Phenylketonuria: Signs, Symptoms, Causes, Pathophysiology, Treatment, History and Research

It is an inborn error of the metabolism that produces a decrease in the metabolism of the amino acid phenylalanine.

Untreated phenylketonuria can cause intellectual disability, seizures, behavioral problems, and mental disorders.

It can also result in a musty smell and lighter skin. Babies born to mothers who have poorly treated phenylketonuria may have heart problems, a small head, and low birth weight.

Phenylketonuria is a genetic disorder inherited from a person’s parents. This results in the accumulation of phenylalanine in the diet at potentially toxic levels.

There are two main types, classical phenylketonuria and variant phenylketonuria, depending on whether there is any enzymatic function remaining.

Those with a copy of a mutated gene usually have no symptoms. Many countries have screening programs for the disease in newborns.

The treatment is with a diet low in foods that contain phenylalanine and special supplements. Babies should use a special formula.

The effectiveness is controlled through periodic blood tests. The drug sapropterin dihydrochloride may be useful in some.

The disease was discovered in 1934 by Ivar Asbjørn Følling with the importance of the diet determined in 1953. Gene therapy, although promising, requires much more study as of 2014.

Signs and symptoms of phenylketonuria

Untreated phenylketonuria can cause intellectual disability, seizures, behavioral problems, and mental disorders. It can also result in a musty smell and lighter skin.

Babies born to mothers who have poorly treated phenylketonuria may have heart problems, a small head, and low birth weight.

Because the mother’s body can break down phenylalanine during pregnancy, babies with phenylketonuria are normal at birth. The disease is not detectable by physical examination at that time, because no damage has yet occurred.

However, a blood test can reveal elevated levels of phenylalanine after one or two days of normal infant feeding.

This is the purpose of the screening test in the newborn, to detect the disease with a blood test before any damage is done, so that the treatment can prevent the damage from occurring.

If a child is not diagnosed during the routine screening of newborns (usually performed 2-7 days after birth, using specimens removed by neonatal heel puncture) and a diet restricted in phenylalanine is not introduced, phenylalanine levels in the blood they will increase with time.

Toxic levels of phenylalanine (and insufficient levels of tyrosine) can interfere with childhood development in ways that have permanent effects.

The disease can present clinically with seizures, hypopigmentation (excessively clear hair and skin) and a “musty odor” in the baby’s sweat and urine (due to phenylacetate, a carboxylic acid produced by the oxidation of phenylketone).

Hyperactivity, electroencephalographic abnormalities, and seizures and severe learning disabilities are important clinical problems later in life.

A characteristic “moldy or mousy” smell on the skin, as well as a predisposition for eczema, persists throughout life in the absence of treatment.

The damage caused to the brain if phenylketonuria is not treated during the first months of life is not reversible. It is critical to control the diet of infants with phenylketonuria very carefully so that the brain has the opportunity to develop normally.

Affected children who are detected at birth and receive treatment are much less likely to develop neurological problems or to suffer from seizures and intellectual disability (although such clinical disorders are still possible).

In general, however, the results for people treated for phenylketonuria are good. The treated persons may not have any physical, neurological or developmentally detectable problem.

Many adults with phenylketonuria who were diagnosed with newborn screening and who have received treatment since birth have high academic achievement, successful careers and satisfying family lives.


Phenylketonuria is an autosomal recessive metabolic genetic disorder. As an autosomal recessive disorder, two alleles of phenylketonuria are required for an individual to experience the symptoms of the disease.

If both parents are carriers of phenylketonuria, there is a 25% chance that any child born with the disorder, a 50% chance of the child being a carrier and a 25% chance that the child will not develop or be carrier for the disease

Phenylketonuria is characterized by homozygous or heterozygous mutations composed of the hepatic enzyme phenylalanine hydroxylase (PAH) gene, which makes it nonfunctional.

This enzyme is needed to metabolize the amino acid phenylalanine (Phe) to the amino acid tyrosine (Tyr). When the activity of the phenylalanine hydroxylase gene is reduced, phenylalanine accumulates and becomes phenylpyruvate (also known as phenyl ketone), which can be detected in the urine.

The carriers of a single allele of phenylketonuria do not show symptoms of the disease, but appear to be protected to some extent against the fungal toxin Ochratoxin A.

This explains the persistence of the allele in certain populations, since it confers a selective advantage, in other words being a heterozygote is advantageous

The phenylalanine hydroxylase gene is found on chromosome 12 in the bands 12q22-q24.1. More than 400 disease-causing mutations have been found in the phenylalanine hydroxylase gene.

Phenylketonuria may exist in mice, which have been widely used in experiments to find an effective treatment for it.

Pathophysiology of phenylketonuria

When phenylalanine can not be metabolized by the body, a typical diet that would be healthy for people without phenylketonuria causes abnormally high levels of phenylalanine to accumulate in the blood, which is toxic to the brain.

If left untreated, complications of PKU include severe intellectual disability, abnormal brain function, microcephaly, mood disorders, irregular motor functioning, and behavioral problems such as attention deficit hyperactivity disorder and physical symptoms. as a “moldy” smell, eczema, and an unusual coloration of the skin and hair.

Phenylcetonuria clásica

Classical phenylketonuria, and its less severe forms, “mild phenylketonuria” and “mild hyperphenylalaninemia”, are caused by a mutated gene of the enzyme phenylalanine hydroxylase (PAH), which converts the amino acid phenylalanine (Phe, its acronym in English) in other essential compounds of the body, in particular tyrosine.

Tyrosine is an amino acid conditionally essential for patients with phenylketonuria because without phenylalanine hydroxylase it can not be produced in the body through the breakdown of phenylalanine.

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

Deficiency of phenylalanine hydroxylase causes a spectrum of disorders, including classic phenylketonuria (PKU) and mild hyperphenylalaninemia (also known as “hyperphe” or “mild phenylalanine hydroxylase”), a less severe accumulation of phenylalanine

Patients with “hyperphe” may have a more functional phenylalanine hydroxylase enzyme and tolerate greater amounts of phenylalanine in their diets than those with classical phenylketonuria, but unless the dietary intake is at least somewhat restricted, their blood phenylalanine levels are still higher than the levels in people with normal activity of phenylalanine hydroxylase.

Phenylalanine is a large and neutral amino acid (LNAA, for its acronym in English).

Recent research suggests that the neurocognitive, psychosocial, quality of life, growth, nutrition and bone pathology are slightly lower than ideal for patients receiving treatment and maintain their phenylalanine levels in the target range, if their diet it is not complemented with other amino acids.

Classic phenylketonuria dramatically affects myelination and tracts of white matter in untreated babies; This may be one of the main causes of the neurological disorders associated with phenylketonuria.

The differences in the development of the white matter are observed with the magnetic resonance. Abnormalities in the gray matter can also be detected, particularly in the motor cortex and premovil, the thalamus and the hippocampus.

It was recently suggested that phenylketonuria may resemble amyloid diseases, such as Alzheimer’s disease and Parkinson’s disease, due to the formation of toxic phenylalanine-like amyloid pools.

Other mutations that are not phenylalanine hydroxylase can also cause phenylketonuria.

Hyperphenylalaninemia deficient in tetrahydrobiopterin

A rarer form of hyperphenylalaninemia is tetrahydrobiopterin deficiency, which occurs when the enzyme phenylalanine hydroxylase is normal and a defect is found in the biosynthesis or recycling of the cofactor tetrahydrobiopterin (BH4).

BH4 is necessary for the proper activity of the enzyme phenylalanine hydroxylase, and this coenzyme can be supplemented as a treatment.

Those who suffer from this form of hyperphenylalaninemia may have a tyrosine deficiency (which is created from phenylalanine by phenylalanine hydroxylase), in which case the treatment is the administration of tyrosine supplements to explain this deficiency.

Dopamine levels can be used to distinguish between these two types. Tetrahydrobiopterin is necessary to convert phenylalanine to tyrosine and is required to convert tyrosine to L-DOPA (amino acid) through the enzyme tyrosine hydroxylase.

L-DOPA, in turn, becomes dopamine. Low levels of dopamine lead to high levels of prolactin. In contrast, in classical phenylketonuria (without involvement of dihydrobiopterin), prolactin levels would be relatively normal.

Metabolic pathways

The enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino acid tyrosine.

The elevated levels of phenylalanine in the blood and the detection of phenylketones in the urine are diagnostic, however, most patients are diagnosed through the detection of newborns.

Detection of newborns

Phenylketonuria is commonly included in the screening panel of newborns in many countries, with various detection techniques.

The measurements made using MS / MS determine the concentration of phenylalanine and the proportion of phenylalanine to tyrosine, the ratio will be high in phenylketonuria.

Treatment for phenylketonuria

Phenylketonuria is not curable. However, if phenylketonuria is diagnosed early enough, an affected newborn can grow up with normal brain development by administering and controlling phenylalanine (“Phe”) levels through diet or a combination of diet and medications.


People who follow the prescribed dietary treatment from birth may not have symptoms. Your phenylketonuria would be detectable only by a blood test. People must comply with a special diet low in phenylalanine for optimal brain development.

For people who do not have phenylketonuria, the whole of the US Institute of Medicine. UU Recommended at least 33mg / kg body weight / day of phenylalanine plus tyrosine for adults 19 years of age and older.

For people with phenylketonuria, a recommendation for children up to 10 years old is 200mg to 500 mg / day; for older children and adults from 220 mg to 1200 mg / day. Where in the range depends on body weight and age, and to control blood concentration.

The optimal health ranges (or “target ranges”) are between 120μmol and 360μmol / L or equivalently 2mg to 6mg / dL, and are intended to be achieved for at least the first 10 years, to allow the brain to develop normally.

The age at which people with phenylketonuria can leave the diet safely is subject to some debate. The diet should be maintained at least until the age of eight or ten.

Some evidence supports the interruption after 10 years as a normal diet after it does not seem to have negative effects. However, a study has shown temporary detrimental effects when it is not in the diet.

There is no evidence of permanent brain damage in people who have left the diet in adulthood. In case of mild neurocognitive impairment, reintroduction of the diet is indicated.

Usually, a food diary is kept to record the amount of phenylalanine consumed with each meal, snack or drink.

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


Supplemental “protein substitute” formulas are typically prescribed for people with phenylketonuria (beginning in childhood) to provide the amino acids and other necessary nutrients that would otherwise be lacking in a diet low in phenylalanine.

Tyrosine, which is usually derived from phenylalanine and is necessary for normal brain function, is usually supplemented.

The consumption of protein substitute formulas can actually reduce phenylalanine levels, probably because it stops the process of protein catabolism by releasing phenylalanine stored in muscles and other tissues in the blood.

Many patients with phenylketonuria have their highest levels of phenylalanine after a period of fasting (such as during the night), because fasting triggers catabolism.

A diet low in phenylalanine but that does not include protein substitutes can not lower phenylalanine levels in the blood either, since a nutritionally insufficient diet can also trigger catabolism.

For all these reasons, the prescription formula is an important part of the treatment for patients with classic phenylketonuria.

Oral administration of tetrahydrobiopterin (or BH4) (a cofactor for the oxidation of phenylalanine) may reduce blood levels of this amino acid in some people. Most people, however, with the “classical” sequence of mutations, will have little or no benefit.

Tentative evidence supports dietary supplementation with large neutral amino acids (LNAA).

Large neutral amino acids (eg, Leu, tyr, trp, met, his, ile, val, thr) can compete with phenylalanine for specific transport proteins that transport large neutral amino acids through the intestinal mucosa into the blood and into the blood. Brain blood barrier in the brain.

Its use is only indicated in adults who will not follow an adequate diet. Another interesting treatment strategy is the casein glycine-peptide (CGMP), which is a milk peptide naturally free of phenylalanine in its pure form.

The casein glycomacropeptide can substitute the main part of the free amino acids in the diet of phenylketonuria and provides several beneficial nutritional effects compared to amino acids.

The fact that the casein glycomacropeptide is a peptide ensures that the absorption rate of its amino acids is prolonged compared to free amino acids and, therefore, results in better protein retention and greater satiety compared to free amino acids.

Another important benefit of the casein glycomacropeptide is that the taste is significantly improved when the casein glycomacropeptide replaces part of the free amino acids and this may help to ensure better compliance with the phenylketonuria diet.

In addition, glycomacropeptide casein contains a large amount of phenylalanine which reduces the large neutral amino acids, which constitutes approximately 41g per 100g of protein and, therefore, will help maintain plasma phenylalanine levels in the target range.


For women with phenylketonuria, it is important for their children’s health to keep phenylalanine levels low before and during pregnancy.

The child may develop congenital heart disease, growth retardation, microcephaly, and intellectual disability as a result.

Women affected by phenylketonuria by themselves do not risk additional complications during pregnancy.

Women with phenylketonuria who wish to have children should reduce their blood levels of phenylalanine, this is achieved by periodic blood tests and strict compliance with a diet, usually monitored daily by a dietitian metabolic metabolism specialist.

In many cases, as the liver of the fetus begins to develop and produces phenylalanine hydroxylase normally, the levels of phenylalanine in the mother’s blood will decrease, which will require an increase in intake to remain within the safe range of 2-6. mg / dL.

The daily intake of phenylalanine from the mother can double or even triple by the end of pregnancy, as a result.


The average number of new cases of phenylketonuria varies in different human populations. Caucasians in the United States are affected at a rate of 1 in 10,000.

Turkey has the highest documented rate in the world, with 1 in 2,600 births, while countries such as Finland and Japan have extremely low rates with less than one case of phenylketonuria in 100,000 births.

A Slovak study of 1987 reports a gypsy population with an extremely high incidence of phenylketonuria (one case in 40 births) due to extensive endogamy. It is the most common amino acid metabolic problem in the United Kingdom.


Before the causes of phenylketonuria were understood, phenylketonuria caused severe disability in the majority of people who inherited the relevant mutations.

Nobel Prize winning author and Pulitzer Prize winner, Pearl S. Buck , had a daughter named Carol , who lived with phenylketonuria before the treatment was available, and wrote a moving account of its effects in a book called The Boy Who Never Grows. .

Many patients with untreated phenylketonuria born before generalized screening in newborns are still alive, mainly in dependent households / institutions.

Phenylketonuria was discovered by the Norwegian doctor Ivar Asbjørn Følling in 1934 when he noticed that hyperphenylalaninemia (HPA) was associated with intellectual disability.

In Norway, this disorder is known as Følling’s disease , named after its discoverer. Følling was one of the first doctors to apply detailed chemical analyzes for the study of the disease.

In 1934 at Rikshospitalet, Følling saw a young woman named Borgny Egeland . He had two children, Liv and Dag , who had been normal at birth, but later developed an intellectual disability.

When Dag was about a year old, the mother noticed a strong smell of urine. Føllingobtained urine samples from the children and, after many tests, discovered that the substance that caused the smell in the urine was phenylpyruvic acid.

The children, he concluded, had an excess of phenylpyruvic acid in their urine, the condition called phenylketonuria (PKU).

His careful analysis of the urine of the two affected brothers led him to ask many doctors near Oslo to test the urine of other affected patients. This led to the discovery of the same substance he had found in eight other patients.

He carried out tests and found reactions that gave rise to benzaldehyde and benzoic acid, which led him to conclude that the compound contained a benzene ring. Additional tests showed that the melting point was the same as phenylpyruvic acid, which indicated that the substance was in the urine.

In 1954, Horst Bickel , Evelyn Hickmans and John Gerrard published a paper describing how they created a diet low in phenylalanine and the patient recovered. Bickel , Gerrard and Hickmans received the John Scott Medal in 1962 for their discovery.

Phenylketonuria was the first disorder that was diagnosed routinely through the generalized detection of newborns. Robert Guthrie introduced the screening test for phenylketonuria in newborns in the early 1960s.

With the knowledge that phenylketonuria could be detected before symptoms were evident and treatment was initiated, detection was quickly adopted worldwide. Austria began to detect Phenylketonuria in 1966 and England in 1968.


Other therapies are currently under investigation, including gene therapy.

Biomarin is currently conducting clinical trials to investigate PEG-PAL (phenylalanine ammonia lyase phenylalanine or “PAL”) is an enzyme replacement therapy in which the missing phenylalanine hydroxylase enzyme is replaced by an analogous enzyme that also breaks down phenylalanine.

PEG-PAL is now in phase 2 of clinical development.