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What is PKU? |
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PKU (Phenylketonuria) is
an inherited metabolic disorder caused by a deficiency
of the enzyme, phenylalanine hydroxylase (PAH). This
enzyme is required for the breakdown of phenylalanine
(Phe), an amino acid found in most protein-containing
foods. Without sufficient amounts or activity of PAH,
Phe accumulates to abnormally high levels in the blood
and other tissues. Clinical manifestations of sustained
high Phe levels include a variety of serious neurological
complications, including:
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Mental retardation and brain damage |
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Mental illness |
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Seizures and tremors |
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Cognitive problems |
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As a result of global newborn screening efforts
implemented in the 1960s and early 1970s, virtually
all people living with PKU who are under the age
of 40 and living in developed countries have been
diagnosed in the newborn period. PKU is characterized
by elevated blood Phe levels. Those with the mild
to moderate form of PKU have some residual active
PAH enzyme and blood Phe levels ranging from approximately
600 µmoles/L to 1200 µmoles/L. Those
with a more severe form of the disease have very
little, if any, active PAH enzyme and blood Phe
levels greater than 1200 µmoles/L. |
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People living with PKU strive to manage their disease
and maintain normal, non-toxic blood Phe levels
by adhering to a highly restricted diet. This diet
consists of natural foods that are low in phenylalanine,
modified low protein foods, and specially formulated
medical foods. It is very difficult to adhere to,
especially through adolescence and adulthood, for
the reasons listed below:
| 1) |
Most natural foods contain phenylalanine.
Milk and dairy products, meat, fish, chicken,
eggs, beans and nuts contain very high Phe levels
and must be excluded from the diet. Fruits,
vegetables, and breads and pastas also contain
Phe, but since the Phe levels in these foods
are low, measured amounts can be included in
the diet. |
| 2) |
Medical food diets that are low in Phe and
provide necessary nutrients (e.g. tyrosine)
are expensive and can be unpalatable. |
In October 2000 the consensus panel convened by the
National Institutes of Health met to review the available
information on PKU, including management of blood
Phe levels. The panel concluded that maintaining normal,
non-toxic blood Phe levels “can be difficult
to achieve, and poor control can result in significant
decline of mental and behavioral performance. “
They also noted that, "Metabolic control is necessary
across the lifespan of individuals with PKU.”
The NIH consensus panel further concluded that research
on non-dietary alternatives to treatment of PKU is
strongly encouraged. |
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Today, researchers are working to develop alternate
treatment options for people living with PKU. The
following are some of the approaches currently being
evaluated for the treatment of PKU:
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Enzyme Cofactors:
Enzyme cofactors are naturally
occurring molecules that are required by enzymes
to carry out biochemical reactions. By administering
an enzyme cofactor (e.g. 6R-BH4), researchers
hope to enhance the activity of the existing
PAH enzyme, enabling it to metabolize Phe
more efficiently. |
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Enzyme Therapy: Enzyme therapy seeks to address the underlying enzyme deficiency associated with PKU by providing patients with enzyme capable of metabolizing Phe. Researchers are evaluating the use of various enzymes and routes of administration (e.g. oral and subcutaneous injection) for this purpose. |
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Gene Therapy:
Gene therapy is being evaluated in preclinical
studies as a means to allow in vivo
(within a living body) production of the PAH
enzyme. Like enzyme therapy, this approach is
designed to address the underlying enzyme deficiency. |
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LNAA Therapy:
Phe is one of several large neutral amino acids
(LNAA) that cross the blood-brain barrier via
a specific type of carrier. To prevent elevated
levels of Phe from entering the brain and causing
neurological damage, researchers are evaluating
the use of supplemental levels of other naturally
occurring LNAA. It is hypothesized that large
quantities of LNAAs ‘compete’ for
the same carrier that transports Phe across
the blood-brain barrier thereby blocking Phe
from entering the brain. |
Kuvan, a therapy based on the enzyme cofactor 6R-BH4,
is the first FDA-approved treatment for PKU. The
remainder of these approaches are in the investigational
stage of product development--some in preclinical
studies (involving animal models) and some in clinical
studies (involving humans)--and have not received
marketing authorization from regulatory agencies. |
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For additional information about PKU, please visit
the following websites and others listed in the Patient/Physician
Resource Library:
Note: These listings are provided by BioMarin as additional information for patients, their families and their healthcare providers. The web pages and their content are maintained by the organizations listed above. With the exception of its own websites, BioMarin does not endorse any particular organization or the content contained on their website. | |
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