INTRODUCTION
Metabolic disorders are a pathological state in which abnormal metabolic processes occur. They arise due to functional organ changes and also genetic causes. Phenylketonuria (hyperphenylalaninemia) is among inherited metabolic disorders with an incidence in Slovakia of 1:7-10 000.
A child with phenylketonuria is born without symptoms of the disease, and phenylalanine as an essential amino acid increases in the blood only after protein-containing food is introduced. The new organization of phenylketonuria screening in Slovakia has, since 1995, brought a substantial improvement in early disease detection and shortening the time to establish a definitive diagnosis. Today, the disease has very well-developed diagnostic and therapeutic options. Treatment is lifelong and its main goal is to achieve the best possible quality of life for patients, which is enabled by high-quality screening, early treatment, and the use of new therapeutic and nutritional approaches. A current topic and one of the options for preventing the development of complications, as well as a way to manage newly arising situations and problems related to the patient’s condition, is also parental health literacy, and later the patient’s own health literacy. A key educational goal is to teach parents, together with the child, the need to adhere to the diet, including self-monitoring, by linking acquired theoretical knowledge with practical skills.
PHENYLKETONURIA
Phenylketonuria is an autosomal recessive genetic, incurable disease characterized by the inability to metabolize the amino acid phenylalanine caused by a deficiency of the enzyme phenylalanine hydroxylase. The consequence is excessive accumulation of phenylalanine in the blood and other tissues and its crossing of the blood–brain barrier. The essence of the disease is therefore reduced activity or complete absence of the enzyme in intermediate metabolism, as a result of which metabolites accumulate upstream of the block, causing tissue damage in the child’s body, especially the central nervous system. (1) In phenylketonuria this means the body is unable to convert phenylalanine to tyrosine due to a deficiency of phenylalanine hydroxylase (PAH) in the liver, which catalyzes hydroxylation of phenylalanine in the presence of the cofactor BH4 (tetrahydrobiopterin) to tyrosine. A large amount of phenylpyruvic acid is excreted in urine, which causes the characteristic mouse-like odor of the patient’s sweat and urine. In the PAH gene, whose locus is on the q arm of chromosome 12, many mutations are currently known, which are the cause of type I hyperphenylalaninemia—classical phenylketonuria. The most common mutation in classical phenylketonuria in our population is R 408 W; in the Roma ethnicity in Slovakia, it is R 252 W. The disease is inherited in an autosomal recessive manner and therefore manifests only in the homozygous state. Heterozygous parents have 25% affected children and 25% healthy children, and 50% heterozygous carriers of the pathogenic gene. (1,2)
Phenylalanine (PHE) is an essential amino acid needed for normal development of the body and tissue regeneration. It participates in many biochemical reactions in the body. In a healthy population, PHE is physiologically converted to tyrosine, of which 10% is fully metabolized and used for building new tissues; the remaining 90% participates in several biochemical processes, such as the synthesis of neurotransmitters, catecholamines, thyroid hormones, and melanin. Its normal blood level is 50–110 μmol/l. Individuals with levels of 120–600 μmol/l are classified as hyperphenylalaninemia, with 600 μmol/l as mild PKU and above 1200 μmol/l as classic PKU. (3,4)
History of phenylketonuria
In 1909, a new chapter in medicine began, when Garrod published a monograph on congenital metabolic disorders. It became clear that the human being is an individual not only genetically, but also biochemically. Of the known amino acid metabolic disorders, the clinically most significant defect is phenylalanine metabolism. Its discovery began in Norway. In 1934, a dentist became sensitive to an unusual odor in the sweat and urine of his two intellectually disabled children. Through comprehensive examination, Ivar Asbjorn Folling found, in them, a previously unknown color reaction in urine. A further analysis demonstrated the presence of phenylpyruvic acid. A similar finding was also detected in several intellectually disabled individuals at a local sheltered home. Later, a new diagnosis, imbecilita phenylpyruvica, was introduced into practice. In 1947, physician George Jervis demonstrated that the essence of this disease is a defect of phenylalanine hydroxylase. In 1963, Guthrie introduced into practice a microbiological screening method allowing diagnosis of this disease already in the early postnatal period. In 1972, phenylketonuria screening was introduced in Slovakia, when phenalanine concentration was determined semi-quantitatively by Guthrie’s method. This method was appropriate but was burdened by a high percentage of recall examinations, which lengthened the time to definitive diagnosis, with the child’s average age at diagnosis being 6.3 weeks. In 1995, there was a fundamental change in screening organization. The method changed to quantitative determination of phenylalanine concentration from a dried blood spot. (1, 5, 6) Currently, two basic types of phenylketonuria are recognized—classical and maternal. Up to 280 mutations of the phenylalanine hydroxylase enzyme are known, and they play a major role in the development of this disease.
Symptoms of untreated phenylketonuria begin to appear progressively 3-4 months after birth, because fetal blood metabolite changes are compensated by the mother’s organism through the placenta. The child gradually falls behind in development and mental retardation develops. During 6.-12 months, the first epileptic seizures appear, later of the grand mal type, unresponsive to anticonvulsants. The mouse-like odor of sweat and urine is caused by increased excretion of phenylacetate, phenylpyruvate, and phenyllactate. As a result of tyrosine depletion, melanin pigment production is reduced, which is reflected in reduced pigmentation of hair and skin, and eyes with a pale coloration. Skin is often dry, rough, and susceptible to eczema. Depletion of tyrosine leads to depletion of neurotransmitters, especially biogenic amines (adrenaline, noradrenaline, serotonin, dopamine). Other neurological disorders are also often present (spasticity, tremor, tics), behavioral and concentration disorders (restlessness, aggression, autism, hyperactivity, depression, apathy, fear, anxiety), and macrocephaly. Attention also needs to be paid to non-specific signs: the occurrence of inherited metabolic disorders or sudden infant death syndrome in the family, sibling death in the neonatal (infant) period, often due to sepsis of unknown etiology, atypical course of common disease, ineffectiveness of usual treatment, minor stigmata and dysmorphisms, muscle hypotonia, thermoregulation disorders, vomiting without an apparent cause. A broad range of symptoms of variable expression includes abnormal EEG, abnormal auditory or visual evoked potentials, sleep disturbances, increased muscle tone, hyperkinesia, autism, a protruding upper jaw, wide bites, spaces between the teeth, and some changes resembling fetal alcohol syndrome. The disease is also associated with disturbed growth, reduced development of bone mass, a tendency to obesity mainly in girls, reduced sperm production in boys, significantly reducing future reproductive activity. Also noteworthy is increased formation of varices and scleroderma. Overall, quality of life is reduced, sociodemographic relations are disturbed, and the child is more dependent on the family, whose situation is often complicated. It is necessary to come to terms with the initial shock after diagnosis is announced and to prepare for the increased demands associated with raising an affected child. The economic impact on the family in connection with the diet is also important. (7, 2) Pregnancy imposes higher demands on a woman’s body, so proper life habits must be maintained. A mother’s nutrition affects her health, the course of pregnancy, delivery, and fetal development. During pregnancy, the woman’s body undergoes many morphological and functional changes, and her nutritional needs change. In metabolic changes, the placenta plays an important role by producing hormones that affect the metabolism of individual nutrients. (8, 9) In mothers with phenylketonuria, emphasis must be placed on control of food intake and self-monitoring of phenylalanine levels, since a high phenylalanine level leads to spontaneous abortion and embryopathies. Babies are born with low birth weight, facial dysmorphia, nervous system damage, and intellectual disability; cardiomyopathies are also common. Conversely, inadequate protein intake in pregnancy may cause hypoproteinemia accompanied by edema in the mother, intrauterine growth restriction of the fetus and placenta, and low birth weight of the newborn. (10, 6)
Diagnosis and treatment
Early diagnosis of the disease is performed by newborn screening, which is usually carried out on the third day after birth, because blood Phe rises during the first week of life. A drop of blood is taken by heel prick, then allowed to dry on filter paper and sent to the central laboratory for determination of phenylalanine and tyrosine. If an elevated phenylalanine level is confirmed (150 μmol.l-1 and above), it must be repeated, diagnosis confirmed by genetic tests, and the gene mutation determined. Subsequently, rapid initiation of treatment is required, which can ensure appropriate somatic and psychological development of children. (11, 6) For each patient, it is necessary to choose the most optimal treatment regimen, which requires regular and comprehensive monitoring of adherence to regimen recommendations, treatment effectiveness, child development, and cooperation with the family. Immediately after diagnosis it is essential to start diet therapy consisting of restricting foods rich in proteins with precisely calculated phenylalanine content in daily intake, restricting intake of beverages with aspartame, maintaining a balanced intake of amino acid mixtures (dietary preparations), adequate energy intake, and regular monitoring of patient blood phenylalanine concentrations.
Diet treatment with low-phenylalanine was introduced by Horst Bickel in 1953, which made it possible to prevent irreversible brain damage in an affected child. He reached this discovery through the simple reasoning that, since it is not possible to remove the inherited blockade in phenylalanine processing, one should simply bypass it by limiting phenylalanine in the diet. People with this disease must follow a specially adapted meal plan that precisely accounts for their individual ability to absorb ingested phenylalanine, since in isolated cases some ability to process phenylalanine is preserved to a certain extent. Repeated monitoring of phenylalanine values is needed at monthly intervals (when the values are above 8-10 mg.100 ml-1, phenylalanine intake should be reduced; when the value is below 5 mg.100 ml-1, its intake should be increased). When constructing an individual menu, it is necessary to observe the amount of phenylalanine per day permitted by the physician (well tolerated up to 50mg; glutamine and glutamate have a beneficial effect). In marked restriction of protein intake with phenylalanine content, it is necessary to supplement the required amount of protein with special commercially manufactured dietary preparations without phenylalanine. In European Union countries, these are classified as foods for special medical purposes and are available to patients on medical prescription. Typical phenylketonuric nutrition does not contain traditional sources of omega-3 polyunsaturated fatty acids, which are essential for healthy development of the nervous system, cognitive functions, mental health, retinal development, cardiovascular functions, and other important systems. A key requirement became that omega-3 polyunsaturated fatty acids become a standard part of the diet. This requirement is addressed by modern dietary preparations. Concentrated low-volume protein products, which are also effective and well tolerated by patients, can replace one or several doses of a dietary preparation, thereby improving compliance, especially in older patients. Sufficient energy intake is also important, eliminating the negative impact of catabolism that leads to paradoxical rises in blood phenylalanine concentrations, which occur from breakdown of the body’s own proteins. Energy intake must be strictly controlled and increased according to the individual load and needs of the patient. Although carbohydrates and fats are not restricted in intake, control values of PHE in blood often improve only after adding oligosaccharides (maltodextrin). (6, 11)
Low-protein diet
Because phenylalanine is present in every protein, total protein intake must be restricted and blood phenylalanine concentration kept at an optimal level. Foods with high protein content must be completely excluded. The patient can take only a small part of proteins in natural food; the remainder must be supplemented as artificial amino acid blends. Individual meal portions need to be carefully counted and weighed. Among the so-called permitted foods are fruit, vegetables, and other foods with low protein and phenylalanine content. Carbohydrates and fats are not restricted in the diet. Diets are not the same for different age categories. The strictest is approximately up to 15 years of age and for pregnant women. In adolescence and adulthood, the diet can be somewhat relaxed, but not discontinued. (12, 5, 13, 1, 2) Adherence to dietary regimen measures is fully in the hands of parents, and later of the patient. Discipline and respect for regimen measures play a major role in achieving effective compensation of the disease.
Table 1 Foods suitable/unsuitable for patients with phenylketonuria
Source: own processing according to (11, 12)
Within adherence to the permitted phenylalanine intake, it is necessary to monitor its content as stated on food and product labels. On food labels, the amount of protein is usually listed per 100 g of product. To calculate phenylalanine content in a product, the formula applies: 1 g protein = 50 mg PHE. For ensuring all biochemical processes and reactions necessary for survival of every living organism, water forms the basis. Within nutrition therapy, it is also important to maintain a hydration regimen. It is suitable to offer tea, mineral waters, infant waters, lemon juice-flavored water; adults may enjoy coffee as a treat. (14)
Current modern treatment is based on a strict low-protein diet combined with quality amino acid mixtures that contain the exact ratio of individual amino acids and micronutrients needed for each age category, depending on patient weight. Important is also precise adherence to the protein and energy dose to counteract the negative effect of catabolism and thus the paradoxical increase of blood phenylalanine concentrations, which comes from breakdown of the body’s own proteins. It is very important to eat regularly 3 to 5 times per day. Food can be prepared by boiling, baking, frying, grilling, and braising. Sensory properties of the food can be improved by adding herbs or spices.
Newborn treatment for phenylketonuria has a special position. New modern treatment preparations without phenylalanine and with sufficient protein and energy content allow a combination of dietary treatment and breastfeeding in almost all cases. This is a significant change in previous PKU treatment strategy, in which breastfeeding was contraindicated because preparations were of lower quality. It should be emphasized that, just as high phenylalanine concentrations in the patient’s serum cause CNS damage, so do very low values. The latter cause dystrophy of the child, growth disorders, delayed bone maturation and bone formation, anemia, and aminoaciduria from catabolism. It has now been found that many patients respond favorably to treatment with tetrahydrobiopterin-sapropterin (BH4), which, as a cofactor of phenylalanine hydroxylases, is a prerequisite for phenylalanine hydroxylase activity and thus conversion of phenylalanine to tyrosine. BH4 increases thermal stability and protection from proteolytic degradation and oxidative inactivation of the mutated protein. (2) In practice, enzyme replacement therapy is also currently used, whose essence is administration of the enzyme phenylalanine ammonia-lyase (PAL), which reduces phenylalanine absorption from the intestinal lumen by converting it to less toxic metabolites—trans-cinnamic acid and ammonia. However, the problem is its inactivation by digestive enzymes. Phenylalanine and other large neutral amino acids (LNAA – tyrosine, tryptophan, leucine, isoleucine, valine, methionine) are transported across the blood–brain barrier via an L-type amino acid transporter, competing with each other. Therapy with LNAA supplementation besides phenylalanine is based on this principle, as it blocks phenylalanine passage through the blood–brain barrier, thereby lowering its cerebral concentration. Initially, this therapy appeared suitable for adolescent and adult patients who had problems with adherence to the diet. Fifteen years of experience, however, did not find a difference in quality of cognitive functions between these patients and patients treated conventionally. Since 2009, a drug with the active substance sapropterin dihydrochloride has been available in Slovakia, allowing more effective control of blood phenylalanine concentration, helping to achieve target values, and increasing its tolerance. The patient can therefore allow more natural food and fewer dietary preparations. (4,15,2)
Conclusion
Treatment of phenylketonuria is lifelong. Its main goal is to achieve the best possible quality of life for patients, which is conditioned by high-quality and consistent screening, timely diet therapy, and the implementation of new, modern treatment approaches. Dietary treatment is demanding and restrictive, and especially in older children, adolescents, and adults compliance decreases. Implementation of nutritional recommendations into the process of self-care is considered an inseparable part of comprehensive care for a patient with phenylketonuria. Success of treatment, prevention, and development of complications depend mainly on the attitude of parents and the patient toward the disease, on their willingness to respect and follow recommendations from the physician and nurse, for which effective education should help.
Author: PhDr. Mgr. Ing. Trnková Ľubica, PhD. MPH
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