Phenylketonura (PKU)

Autosomal recessive process of deficiency of phenylalanine hydroxylase or in some cases of its cofactor tetrahydrobiopterin.

With a lack of this enzyme phenylalanine builds up and there is an inability to produce tyrosine.

Insufficient amounts of phenylalanine hydroxylase result in phenylketonuria, a metabolic disorder that leads to intellectual deficits unless treated by dietary manipulation.

With excess phenylalanine it is converted into the phenylketones phenylpyruvate, phenyllactate, and phenylacetate.

Incidence of 1 in 13500-19,000 live births.

Infants present within 6-12 months with CNS symptoms of developmental delay, seizures and failure to thrive.

Patients are hypo pigmented, with fair hair, blue eyes, and pale skin.

All neonates are screened for this process.

Treatment is with restriction dietary intake of phenylalanine, increased dietary tyrosine and monitoring blood levels of phenylalanine.

Refers to an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine.

Phenylketonuria affects about 1 in 12,000 babies.

Males and females are affected equally.

It is due to mutations in the PAH gene, which results in low levels of the enzyme phenylalanine hydroxylase.

Results in the buildup of dietary phenylalanine to potentially toxic levels.

Classical PKU, and its less severe forms mild PKU and mild hyperphenylalaninemia are caused by a mutated gene for the enzyme phenylalanine hydroxylase, which converts the amino acid phenylalanine to other essential compounds in the body, in particular tyrosine.

Tyrosine is a conditionally an essential amino acid for PKU patients because without phenylalanine hydroxylase it cannot be produced in the body through the breakdown of phenylalanine.

Tyrosine is necessary for the production of neurotransmitters like epinephrine, norepinephrine, and dopamine.

Phenylalanine hydroxylase deficiency causes a spectrum of disorders, including classic phenylketonuria (PKU) and mild hyperphenylalaninemia, a less severe accumulation of phenylalanine.

When untreated, can lead to intellectual disability, seizures, behavioral problems, and mental disorders.

Untreated children often fail to attain early developmental milestones, develop microcephaly, and demonstrate progressive impairment of cerebral function.

Clinical problems later in life may manifest hyperactivity, EEG abnormalities, and seizures, and severe learning disabilities.

Patients may have a musty smell and lighter skin color.

The musty smell is of sweat and urine.

The musty smell is due to phenylacetate, a carboxylic acid produced by the oxidation of phenylketone.

Babies born to mothers who have PKU that has been poorly managed may have heart problems, a small head, and low birth weight.

There is a predisposition for eczema, that persists throughout life in the absence of treatment.

Usual onset is at birth.

An autosomal recessive disease.

PKU tested as newborn screening test.

Screening for PKU is done with bacterial inhibition assay, immunoassays using fluorometric or photometric detection, or amino acid measurement using tandem mass spectrometry.

Treatment is with a diet low in foods that contain phenylalanine, and special supplements.

Occurs in about 1 in 12,000 newborns.

Because the mother’s body is able to break down phenylalanine during pregnancy, infants with PKU are normal at birth.

The disease is not detectable by physical examination at that time of birth, because no damage has yet been done.

Newborn screening is performed to detect the disease before any damage is done.

The blood sample is usually taken by a heel prick, typically performed 2–7 days after birth.

This test can reveal elevated phenylalanine levels after one or two days of normal infant feeding.

Can manifest normal health with treatment.

There are two main types, classic PKU and variant PKU, depending on if any enzyme function remains.

Patients with one copy of a mutated gene typically do not have symptoms.

Babies should use a special formula.

The diet is begin as soon as possible after birth and be continued for at least 10 years, if not lifelong.

Patients diagnosed early and maintain a strict diet can have normal health and a normal life span.

Effectiveness of the diet is monitored through periodic blood tests.

Toxic levels of phenylalanine can interfere with infant development, with permanent effects.

Brain damage that occurs if PKU is untreated during the first months of life is irreversible.

It is essential to carefully control the diet of infants with PKU very carefully so that the brain has an opportunity to develop normally.

Affected children who are detected and treated treated from birth are much less likely to develop neurological problems or have seizures and intellectual disabilities.

Outcomes for people treated for PKU are good, as treated individuals may have no detectable physical, neurological, or developmental problems at all.

In mild hyperphenylalaninemia patients may have more functional phenylalanine hydroxylase enzyme and be able to tolerate larger amounts of phenylalanine in their diets than those with classic PKU, but unless dietary intake is at least somewhat restricted, their blood phenylalanine levels are still higher than the levels in people with normal PAH activity.

Phenylalanine is a large, neutral amino acid (LNAA), and competes for transport across the blood–brain barrier (BBB) via the large neutral amino acid transporter (LNAAT).

Excess phenylalanine saturates the transporter, and tends to decrease the levels of other large amino acids in the brain.

As these large amino acids are necessary for protein and neurotransmitter synthesis, phenylalanine buildup hinders the development of the brain’s intellectual abilities.

Studies suggests that neurocognitive, psychosocial, quality of life, growth, nutrition, bone pathology are slightly suboptimal even for patients who are treated and maintain their phenylalanine levels in the target range.

Classic disease affects myelination and white matter tracts in untreated infants, and observable with magnetic resonance imaging.

PKU may resemble amyloid diseases, such as Alzheimer’s disease and Parkinson’s disease, due to the formation of toxic amyloid-like assemblies of phenylalanine.

PKU is not curable, but patients following the appropriate diet

may have no symptoms, and their process would be detectable only by a blood test.

Patients must adhere to a special diet low in phenylalanine for optimal brain development.

Because phenylalanine is necessary for the synthesis of many proteins, and it is required for appropriate growth, its levels must be strictly controlled.

The recommended daily intake of phenylalanine plus tyrosine is at least 33 mg/kg body weight/day for adults 19 years and older.

For people with PKU, a recommendation for children up to age 10 years is 200 to 500 mg/d; for older children and adults 220 to 1200 mg/day of phenylalanine.

Optimal target ranges are between 120 and 360 µmol/L or equivalently 2 to 6 mg/dL, and aimed to be achieved during at least the first 10 years, to allow the brain to develop normally.

The low phenylalanine diet should be maintained at least until the age of eight or ten.

Discontinuance after 10 years does not appear to have negative effects.

Some evidence supports discontinuing diet after 10 years, as a normal diet after that does not appear to have negative effects.

Temporarily detrimental effects when off the diet, have been reported, without evidence for permanent brain damage.

In case of mild neurocognitive impairment, the re-introduction of diet is indicated.

The diet requires restricting or eliminating foods high in phenylalanine: soybeans, egg whites, shrimp, chicken breast, spirulina, watercress, fish, nuts, crayfish, lobster, tuna, turkey, legumes, and lowfat cottage cheese.

While starchy foods, such as potatoes and corn are generally acceptable, the quantity of phenylalanine consumed from these foods must be monitored.

A food diary is kept to record the amount of phenylalanine consumed.

Food substitutes are often used in place of normal bread, pasta, and other grain-based foods, which contain a significant amount of phenylalanine.

Fruits and vegetables are lower in phenylalanine and can be eaten in larger quantities, for the most part.

Infants may still be breastfed.

The sweetener aspartame, must also be avoided, as aspartame is metabolised into phenylalanine.

Regular blood tests are used to determine the effects of dietary phenylalanine intake on blood phenylalanine levels.

Supplementary protein substitute formulas are prescribed, starting in infancy, to provide the amino acids and other necessary nutrients that would otherwise be lacking in a low-phenylalanine diet.

Tyrosine, is usually supplemented as it is normally derived from phenylalanine and is necessary for normal brain function.

Protein substitute formulas can reduce phenylalanine levels, stopping the process of protein catabolism from releasing phenylalanine stored in the muscles and other tissues into the blood.

Fasting triggers catabolism and is associated with the highest

phenylalanine levels.

A diet that is low in phenylalanine but does not include protein substitutes may also fail to lower blood phenylalanine levels, since a nutritionally insufficient diet may also trigger catabolism.

The medication sapropterin dihydrochloride may be useful in some.

Casein glycomacropeptide (CGMP), which is a milk peptide naturally free of phenylalanine in its pure form and can substitute the main part of the free amino acids in the PKU diet and provides several beneficial nutritional effects compared to free amino acids.

For women with PKU, it is important for the health of their children to maintain low phenylalanine levels before and during pregnancy.

The intrauterine environment can have very high levels of phenylalanine, which can cross the placenta, and the child may develop congenital heart disease, growth retardation, microcephaly and intellectual disability as a result.

Pregnant women with phenylketonuria are not at risk of additional complications during pregnancy.

Women with PKU who wish to have children are advised to lower their blood Phe levels before they become pregnant, and carefully control their levels throughout the pregnancy.

When low phenylalanine levels are maintained during pregnancy, there are no elevated levels of risk of birth defects compared with a baby born to a non-PKU mother.

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