OVERVIEW: What every practitioner needs to know

Are you sure your patient has Phenylketonuria? What are the typical findings for this disease?

Phenylketonuria (PKU) is a treatable autosomal recessive condition which, without treatment, causes progressive mental retardation. It is due to the inherited deficiency of the enzyme phenylalanine hydroxylase (PAH). Because dietary restriction of phenylalanine will prevent mental retardation, screening for hyperphenylalaninemia is part of most, if not all, international newborn screening programs.

Affected infants appear normal during the first few months of life but soon demonstrate progressive developmental (intellectual) delay, with mean IQ’s generally reaching the 40’s by age 4 if untreated. In addition, the children generally demonstrate relative hypopigmentation of both skin and hair compared to other family members, and variably demonstrate eczematoid and other skin related problems, seizures, microcephaly, behavioral abnormalities, including autistic features, and abnormalities of tone, including some with findings consistent with cerebral palsy or other forms of severe psychomotor retardation. Some of these patients have a mousy odor due to the phenylketone compounds in their urine and body fluids (i.e. phenylacetate).

Most affected children are now identifed by newborn screening programs. Treatment by 2 weeks of age with dietary protein (phenylalanine) restriction and close biochemical and nutritional monitoring usually produces a child with normal intellect and thus few, if any, clinical features other than the variable lighter pigmentation. There may be subtle neuropsychological and performance deficits compared to siblings, but usually patients appear normal throughout life if appropriately treated.

Recommended dietary restriction is lifelong but many children have discontinued this diet at ages that vary from 5 years of age through adulthood. Although variable, a wide range of intellectual deficits (fall in IQ from 5-30 points), EEG abnormalities, magnetic resonance imaging (MRI) white matter changes, and neuropsychological abnormalities may progressively develop with time off treatment.

What other disease/condition shares some of these symptoms?

The causes of isolated mental retardation are numerous but may include abnormalities of plasma amino acids. In the case of PKU, hyperphenylalaninemia is the identified finding leading to the diagnosis. The level of phenylalanine while taking a normal diet has in the past been used for clinical classification to reflect the likely clinical outcome. Those with the highest levels (usually above 1000 micromoles per liter) associated with normal diet were given the diagnosis of phenylketonuria ("classic PKU").

Patients with lower but nonetheless elevated levels of phenylalanine on normal diet were referred to as either non-PKU hyperphenylalaninemia and variant PKU or as moderate PKU, mild PKU, or mild hyperphenylalaninemia. These terms do not reflect different conditions or disease states, simply differences in the inherited deficiencies of the individual patient’s PAH enzymatic activity and the likelihood of developing symptoms of some form (i.e. range of associated intellectual deficiency) if not fed a restricted diet.

About 2% or more of all patients with hyperphenylalaninemia will not have PAH deficiency but instead have a deficiency of the cofactor for PAH, tetrahydrobiopterin. Inherited deficiencies in both the synthesis (GTP cyclohydrolase [GCH1 gene] and 6-pyruvoyltetrahydropterin synthase [PTPS]) and recycling (dihydropteridine reductase [QDPR] and pterin-4 acarbinolamine dehydratase [PCBD]) of this important cofactor will produce similar symptoms to PKU.

Biopterin cofactor deficiencies result in variable mental retardation, microcephaly and neurologic abnormalities including hypotonia/hypertonia and cerebral palsy-like conditions, progressive dystonias, seizures and other movement disorders, swallowing difficulties, dysautonomias (i.e. hyperthermia, hypersalivation) and behavioral abnormalities. Every child with an elevated blood phenylalanine should have testing for biopterin cofactor deficiency since this too is a condition that is treatable with tetrahydrobiopterin and other supplements.

Elevations of phenylalanine in the blood are also seen occasionally in infants with increased protein intake (certain formulas), deficiencies in the contiguous tyrosine catabolic pathway (tyrosinemias type I, II, III), and systemic disease conditions (for example, sepsis) clearly affecting liver function.

What caused this disease to develop at this time?

PKU is an autosomal recessive disorder, thus requiring the presence of two disease causing alleles.

The enzyme phenylalanine hydroxylase (PAH) converts phenylalanine, an essential amino acid, to tyrosine. Inherited deficiency of this enzyme results in the accumulation of phenylalanine, which then accumulates in body fluids following birth and may be converted to a number of compounds including phenyllactate, and phenylketones (phenylpyruvate and phenylacetate) which are excreted and easily identifiable in the urine (hence "phenylketonuria").

Excess phenylalanine and/or its resultant converted products are toxic to the developing central nervous system. These toxicities are associated with abnormal myelination and neuronal maturation of synapses and dendrites. Elevated phenylalanine may also competitively inhibit the transport of other amino acids into the brain. This is seen in the CNS utilization of tyrosine and 5-hydroxytryptophan, leading to effects on the production of catecholamines (dopamine, noradrenaline, adrenaline), serotonin, and melanin.

The severity of signs and symptoms observed in the hyperphenylalaninemic conditions including PKU is due to complicated, not well understood, interacting processes. What is clear is that plasma levels of phenylalanine are generally correlated with clinical outcome. These levels also are correlated with the degree of absence of enzymatic activity, with the clinical condition PKU being defined as the complete or near complete deficiency of PAH activity due to a variety of mutations of the PAH gene.

The plasma levels of PKU, in turn, are affected by dietary intake of phenylalanine and for that reason, early initiation of dietary restriction can ameliorate the majority of the clinical consequences. An exact correlation between dietary intake, plasma phenylalanine levels, and clinical consequences is not apparent and every patient must have an individualized approach to therapy and ongoing testing for clinical consequences. Even within family members exhibiting the same set of PAH mutations, individual variability in clinical outcome is apparent.

The incidence of PKU overall is about 1/10,000 in the United States but geographic and ethnic variation in incidence abounds. Similarly, hundreds of disease associated PAH alleles exist. Allele testing is not required for the diagnosis but is helpful in family counseling and may contribute to considerations of dietary restriction. The PAH enzyme is expressed in the liver but hepatic biopsy for enzyme testing is not required for diagnosis of these conditions. In general, response of plasma phenylalanine levels to normal dietary intake of phenylalanine (i.e. natural protein) should be sufficient for diagnosis.

A similar but genetically distinct set of conditions due to lack of the PAH enzyme associated cofactor tetrahydrobiopterin (BH4) results in deficient PAH activity and elevations in plasma phenylalanine. These biopterin cofactor disorders also are associated with intellectual disability but generally cause more consistent disorders of tone (mixed hypo/hypertonias, dystonias), movement disorders (choreoathetosis), and seizures as well. They may or may not be associated with elevations of plasma phenylalanine, and the elevations observed are variable. Every neonate or child identified with any elevation above normal for phenylalanine requires specific testing for these tetrahydrobiopterin cofactor disorders.

Tetrahydrobiopterin cofactor disorders are autosomal recessive disorders due to mutations in either of four genes, GCH1, PTS, PCBD, and QDPR. Mutations in PTS and QDPR account for 61% and 31% respectively of the disorders that cause tetrahydrobiopterin deficiency associated with hyperphenylalaninemia. With both disease conditions, hyperphenylalaninemia (including PKU) due to PAH deficiency and hyperphenylalaninemia due to tetrahydrobiopterin deficiency, outcome is dependent on timing of treatment, because CNS damage appears irreversible beyond a certain point. This is probably variable for each individual patient but clearly underscores the need for earliest possible diagnosis and initiation of appropriate treatment for optimal outcome.

A growing epidemiologic problem is the presence of a number of PKU women who have gone off the restricted diet therapy since childhood and are now of child bearing age. Their pregnancies are at risk of producing infants with intrauterine growth retardation, microcephaly, congenital heart disease, and a variety of major and minor anomalies, including intellectual disability. These findings are associated with elevated neonatal plasma phenylalanine levels reflecting prior elevated fetal levels derived from the elevated maternal blood phenylalanine levels of pregnant mothers not on dietary phenylalanine restriction. These babies are described as maternal PKU syndrome and followup studies have demonstrated permanent intellectual disability in the children, despite the fact that their elevated phenylalanine levels normalize very shortly after birth.

These adverse consequences in the offspring can be prevented by placing the mother on appropriate dietary phenylalanine restriction, preferably prior to the onset of the pregnancy.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Following the identification of a neonate with elevated phenylalanine by neonatal screening, a quantitative plasma amino acid assay should be performed while the infant has been on normal amount of protein containing diet. If elevated phenylalanine and normal or reduced tyrosine is noted (ratio phe/tyr usually >3), the patient is categorized as being in a hyperphenylalaninemic state, with the designation of PKU if the levels are above 1000 micromoles/liter (normal is less than 120 micromoles per liter). At that point, restricted phenylalanine diet should be initiated and plasma phenylalanine responses noted with appropriate dietary adjustments.

At the same time, evaluation for tetrahydrobiopterin (BH4) cofactor defects should be initiated by assaying urine pterins and RBC DHPR enzyme activity. If both are normal, the patient has PKU or a similar hyperphenylalaninemic state due to deficiency of PAH, and dietary management is continued.

PAH genotyping may be considered - some centers feel it is required since the results may suggest what to expect during subsequent dietary management. If quantitative plasma amino acids are normal, i.e. no elevated phenylalanine when on full dietary intake of normal amounts of protein, the patient is considered to have had a false positive newborn screening result and no further action is required. If elevated phenylalanine and either biopterin cofactor screen is abnormal (urine pterins abnormal or RBC DHPR activity deficiency), the patient will need further specific evaluation for specific pterin defects, including analysis of folates and neurotransmitter metabolites in CSF, enzyme activity measurements, and DNA sequence analysis of appropriate gene. These patients should be started on tetrahydrobiopterin supplementation to determine response of plasma phenylalanine to dietary intake of phenylalanine.

Infants of mothers with PKU who initially demonstrated an elevated plasma phenylalanine during the first days of life should be retested on a full diet. If the elevation is due solely to maternal PKU syndrome, the phenylalanine levels in the infant should normalize within days after. Persistent elevated plasma phenylalanine suggests PKU/clinical hyperphenylalaninemic state, about a 1% occurrence since infants of mothers with PKU are obligate heterozygotes for PAH deficiency alleles but are at 50% risk to inherit a PKU causing PAH allele if their father is a carrier.

Two classification schemes have been proposed for the results obtained from the above testing. The first differentiates classic PKU, with plasma phenylalanine concentrations greater than 1000 micromoles/liter, from "non-PKU" hyperphenylalaninemia, with levels above normal (plasma phenylalanine >120 micromoles/liter) but less than 1000 micromoles/liter when an individual is on normal diet. Variant PKU is the term reserved for those individuals who do not fit the above two descriptions.

In contrast, a different classification scheme stratifies clinical type by tolerance to the amount of phenylalanine in diet. Classic PKU is used to refer to patients unable to tolerate dietary phenylalanine intakes of 250-350 mg per day and maintain plasma phenylalanine levels at < 300 micromoles/liter (felt to be the safely tolerated level in these patients). Moderate PKU is for individuals who tolerate 350-400 mg dietary phenylalanine per day and mild PKU are those who tolerate 400-600 mg dietary phenylalanine per day. Mild hyperphenylalaninemia refers to those infants who demonstrate plasma phenylalanine levels <600 micromoles per liter (10 mg/dl) on a normal phenylalanine containing diet.

There is not universal agreement on the threshold "safe level" of hyperphenylalaninemia associated with optimal neurologic development and physicians in different practices may vary on the targeted dietary blood phenylalanine level. In fact, the clinical distinction between the groups termed nonclassical PKU patients is arbitrary, since there will be a continuum of residual PAH activities observed in individual patients due to the numerous PAH mutations and myriad of epigenetic effects. Therefore, patients nowadays are often referred to as having either classic PKU or hyperphenylalaninemia requiring or not requiring treatment.

PAH gene mutation analysis may help sort this out. The two conditions fall under the same OMIM (online edition of McKusick’s Mendelian Inheritance in Man) category number 261600 reflecting PAH deficiency, combining both PKU and non PKU hyperphenylalaninemic conditions. Patients who have hyperphenylalaninemia due to any of the tetrahydrobiopterin (BH4) defects are referred to as BH4 deficient hyperphenylalaninemia.

Older patients with overt neurologic symptoms including mental retardation should be similarly evaluated as described above when quantitative plasma amino acids demonstrate elevated phenylalannine.

Would imaging studies be helpful? If so, which ones?

In general imaging studies are not utilized for the diagnosis of PKU. When untreated children and/or adults have been studied, variable white matter changes, likely reflecting loss of myelin, have been noted in some patients, especially in the posterior portions of the cerebrum. This is more likely to be observed in magnetic resonance imaging (MRI) than in computerized tomography (CT) imaging modalities. Occasional mild cerebral atrophy may be also noted as well as sporadic findings (i.e. brain calcifications). In contrast, osteopenia has been noted in both treated and untreated patients. It is therefore recommended that DEXA studies be performed in adolescents and adults to determine the extent of osteopenia and need for interventional dietary therapies.

Confirming the diagnosis

Algorithms similar to that presented in the above laboratory section are available from a number of resources. Followup of positive newborn screening results for individual sites are usually available on line. In the United States, the ACT guidelines prepared by the American College of Medical Genetics are generally used and are available at under the section Newborn ACT sheets and confirmatory algorithms. All children with a positive newborn screen for elevated phenylalanine should be referred to a center specializing in that disorder as quickly as possible, both for confirmation of the disorder and rapid initiation of the required dietary restrictions.

If you are able to confirm that the patient has Phenylketonuria, what treatment should be initiated?

Treatment of PKU/hyperphenylalaninemia by dietary restriction of phenylalanine intake should be initiated as soon as possible for best possible outcomes. Since patients are usually identified by newborn screening programs, the goal is to establish the diagnosis by laboratory followup testing and treatment by restricting phenylalanine dietary intake within a few weeks of life for optimal long term results. Levels of plasma phenylalanine above 360-600 micromoles/liter (6-10 mg/dl) are indications for treatment but absolute cutoffs vary by international location. In the United States, dietary treatment is generally started at >400 micromoles/liter while in Germany and France it is 600 micromoles per liter.

These differences reflect differing opinions regarding the evidence presented for associated long term outcomes of untreated patients at these levels. In cases close to the cutoffs, normal feeding is continued with close monitoring of plasma phenylalanine levels to ensure that they stay within acceptable levels. In these cases, some centers advocate a 3-day challenge test at 5 months of age of 180 mg phenlalanine/kg/day with a followup 72-hour plasma phenylalanine level determination. The important point is close followup with ongoing dietary phenylalanine challenges until a safe dietary threshold is established.

Once treatment is indicated at any time, dietary therapy consists of carefully restricting natural protein foods and using a synthetic formula containing all amino acids except phenylalanine so that a calculated restricted intake of phenylalanine is achieved. The diet is adjusted based on plasma phenylalanine levels. It is not unusual for some patients to be initially overly restricted but to later demonstrate ability to tolerate a more liberal but nonetheless phenylalanine restricted diet. Similarly, with age, phenylalanine requirements decline and increased restriction of phenylalanine intake may be indicated.

Intervening normal growth spurts, puberty and illnesses provoking catabolism will alter the individual phenlalanine dietary requirements. Phenylalanine and other dietary requirements for normal growth and development which change with age therefore require close monitoring by an experienced nutritionist and/or biochemical geneticist (metabolic specialist). Breast milk has a relatively low phenylalanine content and may be used in infancy under the guidance of an experienced nutritionist, usually by having some partial restriction of breast milk accompanied by substitution with phenylalanine deficient synthetic formula.

During catabolism from illnesses, dietary reduction of phenylalanine intake by substitution of nonprotein caloric formulas may be indicated. The overall goal is to keep the average plasma phenylalanine levels within certain guidelines, available from several subspecialty resources. All other dietary requirements must be monitored and supplemented as needed, since the dietary restrictions may produce a suboptimal source for otherwise normally attained nutrients and vitamins.

Pharmacologic doses of tetrahydrobiopterin (sapropterin dihydrochloride, 6R-BH4) have recently been used to allow for liberalization of dietary phenylalanine restrictions. This 6R-BH4 cofactor therapy appears to be effective for patients with certain PAH mutations that produce defective enzyme with residual activities that can be stimulated to higher levels. In some patients it may be an alternative to dietary restriction, and normal diets may be achieved. A positive response is often observed within 15 hours of a test dose, with blood phenylalanine levels declining by 30% of baseline. The usual United States approach is to check phenylalanine levels at 24 hrs, 1 week and 2 weeks after starting a recommended therapeutic dose, while European centers often use a 48-hour protocol. All of these protocols are subject to change (see Camp KM et al. in references).

Perhaps as many as 50% of the nonclassical PKU hyperphenylalaninemics (phenylalanine levels <1200 micromoles/liter but nonetheless with a demonstrated requirement for dietary restriction), may benefit from this pharmacologic approach. It may be especially useful in those women off diet since childhood who are interested in pregnancy and preventing maternal PKU syndrome since reinitiation of full dietary restriction during adult life is extremely difficult to achieve in a timely fashion. There have now been several successful pregnancies of women with PKU who have used sapropterin dihydrochloride.

What are the adverse effects associated with each treatment option?

Dietary restriction of natural protein may not be simple to achieve, especially beyond the infant years. The low protein substitutes and synthetic formula supplements for natural protein products may be nonpalatable. Expense may be an issue. Dietary restrictions may limit social interactions. Ongoing physician visits and laboratory testing requiring blood sampling may be burdensome and expensive. All of these problems are certainly surmountable but do contribute a certain amount of difficulty for patients and their families.

Sapropterin dihydrochloride (6R-BH4) pharmacologic cofactor therapy does offer chances for liberalization of dietary restrictions, alleviating some of the above problems. There have been no serious side effects thus far reported. Gastrointestinal complications include gastric distress, nausea, and diarrhea. These are usually mild and self limited and may be avoided in many by taking the medicine with food. The full effects of this therapy on pregnancy remain to be observed but its use in several pregnancies has been tolerated without complication.

What are the possible outcomes of Phenylketonuria?

Patients with classic PKU demonstrate mental retardation (often IQs of 50 or less) if untreated in the vast majority of cases. Some studies suggest a loss of up to 50 IQ points during the first infant year on unrestricted diet. Only approximately 2% of classic PKU patients appear to have normal intelligence following a childhood life on unrestricted diet. In contrast, patients placed on dietary restriction of phenylalanine within the first few weeks of life have outcomes that fall within the normal range.

There are slight differences between PKU patients and their age-matched non-PKU siblings in measures of intelligence and behavior. These include increased frequency of ADHD, decreased autonomy, and increased school problems compared to either healthy controls or chronically ill peers. It is currently not known whether lifetime outcomes will change if sapropterin dihydrochloride (6R-BH4) therapy is used concurrently with restricted diet.

Restricted diet is recommended lifelong, although once past 12 years of age, some liberalization appears to be well tolerated. Prematurely normalizing the diet has been associated with loss of a few but variable IQ points, abnormal mannerisms, hyperactivity, signs of anxiety, and variable other behavioral and school performance issues.

The problems of restarting the restricted diet to prevent maternal PKU syndrome has been addressed in the above sections.

For all these reasons, lifelong dietary restriction starting as early as possible in the infant’s life is advocated, with close followup by an experienced metabolic team of physicians and nutritionists. Treatment of patients with plasma phenylalanine levels of <600 micromoles/liter remains controversial among many international sites but several specialists have observed progressively higher levels as they follow some untreated infants during the first few months of life, and for that reason many advocate a more conservative approach to initiating dietary therapy during infancy.

Specialists in the United States and many other sites prefer to see levels remain less than 360 micromoles per liter during the first 8-12 childhood years, with liberalization thereafter. However, females with PKU/hyperphenylalaninemia will need to maintain phenylalanine levels of 120-360 micromoles/liter to minimize the effects of maternal PKU during pregnancy. This usually will be achieved only through prompt acceptance of full dietary restriction. This is another reason for the practice of lifelong dietary restriction.

Despite lifelong treatment with restricted diet, there still is an increased risk for psychiatric abnormalities, attention deficits, anxiety, and other social disabling conditions. Overall, however, the outcomes of early treatment are considered excellent with few risks and limited hardships compared to the benefits.

What causes this disease and how frequent is it?

PKU is considered the most common aminoaciduria and identified inborn error of metabolism associated with mental retardation. Hyperphenylalaninemia, of which PKU is the "classic" severe form, is an autosomal recessively inherited disorder due to mutations in the phenylalanine hydroxylase encoding gene (PAH).

Although the worldwide incidence overall is about 1:10,000, such as observed in most of the United States and Europe, there is widespread ethnic/geographic variability. For example, Finland has a very low incidence, 1:200,000, similar to the low incidence observed in the Ashkenazi Jewish populations in several geographic locations. In contrast, Ireland (1:4,500) and Turkey (1:2,600) have much higher incidences, suggesting a 50-100 fold range in prevalence by population. Similarly, the percentage of tetrahydrobiopterin cofactor defects accounting for hyperphenylalanemia is about 2% of the hyperphenylalaninemic population but may vary up to 10-15% in some populations.

How do these pathogens/genes/exposures cause the disease?

As explained above, insufficient PAH activity allows accumulation of excess phenylalanine in body tissues. This amino acid and its converted metabolites (ie., phenylketones) are progressively toxic to the developing infant central nervous system, manifesting a wide variety of histologic and functional abnormalities at later stages of life.

Other clinical manifestations that might help with diagnosis and management


What complications might you expect from the disease or treatment of the disease?

As discussed above, untreated patients demonstrate mental retardation, and various behavioral abnormalities including irritability, hyperactivity, abnormal mannerisms, signs of anxiety, and hyperactivity, as well as variable hypogimentation of skin and hair, eczematoid skin rash, signs of cerebral palsy in some including hypertonicity, functional spasticities with or without over contractures, and gait abnormalities, seizures (25%) and/or EEG abnormalities (75%) and mild increased incidence in congenital heart disease.

Appropriate treatment prevents the mental retardation but there may be variable mild abnormalities in intelligence, behavior and neuropsychiatric attributes. Patients on treated with dietary restriction must be closely monitored for other nutritional deficiencies.

Are additional laboratory studies available; even some that are not widely available?


How can Phenylketonuria be prevented?

PKU/hyperphenylalaninemia is usually due to an autosomal recessive condition affecting the PAH gene which produces the liver enzyme phenylalanine hydroxylase (PAH). There are hundreds of mutant PAH alleles identified. Most of these are not spontaneous but rather associated with geographic and/or ethnic origin. Approximately 1/50 people are carriers of these alleles, but this frequency is highly influenced by geographic and ethnic considerations. If both parents are known carriers, they have a 25% chance of having a child that inherits both parental alleles. Usually a first child with PKU is identified in the family (such as by neonatal screening) and subsequent mutation testing identifies carrier status in other family members.

Prenatal diagnosis is available through chorionic villus sampled cells or amniotic fluid cells obtained during pregnancy and allows for reproductive choices. Similarly, knowledge of a family history of PKU/hyperphenylalaninemia alerts the families and physician caretakers to ensure neonatal testing as soon as possible.

Widespread newborn screening for hyperphenylalaninemia/PKU has eliminated the majority of mental retardation that would otherwise be associated with patients with this condition. This has been achieved through standardized neonatal screening efforts coordinated with close followup of positive results. Dietary restriction of phenylalanine intake is initiated while testing for the rare biopterin cofactor defects is pursued, since the latter will require some differences in treatment supplements.

Prevention of the development of mental retardation is tied directly to the time of initiation and continuity of dietary restriction in the vast majority of cases. Dietary recommendations require ongoing nutritional counseling from experienced professionals. Knowledge of harmful components in offered foods requires provision of constantly updated information to patients and their families.

For example, the widespread use of the artificial sweetener aspartame (N-aspartylphenylalanine ester) represents a potential source of unaccounted for phenylalanine in an otherwise restricted diet. This compound is hydrolyzed by the intestinal luminal digestive process to release free L-phenylalanine, which is directly absorbed into the bloodstream. Similar components of foods and drinks may be introduced into the commercial market at any time, and the caretakers and families need to be aware in order to assure optimal dietary management and outcomes. The use of sapropterin dihydrochloride (6R-BH4, Kuvan) therapy may allow liberalization of dietary restrictions and/or provide further prevention of PKU complications by assisting adherence to dietary regimens.

What is the evidence?

"ACT protocol sheet for elevated phenylalanine on newborn screen, American College of Medical Genetics". 2009.

Mitchell, JJ, Pagon, RA, Bird, TD, Dolan, CR. "GeneReviews [Internet]". Seattle. Seattle. 2013.

(A comprehensive review of the genetics, classification schemes, and approaches to diagnosis and treatment. An excellent but lengthy review for clinicians.)

Camp, KM. "Phenylketonuria Scientific Review Conference: State of the science and future research needs". Mol Genet Metab. vol. 112. 2014. pp. 87-122.

(A very comprehensive review of the current state of diagnosis and treatment, including clarifications of historical categorizations, and consensus approaches to treatments and future research. Includes BH4 pharmacologic interventions.)

Burgard, P, Luo, X, Hoffmann, GF, Sarafoglou, K, Hoffmann, GF, Roth, KS. "Chapter 13 Phenylketonuria". Pediatric Endocrinology and Inborn Errors of Metabolism 2009. pp. 163-168.

(An excellent clinically oriented discussion of the approaches to diagnosis and treatment, as well as approaches to screening.)

Nyhan, WL, Barshop, BA, Ozand, PT. "Phenylketonuria in Atlas of Metabolic Diseases". Hodder Arnold. 2005. pp. pp127-135.

(An excellent clinical review of the condition, including a comprehensive protocol for diagnosis and treatment.)

Donlon, J, Levy, H, Scriver, CR. "Chapter 77 Hyperphenylalaninemia: Phenylalanine Hydroxylase Deficiency. in OMMBID: The Online Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill Companies, Inc". pp. pg1-150.

(An excellent comprehensive review of all aspects of biochemistry and genetics of the disease and its clinical complications.)
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