phenyketonuria

8/7/2019 PHENYKETONURIA

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WESLEYAN UNIVERSITY-PHILIPPINES

MABINI EXT. CABANATUAN CITY

College of Nursing

Submitted by:

Lielani C. Martinez

Joana Marie P. Oseo

BSN IV Blk. 8


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Submitted to:

Eric T. Del Rosario, R.N.

Clinical Instructor

DEFINITION

Phenylketonuria (PKU) is a rare condition in which a baby is born without the ability to properly break

down an amino acid called phenylalanine. It is an inherited autosomal recessive trait that causes

negative impact on development and mental retardation.

Alternative names: Neonatal Phenylketonuria Deficiency Disease, Phenylalanine Hydroxylase ; Folling

Disease/Folling's Disease ; Phenylalanine Hydroxylase Deficiency Disease ; PAH Deficiency; Phenylpyruvic

Oligophrenia.

CAUS E S

Phenylketonuria (PKU) is inherited, which means it is passed down through families. Both parents must

pass on the defective gene in order for a baby to have the condition. This is called an autosomal

recessive trait. Babies with PKU are missing an enzyme called phenylalanine hydroxylase, which is

needed to break down an essential amino acid called phenylalanine. The substance is found in foods

that contain protein. Without the enzyme, levels of phenylalanine and two closely-related substances

build up in the body. These substances are harmful to the central nervous system and cause brain

damage.

Carrier test information for autosomal recessive diseases

One parent is a carrier Both parents are carriers


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If only one parent carries the abnormal gene, there

is:

y

A 50% chance in each pregnancy that their child

will receive the defective gene and be a carrier.

y


will not receive the defective gene and will not

be a carrier or have the disease.

y

No chance (0%) that their child will have the

disease.

If both parents carry the abnormal gene, there is:

y


will inherit the defective gene from each parent

(two genes) and have the disease.

y


will receive one defective gene and be a carrier.

y


will not receive the defective gene and will not

be a carrier or have the disease.

Note: If neither parent carries the abnormal gene, their child will not have this type of disease.

Each person inherits 23 chromosomes from each parent and so has 23 pairs of chromosomes. Each

chromosome contains genes. One or both of the chromosomes in a pair can carry a mutation and beabnormal or defective in a way that causes a genetic disease. In an autosomal recessive disease, both

chromosomes in a pair must have a defective gene for the person to have the disease. If only one gene

is defective, the person is a carrier of the disease but does not have any symptoms.

SYMP TO MS

Phenylalanine hydroxylase enzyme is responsible for the conversion of phenylalanine (an essential

amino acid) to tyrosine. The nonessential amino acid, tyrosine, is a significant element for someneurotransmitters such as dopamine, norepinephrine, epinephrine and serotonin. It is also essential in

the production of melanin and function of the hormone regulating organs such as thyroid, pituitary, and

adrenal glands.

Phenylalanine plays a role in the body's production of melanin, the pigment responsible for skin and hair

color. Therefore, infants with the condition often have lighter skin, hair, and eyes than brothers or

sisters without the disease.

Other symptoms may include:

Delayed mental and social skills

Head size significantly below normal

Hyperactivity

Jerking movements of the arms or legs

Mental retardation


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Seizures

Skin rashes

Tremors

Unusual positioning of hands

Consequences of absent liver enzyme in children with PKU would result to deficient tyrosine leading tothe following conditions:

Absence of serotonin, dopamine and epinephrine

Result: Faulty nerve (Nervous System) transmission

Neurotransmitters communicate impulses to the nerve cells. Lack of tyrosine would lead to

deterioration of this function. Mood regulation is also connected to the presence of these

chemicals (dopamine, serotonin, and epinephrine); therefore, alteration of one s disposition and

temperament will be expected.

D eficient Melanin levels

Result: Unusual skin color

Melanin is responsible for skin pigmentation. Deficient levels of melanin lead to a very fair

complexion, a light blond hair and blue eyes.

H yposecretion of thyroid hormones

Result: Permanent brain damage (Mental Retardation) and developmental delay

Thyroid glands are located at the throat that comprises the two lateral masses on each side of

the trachea. Before the two active thyroid hormones are produced, a process known as iodide

trapping (iodide ion is concentrated within the thyroid) occurs. Then iodide is dissolved inside

the follicular cells of the thyroid to become iodine and later released as a colloid. Colloids

contain thyroglobulins which are made up of the amino acid tyrosine. Iodide when combined

with tyrosine produces Monoiodotyrosine (MIT) and Diiodotyrosine (DIT). Conversion of MIT and

DIT would form the two active thyroid hormone, triiodothyronine (T3) and Thyroxine (T4). These

hormones are stored in the follicular cells until needed. T3 and T4 are primarily responsible for

cellular metabolism affects nearly all cells in the body. They play a vital role for normal

development to occur. In PKU, no Monoiodotyrosine (MIT) and Diiodotyrosine (DIT) is formed

due to absence of tyrosine. Production of T3 and T4 would be inevitable causing decrease basal

metabolism, cessation of cognitive and physical development. Most children with PKU are

cognitively challenged having an IQ of less than 20.


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Increase Phenylalanine levels

Result: Mousy urine odor

Phenylalanine levels increase due to the absence of the liver enzyme. The end product of

phenylalanine metabolism is phenylpyruvic acid (a keto acid). The by-product spills into the urine

that gives it a strong mousy or musty odor that often spreads through the entire body of the

infant or child. This is the reason why the disorder is called phenylketonuria (meaning there is

phenylpruvic or keto acid in the urine)

The most severe form of this disorder is known as classic PKU.

Infants with classic PKU appear normal until they are a few months old.

Without treatment with a special low-phenylalanine diet, these children develop permanent

intellectual disability.

Seizures, delayed development, behavioral problems, and psychiatric disorders are also

common.

Untreated individuals may have a musty or mouse-like odor as a side effect of excess

phenylalanine in the body.

Children with classic PKU tend to have lighter skin and hair than unaffected family members and

are also likely to have skin disorders such as eczema.

Less severe forms of this condition, sometimes called variant PKU and non-PKU hyperphenylalaninemia,

have a smaller risk of brain damage. People with very mild cases may not require treatment with a low-

phenylalanine diet.


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Babies born to mothers with PKU and uncontrolled phenylalanine levels (women who no longer follow a

low-phenylalanine diet) have a significant risk of intellectual disability because they are exposed to very

high levels of phenylalanine before birth.

These infants may also have a low birth weight and grow more slowly than other children.

Other characteristic medical problems include heart defects or other heart problems, an

abnormally small head size (microcephaly), and behavioral problems.

Women with PKU and uncontrolled phenylalanine levels also have an increased risk of pregnancy

loss.

IMP ORT A N C E OF E A RL Y DETE C TION

Newborn screening has been implemented in the U S since the

1960s. The introduction of tandem mass spectroscopy to

routine neonatal screening programs in 1990 led to an increase

in the number of inherited metabolic disorders that could be

detectable in neonates, extending the possibilities of early

diagnosis and treatment for generally presymptomatic

diseases. PKU is identified by an increased concentration of phenylalanine in a blood spot, as well as an increased ratio of phenylalanine to tyrosine. A follow-up test

of plasma amino acids is required to quantitatively confirm elevated phenylalanine concentrations.

Subsequent testing is necessary to determine whether PKU is due to an alteration in the PAH gene or in

either synthesis or recycling of BH4.

The vast majority of PKU cases in infants born in the U S are detected by screening, confirmed, and

treated with diet. However, although PKU screening has been quite effective, there are concerns that

cases of PKU could be missed due to errors at any step of the screening process specimen collection,laboratory procedures, treatment initiation, or clinical follow-up. A consensus statement from the

National Institutes of Health (NIH) has addressed the concern that the variations in quality between

state-run screening programs and poor laboratory performance could result in missed cases of PKU a

problem that could be remedied by adopting a national policy toward newborn screening to replace the

current regionalized state-by-state approach. Missed cases of PKU are considered to be extremely rare.


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Clinical presentation of PKU is usually completely asymptomatic at birth. Without treatment, as the

infant grows tyrosine deficiency leads to thyroid insufficiency and, possibly, to poorly healed dermatitis.

In some cases, excess phenylalanine is diverted into other metabolic pathways to generate other by-

products, such as phenylacetate, the compound responsible for the pungent, mousey smell in some

patients. The human brain develops very rapidly in early life, and even before birth, but because

untreated PKU can impair brain growth and lead to microencephaly within the first few crucial months

of development, severe and irreversible mental retardation can result within the first few months of life.

The precise mechanism linking high phenylalanine concentrations to this intellectual impairment

remains unknown. While tyrosine deficiency and phenylalanine metabolites have been implicated in the

neurotoxicity in PKU, tyrosine supplements have been unable to prevent developmental defects.

Moreover, administering the phenylalanine metabolites does not reproduce neurological symptoms

observed in untreated PKU. Elevated phenylalanine concentrations have been proposed to out-compete

neurotransmitter precursors (e.g. tyrosine, tryptophan) and all other large neutral amino acids (LNAAs)

for the L-type transport system across the blood brain barrier. As a result, excess brain phenylalanine

concentrations can lead to impaired synthesis and re-uptake of these neurotransmitters and,

potentially, to some of the neurological deficits of PKU.

TRE A T M ENT OF PH EN Y LKETON U RI A DIET FOR LIFE

PKU is a treatable disease. The main goal of PKU treatment is to maintain safe blood phenylalanine

concentrations to correct the inborn metabolic imbalance, thereby preventing mental retardation and

promoting normal physical growth and development, as well as a healthy lifestyle through to

adolescence and beyond. Clinicians commonly advocate phenylalanine concentrations of 2 6mg/dl

(120 360 M) for patients up to 12 years of age and 2 10mg/dl (120 600 M) for patients over 12 years

of age.1 These concentrations can be achieved by introduction of a low-phenylalanine diet; this is the

mainstay of PKU treatment to which all patients with classic PKU will respond.

Treatment involves a diet that is extremely low in phenylalanine, particularly when the child is growing.

The diet must be strictly followed. This requires close supervision by a registered dietitian or doctor, and

cooperation of the parent and child. Those who continue the diet into adulthood have better physical

and mental health. Diet for life has become the standard recommended by most experts. This is

especially important before conception and throughout pregnancy.


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Phenylalanine occurs in significant amounts in milk, eggs, and other common foods. The artificial

sweetener Nutra Sweet (aspartame) also contains phenylalanine. Any products containing aspartame

should be avoided.

A special infant formula called Lofenalac is made for infants with PKU. It can be used throughout life as a

protein source that is extremely low in phenylalanine and balanced for the remaining essential amino

acids.Taking supplements such as fish oil to replace the long chain fatty acids missing from a standard

phenylalanine-free diet may help improve neurologic development, including fine motor coordination.

Other specific supplements, such as iron or carnitine, may be needed.

The semi-synthetic PKU diet excludes high-protein foods and consists largely of naturally occurring low-

protein foods such as fruits and vegetables to meet the required amount of phenylalanine. Specially

manufactured medical foods are recommended for supplementing the diet. The restrictions on

phenylalanine-containing animal foods mean that patients end up with high concentrations of

carbohydrate, low concentrations of saturated and polyunsaturated fat, and low amounts of dietary

cholesterol, although some medical foods do contain high levels of saturated fat. Reducing dietary

phenylalanine by restricting protein intake is insufficient because patients would then suffer from

protein malnutrition and nutrient deficiency. As a result, PKU diets necessitate use of synthetic

phenylalanine-free formulas containing adequate concentrations of essential and conditionally essential

amino acids; these products typically provide 52 80% of total dietary protein. Some metabolic formulas

may also include vitamins and minerals, along with the macronutrients, carbohydrates, and fats.

However, the taste and smell of these commercially available dietary products are unpalatable, and are

frequently a source of difficulty in diet compliance.

N U TRITION A L A ND LIFE S T Y LE CHA NGE S

Integration of a PKU diet into a conventional lifestyle is

not easy. Families have to be taught the importance of

managing a diet, how phenylalanine and protein in foods

are monitored, how to choose foods and track dietary

intake, and how to maintain blood phenylalanine

concentrations in the therapeutic range. There is little

opportunity to be spontaneous with foods; meals can

become routine and monotonous in an attempt to

facilitate meal planning and reduce the effort needed to


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prepare meals. Patients have to rely on food manufacturers to provide phenylalanine or protein

contents, or extrapolate quantities themselves.

The low-phenylalanine diet is initiated very early, as soon as the diagnosis is confirmed after the initial

results from newborn screening. The naturally low amount of phenylalanine contained in breast milk or

commercial infant formulae is considered sufficient intake for babies, and it is fairly easy to include andfeed a metabolic formula containing the essential components of a balanced diet to an infant. However,

the difficulty of integration becomes apparent when solid foods are introduced to infants, which asks

families to allocate a certain amount of daily proteins for children and calculate daily protein intake for

older children. This is accomplished by measuring and weighing foods and keeping diet logs, which are

used by dieticians in tandem with regular blood phenylalanine tests to monitor and adjust the diet of

their patients accordingly.

As children start school and socialize with peers, parents gradually relinquish their control of the child sdiet to the child, while having to teach the child the importance of diet and continuing on the regimen.

Although patients initially follow the diet closely using scales and measuring devices, many begin to

estimate measures of their prescribed amounts of phenylalanine as they get older with the assumption

that it is within the therapeutic range, without realizing that they are usually overestimating.

Maintaining the diet is especially difficult in adolescence as it differs from that of the patient s peers,

and there are social situations where teenagers may feel torn between the need to fit in and the need to

follow their own dietary restrictions. Many teenagers also opt to curb hunger and supplement their

caloric intake with lots of carbohydrates, sugar beverages, and soda. S tudies have shown that PKU

patients have a tendency to become overweight, and this may be partly due to the fact that the only

foods that PKU patient can eat freely without any risk to their phenylalanine concentrations, and

without having to monitor their dietary intake, are sugar- and fat-based foods. The biggest difficulty in

integrating diet into lifestyle is unarguably the inconvenience of the diet; patients need to take their

own foods and metabolic formulas whenever they go out, the latter of which have a very infantile

appearance. Although medical food companies are starting to produce different types of product that

appear similar to normal foods, the inconvenience remains a big limitation for patients with PKU.

Although some patients choose to relax or discontinue the PKU diet in late adolescence and adulthood,

an increasing majority of metabolic clinics advocate diet for life. There are several problems associated

with discontinuing the PKU diet. Many patients abandon metabolic formulas while choosing to continue

on a low-protein diet, but in doing so create a dietary imbalance that can leave them deficient in

essential nutrients and vitamins. From a clinician s perspective, it would almost be preferential for these


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It is difficult for patients to adhere to

the phenylketonuria diet for life, and

families of patients are always asking for

alternatives to the phenylalanine

restrictive diet.

older patients to adopt a normal diet and have elevated phenylalanine concentrations than suffer from

nutritional deficiencies. Although there are no definitive studies on the effect of diet in adults, data

suggest that elevated phenylalanine concentrations in adolescence and adulthood have adverse effects

on aspects of cognition, such as delayed processing and lower intellectual function, as well as nutrition,

such as osteopenia and osteoporosis. Given the potential to prevent the onset of neurological deficits

and nutritional insufficiencies and maintain a healthy lifestyle and good quality of life, is it not worth

urging PKU patients to remain on the diet for life. Indeed, these factors stress how important it is for

children to learn about their diet and for them to understand from a young age why strict adherence to

their diet is necessary.

E M ERGING T H ER AP IE S IN PH EN Y LKETON U RI A

The recent designation of sapropterin dihydrochloride

(Kuvan , BioMarin Pharma) as an orphan medicinal

product was an important milestone for patients with

PKU. This orally available synthetic form of BH4 can

activate residual PAH enzymes and improve naturalphenylalanine metabolism,8 therefore reducing blood

phenylalanine concentrations in patients and allowing patients to be more relaxed with their diets.

However, unlike the dietary regimen, where response is universal among PKU patients, clinical studies

found that only approximately 20 56% of PKU patients were responsive to treatment. It is not yet

possible to pre-determine by laboratory testing which patients belong to this subgroup of BH4-

responsive PKU patients, and response can be determined only by giving sapropterin to patients in a

therapeutic trial and monitoring blood phenylalanine concentrations.

Sapropterin has been shown to be safe and effective in responsive patients, and is currently indicated

for the reduction of blood phenylalanine concentrations in patients with BH4-responsive PKU as an

adjunct to a low-phenylalanine diet. Although this pharmacological option provides a subgroup of PKU

patients with the opportunity to have a more normalized diet, it is still advisable for these patients to

use metabolic foods and formulas.


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The mystery surrounding the

underlying pathophysiology of

phenylketonuria warrants further

research as to why phenylalanine

is so toxic to the brain.

Enzyme replacement therapy has been proposed as an alternative for patients who are unresponsive to

sapropterin, presumably because residual PAH concentrations are too low for sufficient stimulation by

BH4. Although replacement of PAH could be facilitated by liver transplantation, the risks of major

surgery and life-long immunosuppression preclude routine implementation of this tactic.

As high concentrations of phenylalanine had beenproposed to out compete other LNAAs for the L-type

transport system in PKU, trials have tested the role of

LNAA supplementation. S tudies have shown that

increasing blood concentrations of various LNAAs can

reduce the brain and blood concentrations of

phenylalanine. LNNA supplements are designated as medical foods in the U S as an optional addition to a

PKU diet.

It is difficult for patients to adhere to the PKU diet for life, and families of patients are always asking for

alternatives to the phenylalanine-restrictive diet. The introduction of a pharmaceutical option is

important in PKU because, despite the fact that diet has been the mainstay of treatment for decades,

certain families do not comply with the strict observation, preparation, and administration of food that

is necessary in a PKU diet. Furthermore, as patients get older they want to have a normal diet and social

life; as a result, they become more relaxed in their lifestyle and diet, and the average level of

phenylalanine in patients gradually increases with age. For these reasons, pharmacological therapy as an

adjunct to dietary therapy can be a good option in helping to maintain adequate phenylalanine

concentrations in PKU patients who are responsive to therapy, allowing for a potential improvement in

quality of life.

From the viewpoint of the clinician and dietician, however, a low phenylalanine diet remains key in the

treatment of PKU. While all patients with classic PKU respond to diet, not everyone responds to

pharmacological therapy. Furthermore, the major disadvantage of introducing the pharmaceutical

options is that patients tend to ignore their diets, despite the fact that diet is still the foundation of treatment that can keep phenylalanine concentrations in a therapeutic range. This disadvantage is also

found in other disorders that are treated by diet, such as diabetes and obesity; patients are reluctant to

stick to a dietary regimen, and so they respond to the more convenient option of drugs.

While families of patients may prefer pharmaceuticals for the convenience they offer, it is more

important that patients and their families are taught about the importance and rationale behind a low


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phenylalanine diet and are provided with the tools that will allow them to monitor and modulate their

dietary intake in accordance with their recommended therapeutic concentrations, which will ultimately

require them to follow a very strict diet.

O U TLOOK ( P ROGNO S IS)

The outcome is expected to be very good if the diet is closely followed, starting shortly after the child's

birth. If treatment is delayed or the condition remains untreated, brain damage will occur. School

functioning may be mildly impaired.

If proteins containing phenylalanine are not avoided, PKU can lead to mental retardation by the end of

the first year of life.

P O SS IBLE C O MP LI CA TION S

Severe mental retardation occurs if the disorder is untreated. ADHD (attention-deficit hyperactivity

disorder) appears to be the most common problem seen in those who do not stick to a very low-

phenylalanine diet.

P REVENTION

An enzyme assay can determine if parents carry the gene for PKU. Chorionic villus sampling can be done

on the pregnant women to screen the unborn baby for PKU.

It is very important that women with PKU closely follow a strict low-phenylalanine diet both before

becoming pregnant and throughout the pregnancy, since build-up of this substance will damage the

developing baby even if the child has not inherited the defective gene.

phenyketonuria

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