURIA
When severe hyperphenylalaninemia (>20mg/dl in plasma) remain untreated it
shows sign symptoms of classic PKU except rare cases.
Clinical Features:
• The neurological features can be intellectual disability, seizure, behavioural
problems, delayed development etc.
• Excess phenylalanine also interfere with the neurotransmitters like dopamine and
serotonin causing depression.

19. CLASSIC PHENYLKETONURIA
When severe hyperphenylalaninemia (>20mg/dl in plasma) remain untreated it
shows sign symptoms of classic PKU except rare cases.
Clinical Features:
• High level of phenylalanine also impede the melanin production that leads to
light colour of the eye, skin and hair.
• Excretion of the phenyl acetic acid (phenyl ketone) in urine and sweat causes
musty or mousy odour of the body.

20. MILD HYPERPHENYLALANINEMIA
When the plasma concentration of phenylalanine is between 2-20 mg/dl is called
mild hyperphenylalaninemia or non-PKU hyperphenylalaninemia.
• The infants suffering from mild hyperphenylalaninemia have partial deficiency of
the phenylalanine hydroxylase enzyme or Tetrahydrobiopterin (BH4)
Clinical features:
• Clinically these infants don’t reveal any sign symptoms but progressive brain
damage may occur with age.

21. DIAGNOSIS
PHYSICAL EXAMINATION FOR CLASSICAL PKU
• The affected infants have lighter eye, skin and hair colour as compare to the
normal infants.
• They may have Musty or mousy body odour. Microcephaly, Growth retardation,
wide gap between the teeth also can be seen.

22. DIAGNOSIS
LAB INVESTIGATIONS
According to the recommendation of American academy of pediatric PKU
screening should be repeated by two weeks of age if it is performed before the
newborn was 24h of age. PKU screening can be performed by the following
methods:
• Guthrie Bacterial Inhibition Assay
• McCamon Robins Flurometric test
• Tandem mass spectrometry

23. DIAGNOSIS
DNA analysis:
It is useful to detect specific mutation in the affected gene for which following methods are used:
• Sanger sequencing
• Next Generation sequencing (NGS)
• Multiplex ligation dependent probe amplification (MLPA)
• Whole exome sequencing
• PCR based technique

24. DIAGNOSIS
IMAGING STUDY:
• In research studies cranial CT scan on patients with 6-pyruvoyl tetrahydropterin
synthase (PTPS) deficiency revealed calcification in the lentiform nuclei and in
patients with Dihydropteridine reductase (DHPR) deficiency there was severe
cortical and subcortical atrophy.

25. DIAGNOSIS
IMAGING STUDY:
• MRI studies on patients with BH4 deficiency showed white matter changes and on
patients with PTPS deficiency showed delayed myelination and abnormal high
intensity signals in cerebral white matter.
• So imaging study can be used to understand and monitor the neurophysiological
changes of the affected patients but this may not be appropriate for a newborn.

26. TREATMENT
Diet therapy:
• The aim of the treatment is to lower and maintain the plasma phenylalanine level
between 2-6 mg/dl at least till 12 years of age.
• The infant with persistent plasma phenyl alanine level >6mg/dl are treated with
phenylalanine restricted diet.
• But infant having plasma phenylalanine level between 2-6mg/dl are not required
any diet restriction.

27. TREATMENT
Diet therapy:
• The foods that contains high amount of phenylalanine are fish, meat, eggs, nuts,
legumes, wheat, milk, beans etc. therefore should be avoided.
• As the body do not produce phenylalanine the infant should not be over treated
when the infant is under diet restriction otherwise it may leads to phenylalanine
deficiency.

28. TREATMENT
Diet therapy:
• There is a controversy regarding the duration of the diet restriction as
discontinuation of the therapy leads to IQ deterioration and cognitive
impairment. Current recommendation says diet restriction should be continued
lifelong.

29. TREATMENT
Pharmacological therapy:
• In case of mild form of hyperphenylalanine oral administration of
Sapropterin dihydrochloride (Tetrahydrobiopterin) is effective in reducing plasma
phenylalanine level. It is also effective in case of BH4 deficient PKU.
• Phenylalanine ammonia lyase (PAL) is currently under clinical trial which is
used as an alternative to the PAH enzyme therefore can be used in case of classic
form of phenylketonuria

30. TREATMENT
NURSING MANAGEMENT:
• Educate the family members about the diet containing phenylalanine, need and
duration of the restriction.
• Care givers of the infant need to be counselled regarding the process and
transmission of the disease from one generation to another.
• Emotional support should be provided to the parents so that they can cope with
the stress and adverse situation.
• Educate the caregivers regarding safety measures during seizure.

31. THANK YOU