phenylketonuria #

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PHENYLKETONURIA By : NATHIYA

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Page 1: Phenylketonuria #

PHENYLKETONURIA

By :

NATHIYA

Page 2: Phenylketonuria #

Case report :

Summary :

A.R. is a six year old Malay boy was referred

to Hospital with the problem of aggressive behaviour

and developmental delay. He was born in Mecca,

Saudi Arabia after an uneventful pregnancy.

His mother noticed at the age of three months

that her child was rather quiet and could not hold his

head up. He rolled over at eight months, sat without

support at twenty months, walked at two years and

talked with meaning at three years of age.

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At about one year old the mother noticed that

his normal black hair gradually changed to light

brown.

There was no history of light hair on both

parental sides. The child also had no history of

fits or skin rashes.

The parents were first cousins and one of the

maternal grandfathers was mentally retarded.

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WHAT PKU IS ?

Phenylketonuria is an autosomal recessive disorder

caused by mutations in the phenylalanine hydroxylase

(PAH) gene.

It results in the accumulation of phenylalanine (Phe),

an essential amino acid mainly metabolized in the liver

by the phe hydroxylase (PAH) system.

This enzyme hydroxylates Phe to tyrosine requiring

tetrahydrobiopterin (BH4) as a co-factor.

Defects in either PAH or the production or recycling of

BH4 may result in hyperphenilalaninemia which can

cause intellectual disability if untreated.

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Clinical examination :

A stunted child with height and weight below the 3rd

centile and with light brown hair.

He was very playful, hyperactive and shouted whenever

he wanted something.

He was very destructive and aggressive towards other

children.

He could not follow simple instructions and was unable

to read, write alphabetical letters or even perform simple

arithmatics.

The gross motor development was normal.

His mental age was assessed to be below 3.5 years old.

Apart from mental retardation the neurological

examination was normal.

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Investigations :

normal blood counts, blood glucose and electrolytes.

Urine ferric chloride test was positive .

Dinitro-phenyl hydrazine test (ANPH) was also positive.

Plasma amino-acid chromatography revealed the

phenylalanine band was increased.

The other siblings and the parents were screened but did

not reveal- any abnormality: EEG and computerised

tomography of the brain were normal.

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The PAH gene is located on chromosome 12 in the band

12q22-12q24.2 . More than 400 disease-causing

mutations have been found in the PAH gene. This is an

example of allelic genetic heterogeneity.

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# Mutations in PAH gene mostly result from an arginine111 to tyrosine111 in exon3 point mutation of the PAH gene.

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PKU AFFECTED INFANTS :

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Classic PKU (PHE LEVELS : >20mg/dl)

Classical PKU, and its less severe forms "mild PKU" and

"mild hyperphenylalaninemia" are caused by a mutated

gene for the enzyme phenylalanine hydroxylase (PAH),

which converts the amino acid phenylalanine to

tyrosine.

Tyrosine is necessary for the production of

neurotransmitters like epinephrine, norepinephrine, and

dopamine.

PKU may resemble amyloid diseases, such as

Alzheimer's disease and Parkinson's disease, due to the

formation of toxic amyloid-like assemblies of

phenylalanine.

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White matter abnormalities:A decrease in

myelination levels of

extrapyramidal neurons

and glial cells where this

reduction is caused by

the transformation

of oligodendrocytes to

non-myelinating

phenotypes. This loss of

white matter is more

visible in periventricular

regions and the forceps

major and minor of the

corpus callosum in cortex.

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Gray matter abnormalities :

gray matter loss is most

prominent in motor and pre-

motor cortex, thalamus and

the hippocampus.

Interestingly, in certain

studies, an increase in gray

matter volume is observed in

ventral regions of striatum.

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Atypical Phenylketonuria: Tetrahydrobiopterin-deficient hyperphenylalaninemia

A rarer form of hyperphenylalaninemia.

Occurs when the PAH enzyme is normal, and a defect is found in

the biosynthesis or recycling of the cofactor tetrahydrobiopterin .

BH4 is necessary for proper activity of the enzyme PAH, and

this coenzyme can be supplemented as treatment.

Tetrahydrobiopterin is a cofactor in the production of L-DOPA from

tyrosine and 5-hydroxy-L-tryptophan from tryptophan, which

must be supplemented as treatment in addition to the

supplements for classical PKU.

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Genetic defects:

Tetrahydrobiopterin deficiency can be caused by defects in four genes.

They are known as HPABH4A, HPABH4B, HPABH4C, and HPABH4D.

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Maternal PKU:

It was discovered that almost all offspring of women

with PKU not treatement are clinically abnormal (

delayed development , microcephaly , growth imparment

).

As predicted by mendelian inheritance all children are

heterozygotes.

Therefore their neurological development delay is not

due to their genetic constitution but due to

highly teratogenic effect of elevated effect of

phenylalanine in the maternal circulation .

Accordingly, a women with PKU who Is planing

pregnancies commence a low – phenylalanine diet

before and throughout her pregnancy.

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SYMPTOMS:

seizures,

hypopigmentation (excessively fair hair and skin), and

a "musty odor" to the baby's sweat and urine (due

to phenylacetate, a carboxylic acid produced by the oxidation

of phenylketone) , pale hair and skin.

If untreated,

Children often fail to attain early developmental milestones,

develop microcephaly, and demonstrate progressive impairment of

cerebral function. Hyperactivity and severe learning disabilities are

major clinical problems .

A characteristic "musty or mousy" odor on the skin, as well as a

predisposition for eczema.

The damage done to the brain if PKU is untreated during the

first months of life is not reversible.

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Diagnosis:

1.Classic PKU :

The method of choice is TANDEM MASS

SPECTROMETRY (MS/MS) identifies with low – false

positive rate , excellent accuracy and precision .

dietary phe deficiency can be manifested by

lethargy, failure to thrive , anorexia , anemia ,

rashes , diarrhea and even death.

normal plasma phe levels : neonates (under 12yrs ) -

b/w 2-6 mg/dl.

Older individuals - b/w 2-10mg/dl.

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2. hyperphenylalanemia due to

deficiency of BH4:

• Hyper salivation

• Measurement of neopterin and biopterin in body fluids especially in urine.

1. CSF examination-analysing the

decresed levels of dopamine,seratonin & their metabolities.

2. BH4 loading test

3. Enzyme assay – DHPR measurement in dry blood spots.

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Are there any prenatal test for pku?

Chorionic villus

sampling (CVS) is a

prenatal test that is used

to detect birth defects,

genetic diseases, and

other problems during

pregnancy.

During the test, a

small sample of cells

(called chorionic villi) is

taken from the placenta

where it attaches to the

wall of the uterus.

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Newborn screening:

Newborn screening is the process of testing newborn babies for some serious, but treatable, conditions.

NBS can include a heel stick, hearing screen, and pulse oximetry.

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Medication for pku :

The U.S. Food and Drug Administration (FDA)

has approved the drug sapropterin

dihydrochloride (Kuvan®) for the treatment of PKU.

Kuvan® is a form of BH4, which is a substance

in the body that helps break down

phenylalanine.

Even if the medication helps, it will not

decrease the phenylalanine to the desired

amount and must be used together with the

PKU diet.

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Life long supplementation with neurotransmitter

precursors such as L-dopa and 5 –

hydroxytryptophan, along with carbidopa.

Supplementation with follinic acid in patient with

DPHR deficiency.

Some drugs such as trimethoprim-sulfamethoxazole,

methotrexate,and other antileukemic agents are

known to inhibit DHPR enzyme activity and should

be used in great causion in patients with BH4

deficiency .

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Gene therapy:

A functional recombinant PAH gene is targeted to the liver, since the activity of PAH is

primarily in the liver.

Fang et al. (1994) infused a recombinant adenoviral vector containing the human PAH-

cDNA into the liver through the portal vein of PKU mice.

Within one week, complete normalization of the serum phenylalanine levels was achieved

in these PKU mice .

Furthermore, correction did not persist beyond 40 weeks with blood phe returning to

pretreatment levels .

The use of self-complementary AAV vectors resulted in normalisation of

hyperphenylalaninaemia for up to 80 weeks in both males and females .

Although correction in females was achieved, gender specific differences were also

apparent using this vector, and therefore larger doses of the vector had to be used for

females.

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Dietary therapy:

To prevent any irreversible neurological damage that results from excess blood

and consequently brain Phe in PKU patients, dietary treatment must commence

in the neonatal period and adhered to for life.

Complications :

(I) dietary compliance due to unpalatability of the diet;

(II) persisting neurological or psychosocial issues and poor quality of life despite

early intervention;

(III) potential nutritional deficiencies resulting from restrictive diet;

(IV) financial burden due to the cost of special medical food and dietary

supplements.

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Other treatments :

Enzyme therapy

Phenylalanine ammonia-lyase (PAL)

PAL is an enzyme that catalyses the conversion of Phe to transcinnamic acid and insignificant amounts of ammonia .

Unlike the mammalian enzyme (PAH), PAL is a monomer and requires no cofactors .

Oral administration is one of the most convenient ways of delivering drugs, as it is less invasive than intravenous or subcutaneous injections. However, in general oral delivery of enzymes have been complicated by the low gastric pH.

To increase oral bioavailability of enzymes, various strategies have been used, such as encapsulation of the protein or the use of live microorganisms as delivery system.

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• Probiotics : “live microorganisms which, when

administered in adequate amounts, confer a health

benefit on the host”

*Bifidobacteria

*lactic acid bacteria

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References:

1) Matalon R, Michals K. Phenylketonuria: screening, treatment and maternal

PKU. [PubMed]

2) Gonzalez, Jason; Willis, Monte S. (Feb 2010). "Ivar Asbjorn Folling

Discovered Phenylketonuria (PKU)". Lab Medicine. 41 (2): 118–119.

3) Marsden DL, Rohr FJ, Costas KC. Inborn errors of metabolism: Nutritional

Management of Phenylketonuria. In: Benjamin C, editors. Encyclopedia of

Human Nutrition. Oxford: Elsevier, 2005:22-7.

4)Williams, Robin A; Mamotte, Cyril DS; Burnett, John R

(2008). "Phenylketonuria: An Inborn Error of Phenylalanine Metabolism". The

Clinical Biochemist.

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