Phenylketonuria PKU

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Phenylketonuria (PKU)
March 12, 2008
William Chung (william.chung_at_utoronto.ca) Grace
Ho (gracewy.ho_at_utoronto.ca) Kevin Lau
(kevinhk.lau_at_utoronto.ca) Katie Kit Yi Mok
(katie.mok_at_utoronto.ca)
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CASE - My PKU Diet Story by Kristin Larocque
Kristin Larocque, Age 10, Peterborough Ontario,
Canada Imagine youre a new born baby and you
just got back from the hospital, you think, "What
could possibly go wrong?" DRING, DRING, DRING.
Just one phone call changed everything. Good
afternoon honorable judges, teachers, and fellow
classmates. That phone call introduced my parents
to PKU. PKU is a genetic condition, and with that
comes responsibilities such as understanding what
PKU is, going to Toronto to visit my dietician,
and being careful about what I eat. By the end of
my speech youll be an expert on PKU! There is a
lot of information to learn about PKU. When
someone has PKU they have to follow a low protein
diet because their body cant break down a part
of protein (so theyre a little different from
you!). There is a part in protein called PHE...
that is the part that I cant have. Some people
choose to go on diets to lose weight, but I
didnt have a choice... I was diagnosed with PKU
when I was a baby. When I got home from the
hospital my parents got a phone call from my
doctor, and they were told to go to Sick
Childrens Hospital in Toronto. It was a scary
shock for my mom and dad... but they handled it
well. PKU is not a very common condition in
fact, in Ontario about 1 child in 12,000 is born
with PKU, so as you can see this is a very rare
condition. However, believe it or not there is
another person with PKU who lives around the
corner from me! I do meet other children with PKU
when I go to Childrens Hospital. Another
responsibility I have is to go to the hospital
every 6 months. I get really excited because I
get to miss one whole day of school! I go all the
way to Toronto to visit my dietician. Her name is
Valerie Austin. She helps me with controlling my
diet. She suggests new foods and makes
adjustments to my formula. She also tells me how
my protein levels have been. After I visit her, I
usually go to doctor Fagonbom. She tests my
abilities and sees how much concentration I have.
And then comes the worst part of going to
Childrens Hospital. I have to get a needle, yes
a needle to see how much protein Ive had. I also
have a pen at my house that I use to prick my
thumb every month and then I send a sample of my
blood to the hospital, and they send me my
protein levels. I think going to Toronto is one
of the best parts of having PKU. Though it may
be tempting I cant just go and gobble up a big
plate of lasagna! I have to be careful about what
I eat. I cant have many of the dairy or grain
products, but definitely none of the meat and
alternatives. I can have 24 equivalents a day, so
I can have puddings, cookies, crackers, and foods
like that. But youre probably still thinking,
"What does that girl eat?" Well I eat a lot of
fruits and vegetables but Im very lucky to have
my own low protein foods. I have bagels, pasta,
cheese, chocolate and much more and theyre all
protein free! So I can have as much as I want.
Another stop I make when I go to Childrens
Hospital is the specialty food shop where I get
all of my food. And if I ever run out of food, my
mom can just order some more right over the
telephone! I need to be a healthy and strong girl
when I grow up so I need to have nutrition. I
take that in my formula. I have to have my
formula 3 times a day, morning, lunch, and
supper. And did you know if Im ever getting
bored of what Im eating I can just pull out the
PKU cookbook and experiment!!! Though one of the
foods Ill never get tired of is my bagel. I have
it twice a day. Im sure there are a lot more low
protein foods to come and waiting for me to try !
Overall there are a lot of responsibilities when
having PKU, knowing and understanding what PKU
is, going to Toronto to visit my dietician, and
being careful about what I eat. Although I am a
little different from you, PKU is not something
serious like cancer or a deadly allergy. God made
us unique and special with our own personal
challenges to deal with and mine is PKU!  
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What are amino acid disorders?

• Amino acid disorders are inherited metabolic
  conditions where certain amino acids are unable
  to be broken down by the body or produced
• This causes either a toxic accumulation of the
  amino acid or severe deficiencies required for
  body function

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What is PKU?

• PKU is an autosomal recessive disease in which
  the body is unable to process the amino acid
  phenylalanine (gt20mg/dL), causing it to build up
  in the blood
• Phenylalanine is found in foods containing
  protein, such as eggs, milk, cheese, fish, meat
• The enzyme involved is phenylalanine hydroxylase,
  which converts phenylalanine to tyrosine
• Infants with the disease are usually normal at
  birth but may have blue eyes and fairer skin
  compared to other family members due to
  phenylalanines role in pigment production

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Signs Symptoms

• Lighter hair, skin and eyes than siblings without
  the disease
• Mousy or musty odour on breath, skin and in urine
  due to phenylalanine build-up
• Other symptoms may include
• Delayed mental and social skills
• Microcephaly (small head)
• Hyperactivity
• Jerking movements of the arms or legs
• Mental retardation
• Seizures
• Skin rashes
• Tremors
• Unusual positioning of hands

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Pathophysiology

• Enzyme that breaks down phenylalanine,
  phenylalanine hydroxylase (PAH), is completely or
  nearly completely deficient due to defective PAH
  gene

Phenylalanine hydroxylase

• Rarer form? PAH normal but defect in
  biosynthesis or recycling of cofactor
  tetrahydrobiopterin (BH4)
• PAH, produced in the liver, converts
  phenylalanine to tyrosine
• Get phenylalanine accumulation in blood and body
  tissues, tyrosine deficiency
• Accumulated phenylalanine converted to
  phenylpyruvate
• (aka phenylketone)

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Simplified Version of phenylalanine metabolism
NORMAL
MUTATION
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PKU- Genetics

• Autosomal recessive
• ?PAH gene on
• chromosome 12
• Over 500 different
• mutations identified
• 1 in every 10,000 to 20,000
• Caucasian or Oriental
• Births
• Male Female
• For parents, diagnosis of child is usually how
  they find out if they are a carrier

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Pathophysiology- contd

• Normal blood phenylalanine level is about 1
  mg/dl. In PKU, levels may range from 6 to
  80mg/dl, usually greater than 30mg/dl
• Too much phenylalanine in blood is toxic to
  brain? can lead to mental retardation
• It is unknown why extra phenylalanine causes
  mental retardation

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Pathophysiology contd
Possible Causes of Mental Retardation

• Saturation of transporter across blood brain
  barrier (BBB)

? Decrease level of other amino acids in brain
required for neurotransmitter synthesis and
protein synthesis
?Lower dopamine levels

• Extra phenylalanine slows development of
  neurons inside cerebral cortex

• Undersized neurons that fail to make connections
  with other neurons

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Treatment

• A strict diet control
• Restricting high protein foods (ie. Breast milk,
  meat, fish, nuts, legumes, cheese and other dairy
  products)
• Starchy food (ie. Potatoes, bread, pasta, and
  corn) must be monitored
• Diet foods and diet soft drinks that contain
  sweetener aspartame (consists of phenylalanine
  and aspartic acid) must be avoided
• For infants, supplementary formulas are used,
  such as Phenyl-Free, which contains protein,
  vitamins and minerals with no phenylalanine
• Older children and adults are recommended to
  continue to drink several glasses of formula each
  day, as directed by a doctor or dietitian
• In those patients with a deficit in BH4
  production, or with a PAH mutation resulting in a
  low affinity of PAH for BH4, treatment consists
  of giving BH4 as a supplement this is referred
  to as BH4 responsive PKU
• In the past, PKU-affected people were allowed to
  go off diet after 8 years of age. However,
  physicians now recommend that this special diet
  should be continued throughout life
• Babies with PKU may drink breast milk, while also
  taking their special metabolic formula, though
  during breastfeeding, the mother must maintain a
  strict diet to keep their phenylalanine levels
  low

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Treatment contd

• A drug called Kuvan (sapropterin dihydrochloride)
  has been approved by FDA for treatment of the
  rare genetic disorder tetrahydrobiopterin
  (BH4)-responsive PKU
• It is a form of the PAH cofactor called BH4
• When given in large doses, it causes the residual
  enzyme to work harder to reduce blood Phe level
• Kuvan must be used in combination with the
  special diet, and patients on the drug must have
  blood levels of phenylalanine checked frequently
• In general, the goal is to consume enough amount
  of phenylalanine that is necessary for normal
  growth and body functions, but no more

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Maternal Phenylketouria

• Developmental defects of the fetus caused by the
  mothers high blood level of phenylalanine since
  high levels of phenylalanine can cross the
  placenta (the fetus does not have to have PKU)
• For women affected with PKU, it is essential for
  the health of their child to maintain low
  phenylalanine levels before and during pregnancy
• This is achieved by performing regular blood
  tests and adhering very strictly to a diet with a
  day-to-day monitoring by a dietitian

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Screening

• Newborn screening ( 3 days after birth) allows
  early identification and early implementation of
  treatment
• A few drops of blood are placed on a card and
  then sent for measurement
• The goal of PKU treatment is to maintain the
  blood level of phenylalanine between 2 and 10
  mg/dl

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How is PKU monitored

• Monthly blood phenylalanine levels
• Regular visits to the PKU Clinic
• Monthly food records in the form of a diary

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Application to Pharmacy

• Pharmacists can play a diverse role in the
  management of PKU
• Be empathetic as the patient (and family) may
  need to undergo changes to diet and lifestyle
• Refer patients to MDs and PKU clinics
• Ensure patient monitors blood Phe levels
• Assist patients in keeping a food diary/record
• Recommend supplementary formulas
  Phenyl-Free
  for infants, and Phenyl-Ade products
  to assist in
  long-term dietary compliance
• Educate the caregiver to ensure prompt and
  continuous treatment
• Collaborate with physicians and dieticians
• Dietary control is suboptimal in adolescence and
  adulthood pharmacists can explore alternative
  treatments such as large neutral amino acids,
  phenylalanine ammonia lyase, tetrahydrobiopterin
  and gene replacement

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PKU - Future

• Somatic Gene Therapy
• In a study by Dr. Savio Woo and Li Chen,
  Correction in Female PKU Mice by Repeated
  Administration of mPAH cDNA Using phiBT1
  Integration System, genes were inserted into the
  non-coding regions of the mice genome without
  interfering with normal functions.
• Woo and Chen were able to cure PKU in mice with
  just three intravenous injections. The levels of
  phenylalanine in the treated mice dropped to
  normal range and remained stable. Their fur
  colour also changed from grey to black,
  indicating that they were now producing normal
  levels of melanin, a pigment that is
  under-produced in mice and humans with PKU.
• Woo and Chen indicate that the current
  challenge is to identify a suitable means of
  introducing DNA into liver cells. Once that
  technology is developed, this new technique will
  provide a safe and efficient means of integrating
  the DNA into the cell's genome."

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PKU- Summary

• PKU is an autosomal recessive disease in which
  the body is unable to process the amino acid
  phenylalanine, causing it to build up in the
  blood
• Symptoms include lighter hair, skin and eyes
  than siblings without the disease musty odour on
  breath, skin and in urine delayed mental and
  social skills microcephaly mental retardation
  seizures skin rashes tremors unusual
  positioning of hands
• Enzyme that breaks down phenylalanine,
  phenylalanine hydroxylase (PAH), is completely or
  nearly completely deficient due to defective PAH
  gene
• Phenylalanine accumulates in blood and body
  tissues and is converted to phenylpyruvate also
  results in tyrosine deficiency
• Too much phenylalanine in blood is toxic to
  brain? can lead to mental retardation possibly
  due to transporter saturation or impedement of
  neuronal growth
• There is no cure. A strict diet control is
  necessary restrict high protein foods, avoid
  aspartame, use supplementary formulas, etc.
• A drug called Kuvan (sapropterin
  dihydrochloride) has been approved by FDA for
  treatment of BH4-responsive PKU. It is a form of
  the PAH cofactor called BH4 that induces
  phenylalanine hydroxylase
• Maternal PKU For women affected with PKU, it is
  essential for the health of their child to
  maintain low phenylalanine levels before and
  during pregnancy. Regular blood tests and strict
  diets are required.
• Newborn screening ( 3 days after birth) allows
  early identification and early implementation of
  treatment.
• PKU is monitored by Monthly blood phenylalanine
  levels, regular visits to the PKU Clinic, monthly
  food records in the form of a diary
• Pharmacists can assist PKU patients in all
  aspects of PKU management diet, medications,
  etc.
• Somatic gene therapy may be an option in the
  future.

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References
DiLella, A. G., Kwok, S. C. M., Ledley, F. D.,
Marvit, J., Woo, S. L. C. (1986). "Molecular
structure and polymorphic map of the human
phenylalanine hydroxylase gene". Biochemistry 25
743-749. Green, A., (2007). Phenylketonuria.
MedlinePlus Medical Encyclopedia. Accessed March
9, 2007 from http//www.nlm.nih.gov/medlineplus/en
cy/article/001166.htm How is PKU monitored.
University of Washington PKU Clinic. Accessed on
March 10, 2008 from http//depts.washington.edu/pk
u/monitor.html Li, C., Woo,S. (2007).
Correction in Female PKU Mice by Repeated
Administration of mPAH cDNA Using phiBT1
Integration System. Molecular Therapy (15) 10
1789-1795. Phenylketonuria. Dolan DNA Learning
Centre. Accessed March 8, 2008 from
http//www.ygyh.org/pku/whatisit.htm
Phenylketonuria. MayoClinic. Accessed March 10,
2008 from http//www.mayoclinic.com/health/phenylk
etonuria/DS00514/DSECTION8 Phenylketonuria
(PKU). Medhelp International. Accessed March 9,
2008 from http//www.medhelp.org/lib/pku.htm. Phe
nylketonuria. PKU.com. Accessed March 8, 2008
from http//www.pku.com/AboutPKU/AboutPKU.aspx. P
henylketonuria(PKU)- Amino Acid Disorder. Health
Canada. Accessed March 9, 2007 from
http//www.health.gov.on.ca/english/providers/prog
ram/child/screening/pdf/fs_pku.pdf Phenylketonuri
a Screening and Management. National Institutes
of Health Consensus Development Program. Accessed
on March 9, 2008 from http//consensus.nih.gov/200
0/2000Phenylketonuria113html.htm. Pietz, J.,
Kreis, R., Rupp, A., Mayatepek, E., Rating, D.,
Boesch, C., Bremer, H. J. (1999). "Large neutral
amino acids block phenylalanine transport into
brain tissue in patients with phenylketonuria".
Journal of Clinical Investigation 103
11691178. PKU fact sheet. St. Josephs Medical
Centre Pheonix. Accessed March 9, 2007 from
http//www.medhelp.org/lib/pku.htm Surtees, R.,
Blau, N. (2000). "The neurochemistry of
phenylketonuria". European Journal of Pediatrics
169 S109-13.
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Thank you! Questions?