Adjuvant Treatment for Phenylketonuria (PKU)

Адъювантнаятерапияфенилкетонурии (ФКУ)

Comparative Effectiveness Reviews, No. 56

Investigators: Mary Louise Lindegren, MD, ShanthiKrishnaswami, MBBS, MPH, Chris Fonnesbeck, PhD, Tyler Reimschisel, MD, Jill Fisher, PhD, Katie Jackson, BA, MSIV, Tracy Shields, MIS, Nila A Sathe, MA, MLIS, and Melissa L McPheeters, PhD, MPH.

Vanderbilt Evidence-based Practice Center

Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Feb.

Report No.: 12-EHC035-EF


Disorder – нарушение

Buildup – накопление

Seizures – судороги

susceptible to – бытьвосприимчивымк

Prevalence – распространенность

Approximately – примерно

Cereals – злаки

Adherenceto – приверженность к

Unpalatable – неприятный

Negligible – незначительный

Reimbursement – возмещение

Subsequent – последующий

Longitudinal – продольный

Adolescence – подростковый

commonly-used – обычно используемый

Nonetheless – тем не менее

Supplementation - добавки



Phenylketonuria (PKU) is a metabolic disorder in which an inability to properly metabolize the amino acid phenylalanine (Phe) leads to a buildup of Phe in the blood and subsequent neurotoxicity that can cause intellectual disability, delayed speech, seizures, behavior abnormalities, and other medical and mental health problems if untreated. PKU is typically diagnosed soon after birth using biochemical tests that are performed after an abnormal newborn screening result. The most severe form of PKU, classic PKU, is typically characterized by blood Phe levels exceeding 1200 μmol/L while on a normal diet. With adherence to a Phe-restricted diet, poor outcomes can be mitigated. Nonetheless, management of PKU can be difficult and onerous for the patient and the family, leading to interest in identifying new ways of managing this lifelong condition. Further, questions remain as to the empirical basis for the selection of specific blood Phe levels as targets of good dietary control.

Etiology of PKU

The enzyme phenylalanine hydroxylase (PAH) converts phenylalanine to tyrosine in the liver. In PKU, individuals have defective PAH activity, leading to a toxic accumulation of phenylalanine in the blood and multiple tissues.1 High blood levels of Phe in untreated PKU can result in multiple medical problems, including intellectual disability, delayed speech, seizures, and behavior abnormalities.2-4 Individuals with PKU are also susceptible to other adverse outcomes, including impaired executive function, reduced processing speed, attention problems, impaired fine motor skills, and mental health concerns (such as anxiety and depression symptoms).5, 6

Every individual has two copies of the gene that encodes the PAH enzyme. If both copies of the gene have pathologic mutations, then the enzyme will be dysfunctional. However, there are more than 500 known mutations that can occur in this particular gene, and it is likely that particular mutations are related to the severity of PKU. Mutations resulting in little or no enzyme activity may cause classic PKU7 while other mutations result in some residual PAH activity that may be associated with mild or moderate PKU. To date, precise genotype-phenotype relationships have not been consistently reported, and substantial work remains to be done on describing the possible relationship between specific mutations and their clinical implications.

Prevalence and Treatment

Approximately 1 in 13,500 to 19,000 infants in the United States is born with PKU.7, 8 The incidence of PKU varies based on ethnicity, with a higher prevalence among Native American and Caucasian individuals.7, 9 The established treatment for PKU is a special diet that restricts the intake of dietary Phe in order to maintain a safe level of Phe concentration in the blood. The diet for individuals with PKU involves restriction of intact protein tailored to the patients' individual tolerance. The diet consists mostly of vegetables, fruits, cereals, and fats to provide intact protein and nutrients. The remaining amount of protein and essential nutrients needed for body growth, development, and maintenance are provided by medical foods specifically designed for individuals with PKU. Medical foods are typically Phe-free and vary in their micronutrient and macronutrient composition. However, they serve as medically-necessary vehicles for providing adequate protein and calories in a form that is tolerated. Low protein foods provide energy and contribute an acceptable quantity and quality of food In addition to the low-Phe diet, many individuals take vitaminsand minerals daily to replace the nutrients that are absent in their restricted diet, but there is concern that individuals with PKU may suffer from various nutritional deficiencies.10 Adherence to the diet can be difficult for individuals and their families because the medical foods/formula can be unpalatable and expensive, and are frequently not covered by third party payors.2-4 Individuals with PKU may consume protein substitutes, but such substitutes also typically have a poor taste.11

Total Phe intake is the total amount of Phe that an individual ingests each day from food. Based on the severity of the disease, individuals with PKU can tolerate different quantities of total Phe intake. This is referred to as Phe tolerance. In infancy this prescribed amount of dietary Phe is based on body weight and growth. After early childhood it may be prescribed as a daily allowance. Phe levels are monitored frequently and appropriate modifications to the total Phe intake are recommended in order to determine the ideal Phe tolerance for the individual patient.

In a given individual, Phe tolerance changes with age and metabolic demand, such as during periods of accelerated growth,pregnancy, and chronic or acute illness. For example, infants with PKU have their Phe level monitored weekly to monthly. As they get older and depending how regularly they access care, Phe measurements may become less frequent, and healthy adults with well-controlled PKU may only get Phe level measurements a few times a year, despite the recommendation of the National Institutes of Health (NIH) that blood Phe be monitored monthly.8 Historically, Phe levels were only monitored closely during the first six years of life (the “critical period”) because elevated Phe after that age was not believed to be detrimental. However, based on accumulated evidence over the last few decades, it is now standard of care to recommend strict adherence to a Phe-restricted diet and routine monitoring of Phe levels throughout life.8, 12

The efficacy of the dietary restriction is monitored by measuring Phe levels in the patient's blood. In general, the treatment goal is a Phe level of 120 to 360 μmol/L. However, there is some variation in the target blood Phe level between clinics and across countries,8, 10 and questions remain about the empirical basis for selecting a specific Phe level as a target. Furthermore, people with classic PKU require lifelong treatment, but some disagreement remains as to whether individuals with milder PKU can relax dietary restrictions at any point in their lives.7, 13

Role of Pharmacologic Therapy

In 2007 the United States Food and Drug Administration (FDA) approved sapropterin dihydrochloride (Kuvan®, formerly known as Phenoptin), the first pharmacologic treatment for PKU, under the stipulation that additional studies be conducted to assess further the drug's efficacy and long-term safety. The goal of treatment with sapropterindihydrochloride (hereafter, BH4) is to control bloodPhe concentrations. Although treatment with BH4 would potentially allow a relaxation of the low-Phe diet, it is not intended to serve as a complete substitute for dietary intervention.14

The mechanism of action of BH4 is as a cofactor of the phenylalanine hydroxylase enzyme, increasing the activity level of the enzyme and increasing the amount of Phe that can be converted to tyrosine. Hypothetically, it should be more effective in individuals with residual PAH activity than in individuals with negligible to no enzyme activity. However, because the genotype-phenotype relationships in PKU are not fully understood, various loading tests are done to identify potential candidates fortreatment. In loading tests, a trial of BH4 is given to the patient to determine whether they demonstrate initial responsiveness at some predefined level (e.g., 30 percent reduction in blood Phe after one week). In the studies that have been completed, individuals must show some responsiveness to BH4 in the short term (generally a week or up to 1 month) to participate in longer trials of the drug. Loading tests used in practice and in research vary in terms of target reduction and timeframe, and none has been established as optimal for identifying candidates for treatment.

Role of Large Neutral Amino Acids

In addition to a Phe-restricted diet and BH4, another potential adjuvant therapy is large neutral amino acids (LNAAs). Several theories may explain the potential impact of LNAAs on the pathophysiology of PKU.11 LNAAs may primarily decrease the brain Phe concentration by competing with Phe for transport across the blood-brain barrier.15, 16 Because LNAAs inhibit influx of elevated amounts of blood Phe into the brain, they may prevent neurologic damage.17 In addition, LNAAs may lower blood Phe levels by competitively inhibiting the transport of Phe via the carrier protein in the gastrointestinal tract.

In the United States, LNAA products are available under the brand names Lanaflex (marketed by Nutricia/SHS International), PheBloc (marketed by Applied Nutrition), and PreKUnil and NeoPhe (both marketed by Solace Nutrition). LNAAs are considered nutritional supplements and thus are not subject to FDA approval. The products are typically available without a prescription. Dosing is calculated by an individual's medical professional and is based on the amount of natural protein (which provides the dietary Phe prescription) and Phe-free protein contained in the medical food. LNAAs may be covered by insurance, but reimbursement varies depending on specific policies.

Despite potential benefits, there is uncertainty about the efficacy and safety of long-term use of LNAAs and the target patient population, including the appropriateness of its use in pregnant women with PKU. When used in clinical practice, LNAAs generally are offered to individuals who are unable to maintain dietary adherence.

Maternal PKU and Maternal PKU Syndrome

Poorly treated PKU in pregnant women will result in a teratogenic syndrome in the offspring, even if the offspring do not have PKU. Known as maternal PKU syndrome,18 it can cause microcephaly, congenital heart defects, low birth weight, craniofacial abnormalities, and intellectual disability in the child. The syndrome was first recognized in 1956 when Charles Dent observed that women with PKU may have children with intellectual disability even though the children did not have PKU.19 A review of treated and untreated pregnancies by Lenke and Levy in 1980 showed that women may have a differential risk of damage to the offspring based on the concentration of Phe in the mother (and, therefore, in the fetus) during pregnancy.20 However, the best management of women with PKU who were considering pregnancy or who were already pregnant was unknown.

Based on the work on Lenke and Levy, several subsequent longitudinal studies have attempted to determine the optimal management of pregnant women with PKU. The Maternal PKU Collaborative Study was the largest of these initiatives. This prospective study, conducted from 1984 to 1996, was designed to determine the effectiveness of a Phe-restricted diet (Phe goal <360 μmol/L) for preventing morbidity in offspring of American, Canadian, and German women with PKU.21 Other studies also looked at the outcomes of pregnancy in women with PKU.20, 22-32

Consequently, the NIH Consensus Development Conference has written guidelines for the management of PKU in pregnant women.8, 33 In addition to traditional approaches, the guidelines recommend frequent monitoring of blood Phe concentration levels and outreach programs for pregnant woman and women who are of childbearing age to reinforce social support and positive attitudes about a controlled diet.8 However, management of PKU during pregnancy can be very difficult. Some individuals may have discontinued the diet during adolescence, and restarting an unpalatable diet that strictly limits protein can be very challenging. Complicating factors such as morning sickness, balancing severe protein restriction with adequate energy intake, insurance coverage limitations for medical foods and modified low protein foods, maturity of the expectant mother, and her previous food lifestyle before pregnancy contribute to the challenges. Furthermore, women with milder forms of PKU may no longer be followed by healthcare professionals with expertise in PKU.34 Therefore, it currently is recommended that girls and young women with PKU adhere to the Phe-restricted diet throughout their lifetime, especially during the childbearing years of adolescence and young adulthood.

The role of BH4 in pregnant women with PKU is still unclear, but given the benefits of the drug in other groups of individuals with PKU, this is a population of individuals that merit further study.7

Clinical Uncertainties

A Phe-restricted diet throughout life has been well-established as the cornerstone of treatment for PKU by studies such as the PKU Collaborative Study.12 Yet PKU is a rare metabolic disease, and there are limited data on the best adjunct treatment in addition to diet for different ages. Although most clinics use a blood Phe level of 120 to 360 μmol/L as the goal treatment range, evidence is mixed on a specific optimal range for minimizing the clinical and cognitive effects of elevated blood Phe levels across different ages of individuals, including pregnant women. Furthermore, the efficacy, safety, and target populations for the concomitant use of BH4 or LNAAs with a Phe-restricted diet have not been established, and clinicians lack evidence-based support for when to prescribe BH4 or LNAAs and in which patients. The implications of liberalizing the diet in those patients who do achieve blood Phe levels below treatment goals are currently unknown in terms of their effect on short- and long-term clinical and cognitive effects. Finally, the safety and efficacy of the use of BH4 and LNAAs in pregnant women and in children, including infants, are unknown.7, 35 Further complicating clinical decision making is the difficulty in studying such a rare disease. They range in age and severity of clinical disease and thus represent a very small yet highly heterogeneous population. Therefore, not only is research challenging logistically, but little federal funding is available to support such research. The availability and quality of research evidence is unlikely to reach the level of more common clinical conditions; nonetheless, we know with certainty that failure to treat this condition with a Phe-restricted diet with or without concomitant use of BH4 or LNAAs leads to very poor outcomes. Clinicians, patients, and their families must make the best decisions possible about what treatment avenues to pursue in the presence of uncertainty.

Goal of This Comparative Effectiveness Review (CER)

The overall goal of this CER is to inform clinician and patient decisions about adjuvant treatments for PKU in addition to dietary restriction. To this end, this CER summarizes evidence for the effectiveness of BH4 in individuals with PKU, including pregnant women. The review also summarizes the evidence for the effectiveness of LNAAs, including pregnant women, with PKU. We also address harms of BH4 and LNAAs reported in the PKU literature. “Harms” are defined by the Evidence-based Practice Center program as the totality of all possible adverse consequences of an intervention including, but not limited to, side effects oftreatment.36

This review also seeks to examine the evidence for specific blood Phe levels to minimize cognitive impairment in individuals with PKU and whether specific levels may be applicable to specific age groups.



Blood Phe level is positively correlated with the probability of having an IQ of less than 85. This predicted probability exceeds the population probability (approximately 15 percent) at 400 μmol/L and reaches a maximum of about 80 percent at 2000 μmol/L. Thus, the commonly-used blood Phe target of 120 to 360 μmol/L is supported in our meta-analysis.8 Notably, the negative association between Phe and IQ is strongest when Phe is measured at least one year prior to IQ testing. The Phe level obtained more than one year before IQ testing is likely a better indicator of how well Phe has been controlled over the long term, relative to concurrent measurements. This relationship lends support to the principle that cognitive effects accumulate over a long time period, that concurrent measurements are poor predictors of a cognitive effect, and that control should be continued into adulthood. Review of the research on maternal PKU supports the need for dietary control as early as possible before or in pregnancy, and maintenance of Phe control to prevent poor cognitive outcomes in infants.

Dietary management remains the mainstay of treatment for PKU, and as noted above, maintaining control over the lifetime is an appropriate goal. Nonetheless, there is potential for supporting patients in achieving their clinical goals and possibly liberalizing their diet with adjuvant therapy. As a potential adjuvant treatment approved by the U.S. FDA in 2007, BH4 works by enhancing residual enzyme activity present in some individuals with PKU. BH4 has been shown in two RCTs and three open label trials to reduce Phe levels in some patients, with significantly greater reductions seen in treated versus placebo groups.

We do not yet have the ability to reliably predict which patients are most likely to be responders, as all participants in the trials were initially responsive in screening tests, but not necessarily so in the efficacy studies. One RCT also demonstrated increased Phe tolerance using BH4 among children on restricted diets. Overall, harms associated with the drug were minor and did not occur more frequently in the treatment group than in placebo arms. To date, there are no data to directly establish the potential effects of BH4 on longer term clinically important outcomes, including cognition, executive function, and quality of life. Significant gaps in the evidence remain, including effectiveness of the drug in a range of patients outside of the clinical trial setting. Thus, while the strength of evidence is moderate for a large, positive effect of BH4 on reducing Phe levels over the short term in groups of patients showing initial responsiveness, evidence for the effect of BH4 on longer term clinical outcomes is low, and based on indirect associations, including our meta-analysis.

In theory, supplementation of a Phe-restricted diet with LNAAs might have a beneficial effect on cognition as LNAAs may competitively inhibit transportation of Phe through the blood-brain barrier, thereby offering protection by potentially decreasing brain Phe levels. However, there is insufficient evidence to suggest that LNAAs could be a viable treatment option for reducing Phe levels or increasing Phe tolerance. There have been only three very small studies (total number of participants was only 47) with inconsistent results, and there is no evidence that Phe levels were reduced to clinically meaningful levels in the short time they were studied.

In particular, continued studies that include adequate numbers of participants should be conducted in both tightly controlled and nonadherent populations, and among different age groups for both types of adjuvant therapies. In addition, effectiveness in various groups of patients outside the clinical trial setting are needed, including those with variability in adherence,

Registries have been established and will provide important data in the future, as will ongoing studies that directly measure additional outcomes, including behavioral and psychiatric measures. Data are not currently available to understand potential modifiers of treatment effectiveness, including genotype, in order to select the best populations for targeting further research and treatment. Moreover, the significant variability in responsiveness to BH4 is unexplained. It is unclear, in particular, why a high proportion of individuals who have an initial response during screening do not have a durable response even over a few weeks in the efficacy trials.