Phenylketonuria is a disease characterized by the non-assimilation (or non-metabolization) of phenylalanine.

Phenylalanine is an essential amino acid with a fundamental role in the nervous system by stimulating the thyroid gland. It is also an intellectual stimulant.This amino acid is not synthesized by the body and must therefore be supplied by food. Indeed, phenylalanine is one of the constituents of all foods rich in proteins of animal and vegetable origin: meat, fish, egg, soy, milk, cheese, etc.

It is a rare genetic and hereditary disease which affects both girls and boys, without particular preponderance.

If the disease is not detected very early for rapid treatment, an accumulation of this substance can occur in the body and in particular in the nervous system. Too much phenylalanine in the developing brain is toxic.

The excess phenylalanine present in the body is evacuated by the renal system and therefore found in the patient’s urine, in the form of phenylketones. (2)

In France, a phenylalanine screening test is systematic at birth: Guthrie test.

The prevalence (number of people with the disease in a population at a given time), depends on the country concerned and can vary between 1 / 25 and 000 / 1.

In France, the prevalence of phenylketonuria is 1 / 17. (000)

This disease is treated with a diet low in protein to reduce the level of phenylalanine in the patient’s body and limit brain damage.

Early treatment of the disease usually prevents the development of symptoms.

In addition, late treatment leading to an accumulation of this molecule in the brain has particular consequences: (3)

– learning difficulties;

– behavioral disorders;

– epileptic disorders;

– eczema.

Three forms of the disease have been demonstrated after blood tests at birth: (2)

– typical phenylketonuria: with phenylalaninemia (level of phenylalanine in the blood) greater than 20 mg / dl (or 1 μmol / l);

– atypical phenylketonuria: with a level between 10 and 20 mg / dl (or 600-1 µmol / l);

– Permanent moderate hyperphenylalaninemia (HMP) where the phenylalaninemia is less than 10 mg / dl (or 600 μmol / l). This form of the disease is not serious and only requires simple monitoring in order to avoid any aggravation.

Systematic screening at birth makes it possible, in the majority of cases, to limit the appearance of typical symptoms of the disease.

The treatment of the disease is based on a diet low in protein and monitoring of phenylalaninemia also helps prevent the accumulation of phenylalanine in the body and particularly in the brain. (2)

In the event that the neonatal diagnosis is not made, the symptoms of phenylketonuria appear quickly after birth and may be more or less severe depending on the form of the disease.

These symptoms are characterized by:

– a delay in the mental development of the child;

– a delay in growth;

– microcephaly (abnormally small size of the skull);

– convulsions and tremors;

– eczema;

– vomitings ;

– behavioral disorders (hyperactivity);

– motor disorders.

In the case of hyperphenylalaninemia, mutations in the gene encoding a co-factor for converting phenylalanine to tyrosine (co-factor BHA) are possible. These disturbances in the production of tyrosine lead to:

– fair skin;

– fair hair.

Phenylalanine is an inherited genetic disease. It results in autosomal recessive inheritance. This mode of transmission concerns an autosome (non-sexual chromosome) and recessivity results in the need for the subject to have two copies of the mutated allele in order to develop the diseased phenotype. (4)

The origin of the disease is the mutation of the PAH gene (12q22-q24.2). This gene codes for an enzyme allowing hydrolysis (destruction of a substance by water): phenylalanine hydroxylase.

The mutated gene therefore results in a reduction in the activity of phenylalanine hydroxylase and therefore phenylalanine from food is not processed effectively by the body. The level of this amino acid in the blood of the affected subject is therefore increased. Following the increase in this quantity of phenylalanine in the body, its storage will take place in different organs and / or tissues, particularly in the brain. (4)

Other mutations have been demonstrated in the relationship with the disease. These are modifications at the level of the genes encoding BHA (co-factor for the conversion of phenylalanine into tyrosine) and particularly concern the form of hyperphenylalaninemia. (1)

The risk factors associated with the disease are genetic. In fact, the transmission of this disease occurs through an autosomal recessive transfer. Either, that the presence of the two alleles mutated for the gene must be present in the individual to develop the disease.

In this sense, each parent of the sick individual must have a copy of the mutated gene. Because it is a recessive form, parents with only one copy of the mutated gene do not show symptoms of the disease. Nevertheless, they are required, up to 50% each, to each transmit a mutated gene to the offspring. If the father and mother of the child each transmit a mutated gene, the subject will therefore have the two mutated alleles and will then develop the diseased phenotype. (4)

The diagnosis of phenylketonuria is mainly made through the birth screening program: systematic newborn screening. This is the Guthrie test.

 This test is considered to be positive if the level of phenylalanine in the blood is greater than 3 mg / dl (or 180 µmol / l). In the context of excessive phenylalaninemia, a second blood test is performed in a specialized center to confirm or not the presence of phenylketonuria. If the level of phenylalanine is still greater than 3 mg / dl during the second dosage and no other possibly responsible disease has been identified, the diagnosis is then made. (2)

The diagnosis of this disease should be distinguished from that of BH4 deficiency. Indeed, the latter is particularly characteristic of hyperphenylalaninemia and requires only simple monitoring. While the detection of the presence of phenylketonuria in the subject requires special treatment and a low protein diet. (1)

The primary treatment for phenylketonuria is therefore a diet low in phenylalanine, ie a reduction in dietary protein intake. This low protein diet must be implemented as soon as newborn screening is performed. It must be followed throughout life and may be more or less strict depending on the subject and the form of the disease. (2)

In addition to this diet depleted in phenylalanine, sapropterin dihydrochloride can be prescribed to the patient so that his diet is less strict, or even that his diet remains normal. (2)

In addition, food supplements rich in amino acids (excluding phenylalanine), vitamins and minerals may be recommended in order to restore any imbalance in these intakes due to this diet. (3)

Consumption of aspartame (artificial sweetener used in many products such as industrial drinks, food preparations, etc.) should be avoided absolutely for people with phenylketonuria. In fact, once absorbed, aspartame is transformed in the body into phenylalanine. In this sense, increases the risk of accumulation of this molecule in the body and risks being toxic for the sick subject. Aspartame is also present in many drugs, special attention from patients is required when taking certain drugs.

In terms of prevention, since the transmission of the disease is hereditary, families affected by the disease can obtain genetic help and advice.

The prognosis is variable depending on the patient and the form of the disease.