Natasha's T3 resin uptake was increased.

Using all of the information you have been given thus

far, explain this finding.

A finding of increased T3 resin uptake has two possible explanations:

(i) TBG levels are decreased or
(ii) endogenous levels of thyroid hormones are increased.

In Natasha's case of thyrotoxicosis, it was the latter:

increased endogenous thyroid hormones occupied relatively more binding sites on TBG ->
fewer TBG binding sites were available to bind radioactive T3 ->
uptake of radioactive T3 by the resin was increased

PKU is an autosomal recessive genetic disorder that affects the function of the phenylalanine
hydroxylase (PAH) enzyme. The PAH gene is located on chromosome 12 and over 600
mutations, most often missense mutations, have been described. The degree of enzyme
function can vary. PKU is one of the aminoacidopathies belonging to a group of disorders called
toxic accumulation-inborn errors of metabolism (IEMs), that is, the amino acid (Phe)
accumulation or of its metabolite is toxic.

The biochemical abnormality in PKU is an inability to convert Phe into Tyr. Phe, an essential
amino acid, must be acquired through foods that contain protein. Normally, once Phe enters
the body, most of it is converted to Tyr by the enzyme phenylalanine hydroxylase. Tyr is then
turned into neurotransmitters important for normal brain development and function. In normal
children, less than 50% of the dietary intake of Phe is necessary for protein synthesis. The
remainder is converted to Tyr by the phenylalanine hydroxylase system (PAH) (Fig. 1). When
Phe metabolism is blocked because of a lack of PAH enzyme, minor shunt pathways come into
play, yielding several intermediates that are excreted in large amounts in the urine and in the
sweat. These impart a strong musty or mousy odor to affected infants. Concomitant lack of
Tyr (Fig. 1), a precursor of melanin, is responsible for the light color of hair and skin. It is
believed that excess Phe or its metabolites contribute to the brain damage in PKU.

Elevated Phe levels and reduced Tyr levels in PKU can change the way the brain functions. This
is because Phe uses the same transporters to get across the blood-brain barrier as other amino
acids including Tyr and tryptophan. Tyr is needed to synthesize dopamine and norepinephrine,
and tryptophan is needed to synthesize the neurotransmitter serotonin. As Phe levels rise, it
occupies all the transporters, making it hard for Tyr and tryptophan to get across the blood-
brain barrier. As a result, dopamine, norepinephrine, and serotonin levels in the brain begin to
fall, leading to abnormal brain development and intellectual disability (Fig. 2).
Moreover, Of the 600+ mutant alleles of the PAH gene identified, only some cause a severe
deficiency of the enzyme and thus result in classic PKU. Infants with mutations resulting in a
complete lack of PAH activity present with the classic features of PKU, while those with up to
6% residual activity present with milder disease. While 98% of PKU is attributable to mutations
in PAH, approximately 2% occur due to abnormalities in synthesis or recycling of the cofactor
tetrahydrobiopterin BH4 (Fig. 1). It is clinically important to recognize these variant forms of
PKU, because they cannot be treated by dietary restriction of phenylalanine.

Summary:

Phenylketonuria (PKU) is one of the aminoacidopathies belonging to a group of disorders called

toxic accumulation inborn errors of metabolism (IEMs), (i.e., amino acid accumulation or of its
metabolite is toxic). It is most frequently caused by missense mutations in the phenylalanine
hydroxylase (PAH) gene, causing loss of activity or deficiency of PAH to catalyze phenylalanine
(Phe) hydroxylation in order to generate tyrosine (Tyr). Hence, increased blood levels of Phe
and reduced levels of Tyr characterize PKU. Appearing normal at birth, newborns with PKU
manifest the first signs after several months including musty odor from urine, sweat, and
breath, fair skin, eczema, microcephaly, hyperactivity, tremors, and seizures. When untreated,
people with PKU develop symptoms such as severe intellectual disability and psychiatric
disorders.
SCRIPT:

Thank you Jannie! Good morning everyone, Good morning doc nikki!

Describe the biochemical basis and pathogenesis of Phenylketonuria.

PKU is an autosomal recessive genetic disorder that affects the function of the phenylalanine
hydroxylase (PAH) enzyme. The PAH gene is located on chromosome 12 and over 600
mutations, most often missense mutations, have been described. The degree of enzyme
function can vary. PKU is one of the aminoacidopathies belonging to a group of disorders called
toxic accumulation-inborn errors of metabolism (IEMs), that is, the amino acid accumulation (in
this case, Phenylalanine) or of its metabolite is toxic (Stone, Basit & Los, 2023). Next slide please

The biochemical abnormality in PKU is an inability to convert Phenylalanine into tyrosine.

Phenylalanine, an essential amino acid, must of course be acquired through foods that contain
protein. Normally, once Phenylalanine enters the body, most of it is converted to Tyrosine by
PAH. Tyrosine is then turned into neurotransmitters important for normal brain development
and function. However, when this system is blocked because of a lack of PAH enzyme,
Phenylalanine levels build up and tyrosine levels drop. Next please

Here is a schematic overview of the pathogenesis of PKU. Next please

Again, Due to the inability to convert Phe to Tyr, the resulting concomitant lack of Tyr, a
precursor of melanin, is responsible for the light color of hair and skin. The buildup of Phe and
its metabolites drive the transamination reaction toward the formation of phenylpyruvate.
Such an increased phenylalanine level will be reflected in the blood as hyperphenylalaninemia,
which is defined as a plasma phenylalanine level above 120 μmol/L (Regier & Greene, 2017).
Next please

So this buildup are excreted in large amounts in the urine, sweat, and breath. These impart a
strong musty or mousy odor to affected infants. Newborns with PKU appear normal at birth but
manifest the first signs after several months including this musty odor. Moreover, Elevated Phe
levels and reduced Tyr levels can change the way the brain functions. This is because Phe
competes with large neutral amino acids (LNAA) Tyr and tryptophan in getting across the blood-
brain barrier by using the same transporters (large amino acid transporter 1 or LAT-1). As
discussed kanina sa lecture, Tyr is needed to synthesize dopamine and norepinephrine, and
tryptophan is needed to synthesize the neurotransmitter serotonin. Now, as Phe levels rise, it
occupies all the transporters, making it hard for Tyr and tryptophan to get across the blood-
brain barrier. As a result, dopamine, norepinephrine, and serotonin levels in the brain begin to
fall, causing white matter lesions, oxidative damage, hypomyelination, and demyelination. Next
please

Which then leads to abnormal brain development, microcephaly, neurological features, and
intellectual disability. That would be all, thank you.