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Frequently Asked Questions

What is phenylketonuria/PKU?

Phenylketonuria or PKU is a rare inherited disorder, which affects the body’s ability to break down an amino acid called Phenylalanine (Phe) found in foods containing protein. High Phe may trigger brain-related problems throughout life. In infants, the disorder leads to irreversible damage of the developing brain without dietary management. In adults, higher blood Phe levels may lower intelligence and response times; lead to irritability, anxiety and depression; result in an inability to focus or pay attention and cause eczema.

How frequent is phenylketonuria/PKU around the world?

The incidence of PKU varies in different populations. Around the world the mean incidence is about 1 case per 10,000 live births, but it ranges from as little as 1 case per 100,000 live births in Finland to as much as approximately 1 case per 4,000 live births in Turkey. The incidence of the disease it is not known for the large proportion of the world’s countries that do not yet benefit from neonatal screening programs.

What is/are the cause(s) of PKU?

PKU is a genetic autosomal recessive disease. Classical phenylketonuria is caused by mutations in the q22-24 region of chromosome 12, which interfere with the structure and function of the Phenylalanine Hydroxylase (PAH) enzyme. This enzyme is responsible for the transformation of phenylalanine (Phe) into tyrosine (Tyr) in the liver. When PAH activity is decreased, Phe tends to accumulate in blood and tissues, including the central nervous system. The exact way elevated Phe levels cause brain damage is still unclear and includes direct damage and low tyrosine and other large neutral amino acids deficiencies that interfere with neurotransmitter formation and neuronal development.

How and when is PKU clinically present?

Elevated Phe levels produce progressive brain damage with no acute symptoms. During the neonatal period and first months of life, patients seem to be completely normal. Abnormal sweat and urine odor are hardly ever detected. Eczema can be present but is usually mistaken for an atopic skin. The first suspicion something might not be quite right comes when the child does not begin to sit or talk at a normal age. As brain damage progresses during the second year of life, the mannerisms, irritability, aggressiveness and autistic behavior of the classical presentation become evident.

Is PKU a life threatening disease?

No. PKU is a slowly progressive disease that does not cause acute symptoms. During the first months of life it is completely asymptomatic and can only be detected by population screening determinations. In its more severe forms, untreated PKU causes progressive brain damage that affects cognitive function but does not affect life sustaining structures. They have motor mannerisms but most attain walking. Respiratory functions are not usually affected. Therefore, even severely mentally affected patients tend to reach adult ages. During fever, other intercurrent disease, or after committing dietary transgressions patients on treatment will have rises in their Phe level. Some patients refer noticing a decrease in their concentration abilities or reaction time, but these acute peaks are usually not detected clinically. Patients that abandon treatment will suffer from neurological or psychological symptoms such as anxiety or depression, but not an acute and life threatening metabolic derangement as in other diseases.

How can PKU be detected?

In most developed countries, neonatal PKU screening programs have been developed. In these programs, children are taken a blood sample (usually by heal puncture and using dried blood spots in special filter paper) in which Phe levels are measured. If high Phe levels (above 2 mg/dl or 120 µmol/L) are detected, the child should be referred to a centre in which adequate differential diagnosis and follow-up can be made. Both neonatal patients and older PKU patients without treatment have above normal blood Phe levels that can be measured. The body tries to eliminate the excess Phe by alternate pathways that produce pathologic substances (phenylacetic and phenyacetate acid) that are secreted by the urine, and can also be measured. These substances are what give a special odor to the sweat and urine of patients. Other blood and urine parameters need to be measured in order to confirm the diagnosis of PKU and differentiate it from other even rarer diseases that can also cause elevated Phe levels.

How severe is PKU? Do different forms of PKU exist?

Classical PKU is the result of the mutations that affect the formation and activity of the PAH enzyme. Depending on the mutations each patient carries, he or she will have a higher or lower PAH residual activity. In some patients, the residual activity is near normal and therefore their blood Phe levels are higher than normal but not as high as to affect brain development in a detectable way. These patients with benign forms do not require treatment. On the other hand, patients with mutations that determine a very low residual activity will have higher blood Phe levels and are at great risk of brain damage. These patients require treatment in order to lower their Phe levels in an effort to avoid neurological symptoms. Depending on their initial Phe levels and the effort it requires to lower them, patients are classified in mild and classical PKU forms

Is there a treatment for PKU?

Treatment for PKU has focused on reducing circulating Phe levels in order to secondarily lower brain Phe and avoid neurological symptoms. For it to be effective, it should begin during the neonatal period. Beginning treatment any later will ameliorate the behavior of the patient but there might be some irreversible neurological complications. Even after brain development is complete it is recommended to continue on treatment, since many patients that abandon treatment suffer psychological symptoms. Treatment usually consists of a diet that limits natural protein intake in order to avoid Phe intake. This diet needs to be supplemented with special protein and vitamin products without Phe to compensate the resultant nutritionally deficient diet. A minority of patients can be treated with the PAH cofactor, tetrahydrobiopterin (BH4), which enhances PAH residual activity facilitating the reduction of circulating Phe.

Does PKU have an influence on mental function in infants/children?

Untreated, PKU patients can range from a completely normal mental development in the benign forms, to patients affected of very severe mental retardation in the classical forms. Treatment has allowed patients of all forms to attain an adequate neurological development, with intelligence quotients (IQ) in the normal range. Nevertheless, recent studies have shown that these IQs tend to be slightly lower than that of siblings or peers, and that minor neurological symptoms such as hyperactivity, slower reaction times, planning difficulties, etc are still present even in well controlled patients. These minor symptoms could affect school and social performance. There are few reports on this subject, but it seems that PKU patients, while attending normal schools with acceptable results, do not follow superior academic studies with the same frequency as the normal population.

Does PKU have an influence on mental function in adults?

Adolescent and adult patients that abandon treatment are at risk of suffering a small involution of their mental capacities, although this symptom is usually unnoticed unless specific tests are performed. More commonly, patients complain of an increase in irritability and lack of tolerance and concentration that affects both their social and professional life. Some patients suffer from anxiety, depression or even more severe psychological conditions such as paranoia and schizophrenia. All these symptoms ameliorate when treatment is resumed.

Does PKU influence the development of infants and/or children?

The usual treatment for PKU is a restrictive diet supplemented with special products. These special products have progressively included vitamins and oligoelements that patients are deficient of because of their small natural food intake. Nevertheless, there are reports of varied deficiencies such as vitamin B12, carnitine, selenium, etc. Bone density is also diminished in these patients, although whether this is due to the disease itself or to the diet is still to be determined. There is controversy as to whether growth is affected in PKU patients or not. There is consensus and clear concern as to the weight gain observed, especially in adolescence and adulthood.

What is the burden of PKU on daily life in infants/children?

Following a restrictive diet in a chronic manner is a serious burden both for the children and their families. There is an economic cost of the special products and foods that are covered by official entities to a different extent in different countries. Usually the major concern is the difficulty in preparing and planning the diet, which in many cases affect the professional life of the parents and the decision as to what school the child should attend. The social life of the family and the child is also limited, as in restaurants, social gatherings or trips the diet cannot be followed with ease. In adolescents these problems lead to bad treatment compliance, as many patients do not want to feel any different from their peers.

What is the burden of PKU on daily life in adults?

Adults suffer from the same burdens as children do: time burden in the preparation of the diet and social limitations. Diet can interfere with their professional requirements (schedules, restaurant meetings, etc). On the social level, patients tend to live longer in their parent’s house and seem to have more difficulty in finding a partner. This might be due to the difficulty of following the diet without the parent’s supervision but also to their smaller self-esteem. The risk of having a child affected by their PKU condition also limits the number of offspring in PKU women.

If only one parent has PKU, how probable is that offspring will have PKU too?

PKU is an autosomal recessive disease. All offspring of a PKU patient will carry one of the mutations that the affected progenitor has. Therefore, all offspring will be at least carriers of the disease. Whether they will also suffer from the disease or not and with what severity depends on the conditions of the other progenitor and the kind of mutations they both carry. If he or she has no mutations in the PAH gene, all children will be carriers but non will be affected. On the other hand, if the second patient carriers a mutation in one of his or her genes, at least 50% of their children could be affected. If the second parent is a PKU patient as well, then all their offspring will be affected.

Can the PKU condition of a mother affect her fetus during pregnancy?

Yes. PKU mothers have a higher frequency of microcephalic and mentally retarded children, even when the child is unaffected by PAH deficiency. Other congenital abnormalities these children suffer include cardiovascular and urinary system malformations, and a higher frequency of miscarriages has been reported. It has been proven that the frequency of these malformations is in relation with the blood Phe levels the mother has during pregnancy. Phe acts as a toxic agent for the fetus, similar to alcohol or certain medications. If levels are maintained under 3 mg/dl (180 µmol/L) the risk diminishes dramatically. Therefore, PKU women require a stricter treatment during pregnancy. In some areas, screening programs have been developed in order to detect women with mild forms of the disease that might not have been screened before and are at risk of having mentally retarded children.

Can high phenylalanine enter the brain in PKU patients?

Yes. Phenylalanine and other large-neutral amino acids (LNAA) including valine, leucine, isoleucine, tyrosine and tryptophan use the same transport system across the blood–brain barrier (BBB). Depending on the concentration of these amino acids in the blood there is a competition at the BBB. High blood phenylalanine blocks the transport of other LNAA into the brain, resulting in high brain phenylalanine levels and low levels of other LNAA. This has consequences in several biological processes in the brain including synthesis of neurotransmitters, protein synthesis, myelin formation, ultimately leading to the neurological features of PKU.

What is the importance of tetrahydrobiopterin (BH4) in PKU?

Tetrahydrobiopterin (BH4, sapropterin) is the natural cofactor of phenylalanine hydroxylase (PAH), the enzyme that is defective in PKU. BH4 is produced in the body and its concentration regulates the conversion of phenylalanine to tyrosine, mainly in the liver. In the brain BH4 is a cofactor of enzymes responsible for the synthesis of the important neurotransmitters catecholamines and serotonin. In some patients with PKU, BH4 can restore residual enzyme activity and promote phenylalanine degradation. Some PKU patients can completely replace low-phenylalanine diet with the pharmacological therapy with BH4 (sapropterin) and some need a combination of both therapies. Patients with severe forms of PKU cannot benefit from BH4. It is estimated that 20-30% of all PKU patients may benefit from BH4 therapy.

What is the mode of BH4 action in PKU patients?

As a cofactor, BH4 binds to the enzyme phenylalanine hydroxylase (PAH) and together with phenylalanine keeps the enzyme in the active state. PAH is a homotetramer (composed of four identical subunits) and BH4 can also act as a chemical chaperone. Pharmacological chaperones are small molecules (e.g. BH4) which stabilize the correct folding of a protein resulting in a recovery of function lost due to mutation and can be used for medical treatment. Thus, BH4 (sapropterin) can in some PKU patients prevent the enzyme PAH from unfolding, degradation and inactivation and restore its activity in lowering Phe levels.

Is BH4 deficiency the same disease as PKU?

No, but both diseases present with elevated blood phenylalanine levels. In addition BH4-deficient patients present with deficiency of catecholamines and serotonin in the brain. BH4 deficiency is considered to be a more severe disease than PKU and cannot be treated with a low-phenylalanine diet alone. Instead, a substitution with BH4 (sapropterin) and neurotransmitter precursors is essential. It is therefore essential to diagnose these patients as early as possible, in order to prevent irreversible brain damage. BH4 deficiency is a group of heterogeneous disorders with several enzymes being affected, and all of them can be detected through the newborn screening for PKU.

Is mutation analysis (DNA testing) important for PKU patients?

In most cases DNA testing in PKU is of scientific interest. However, with the known genotype patients can be characterized more precisely and treatment can be adequately tailored. This is particularly useful in view of potential treatment with pharmacological doses of BH4 (sapropterin). PKU patients who respond to BH4 (sapropterin) administration have a characteristic genotype (BH4-responsive mutations).

How should PKU be followed by professionals? Is there a standard care? How often is measurement of phenylalanine necessary?

There is no straightforward answer. Knowing the huge association between brain function and blood phenylalanine, measurement of blood phenylalanine is crucial. The frequency is related to aspects such as growth, infections, compliance with the treatment and other factors. Apart from this, we know that blood phenylalanine concentrations are related to brain function especially at a young age, and for that reason the frequency at that stage needs to be high. Some experienced centres advise a frequency of once a week to once every two weeks until two years of age, and then only slightly decreasing the number of measurements to once monthly in adulthood. It should however be taken into account that at certain times there may be reasons to increase rather than decrease the number of samples. Such reasons include not only illness, but also change of school, change in responsibility, transferring the responsibility from the parents to the patients, leaving maternal home, going from school to university or other school programs for adults, starting the labour process.

How can high blood phenylalanine concentrations be lowered?

The most important method for decreasing the phenylalanine concentration is to decrease the intake of natural protein whatever the cause of the high phenylalanine concentration is. However, there are three factors that should be taken into account: (i) the possibility of catabolism due to insufficient intake of phenylalanine, (ii) insufficient intake of other amino acids and (iii) insufficient intake of energy. Regarding the first issue, it is of note that, notwithstanding the fact that it is important to prevent too high intake of phenylalalanine, if the intake is too low this can also result in high blood phenylalanine concentrations. With regard to the second issue, it is important to note that the dietary treatment of PKU consists of a phenylalanine-restricted diet. This means that the total protein intake should be normal, by giving a diet largely restricting the natural protein intake and at the same time guaranteeing a sufficient amount of the amino acids other than phenylalanine that are necessary for the protein synthesis. The third issue is an adequate intake of energy, which means that patients – especially young ones – sometimes need more energy than the healthy population to guarantee the use of protein in the right way.

How much tyrosine should be added to the amino acid mixture?

In healthy individuals phenylalanine is used to build protein and to convert into tyrosine. Conversion into tyrosine is the most important part of the metabolism of phenylalanine, but the precise amount which is converted is unknown and may differ within patients. A theoretical consideration may start with the assumption that almost all phenylalanine is converted into tyrosine in healthy persons. Taking that as a fact, the amount of tyrosine in the amino acid supplement should be the amount of phenylalanine not taken and the normal amount of tyrosine. That more or less doubles the normal amount of tyrosine. However, this seems too much when aiming at normal concentrations of tyrosine in the blood.

How should tyrosine be followed?

There are a few papers showing the importance of tyrosine concentrations and the phenylalanine-to-tyrosine ratio. However, due to the fact that tyrosine has become an essential amino acid and the large amount of tyrosine in the protein substitutes, the tyrosine concentrations in blood change largely within the time before and after a snack, or other food intake, especially when protein substitute is taken as well. Therefore, it is of importance to measure tyrosine in the overnight fasting state to have a realistic idea about the tyrosine concentrations.

What are large neutral amino acids, and what is their relevance?

Phenylalanine is one of the so-called large neutral amino acids (LNAA). Together these LNAA are transported across the blood–brain barrier into the brain in a competitive way, so that high blood concentrations of one amino acid will have two consequences: the amino acid that is high in the blood will be high in the brain, especially when the transport system has a high affinity to that particular amino acid; the other amino acids will have low concentrations in the brain due to the fact that the large transport of the one specific amino acid high in blood interferes with the transport of the other amino acid.

What is home monitoring and what is the importance of home monitoring for day to day practice in PKU?

From the experience with Diabetes mellitus it has been known for a long time that direct knowledge about dietary changes positively influences adherence. However, real-time home measurement is not available yet in PKU. At present, it is home sampling rather than home measurement. In itself, that is a large improvement compared to the old days when patients very often came to the clinic solely to provide a blood sample for amino acid analysis. With blood sampling at home, there are many clinics that give the results to the patients without advice, thus teaching the patients to be responsible for adjustments themselves. This has been shown to be possible. However, at the same time, there is more than one reason why the blood phenylalanine concentration does not decrease that much using home blood sampling and making patients responsible for adjusting their treatment. First of all, patients seem to keep the upper limit of the advised target as the target phenylalanine concentration. Secondly, the frequency of blood sampling has increased tremendously. Where, in the past, patients came to the clinic once every three months, they now get a phenylalanine concentration every 2–4 weeks without the possibility only to adhere to the diet for the week before the blood sampling. New developments are underway and hopefully real-time home measurement is really possible in the near future.

What is the phenylalanine tolerance in PKU in patients on dietary treatment only?

Phenylalanine is severely restricted in PKU dietary management. Phenylalanine tolerance is affected by many factors including the severity of PKU, target blood phenylalanine range, age, adherence with protein substitute and adequate energy intake. The amount of phenylalanine tolerated is titrated according to individual tolerance dependent on blood phenylalanine concentrations and growth phase. Children with moderate or severe PKU, maintaining blood phenylalanine within the target range of 120-360 µmol/l, usually tolerate between 200-500 mg of phenylalanine daily (equivalent to 4 to 10g/daily of intact/natural protein). Phenylalanine requirements are highest in early infancy and generally, after the age of one year, there is a small continuous decline in phenylalanine intake per kg body weight per day in both males and females with PKU. This parallels with decreasing growth rate and protein requirements. Phenylalanine tolerance at the age of two years has been demonstrated to be a reliable predictor of tolerance at the age of 10 years. Ideally phenylalanine intake should be spread throughout the day so that a load of phenylalanine is not given at any one time.

What are the main principles of dietary management in PKU?

There are a number of key elements to dietary management. Firstly in patients with moderate to severe PKU, dietary phenylalanine is restricted to 20% or less of normal intake to maintain blood phenylalanine concentrations within desirable PKU target ranges. As phenylalanine comprises 4-6% of all dietary protein, high protein foods such as meat, fish, eggs, cheese, nuts and soya are not generally permitted in patients with severe PKU, but this does depend on individual phenylalanine tolerance. Secondly, the majority of protein/nitrogen requirements are supplied in the form of a phenylalanine-free protein substitute. The majority of supplements are based on L-amino acids. This protein source may be referred to as: amino acid supplement, protein substitute or medical food. Thirdly, the maintenance of a normal energy intake is important. This is done by giving foods naturally low in phenylalanine and specially manufactured low protein foods such as flour, bread, and pasta. Finally, the provision of all vitamins, minerals, essential fatty acid and longer chain polyunsaturated fatty acids to meet dietary requirements is essential. These can either be added together with the phenylalanine-free protein substitute or as separate modules.

How is dietary phenylalanine allocated in the diet?

Methods of allocating phenylalanine intake vary throughout the world and there has been much debate about the merits of each system and their impact on controlling blood phenylalanine concentrations. Each patient is allocated a daily allowance of phenylalanine. Phenylalanine can either be allocated by (i) a total daily allowance and patients/caregivers calculate the phenylalanine content of all/most foods eaten each day; or (ii) a phenylalanine exchange system. Different exchange systems are used worldwide (anything from 10-50 mg phenylalanine each). For most foods (except fruit and vegetables), a 50 mg phenylalanine exchange is equivalent to the weight of food that yields 1 gram of protein. All systems have their advantages and limitations but all appear to produce satisfactory blood phenylalanine control. It is probably best to try to find the system which patients/caregivers can understand, adhere to without too much difficulty and that allows them some flexibility.

What is Glycomacropeptide?

Glycomacropeptide (GMP) is a whey protein (a peptide released by rennet in cheese manufacture) that is naturally low in phenylalanine. It contains approximately 2.5-5 mg phenylalanine per g of protein. In PKU, it is now being used as a protein source in low phenylalanine protein substitutes or ‘medical foods’. GMP has elevated amounts of threonine and isoleucine and minimal aromatic amino acids, including phenylalanine, tyrosine and tryptophan. When used as the primary source of protein in PKU, it must be supplemented with leucine, histidine, tryptophan and tyrosine. From experimental studies, there is some evidence that GMP when given to animal models of PKU competitively inhibits phenylalanine transport into the brain, and PKU mice show comparable growth and reduced concentrations of plasma and brain phenylalanine when compared to a conventional amino acid source. In short-term human PKU studies, especially adapted GMP (with appropriate amino acid supplementation) has been safely and successfully used as a protein substitute.

What nutritional complications are reported on dietary treatment?

With any artificial diet, there is an increased risk of micronutrient deficiency. In PKU, reports of vitamin and mineral deficiency are common and include selenium and vitamin B12 deficiency, low ferritin, iron, and plasma zinc concentrations, impaired anti-oxidant status and decreased bone mineral density. Vitamin and mineral deficiency may be due to (i) failure of protein substitute or vitamin and mineral supplement to contain a specific micronutrient, e.g. selenium; (ii) low bioavailability of micronutrients added to supplements and (iii) non-compliance with either protein substitute with added vitamin and minerals or separate vitamin and mineral supplements. There is also a suggestion that elevated blood phenylalanine concentrations may alter the metabolism of iron, copper and zinc and may adversely affect bone status in PKU mice. Lower concentrations of omega-3 long chain polyunsaturated fatty acids, particularly decosahexaenoic acid, in both red cell membrane phospholipids and plasma are reported. Growth of children should be normal, although there are some reports of sub-optimal growth in early childhood. There is also some data to suggest a higher prevalence of overweight in adult patients with PKU relative to the general population.