Hereditary pathology, phenylketonuria affects the nervous system and brain.
Phenylketonuria is an inherited genetic disorder caused by a deficiency of phenylalanine hydroxylase (PAH). It prevents the metabolisation of phenylalanine to tyrosine. If left untreated, this condition causes potentially severe mental retardation. For this reason, phenylketonuria is systematically screened for at birth .
1. Definition of phenylketonuria
Phenylketonuria is an autosomal recessive genetic disorder characterised by an accumulation of phenylalanine in the blood plasma and brain. This pathology, which affects the metabolism, results in an enzymatic deficit that normally ensures the conversion of phenylalanine into tyrosine, two amino acids that are essential for the proper functioning of the body. This lack of conversion will lead to an excess of phenylalanine in the blood, which will become toxic for the brain.
Depending on the medical analysis laboratory that carries out the dosage (phenylalaninemia), the phenylalanine level is expressed in milligrams per decilitre of blood (mg/dl) or in micromoles per litre (μmol/l). In order to make the conversion, it is necessary to know that for this amino acid, 1 mg/dl is equivalent to 60 μmol/l. Three types of phenylketonuria are distinguished, depending on the extent of the accumulation of the enzyme in the blood (Orphanet):
- permanent moderate hyperphenylalaninaemia (PMH): phenylalaninaemia is less than 10 mg/dl (600 μmol/l);
- typical phenylketonuria: phenylalaninemia is greater than 20 mg/dl (1200 μmol/l);
- Atypical phenylketonuria: phenylalaninemia is between 10 and 20 mg/dl (600-1,200 µmol/l).
Only the last two forms need to be managed. HMP requires only monitoring. Affecting both girls and boys, the incidence of this condition in the population varies according to geographical area, with higher prevalence in Iceland, Turkey and Ireland. In France, nearly 50 newborns are thought to be affected by phenylketonuria (typical or atypical) each year, which represents approximately 1 in 17,000 newborns according to Orphanet.
2. Symptoms of phenylketonuria
Thanks to systematic screening at birth in France since the 1970s, almost all babies with phenylketonuria benefit from particularly early treatment, which allows normal development. Thus, these babies will not show any symptoms. But in countries where newborn screening does not exist, children will develop clinical signs of the disease. As the disease mainly affects the nervous system and the brain, the first disorders may impact on
- behaviour: difficulties in interacting with peers, aggressiveness, hyperactivity
- cerebral development: microcephaly, cranial perimeter below average... ;
- intellectual development: mental retardation, delayed acquisition of language, and elementary learning
- psychomotor development: difficulty in holding the head, delay in walking, difficulty in grasping small objects;
- neurological functioning: global hypertonia, tremors, epileptic seizures, etc.
As a general rule, the various deficits stabilise after childhood. But other symptoms may also occur in the absence of treatment: urine and sweat with a characteristic smell of wet straw, eczema, skin, hair, and eyes lighter than other members of the family...
3. Causes of phenylketonuria
Phenylalanine is an essential amino acid, i.e. it is not synthesised by the body and must therefore be supplied by the diet. Tyrosine is a non-essential amino acid. It is obtained by the conversion of phenylalanine in the liver. This conversion requires the intervention of, among others, phenylalanine hydroxylase (PAH) and its cofactor, tetrahydrobiopterin (BH4). However, people with phenylketonuria have an anomaly in the PAH gene responsible for the production of the famous enzyme which, if produced in insufficient quantities or in a dysfunctional manner, will not allow the transformation of phenylalanine into tyrosine. The great inter-individual variability of PAH deficiency explains why phenylketonuria can take different forms depending on the patient.
Although there is a route of elimination of phenylketones via the urine, it is generally not sufficiently efficient to compensate for the lack of transformation into tyrosine and to avoid excessive accumulation in the brain, in particular. The brain is the organ most affected, although it is not clear why. Several hypotheses are currently being studied to try to understand why this accumulation is particularly toxic for the brain (Orphanet). For example, alteration of the myelin sheath formation process or communication between nerve cells could potentially be the cause of the mental retardation and cognitive deficiencies observed in the context of undetected phenylalanine.
4. Phenylketonuria: when to consult?
It is generally not necessary to consult a doctor, as phenylketonuria is systematically screened at birth in France. For people born before 1970 who have not benefited from this system, certain signs of a cognitive and neurological nature may however give cause for concern: mental retardation, behavioural problems, muscle tension, etc. Skin and eyes that are lighter than those of other family members are also potential symptoms of phenylketonuria.
5. Diagnosis and testing of phenylketonuria
As mentioned above, the diagnosis of phenylketonuria is made at the time of the systematic neonatal screening of all newborns in France. It is at the maternity hospital, just after birth, that the Guthrie test is performed. This allows the baby's phenylalanine level to be measured, and also to detect other underlying pathologies such as congenital hypothyroidism, cystic fibrosis, or congenital adrenal hyperplasia. Performed on the third day of life, this test consists of a blood sample (a few drops) generally taken from the heel of the newborn. The sample is then placed on a blotter and analysed in the laboratory. When the phenylalanine level is above 3 mg/dl (180 µmol/l), a second sample must be taken at a specialised centre to confirm the diagnosis. Further investigation is also necessary to identify any underlying conditions that may explain the elevated phenylalanine level. If no disease is identified, a BH4 load test (according to the French National Authority for Health) is then recommended: it will enable a therapeutic option to be chosen over another. This test consists of giving the baby a pre-determined amount of BH4 orally, followed by blood and urine tests to assess variations in phenylalanine. To accurately define the form of phenylketonuria, a genetic test is also required.
6. Treatments for phenylketonuria
Treatment is initiated by a referring physician from the regional neonatal screening centre for phenylketonuria. In the majority of cases, a low-phenylalanine diet is a first-line treatment. It is started at diagnosis and should be continued into adulthood. The aim is to maintain phenylalanine levels between 2 and 5 mg/dl, a level which allows normal brain development (Orphanet). After the age of 11, the diet can be progressively less stringent. Since the amount of phenylalanine required for the body to function depends on the degree of PAH enzyme deficiency, the minimum daily intake will vary from patient to patient. In practice, certain protein-rich foods, fruit and vegetables, and cereals should not be consumed, while dietary supplements (amino acids) should be given to avoid deficiencies associated with these avoidances. Around the age of 10/11 years, and if the phenylalanine level remains below 15 mg/dl, then phenylalanine intake can be increased. Regular metabolic checks are essential, usually until early adulthood. At that time, it is often possible to reintroduce certain foods under regular medical supervision. However, a strict diet should be reintroduced in pregnant women (Haute Autorité de santé) to prevent the risk of hyperphenylalanine embryofetopathy. Depending on the results of the BH4 load test, some children will be treated with sapropterin dihydrochloride. This is the synthetic form of the BH4 cofactor. The drug can be given to adults and children over 4 years of age. This will allow them to follow a less strict diet, or even, for some, to maintain an almost normal diet.
7. How can phenylketonuria be prevented?
Unfortunately, it is not possible to prevent the onset of phenylketonuria. Only early detection can ensure rapid and effective treatment to avoid the accumulation of phenylalanine in the blood. In France, diagnosis can only be made at birth, as prenatal screening is only carried out for diseases that are known to be serious and incurable. Throughout the patient's life, the question of diet remains central. Its implementation must be concomitant to the establishment of the diagnosis and carried out in coordination with a referent doctor of the regional neonatal screening centre for phenylketonuria.
Sources :
Orphanet, Haute Autorité de santé, Le Manuel MSD
No comments:
Post a Comment