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Enzyme abnormalities represent a range of inherited genetic illnesses known as inborn errors of
metabolism. The buildup of hazardous chemicals in the body typically causes clinical symptoms.
While the ailment cannot always be treated, supportive care and the right nutrition can help
patients live longer. one example of such illnesses would be Phenylketonuria (PKU) which is a
condition that affects the aromatic amino acid phenylalanine. It is caused by a lack of
disease in autosomal recessive manner. which leads to irreversible intellectual impairment and
other clinical signs if left untreated. PKU affects around one out of every 10,000 Europeans,
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whereas it affects about one out of every 50,000 African-Americans. PKU is uncommon in
Finland and Japan, however the frequency varies significantly between locations.
in the liver, the enzyme phenylalanine hydroxylase (PAH) catalyzes the reduction of
addition to oxygen molecules plus iron, is a cofactor necessary for PAH action. This route is
responsible for the majority of catabolism and disposes of around 75% of dietary phenylalanine,
with the remaining being utilized for protein synthesis. PAH deficiency causes PKU.
Phenylalanine and its metabolites, phenylacetate and phenyl lactate, are found in higher amounts
in the blood and urine as a consequence. Tyrosine levels are usually in the normal range, while
low levels are rarely seen. Approximately 2% of patients with high phenylalanine levels have
Overt clinical signs of PKU are rare, thanks to extensive newborn screening. Prior to the
breast milk or standard infant formula). PKU develops slowly and may not present symptoms
until early childhood if it is not identified during the neonatal period. Irrecoverable intellectual
impairment, epilepsy, behavioral issues, microcephaly, and skin disorders are the hallmarks of
this illness in untreated patients. Increased dietary phenylalanine exposure causes cognitive
impairment during myelination in early childhood, but it settles down after maturation process is
accomplished. Individuals who were treated with continued dietary intervention following a
neonatal screening assessment may still have some neurological consequences, although they are
substantially less severe compared to untreated patients. Executive (frontal lobe) function is one
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domain of cognition that is significantly impaired. Even patients who have strong nutritional
The majority of children with PKU, even those identified by newborn screening and treated
early, have white matter abnormalities on magnetic resonance imaging (MRI). The
periventricular white matter often shows a symmetrical rise in T2-weighted signa. Increased
Dietary status appears to have an impact on the severity of the aberrations. This was observed in
a group of 34 PKU individuals ranging in age from 8 to 33 years old, 25 of whom were identified
by newborn screening. Serum phenylalanine content at the time of the investigation was strongly
linked with the degree of MRI alterations in the early diagnosed group.
molecular testing. In patients with full PAH insufficiency, blood increases can be exceedingly
significant (>20 mg/dL, 1200 micromol/L). Tandem mass spectrometry is the most helpful
laboratory approach for neonatal screening. Additional amino acids, such as tyrosine and
acylcarnitine ester, can be measured using this approach. PKU is diagnosed by a high
phenylalanine content along with a low to low-normal tyrosine levels. In addition, tandem mass
second plasma amino acid study should be performed to confirm elevated phenylalanine levels
ensure a proper nutritional plan is prescribed, a patient may need nutrition counseling with a
registered dietitian. The CDC describes medical nutrition therapy, also called nutrition
become a registered dietary nutritionist one must first earn an accredited bachelor’s or master’s
degree, complete a dietetic internship, pass the commission on Dietetic Registration (CDR)
exam, and finally obtain a state license registration, which must be maintained periodically
throughout that individual RDN’s time practicing. Medical nutrition therapy must be done by a
treatment approach that can help patients better manage chronic diseases (i.e. Phenylketonuria).
A medical nutrition therapy provider (often a registered dietitian nutritionist or RDN) will
begin by assessing the patient’s nutrition. Then, the RDN or provider will assess the patient’s
current state, medical history and any conditions they have. Next, the provider determines the
goal of the therapy, whether it be lowering blood pressure in hypertension and heart disease,
disorders by decreasing certain metabolites. Medical nutrition therapy can be used to treat a
plethora of conditions such as type 2 diabetes, high blood pressure, high cholesterol, obesity,
heart disease, stroke-related issues, osteoporosis and more. Lastly, the RDN or provider of
medical nutrition therapy will develop a meal planning approach for struggling patients. Goals of
medical nutrition therapy in general are to maintain normal function and alleviate symptoms of
As previously explained, dietary status and phenylalanine content of serum and urine
directly influence health in patients with PKU. When unmanaged, buildup of phenylalanine in
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these patients leads to the development, as well as increasing the severity of their symptoms.
This is similar to many other chronic metabolic disorders. Since the buildup of metabolites may
cause the development and/or the exacerbation of symptoms, medical nutrition therapy is an
the harmful effects poor nutrition can have on the body. Regularly consuming too much sodium,
saturated fat, or added sugar can have many insidious effects on the body. Since many chronic
diseases and conditions are risk factors for other conditions, small, seemingly harmless habits of
poor nutrition may have a cascading effect with devastating consequences. Someone who
consumes too much sodium, saturated fat, or added sugar may become overweight or even
morbidly obese. Diet is an extremely important modifiable risk factor for many diseases. And,
since obesity is also risk factor for many other chronic diseases, if that individual doesn’t alter
their eating habits (whether through advice of a registered dietitian nutritionist or on their own
accord) they may in turn go on to develop diseases such as hypertension, high cholesterol,
prediabetes, and eventually even type 2 diabetes. On the flipside, someone who maintains a
healthy and nutritious diet composed of a moderate amount of carbohydrates, proteins, fats,
vitamins, minerals, antioxidants, fiber and water, benefits not only through weight loss and
toning of the body (in those who desire it), but also by decreasing the likelihood of developing
Specifically, using nutritional therapy we can treat PKU with nutritional products which
include two forms of medical foods, the first one would be food that contains protein without
phenylalanine but contains the required amount of other proteins for normal growth and
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development and also other nutrients like carbohydrates, vitamins, fat, and minerals. The second
form is food that is modified to have a low amount of proteins. So we have to determine the
calorie requirement based on the patient’s age and gender to have the required amount for
growth. And we calculate the tolerated amount of phenylalanine in the patients and adjust
accordingly using phenylalanine-counting systems and we correct the large difference between
the intact protein that can be tolerated by the patient and the medical foods that contain no or low
amount of phenylalanine and adjust accordingly. To manage patients with PKU, they should be
provided with treatment by metabolic specialists, and nutritionists. The foundation of PKU
treatment is using nutritional therapy which is a dietary restriction of phenylalanine since there is
impaired metabolism of it. By using foods that don’t have phenylalanine and have substitutes for
it. For example, Patients with PKU have to be careful about any product that contains artificial
sweeteners that can be found in diet versions of fizzy drinks or artificial sweeteners for tea and
coffee as a sugar substitute because they contain aspartame and it will be converted into
phenylalanine in the body. There is a medical food that contains glycomacropeptide which is a
natural protein source that contains a small amount of phenylalanine and also has several large
neutral amino acids which include the essential amino acids threonine, tryptophan,
phenylalanine, histidine, isoleucine, leucine, valine and methionine and also it includes
Infants who have PKU can be breastfed with the supervision of a metabolic dietitian and
are usually limited to around 25% of the feeding and it depends on the disease severity with
alternating feeding of milk formula that doesn’t have phenylalanine. And we have to note that
the restriction of the mother’s diet has no impact on the breast milk composition. Compliance is
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affected especially with older children due to the diet which has protein substitutes as mentioned
before resulting in have poor palatability. The initiation of the treatment for PKU patients should
be early, typically before one week of age, and for patients who have phenylalanine level that is
more than 6mg/dL. Treatment is recommended for newborns whose levels are between 6 - 10
mg/dL and persistent. We also have to consider the consequences of low phenylalanine due to
the restricted diet in PKU patients which will lead to a low concentration of long-chain
polyunsaturated fatty acids (LCPUFA) and docosahexaenoic acid (DHA) in the blood which is
important for neurodevelopment, especially in newborns so we should supply them with both
LCPUFA and DHA. Amino transporters at the blood-brain barrier which transport phenylalanine
can also transport large neutral amino acids as mentioned before and it competes with
phenylalanine for the same transporter. therefore supplementation with large neutral amino acids
significantly reduces the amount of phenylalanine that influxes into the patient’s brain.
To illustrate, A study where early-treated PKU children were compared to their unaffected siblings, the
study showed that kids who were treated by dietary restriction tended to have scores in the average range
in terms of intellectual ability. Although their scores were normal, they were still half of a standard
deviation lower than the unaffected controls. Intellectual disability is a major concern in PKU, therefore,
for the studies to show that cognitive outcome shows a major correlation to the extent of control of blood
early treatment for PKU, IQ decreased by approximately one-half of a standard deviation for each 300
micromol/L (5 mg/dL) increase in blood phenylalanine concentration. Outcomes were nearly normal
when phenylalanine concentration was less than 400 micromol/L (6.7 mg/dL) during early and middle
childhood. Another study showed that there was a 1.3 to 3.9 point decline in IQ score for each 100
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micromol/L increase in phenylalanine concentration. The Agency for Health Research and Quality
conducted a meta-analysis of 17 studies (including 432 individuals with PKU) that examined the
relationship of blood phenylalanine to IQ. They found an increased probability of low IQ (<85) at higher
blood phenylalanine levels, regardless of whether IQ was measured during childhood or beyond, with a
stronger association seen between phenylalanine measured in early childhood and later IQ.
One of many complications of PKU is behavioral problems and this is imminent no matter the age.
Irreversible brain damage as a complication may be a major cause of effects, however, the evidence is
inconsistent. This was examined in a systematic review of four studies that each included more than 20
subjects. The systematic review reported that patients with early-treated PKU appear to have a higher
prevalence of behavior problems and psychological disturbance than controls. The range of problems
reported included excessive sadness, fear, and anxiety; a sense of isolation and poor self-image; and lack
of autonomy and drive. There are other studies seeking to understand whether children with PKU are at
an increased risk of having attention deficit hyperactivity disorder, however, this is extremely
controversial and inconclusive. Another notable complication that is highly disregarded often in patients
with PKU is visual abnormalities. Subclinical visual impairments are often caused by high concentrations
of phenylalanine. This was illustrated by a study of pattern reversal visual evoked potentials (VEPs) in
patients with PKU. VEPs were abnormal in only one of nine children younger than 14 years old who
were on a restricted diet, compared with more than 80 percent of older patients, whether or not they were
still on a low-phenylalanine diet. Studies have demonstrated the efficacy and palatability of certain diets
in patients with PKU, a certain study reported that patients that continued the diet rather than quit had
nearly half the complications of the latter, despite many advances and the appearance of new treatments,
To sum it all up, Enzyme abnormalities represent a range of inherited genetic illnesses known as inborn
PAH deficiency leads to irreversible intellectual impairment and other clinical signs. Increased
phenylalanine concentration is likely to be causing the alterations, which might be irreversible. Proper
nutritional therapy is vital. The CDC describes medical nutrition therapy as “nutrition-based treatment
provided by a registered dietitian nutritionist.”. Medical nutrition therapy can be used to treat a plethora
of conditions such as type 2 diabetes, high blood pressure, high cholesterol, osteoporosis and more. Goals
of medical nutrition therapy in general are to maintain normal function and alleviate symptoms of genetic
metabolic disorders. Improper blood levels of certain metabolites can have many insidious effects on the
body. A healthy diet composed of carbohydrates, proteins, fats, vitamins, minerals, antioxidants, fiber
and water can reduce the likelihood of developing chronic diseases such as diabetes, hypertension and
heart disease. Nutritional therapy for PKU patients is a dietary restriction of phenylalanine since there is
impaired metabolism of it. Patients with PKU have to be careful about any product that contains artificial
sweeteners that can be found in diet versions of fizzy drinks or artificial sweetened tea and coffee as a
sugar substitute. The initiation of the treatment for PKU patients should be early, typically before one
week of age. Treatment is recommended for newborns whose levels are between 6 - 10 mg/dL and
persistent. Low phenylalanine levels lead to a low concentration of polyunsaturated fatty acids
deviation for each 300 micromol/L (5 mg/dL) increase in blood phenylalanine concentration. Early-
treated patients with PKU appear to have a higher prevalence of behavior problems and psychological
disturbance. Studies have effectively shown the relationship of a proper diet with the reduction of
complications in PKU patients, despite many advances and the appearance of new treatments, the dietary
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