PKU & Tay-Sachs Disease

1. Phenylketonuria :
ıt ıs inborn error in metabolism
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It ıs autosomal recessive inheritance pattern mutations in liver enzyme, Phenylaline hydroxylase (PAH)
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It ıs can also be caused by abnormal levels of dietary phenylalanine (environmental)
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WHAT HAPPENS IN PKU?
Phenylketonuria (PKU) is a genetic disorder in which the body can't metabolize phenylalanine due to the
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absence of the phenylalanine-hydroxylase enzyme.
This results in a build up of phenylalanine to toxic levels.
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Thıs causes massıve accumulation of phenylalanine in blood, urine, tissues and brain.
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The PAH enzyme works with the cofactor tetrahydrobioptin or BH form.
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These hydroxylases are critical for the synthesis of monoamine neurotransmitters dopamine, norepinephrine,
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epinephrine and serotonin.
Healthy person :Some Phe needed for protein synthesis, Phenylalanine hydroxylase And Remaining Phe
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converted to Tyr
PERSON WITH PKU: Some Phe needed for protein synthesis, Remaining Phe cannot be converted and
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accumulates, Phenylalanine hydroxylase
Phenylalanine (Phe) metabolism
genetic mutation resulting in obstruction of phenylalanine metabolism
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phenylalanine is an essential amino acid, LNAA
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PAH gene mutation results in defect in function of PAH enzyme (impaired conversion of phenylalanine to
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tyrosine
Population genetics
Pku is a rare disorder that affects males and females in equal numbers.
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Variant, non-phenylketonuria and hyperphenylalaninemia
Variant; Are less severe. It results when mutant PAH enzyme has some residual activity.
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Non-PKU hyperphenylalaninemia; Results from deficiency of enzymes other than PHE hydroxylase.
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Symptoms of PKU
• Skin rashes (eczema), Microcephaly (small head), Tremors
• Spasticity - jerking movements of the arms and legs
• Unusual hand posturing, Seizures! Hyperactivity
• Delayed mental and social skills! Mental retardation
NEWBORN SCREENING
The test is performed after 24 hours of age.
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Blood from a heel prick is assayed in the central laboratory and measurement of phenylalanine levels to tyrosine
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ratio.
PKU treatment-
Early control and maintenance of blood PHE levels in childhood within a range of 2-6 mg/dL are positively
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correlated with normal IQ.
Adults - most treatment centers rec continued PHE restriction for life to avoid decline in cognitive function.
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Tay-Sachs disease
is a rare autosomal recessive genetic disorder that affects the nervous system.
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It occurs when the body lacks (Hex-A), a protein that breaks down gangliosides, a chemical found in nerve
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tissue.
Gangliosides would then grow indefinitely in cells, causing progressive damage.
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When gangliosides accumulate they damage the normal function of the neurons.
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The build up of GM2 gangliosides is poisonous and eventually leads to death.
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2. symptoms
Deafness
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Decreased eye contact, blindness
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Decreased muscle tone (loss of muscle strength)
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Delayed mental and social skills
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Cause
Tay-Sachs Disease is caused by a mutation in the HEX A gene on chromosome 15.
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Doctors Tay and Sachs discovered this by noticing a red spot on the patients' retinas.
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When gangliosides accumulate they damage the normal function of the neurons.
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The build up of GM2 gangliosides is poisonous and eventually leads to death.
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Types
Early onset
Early onset Tay-Sachs starts when babies are born.
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Symptoms: not gaining or losing mental and motor skills, paralysis, and death by age five.
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Adult onset;
Adult onset Tay-Sachs starts lots later in life than the other forms of Tay-Sachs disease.
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Symptoms: muscle cramps, behavioral changes, and slurred speech.
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This is the mildest form of Tay-Sachs disease.
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In adult onset Tay-Sachs you can live a normal lifespan if given the proper medical care, but you will still die at
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about the age of 60 because of Tay-Sachs.
Some adult onset patients have mental retardation and psychotic episodes.
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Treatment
There is no effective treatment or cure of Tay-Sachs.
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Patients with adult onset Tay-Sachs are provided with wheelchairs because of their muscle weakness.
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Frequency
Tay-Sachs is most common among eastern European Jews.
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1 in every 27 Jews in the US is a carrier of Tay-Sachs Disease.
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French Canadians and Cajuns are also frequent carriers of the disease with a 1 in 27 rate.
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In the general population 1 in 250 people are carriers of Tay-Sachs.
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