NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Phenylalanine Hydroxylase Deficiency

Synonym: PAH Deficiency

, MD, PhD, FAAP, FACMG and , MD, FAAP, FACMG.

Author Information

Initial Posting: ; Last Update: October 20, 2016.

Summary

Clinical characteristics.

Phenylalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders. The risk of adverse outcome varies based on the degree of PAH deficiency. Without effective therapy, most individuals with severe PAH deficiency, known as classic PKU, develop profound and irreversible intellectual disability. Affected individuals on an unrestricted diet who have phenylalanine levels above normal but below 1200 μmol/L (20 mg/dL) are at much lower risk for impaired cognitive development in the absence of treatment.

Diagnosis/testing.

PAH deficiency can be detected by newborn screening in virtually 100% of cases based on the presence of hyperphenylalaninemia using tandem mass spectrometry on a blood spot obtained from a heel prick. The diagnosis of PAH deficiency is established in a proband with:

  • A plasma phenylalanine concentration persistently above 120 µmol/L (2 mg/dL) and altered ratio of phenylalanine to tyrosine in the untreated state with normal BH4 cofactor metabolism;
    and/or
  • The finding of biallelic pathogenic variants in PAH by molecular genetic testing.

Management.

Treatment of manifestations: Classic PKU: a low-protein diet and use of a Phe-free medical formula as soon as possible after birth to achieve plasma Phe concentrations of 120-360 µmol/L (2-6 mg/dL). A proportion of individuals with PKU benefit from adjuvant therapy with sapropterin. Large neutral amino acid (LNAA) transporters may also decrease the plasma Phe concentration in affected adolescents and adults. Non-classic HPA: Individuals with plasma Phe concentrations above 600 μmol/L are treated in most centers. It is debatable whether those with plasma Phe concentrations consistently below 600 µmol/L (10 mg/dL) require dietary treatment. Neuropsychiatric testing may be considered to identify learning differences in affected individuals with referral to developmental services, as indicated.

Prevention of primary manifestations: See Treatment of manifestations.

Surveillance: Regular monitoring of plasma Phe, Tyr, and plasma amino acid concentrations in individuals with classic PKU; regular assessment of growth and micronutrient needs; assessment of developmental progress and screening for mental illness at every visit.

Agents/circumstances to avoid: Aspartame, an artificial sweetener that contains phenylalanine.

Evaluation of relatives at risk: Newborn sibs of an individual with PAH deficiency who have not been tested prenatally should have blood concentration of Phe measured shortly after birth (in addition to newborn screening) to allow earliest possible diagnosis and treatment.

Pregnancy management: To minimize or prevent teratogenic effects of phenylalanine, women with PAH deficiency should follow a Phe-restricted diet for at least several months prior to conception in order to maintain plasma Phe concentrations between 120 and 360 µmol/L (2-6 mg/dL); after conception, continuous nutritional guidance and weekly or biweekly measurement of plasma Phe concentration to assure that target levels are met in addition to adequate energy intake with the proper proportion of protein, fat, and carbohydrates. Evaluation for fetal anomalies using high-resolution ultrasound and fetal echocardiogram.

Genetic counseling.

PAH deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the PAH pathogenic variants have been identified in an affected family member.

Diagnosis

Suggestive Findings

Phenylalanine hydroxylase (PAH) deficiency should be suspected in an individual with the following newborn screening results, clinical features (by age), neuroimaging, and supportive laboratory findings:

Newborn screening results

  • Positive newborn screen by tandem mass spectrometry (MS/MS) using dried blood spots collected after 24 hours of age. This method is used in most if not all states in the USA for newborn screening.
  • The ability of current tests to accurately measure Phe concentrations in infants before age 24 hours is a concern, since hyperphenylalaninemia (HPA) manifests itself as a time-dependent increase of Phe concentration in the blood. However, recognition of an altered ratio of phenylalanine and tyrosine may still identify the affected newborn.

Postnatal clinical findings in a newborn. No physical signs of hyperphenylalaninemia (HPA)

Clinical findings in an untreated, older individual (infancy to adulthood)

  • Epilepsy
  • Any level of intellectual disability and behavior problems, including autistic features
  • Parkinson-like features (particularly in an adult)
  • Musty body odor
  • Eczema
  • Decreased skin and hair pigmentation
  • Female with no prior normal offspring who has a history of recurrent pregnancy loss and/or offspring with malformations including any combination of small size, microcephaly/brain malformations, congenital heart defect, limb malformations, and/or tracheoesophageal fistula

Neuroimaging. Progressive white matter disease on brain MRI; observed in 90% of individuals with PAH deficiency even without evidence of neurologic deterioration

  • Advanced-age affected individuals off diet or with poor compliance and those who are untreated have the most severe MRI findings.
  • It is proposed that in untreated affected individuals, Phe prevents myelination and in early-treated affected individuals, myelin is normally made but may be functionally impaired [Anderson & Leuzzi 2010].

Supportive laboratory findings

  • Plasma amino acid analysis. In the untreated state, an elevated plasma phenylalanine (Phe) concentration persistently higher than 120 µmol/L (2 mg/dL) with phenylalanine levels higher than tyrosine (Tyr) levels
    • A normal Phe:Tyr ratio is typically <1; a ratio of >3 is considered useful in the diagnosis of PAH deficiency [Vockley et al 2014].
    • Most severely affected individuals with complete enzyme loss (also called “classic PKU”) have untreated levels of phenylalanine (Phe) of >1200 µmol/L. If diagnosed early and if treatment is begun in the first or second week of life, most severely affected individuals do not attain Phe levels this high.
  • BH4 (tetrahydrobiopterin) cofactor analysis and/or challenge
    • Normal urine pterin studies using liquid chromatography
    • Normal dihydropterin reductase measurement in erythrocytes, typically from a dried blood spot

Establishing the Diagnosis

The diagnosis of PAH deficiency is established in a proband with a plasma phenylalanine concentration persistently above 120 µmol/L (2 mg/dL) and altered ratio of phenylalanine to tyrosine in the untreated state, with normal BH4 cofactor metabolism; and/or the finding of biallelic pathogenic variants in PAH by molecular genetic testing (see Table 1).

Note: (1) It is important that a low phenylalanine diet be initiated prior to receiving the results of the pterins or molecular genetic studies. (2) See Genotype-Phenotype Correlations for information on the clinical utility of a molecular diagnosis.

Molecular testing approaches can include single-gene testing or use of a multi-gene panel.

  • Single-gene testing. Sequence analysis of PAH is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
    Targeted analysis for common pan ethnic pathogenic variants (see Table 2), as well as targeted analysis for founder pathogenic variants, may be performed. Note that founder variants in specific populations may be the same as those found in pan ethnic populations. For a full review of PAH pathogenic variant frequency, see the Phenylalanine Hydroxylase Knowledgebase.
  • A multi-gene panel that includes PAH and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included in the panel and the diagnostic sensitivity of the testing used for each gene varies by laboratory and over time.

Table 1.

Molecular Genetic Testing Used in Phenylalanine Hydroxylase Deficiency

Gene 1Test MethodProportion of Probands with Pathogenic Variants 2 Detectable by This Method
PAHSequence analysis 397%-99%
Gene-targeted deletion/duplication analysis 4<1%-3% 5
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.

This technique has been used to detect abnormal dosage in 20% of uncharacterized PKU alleles [Gable et al 2003] and therefore duplications and deletions may account for up to 3% of pathogenic variants in the Czech population [Kozak et al 2006].

Enzyme analysis is not usually indicated in the diagnosis of PAH deficiency because PAH is a hepatic enzyme and accurate, less invasive methods of diagnosis are available.

Test characteristics. See Clinical Utility Gene Card: Phenylketonuria [Zschocke et al 2012] for information on test characteristics including sensitivity and specificity.

Clinical Characteristics

Clinical Description

Phenylalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders [Vockley et al 2014]. Many terms have been used to describe the various clinical phenotypes that result from PAH deficiency (see Nomenclature). This GeneReview will follow the American College of Medical Genetics and Genomics (ACMGG) recommended convention.

The risk of adverse outcome varies based on the degree of PAH deficiency. Without effective therapy, most individuals with severe PAH deficiency, known as classic PKU, develop profound and irreversible intellectual disability. Affected individuals on an unrestricted diet who have phenylalanine levels above normal but below 1200 μmol/L (20 mg/dL) are at much lower risk for impaired cognitive development in the absence of treatment. However, current understanding of these issues is not complete.

Untreated Individuals with Persistent Severe Hyperphenylalaninemia (i.e., Classic PKU)

Affected individuals almost always show impaired brain development. Signs and symptoms include nearly invariable severe intellectual disability and behavior problems with a high frequency of seizures and variable microcephaly.

The excretion of excessive phenylalanine and its metabolites can create a musty body odor and skin conditions such as eczema.

The associated inhibition of tyrosinase and low tyrosine levels are responsible for decreased skin and hair pigmentation.

Affected individuals also have decreased myelin formation, leading eventually to white matter changes on head MRI.

Significantly elevated Phe levels decrease dopamine, norepinephrine, and serotonin production and can be reflected in electroencephalographic changes, which are reversible if the Phe level is reduced.

Individuals with Classic PKU Identified and Treated from Birth

Intelligence. The correlation between early elevated Phe levels and long-term decreases in IQ has been well studied. The benefit of normalized Phe levels on IQ throughout life has also been shown in studies of affected adults.

Neuropsychological issues. In treated individuals, certain psychological problems are increased – as compared to unaffected sibs or children with other chronic diseases [Brumm et al 2010, Bilder et al 2013].

  • Adults who have increased Phe levels typically due to relaxed Phe-restricted diet tend to have a reduced attention span, slow information-processing abilities, and slow motor reaction time [Channon et al 2007, Moyle et al 2007]. These findings appear to be related to both current and historic phenylalanine levels [Huijbregts et al 2002, Fonnesbeck et al 2013].
  • There is also a higher incidence of anxiety, depression, phobias, and panic attacks in early-treated individuals who discontinued therapy in the second decade of life [Koch et al 2002].

Neurologic. Early-treated adults who discontinue diet are also at risk for minor neurologic abnormalities such as tremor and brisk reflexes [Pietz et al 1998] and, in some cases, more severe neurologic dysfunction, including paralysis. Return to diet often resolves these neurologic symptoms [Camp et al 2014].

PAH with Milder Biochemical and Clinical Phenotypes

Individuals with PAH deficiency and plasma Phe between 600 and 1200 μmol/L (10-20 mg/dL) on an unrestricted diet have not been extensively studied. However, it is well documented that individuals with classic PKU who have levels in this range have both acute and chronic neuropsychological problems. Therefore, treatment with a Phe-restricted diet is recommended for individuals with Phe levels in this range.

Individuals with PAH deficiency who have plasma Phe concentrations consistently below 600 µmol/L (10 mg/dL) on an unrestricted diet are considered by many experts not to be at higher risk of developing intellectual, neurologic, and neuropsychological impairment than are individuals without PAH deficiency. However, since evidence suggests that individuals with classic PKU have demonstrable neurophysiologic changes when Phe levels are between 360 and 600 μmol/L (6 to 10 mg/dL), other experts recommend Phe restriction for any individual who has Phe levels >360 μmol/L (6 mg/dL) on an unrestricted diet. A very small number of programs begin therapy for individuals with Phe levels >240 μmol/L (4 mg/dL). As Phe is an essential amino acid, having inadequate phenylalanine leads to growth restriction, microcephaly and developmental problems. The safety of dietary restriction of Phe for individuals with the milder PAH deficiency has not been systematically studied. Practices vary around the world [Blau et al 2010].

In a few case reports untreated individuals with mild PAH deficiency who had normal intelligence were diagnosed in adulthood as a result of sudden and severe psychiatric deterioration [Weglage et al 2000, Camp et al 2014].

Other

Osteopenia. While numerous studies indicate that individuals with PAH deficiency have a high incidence of osteopenia (as measured by DEXA) [Zeman et al 1999, Pérez-Dueñas et al 2002, Modan-Moses et al 2007], a recent meta-analysis showed that the combined data does not support a high risk based on World Health Organization and International Society for Clinical Densitometry measurement guidelines [Demirdas et al 2015]. Studies to explore the mechanism of low bone density and clinical significance are underway. Until additional studies are performed, it is important to continue to closely monitor the bone health of individuals with PAH deficiency. A recent study of individuals with PAH deficiency by Coakley et al [2016] identified risk factors for lower Z-scores, with the highest significance for dietary prescription compliance in an adult population.

Vitamin B12 deficiency can occur when individuals with PKU relax their diet in adolescence [Robinson et al 2000]. This vitamin is found in natural animal protein; when affected individuals decrease their amino acid supplementation, they often still choose low-protein foods and are therefore at risk for vitamin B12 deficiency.

Children Born to Women with PAH Deficiency

The abnormalities that result from exposure of a fetus to high maternal plasma Phe concentration are the result of maternal PAH deficiency. Risks include the following [Vockley et al 2014]:

  • Intellectual disability (>90%).The threshold for this finding is a maternal Phe concentration consistently above 360 µmol/L during pregnancy with an inverse relationship between cognitive function and maternal Phe level above 360 µmol/L.
  • Poor behavioral outcomes
  • Microcephaly. The risk is 5%-18% in pregnancies in which the maternal Phe level is optimized prior to ten weeks’ gestation and increases to 67% if appropriate Phe levels are not achieved by 30 weeks’ gestation.
  • Congenital heart defect and other malformations. Due to the early formation of the heart, consistently elevated maternal Phe concentrations (>600 µmol/L) during early gestation leads to an approximately 8%-12% risk of cardiac malformations. Minor dysmorphic features and other birth defects have also been reported in infants born to women with maternal PKU, including tracheoesophageal fistula.
  • Intrauterine growth restriction (IUGR). Frequency is not different from that in the general population if maternal Phe levels are controlled by week 10 of gestation; the risk of IUGR increases if the Phe concentration is optimized later in pregnancy.

Genotype-Phenotype Correlations

More than 600 pathogenic variants have been described in PAH (see the Phenylalanine Hydroxylase Knowledgebase). While both genetic (particular pathogenic variant) and environmental (dietary consumption) components contribute to an affected individual’s total plasma Phe level, knowledge of the specific genetic cause can offer insight helpful for long-term management [Zschocke & Hoffmann 2000, National Institutes of Health Consensus Development Panel 2001, Güttler & Guldberg 2006, Santos et al 2010].

In compound heterozygotes with functional hemizygosity (null/missense paired alleles), the less severe of the two PAH pathogenic variants determines disease severity. However, when two pathogenic variants associated with similar severity are present, the phenotype may be milder than predicted by either allele [Kayaalp et al 1997, Guldberg et al 1998, Waters et al 1998].

In general, affected individuals with milder PAH pathogenic variants have a better response to sapropterin (B6BH4, Kuvan™) (see Management). The current guidelines recommend that all affected individuals (except those with two pathogenic null variants in trans) be offered a trial with sapropterin (B6BH4, Kuvan™) because of the difficulty of predicting the phenotype from the genotype [Vockley et al 2014]. See Molecular Genetics for more information on common pathogenic variants in PAH and their reported responsiveness to sapropterin therapy.

Table 2.

Common Pathogenic Changes in PAH and Their Responsiveness to Sapropterin

cDNAProteinCases in PAHdbResponsive to Sapropterin
c.1222C>Tp.Arg408Trp6.7%<10%
c.1066-11G>A
(IVS10-11G>A)
5.3%<10%
c.194T>Cp.Ile65Thr4.1%89%
c.782G>Ap.Arg261Gln3.6%78%
c.842C>Tp.Pro281Leu2.9%None [Leuders et al 2014, biopku​.org]
c.1315+1G>A
(IVS12+1G>A)
2.8%12.5% [biopku​.org]
None [Leuders et al 2014]
c.473G>AArg158Gln2.7%<10%

Data obtained from: PAHdb accessed 5/8/2016 (www​.biopku.org); and Leuders et al [2014]. All changes with >2.5% frequency in the PAHdb database were included. In database searches, homozygosity was assumed for calculations; however, this is a rare finding in consanguineous individuals. It is recommended that all affected individuals be tested for personal responsiveness. Genetic changes shown affect >2.5% of the database population. See www​.biopku.org for the most up-to-date information and additional references.

However, genotype-phenotype correlation becomes more complex when clinical outcomes are also taken into account. While DiSilvestre et al [1991] found that genotype does predict biochemical phenotype (i.e., by Phe loading tests), it does not always predict clinical phenotype (i.e., occurrence of intellectual disability). Some untreated individuals with PAH deficiency and biallelic PAH pathogenic variants that usually result in classic PKU have elevated plasma Phe concentration but normal intelligence. In other instances, sibs with the same genotype have different clinical and metabolic phenotypes. While mechanisms that cause dissimilarities in pathogenesis at the level of the brain in spite of comparable plasma Phe concentrations are not fully understood [Scriver & Waters 1999], there is evidence that variation in transport of Phe across the blood-brain barrier is at least one relevant factor [Weglage et al 2002].

Nomenclature

The 2014 American College of Medical Genetics and Genomics guidelines on the diagnosis and management of PAH (PKU) recommends the term “phenylalanine hydroxylase (PAH) deficiency” to describe all affected individuals, in order to best recognize that there is a spectrum of PAH deficiency. The guideline recognizes that the most severe expression of that spectrum will continue to be termed “classic PKU.” They also recognized that other classification schema in historical use suggested the use of the term hyperphenylalaninemia (hyperPhe or HPA) for those who have Phe levels on an unrestricted diet that are above normal but below 1200 μmol/L (20 mg/dL) [Vockley et al 2014].

Alternative Nomenclature Systems

In the early literature there was no universal system of nomenclature; thus, it was necessary to understand how terms were used in a given report to interpret the significance of the observations regarding PAH activity. In response to this difficulty, various systems of nomenclature have been proposed.

Camp et al [2014] provide, as part of an NIH systematic review of PKU, a recommendation for terminology of PAH deficiency (from most to least severe) of “classic PKU,” “moderate PKU,” “mild PKU,” “mild HPA-gray zone,” and “mild HPA-NT (no treatment),” and a table mapping the various terms to the level of blood Phe when untreated, to the dietary tolerance of Phe, and to the observed or expected level of PAH activity. This table of nomenclature will be of particular value to those wishing to understand the relationship between the various historical systems of nomenclature. See Table 2 in Camp et al [2014].

An early classification scheme proposed by Kayaalp et al [1997] was intended to simplify the nomenclature. In this system:

  • Phenylketonuria (PKU) is the most severe of the three types and in an untreated state is associated with plasma Phe concentrations >1000 µmol/L and a dietary Phe tolerance of <500 mg/day. PKU is associated with a high risk of severely impaired cognitive development.
  • Non-PKU hyperphenylalaninemia (non-PKU HPA) is associated with plasma Phe concentrations consistently above normal (i.e., >120 µmol/L) but lower than 1000 µmol/L when an individual is on a normal diet. Individuals with non-PKU HPA are at a much lower risk for impaired cognitive development in the absence of treatment.
  • Variant PKU includes those individuals who do not fit the description for either PKU or non-PKU HPA.

A classification scheme proposed by Guldberg et al [1998] subdivides PAH deficiency into the following four categories:

  • Classic PKU is caused by a complete or near-complete deficiency of PAH activity. Affected individuals tolerate less than 250-350 mg of dietary phenylalanine per day to keep plasma concentration of Phe at a safe level of ≤300 µmol/L (5 mg/dL). Without dietary treatment most individuals develop profound, irreversible intellectual disability.
  • Moderate PKU. Affected individuals tolerate 350-400 mg of dietary phenylalanine per day.
  • Mild PKU. Affected individuals tolerate 400-600 mg of dietary phenylalanine per day.
  • Mild hyperphenylalaninemia (MHP). Affected infants have plasma Phe concentrations <600 µmol/L (10 mg/dL) on a normal diet.

Prevalence

PAH deficiency varies in frequency from more than 1:5,000 (Turkey, Ireland) to approximately 1:10,000 in those of northern European and East Asian origin (lower in Finland and Japan). Classic PKU was once the most common identifiable etiology of severe intellectual disability in institutions for the developmentally disabled in Europe and North America, but since the adoption of universal newborn screening in many countries, symptomatic classic PKU is less frequently seen. The predicted incidence of severe intellectual disability resulting from PKU in screened populations – fewer than one in a million live births – reflects those children not detected by newborn screening. See Table 3.

Table 3.

Prevalence of PAH Deficiency by Population

PopulationPAH Deficiency in Live BirthsCarrier RateReference
Turks1:2,6001/26Ozalp et al [2001]
Irish1:4,5001/33DiLella et al [1986]
Northern European origin, East Asian1:10,0001/50Scriver & Kaufman [2001]
Japanese1:143,0001/200Aoki & Wada [1988]
Finnish, Ashkenazi Jewish1:200,0001/225Scriver & Kaufman [2001]

Click here (pdf) for a historical perspective.

Differential Diagnosis

Tetrahydrobiopterin (BH4) deficiency. Hyperphenylalaninemia may also result from the impaired synthesis or recycling of tetrahydrobiopterin (BH4), the cofactor in the phenylalanine, tyrosine, and tryptophan hydroxylation reactions. All of the HPAs caused by BH4 deficiency are inherited in an autosomal recessive manner. They account for approximately 2% of individuals with elevated Phe levels in most populations. However, for individuals with elevated Phe from populations in which PAH is less common (e.g., Japan), the risk to the affected individual of having a disorder of pterin metabolism is much higher. BH4 is also involved in catecholamine, serotonin, and nitric oxide biosynthesis (see www.biopku.org).

  • Defects in BH4 synthesis result from guanosine triphosphate cyclohydrolase (GTPCH) deficiency (OMIM) caused by biallelic pathogenic variants in GCH1 or from 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) deficiency (OMIM) caused by biallelic pathogenic variants in PTS.
  • Impaired recycling of BH4 is caused by dihydropteridine reductase (DHPR) deficiency (OMIM) caused by biallelic pathogenic variants in QDPR or by pterin-4 acarbinolamine dehydratase (PCBD) deficiency (OMIM) caused by biallelic pathogenic variants in PCBD1.

Vockley et al [2014] emphasize that all neonates with persistent hyperphenylalaninemia must be screened for the BH4 deficiencies. The following tests are best performed in specialized centers. Prenatal diagnosis is possible for all forms of BH4 deficiencies. The following screening tests are essential:

  • Pterins are measured in urine or blood.
  • Erythrocyte dihydropterin reductase should be measured on whole blood spotted on filter paper. A quantitative assay for urinary neopterin and biopterin can confirm results obtained from the filter paper samples. Reference values are available for different age groups.
  • Abnormal pterin levels and ratios should prompt enzyme testing for possible deficiencies of: GTP cyclohydrolase, 1,6-pyruvoyl-tetrahydrobiopterin synthetase, dihydropteridine reductase, or pterin carbinolamine-4α-dehydratase.

The typical (severe) forms of GTPCH, PTPS, and DHPR deficiency have the following variable, but common, findings: intellectual disability, convulsions, disturbance of tone and posture, drowsiness, irritability, abnormal movements, recurrent hyperthermia without infections, hypersalivation, and swallowing difficulties. Microcephaly is common in PTPS and DHPR deficiencies. Plasma phenylalanine concentrations can vary from slightly above normal (>120 µmol/L) to as high as 2500 µmol/L. Mild forms of BH4 deficiency have no clinical signs.

PCD deficiency, sometimes referred to as 'primapterinuria' is associated with benign transient hyperphenylalaninemia.

In principle, BH4 deficiencies are treatable. Treatment requires the normalization of BH4 availability and of blood Phe concentration and restoration of the BH4-dependent hydroxylation of tyrosine and tryptophan. This is achieved by BH4 supplementation along with dietary modification, neurotransmitter precursor replacement therapy, and supplements of folinic acid in DHPR deficiency. The treatment should be initiated early and probably continued for life [Blau et al 2001, Ponzone et al 2006].

More information on the BH4 deficiencies can be found at www.biopku.org.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with phenylalanine hydroxylase (PAH) deficiency, the following evaluations are recommended:

  • Medical biochemical genetics consultation, if not already done, and evaluation by a metabolic dietician able to begin a low Phe, age-appropriate diet
  • Blood phenylalanine concentration and estimation of phenylalanine tolerance [Kayaalp et al 1997, Guldberg et al 1998]. Because the PAH genotype may not always predict phenotype (see Genotype-Phenotype Correlations), the individual's diet should be tailored to the estimated phenylalanine tolerance irrespective of genotype.
  • For individuals diagnosed outside the newborn period, formal developmental, behavioral, neuropsychological, and mental health evaluation

Treatment of Manifestations

Treatment for affected individuals of all ages can be difficult and is enhanced with the teaching and support of an experienced healthcare team consisting of physicians, nutritionists, genetic counselors, social workers, nurses, and psychologists. See ACMG Management Guidelines for PKU.

Treatment of Classic PKU

Restriction of dietary phenylalanine. The generally accepted goal of treatment for individuals with PAH deficiency is normalization of the concentrations of Phe (phenylalanine) and Tyr (tyrosine) in the blood and thus prevention of the cognitive deficits that are attributable to this disorder [Burgard et al 1999].

Genetic Metabolic Dieticians International (GMDI) has PKU Nutrition Management Guidelines that are continually updated.

Any provider managing the diet of an individual with PAH deficiency should use these resources and work closely with a dietician knowledgeable in the care and management of a person with this diagnosis.

Singh et al [2014] provide the following dietary recommendations:

  • Maintain blood Phe between 120 and 360 μmol/L throughout the life span.
  • Monitor blood Phe most frequently during times of increased anabolism: infancy, childhood, and pregnancy. The NIH recommends measurement of blood phenylalanine levels on a weekly basis for the first year of life, on a biweekly basis until age 13 years, and on a monthly basis thereafter [Camp et al 2014]. Care must be taken to avoid long periods of low blood Phe concentration, which is also harmful to brain development and function.
  • Monitor blood Phe consistently, preferably two to three hours after eating.
  • Evaluate individual nutritional needs, ability to adhere to recommendations, and access to treatment options when choosing appropriate interventions (medical food, modified low-protein food, large neutral amino acids [LNAAs], and sapropterin) to achieve blood PHE in the target range.
  • Include breast milk [Vockley et al 2014] and/or infant formula as sources of Phe in the diet of an infant with PAH deficiency.
  • Recommend that medical food be consumed throughout the day for optimal metabolic control.
  • Track Phe intake by any of several methods, including counting milligrams or exchanges of PHE or grams of protein.
  • Maintain blood Tyr in the normal range.
  • Maintain other nutrients and micronutrients at RDA levels, including calcium, vitamin D, iron, and B vitamins. Due to the protein-restricted dietary components, micronutrients found in animal products must be carefully monitored and supplemented, as needed.
  • Provide counseling and education specific to the needs of the individual with PAH deficiency (and/or his/her caregivers) to help maintain appropriate blood Phe throughout the life span.

Sapropterin (Kuvan®). BH4 responsiveness, as determined by a 30% decrease in Phe plasma levels on plasma amino acid analysis, is determined based on response to a pharmacologic dose of BH4 (10-20 mg/kg per day):

  • All affected individuals except those with two trans pathogenic null variants should ideally undergo a trial with sapropterin supplementation. The trial needs to be conducted when Phe levels have been stable and dietary intake can remain unchanged, so that any change in Phe level is the result of the medication; for some affected individuals it is a challenge to conduct a trial of therapy. The most common dose given is 20 mg/kg per day. Lower trial doses may lead to false negative responsiveness results [Vockley et al 2014].
  • Affected individuals who are responsive should continue this medication with compensatory dietary Phe liberalization, as needed, to maintain a safe Phe level between 120 and 360 μmol/L.
  • The majority of individuals with mild or moderate PKU may be responsive to sapropterin while up to 10% of individuals with classic PKU show a response [Bernegger & Blau 2002, Pérez-Dueñas et al 2004, Zurflüh et al 2006]. Reviewed in Ho & Christodoulou [2014].

Click here (pdf) for more information on the proposed mechanism of action of sapropterin.

Large neutral amino acids (LNAA) transporters. LNAA may decrease the plasma Phe concentration in affected adolescents and adults; however, it should not be used in women of child-bearing age (see Pregnancy Management).

Click here (pdf) for more information on the proposed mechanism of action of LNAA

Treatment for Non-Classic Hyperphenylalaninemia

While debate continues, many experts believe that dietary treatment is unnecessary for many of the individuals in this class.

  • Individuals with Phe levels >600 μmol/L (10 mg/dL) are treated by most centers, in recognition of the finding of head MRI changes and neuropsychological findings in at least some affected individuals.
  • Treatment in individuals with Phe levels consistently <600 μmol/L but >360 μmol/L remains controversial [Weglage et al 2001, Hanley 2011, van Spronsen 2011].
    • Thirty-one individuals with PAH deficiency who were never treated and whose plasma Phe concentrations did not exceed 600 µmol/L had normal cognitive neuropsychological development.
    • The American College of Medical Genetics and Genomics guidelines on the diagnosis and management of PAH (PKU) state: “…treatment of infants with sustained blood Phe levels >360 µmol/L is recommended following appropriate review of the controversy with patients.”
  • If the Phe levels remain between 120 and 360 µmol/L, treatment is not recommended; however, children should be followed for plasma Phe levels closely during the first two years of life, then on an annual or biennial basis [Vockley et al 2014].
  • Care should be taken so that women of childbearing age in this group receive proper counseling about the teratogenic effects of elevated maternal plasma Phe concentration (i.e., ‘maternal HPA/PKU’) on the developing fetus [Weglage et al 2001] (see Pregnancy Management).

Other

Neuropsychiatric testing may be considered to identify learning differences. Referral to appropriate developmental services is indicated to optimize developmental outcome.

Bone health assessment. Current literature regarding the utility of DEXA scans is controversial; however, bone health should be considered in the overall health of an affected individual [Coakley et al 2016].

Prevention of Primary Manifestations

See Treatment of Manifestations.

Surveillance

Plasma Phe and Tyr concentrations in individuals with classic PKU must be monitored regularly [National Institutes of Health Consensus Development Panel 2001] (see Treatment of Manifestations).

  • In infants, frequent in-clinic visits are recommended until Phe levels are stabilized, followed by weekly blood level monitoring of Phe and tyrosine levels until age one with closer monitoring during periods of rapid growth or diet transitions. In addition, plasma amino acid levels should be regularly monitored to foster optimal growth during the first year of life.
  • Between ages one and 12 years, biweekly to monthly sampling may be adequate.
  • In adolescents and adults who are stable and well controlled, blood level monitoring can be monthly.

Nutritional assessment should include growth evaluation and assessment of micronutrient intake and needs.

  • Some clinics perform monitoring of plasma amino acids, transthyretin, complete blood count, ferritin, and 25-OH vitamin D every six months in infants and annually thereafter even if growth is appropriate and analysis of the diet shows adequate intake.
  • If there is evidence for suboptimal dietary intake or over-reliance on nutritionally incomplete medical foods, evaluation of plasma amino acids (full panel), transthyretin, albumin, complete blood count, ferritin, 25-OH vitamin D, electrolytes, renal function, liver function, albumin, vitamin B12, red blood cell essential fatty acids, trace minerals (zinc, copper, selenium), vitamin A, and folic acid should be considered [Singh et al 2014, Vockley et al 2014].

Assessment of developmental milestones and overall developmental progress should take place at every visit.

Screening for mental illness should be considered at every visit and performed at regular intervals by primary care providers.

Agents/Circumstances to Avoid

Aspartame, an artificial sweetener in widespread use, contains phenylalanine. Persons with PKU should either avoid products containing aspartame or calculate intake of Phe and adapt diet components accordingly.

Evaluation of Relatives at Risk

It is appropriate to evaluate sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment. Note: Because phenotypic variability may be significant, previously undiagnosed and even apparently asymptomatic sibs of an affected individual may also be affected [Vockley et al 2014].

Evaluations can include:

  • Measurement of blood concentration of phenylalanine and newborn screening in newborn sibs of an individual with PKU if prenatal testing was not done;
  • Molecular genetic testing if the pathogenic variants in the family are known;
  • Blood concentration of phenylalanine and tyrosine to clarify the disease status of older at-risk sibs if the pathogenic variants in the family are not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women with PAH Deficiency

Women with PAH deficiency who have received appropriate treatment throughout childhood and adolescence have normal physical and essentially normal intellectual and behavioral development. However, if the woman has elevated plasma Phe concentrations during pregnancy, the fetus is at high risk for malformations and intellectual disability, since phenylalanine is a potent teratogen (see Clinical Characteristics) [Rouse & Azen 2004, Prick et al 2012].

The American College of Obstetrics and Gynecology Committee Opinion on the Management of Women with Phenylketonuria, the American College of Medical Genetics and Genomics guidelines on the diagnosis and management of PAH deficiency [Vockley et al 2014], and Singh et al [2014] suggest the following management of an affected woman prior to and during pregnancy.

Preconception

  • Genetic counseling regarding the teratogenic effects of elevated maternal Phe concentration on the developing fetus and recurrence risks for PAH deficiency in the fetus
  • Achievement and maintenance of the maternal Phe concentration at less than 360 µmol/L for three months prior to conception
  • Assessment of early osteopenia risk
  • Discontinuation of LNAA treatment

During pregnancy

  • Co-monitor in conjunction with practitioners from an experienced metabolic center.
  • Maternal Phe concentration of 120-360 µmol/L during pregnancy is recommended. In unplanned pregnancies, rapid re-initiation of a Phe-restricted diet should be advised based on current knowledge of the fetal risks.
  • Despite limited data, sapropterin supplementation may be appropriate in addition to dietary therapy.
  • Monitor dietary intake of pregnant women with PAH deficiency to ensure nutrient adequacy with proper proportion of protein, fat, and carbohydrates.
  • Evaluate for fetal anomalies by high resolution ultrasound and fetal echocardiogram.

Post partum

  • Provide coordinated care in the post-partum period
  • Breast feeding may be pursued if the infant does not have PAH deficiency.

Therapies Under Investigation

Although the treatment of PKU with phenylalanine-restricted diets has been hugely successful, the poor palatability of the diet results in poor compliance in adolescence and adulthood. A number of attempts to find other treatment modalities for PKU are ongoing.

Enzyme substitution. Under investigation is the administration of the enzyme phenylalanine ammonia lyase (PAL), a plant-derived enzyme that converts phenylalanine to trans-cinnamic acid and ammonia. The version currently under investigation is the PEGylation (conjugation with polyethylene glycol) of PAL, since it has been found to decrease the immune response to PAL [Gámez et al 2005, Sarkissian & Gámez 2005]. Clinical trials with this protected form of injectable enzyme are currently underway. The results of the Phase I trial showed effectiveness by reducing blood Phe by 54% in the participants receiving the highest dose. The Phe level nadir was at six days and response lasted 21 days. Adverse reactions included rash, antibody accumulation to both PAL and the PEGylation component, and injection site reaction [Longo et al 2014].

Cell-directed therapies. Liver repopulation with PAH-expressing cells is being investigated. Hepatocyte transplantation has been successful in animal models and in humans for other liver-based inborn errors of metabolism, such as glycogen storage disorders and urea cycle defects. Research continues to identify the best ways to allow for transferred hepatocytes to have cell growth advantage over native hepatocytes (reviewed in Strisciuglio & Concolino [2014]).

Gene therapies. Liver-directed gene therapy does not result in a permanent correction of PAH activity in animal models. Delivery to muscle was successful in increasing conversion of Phe to Tyr in mice [Reviewed in Strisciuglio & Concolino 2014].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Phenylalanine hydroxylase (PAH) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one PAH pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

Offspring of a proband

  • Children born of one parent with PAH deficiency and one parent with two normal PAH alleles are obligate heterozygotes.
  • If one parent is affected and the other parent is a carrier, offspring have a 50% chance of being heterozygous and a 50% chance of being affected.
  • If the mother is the affected parent, maternal HPA/PKU is a critical issue (see Clinical Characteristics, Children Born to Women with PAH Deficiency).

Other family members. Each sib of the proband’s unaffected parents is at a 50% risk of being a carrier of a PAH pathogenic variant.

Carrier (Heterozygote) Detection

Molecular genetic testing for at-risk relatives requires prior identification of the PAH pathogenic variants in the family. ACMG guidelines recommend the use of molecular genetic testing to identify carriers in a family with a known PAH pathogenic variant [Vockley et al 2014]. If molecular genetic testing is not possible, biochemical analysis can be used.

Biochemical testing relies on plasma Phe concentration and the Phe/Tyr ratio, with or without phenylanine loading [Freehauf et al 1984, Blitzer et al 1986]. Hormones associated with pregnancy have been shown to alter the Phe/Tyr ratio; thus, biochemical analysis cannot be used to determine carrier status during pregnancy, shortly after pregnancy, or with oral contraceptive use.

Partners of an individual affected with or known to be a carrier of PAH deficiency may be interested in carrier testing. Analysis of PAH can be offered, with appropriate counseling about limits of sensitivity. Guidelines for biochemical carrier testing have not been established; and the predictive value of biochemical testing has been studied on a limited basis only.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • Young women affected with PAH deficiency should receive counseling regarding the teratogenic effects of elevated maternal plasma Phe concentration (i.e., 'maternal HPA/PKU') when they reach childbearing age [Weglage et al 2001] (see Pregnancy Management).
  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the PAH pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk for PAH deficiency and preimplantation genetic diagnosis are possible options.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Prenatal diagnosis has been found by some families to be of value when decisions need to be made prenatally that will affect care of their child. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Phenylalanine Hydroxylase Deficiency: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Phenylalanine Hydroxylase Deficiency (View All in OMIM)

261600PHENYLKETONURIA; PKU
612349PHENYLALANINE HYDROXYLASE; PAH

Gene structure. PAH contains 13 exons and spans 90 kb (PAHdb); the genomic sequence is known to code for a 2.6-kb mature messenger RNA. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. More than 600 different pathogenic variants in PAH have been identified to date; see Table A, PAH Locus Knowledgebase and HGMD. The PAH Locus Knowledgebase provides information on pathogenic variants, associated phenotypes, gene structure, enzyme structure, clinical guidance, and much more [Scriver et al 2003]. The majority of pathogenic variants in PAH are missense, nonsense, frameshift, and splice variants (PAHdb). Large deletions account for fewer than 1% of disease alleles in most populations, but accounted for 3% of disease alleles in the Czech population [Kozak et al 2006].

Table 4.

PAH Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias) 1
Predicted Protein ChangeReference Sequences
c.194T>Cp.Ile65ThrNM_000277​.1
NP_000268​.1
c.473G>AArg158Gln
c.782G>Ap.Arg261Gln
c.842C>Tp.Pro281Leu
c.1066-11G>A
(IVS10-11G>A)
c.1222C>Tp.Arg408Trp
c.1315+1G>A
(IVS12+1G>A)

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

See www​.pahdb.mcgill.ca and biopku​.org for gene lists and databases.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. The normal product of PAH is the protein phenylalanine hydroxylase (PAH), containing 452 amino acids (NP_000268.1). PAH enzymes can exist as tetramers and dimers in equilibrium [Hufton et al 1998]. The PAH enzyme hydroxylates phenylalanine to tyrosine, this reaction being the rate-limiting step in the major pathway by which phenylalanine is catabolized to CO2 and water [Scriver & Kaufman 2001].

Abnormal gene product. The pathogenic variants that confer the most severe phenotypes are known or predicted to completely abolish PAH activity. These ‘null’ variants are of various types. Missense pathogenic variants usually permit the enzyme to retain some degree of residual activity; however, it is difficult to assess severity in vivo because the in vivo activity is not the simple equivalent of the in vitro enzymatic phenotype [Waters et al 1998, Gjetting et al 2001].

References

Published Guidelines/Consensus Statements

  1. Canadian Task Force on the Preventive Health Care. Screening for phenylketonuria. Available online. 1994. Accessed 10-12-16.
  2. Committee on Genetics. Management of woman with phenylketonuria. American College of Obstetricians and Gynecologists Committee Opinion June 2015. Number 636. Available online. 2015. Accessed 10-11-16.
  3. Singh RH, Rohr F, Frazier D, Cunningham A, Mofidi S, Ogata B, Splett PL, Moseley K, Huntington K, Acosta PB, Vockley J, Van Calcar SC. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genet Med. 2014;16:121–31. [PMC free article: PMC3918542] [PubMed: 24385075]
  4. US Preventive Services Task Force. Screening for phenylketonuria (PKU). Available online. 2008. Accessed 10-11-16.
  5. Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA; American College of Medical Genetics and Genomics Therapeutics Committee. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Available online. 2014. Accessed 10-13-16.

Literature Cited

  1. Anderson PJ, Leuzzi V. White matter pathology in phenylketonuria. Mol Genet Metab. 2010;99 Suppl 1:S3–9. [PubMed: 20123467]
  2. Antshel KM. ADHD, learning, and academic performance in phenylketonuria. Mol Genet Metab. 2010;99 Suppl 1:S52–8. [PubMed: 20123471]
  3. Aoki K, Wada Y. Outcome of the patients detected by newborn screening in Japan. Acta Paediatr Jpn. 1988;30:429–34. [PubMed: 3150232]
  4. Bernegger C, Blau N. High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: a study of 1,919 patients observed from 1988 to 2002. Mol Genet Metab. 2002;77:304–13. [PubMed: 12468276]
  5. Bilder DA, Burton BK, Coon H, Leviton L, Ashworth J, Lundy BD, Vespa H, Bakian AV, Longo N. Psychiatric symptoms in adults with phenylketonuria. Mol Genet Metab. 2013;108:155–60. [PubMed: 23339767]
  6. Blau N, Bélanger-Quintana A, Demirkol M, Feillet F, Giovannini M, MacDonald A, Trefz FK, van Spronsen F. European PKU centers. Management of phenylketonuria in Europe: survey results from 19 countries. Mol Genet Metab. 2010;99:109–15. [PubMed: 19800826]
  7. Blau N, Thöny B, Cotton RGH, Hyland K. Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR, Kaufman S, Eisensmith E, Woo SLC, Vogelstein B, Childs B, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York: McGraw Hill; 2001:1725-76.
  8. Blitzer MG, Bailey-Wilson JE, Shapira E. Discrimination of heterozygotes for phenylketonuria, persistent hyperphenylalaninemia and controls by phenylalanine loading. Clin Chim Acta. 1986;161:347–52. [PubMed: 3802540]
  9. Brumm VL, Bilder D, Waisbren SE. Psychiatric symptoms and disorders in phenylketonuria. Mol Genet Metab. 2010;99 Suppl 1:S59–63. [PubMed: 20123472]
  10. Brumm VL, Grant ML. The role of intelligence in phenylketonuria: a review of research and management. Mol Genet Metab. 2010;99 Suppl 1:S18–21. [PubMed: 20123465]
  11. Burgard P, Bremer HJ, Bührdel P, Clemens PC, Mönch E, Przyrembel H, Trefz FK, Ullrich K. Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997. Eur J Pediatr. 1999;158:46–54. [PubMed: 9950308]
  12. Burton BK, Leviton L, Vespa H, Coon H, Longo N, Lundy BD, Johnson M, Angelino A, Hamosh A, Bilder D. A diversified approach for PKU treatment: Routine screening yields high incidence of psychiatric distress in phenylketonuria clinics. Mol Genet Metab. 2013;108:8–12. [PubMed: 23266195]
  13. Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, Bodamer OA, Brosco JP, Brown CS, Burlina AB, Burton BK, Chang CS, Coates PM, Cunningham AC, Dobrowolski SF, Ferguson JH, Franklin TD, Frazier DM, Grange DK, Greene CL, Groft SC, Harding CO, Howell RR, Huntington KL, Hyatt-Knorr HD, Jevaji IP, Levy HL, Lichter-Konecki U, Lindegren ML, Lloyd-Puryear MA, Matalon K, MacDonald A, McPheeters ML, Mitchell JJ, Mofidi S, Moseley KD, Mueller CM, Mulberg AE, Nerurkar LS, Ogata BN, Pariser AR, Prasad S, Pridjian G, Rasmussen SA, Reddy UM, Rohr FJ, Singh RH, Sirrs SM, Stremer SE, Tagle DA, Thompson SM, Urv TK, Utz JR, van Spronsen F, Vockley J, Waisbren SE, Weglicki LS, White DA, Whitley CB, Wilfond BS, Yannicelli S, Young JM. Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol Genet Metab. 2014;112:87–122. [PubMed: 24667081]
  14. Channon S, Goodman G, Zlotowitz S, Mockler C, Lee PJ. Effects of dietary management of phenylketonuria on long-term cognitive outcome. Arch Dis Child. 2007;92:213–8. [PMC free article: PMC2083434] [PubMed: 17068073]
  15. Coakley KE, Douglas TD, Goodman M, Ramakrishnan U, Dobrowolski SF, Singh RH. Modeling correlates of low bone mineral density in patients with phenylalanine hydroxylase deficiency. J Inherit Metab Dis. 2016;39:363–72. [PubMed: 26883219]
  16. Demirdas S, Coakley KE, Bisshop PH, Hollak CE, Bosch AM, Singh RH. Bone health in phenylketonuria: a systematic review and meta-analysis. Orphanet J Rare Dis. 2015;10:17. [PMC free article: PMC4340652] [PubMed: 25758373]
  17. DiLella AG, Kwok SC, Ledley FD, Marvit J, Woo SL. Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene. Biochemistry. 1986;25:743–9. [PubMed: 3008810]
  18. DiSilvestre D, Koch R, Groffen J. Different clinical manifestations of hyperphenylalaninemia in three siblings with identical phenylalanine hydroxylase genes. Am J Hum Genet. 1991;48:1014–6. [PMC free article: PMC1683043] [PubMed: 2018035]
  19. Fonnesbeck CJ, McPheeters ML, Krishnaswami S, Lindegren ML, Reimschisel T. Estimating the probability of IQ impairment from blood phenylalanine for phenylketonuria patients: a hierarchical meta-analysis. J Inherit Metab Dis. 2013;36:757–66. [PubMed: 23197105]
  20. Freehauf CL, Lezotte D, Goodman SI, McCabe ER. Carrier screening for phenylketonuria: comparison of two discriminant analysis procedures. Am J Hum Genet. 1984;36:1180–9. [PMC free article: PMC1684636] [PubMed: 6517048]
  21. Gable M, Williams M, Stephenson A, Okano Y, Ring S, Hurtubise M, Tyfield L. Comparative multiplex dosage analysis detects whole exon deletions at the phenylalanine hydroxylase locus. Hum Mutat. 2003;21:379–86. [PubMed: 12655547]
  22. Gámez A, Sarkissian CN, Wang L, Kim W, Straub M, Patch MG, Chen L, Striepeke S, Fitzpatrick P, Lemontt JF, O'Neill C, Scriver CR, Stevens RC. Development of pegylated forms of recombinant Rhodosporidium toruloides phenylalanine ammonia-lyase for the treatment of classical phenylketonuria. Mol Ther. 2005;11:986–9. [PubMed: 15922970]
  23. Gjetting T, Petersen M, Guldberg P, Güttler F. In vitro expression of 34 naturally occurring mutant variants of phenylalanine hydroxylase: correlation with metabolic phenotypes and susceptibility toward protein aggregation. Mol Genet Metab. 2001;72:132–43. [PubMed: 11161839]
  24. Guldberg P, Rey F, Zschocke J, Romano V, François B, Michiels L, Ullrich K, Hoffmann GF, Burgard P, Schmidt H, Meli C, Riva E, Dianzani I, Ponzone A, Rey J, Güttler F. A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. Am J Hum Genet. 1998;63:71–9. [PMC free article: PMC1377241] [PubMed: 9634518]
  25. Güttler F, Guldberg P. Genotype/phenotype correlations in phenylalanine hydroxylase deficiency. In: Blau N, ed. PKU and BH4 – Advances in Phenylketonuria and Tetrahydrobiopterin. Heilbronn, Germany: SPS Verlagsgesellschaft; 2006:211-320.
  26. Hanley WB. Non-PKU mild hyperphenylalaninemia (MHP)--the dilemma. Mol Genet Metab. 2011;104:23–6. [PubMed: 21632269]
  27. Ho G, Christodoulou J. Phenylketonuria: translating research into novel therapies. Transl Pediatr. 2014;3:49–62. [PMC free article: PMC4729111] [PubMed: 26835324]
  28. Hufton SE, Jennings IG, Cotton RG. Structure/function analysis of the domains required for the multimerisation of phenylalanine hydroxylase. Biochim Biophys Acta. 1998;1382:295–304. [PubMed: 9540801]
  29. Huijbregts SC, de Sonneville LM, Licht R, van Spronsen FJ, Sergeant JA. Short-term dietary interventions in children and adolescents with treated phenylketonuria: effects on neuropsychological outcome of a well-controlled population. J Inherit Metab Dis. 2002;25:419–30. [PubMed: 12555935]
  30. Jahja R, van Spronsen FJ, de Sonneville LM, van der Meere JJ, Bosch AM, Hollak CE, Rubio-Gozalbo ME, Brouwers MC, Hofstede FC, de Vries MC, Janssen MC, van der Ploeg AT, Langendonk JG, Huijbregts SC. Social-cognitive functioning and social skills in patients with early treated phenylketonuria: a PKU-COBESO study. J Inherit Metab Dis. 2016;39:355–62. [PMC free article: PMC4851698] [PubMed: 26914933]
  31. Kayaalp E, Treacy E, Waters PJ, Byck S, Nowacki P, Scriver CR. Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype-phenotype correlations. Am J Hum Genet. 1997;61:1309–17. [PMC free article: PMC1716084] [PubMed: 9399896]
  32. Koch R, Burton B, Hoganson G, Peterson R, Rhead W, Rouse B, Scott R, Wolff J, Stern AM, Güttler F, Nelson M, de la Cruz F, Coldwell J, Erbe R, Geraghty MT, Shear C, Thomas J, Azen C. Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis. 2002;25:333–46. [PubMed: 12408183]
  33. Kozak L, Hrabincova E, Kintr J, Horky O, Zapletalova P, Blahakova I, Mejstrik P, Prochazkova D. Identification and characterization of large deletions in the phenylalanine hydroxylase (PAH) gene by MLPA: evidence for both homologous and non-homologous mechanisms of rearrangement. Mol Genet Metab. 2006;89:300–9. [PubMed: 16931086]
  34. Leuders S, Wolfgart E, Ott T, du Moulin M, van Teeffelen-Heithoff A, Vogelpohl L, Och U, Marquardt T, Weglage J, Feldmann R, Rutsch F. Influence of PAH Genotype on Sapropterin Response in PKU: Results of a Single-Center Cohort Study. JIMD Rep. 2014;13:101–9. [PMC free article: PMC4110336] [PubMed: 24190797]
  35. Longo N, Harding CO, Burton BK, Grange DK, Vockley J, Wasserstein M, Rice GM, Dorenbaum A, Neuenburg JK, Musson DG, Gu Z, Sile S. Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial. Lancet. 2014;384:37–44. [PMC free article: PMC4447208] [PubMed: 24743000]
  36. Modan-Moses D, Vered I, Schwartz G, Anikster Y, Abraham S, Segev R, Efrati O. Peak bone mass in patients with phenylketonuria. J Inherit Metab Dis. 2007;30:202–8. [PubMed: 17347917]
  37. Moyle JJ, Fox AM, Arthur M, Bynevelt M, Burnett JR. Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU. Neuropsychol Rev. 2007;17:91–101. [PubMed: 17410469]
  38. National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 16-18, 2000. Pediatrics. 2001;108:972–82. [PubMed: 11581453]
  39. Ozalp I, Coskun T, Tokatli A, Kalkanoglu HS, Dursun A, Tokol S, Koksal G, Ozguc M, Kose R. Newborn PKU screening in Turkey: at present and organization for future. Turk J Pediatr. 2001;43:97–101. [PubMed: 11432505]
  40. Pérez-Dueñas B, Cambra FJ, Vilaseca MA, Lambruschini N, Campistol J, Camacho JA. New approach to osteopenia in phenylketonuric patients. Acta Paediatr. 2002;91:899–904. [PubMed: 12222712]
  41. Pérez-Dueñas B, Vilaseca MA, Mas A, Lambruschini N, Artuch R, Gómez L, Pineda J, Gutiérrez A, Mila M, Campistol J. Tetrahydrobiopterin responsiveness in patients with phenylketonuria. Clin Biochem. 2004;37:1083–90. [PubMed: 15589814]
  42. Pietz J, Dunckelmann R, Rupp A, Rating D, Meinck HM, Schmidt H, Bremer HJ. Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr. 1998;157:824–30. [PubMed: 9809823]
  43. Ponzone A, Ferraris S, Baglieri S, Spada M. Treatment of tetrahydrobiopterin deficiencies. In: Blau N, eds. PKU and BH4 Advances in Phenylketonuria and Tetrahydrobiopterin. Heilbronn, Germany: SPS Verlagsgesellschaft; 2006:612-37.
  44. Prick BW, Hop WC, Duvekot JJ. Maternal phenylketonuria and hyperphenylalaninemia in pregnancy: pregnancy complications and neonatal sequelae in untreated and treated pregnancies. Am J Clin Nutr. 2012;95:374–82. [PubMed: 22205310]
  45. Robinson M, White FJ, Cleary MA, Wraith E, Lam WK, Walter JH. Increased risk of vitamin B12 deficiency in patients with phenylketonuria on an unrestricted or relaxed diet. J Pediatr. 2000;136:545–7. [PubMed: 10753257]
  46. Rouse B, Azen C. Effect of high maternal blood phenylalanine on offspring congenital anomalies and developmental outcome at ages 4 and 6 years: the importance of strict dietary control preconception and throughout pregnancy. J Pediatr. 2004;144:235–9. [PubMed: 14760268]
  47. Santos LL, Fonseca CG, Starling AL, Januário JN, Aguiar MJ, Peixoto MG, Carvalho MR. Variations in genotype-phenotype correlations in phenylketonuria patients. Genet Mol Res. 2010;9:1–8. [PubMed: 20082265]
  48. Sarkissian CN, Gámez A. Phenylalanine ammonia lyase, enzyme substitution therapy for phenylketonuria, where are we now? Mol Genet Metab. 2005;86 Suppl 1:S22–6. [PubMed: 16165390]
  49. Scriver CR, Hurtubise M, Konecki D, Phommarinh M, Prevost L, Erlandsen H, Stevens R, Waters PJ, Ryan S, McDonald D, Sarkissian C. PAHdb 2003: what a locus-specific knowledgebase can do. Hum Mutat. 2003;21:333–44. [PubMed: 12655543]
  50. Scriver CR, Kaufman S. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly SW, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York, NY: McGraw-Hill; 2001:1667-724.
  51. Scriver CR, Waters PJ. Monogenic traits are not simple: lessons from phenylketonuria. Trends Genet. 1999;15:267–72. [PubMed: 10390625]
  52. Strisciuglio P, Concolino D. New strategies for the treatment of phenylketonuria (PKU). Metabolites. 2014;4:1007–17. [PMC free article: PMC4279156] [PubMed: 25375236]
  53. van Spronsen FJ. Mild hyperphenylalaninemia: to treat or not to treat. J Inherit Metab Dis. 2011;34:651–6. [PMC free article: PMC3183992] [PubMed: 21347590]
  54. Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014:188–200. [PubMed: 24385074]
  55. Waisbren SE, Noel K, Fahrbach K, Cella C, Frame D, Dorenbaum A, Levy H. Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab. 2007;92:63–70. [PubMed: 17591452]
  56. Waters PJ, Parniak MA, Nowacki P, Scriver CR. In vitro expression analysis of mutations in phenylalanine hydroxylase: linking genotype to phenotype and structure to function. Hum Mutat. 1998;11:4–17. [PubMed: 9450897]
  57. Weglage J, Oberwittler C, Marquardt T, Schellscheidt J, von Teeffelen-Heithoff A, Koch G, Gerding H. Neurological deterioration in adult phenylketonuria. J Inherit Metab Dis. 2000;23:83–4. [PubMed: 10682311]
  58. Weglage J, Pietsch M, Feldmann R, Koch HG, Zschocke J, Hoffmann G, Muntau-Heger A, Denecke J, Guldberg P, Güttler F, Möller H, Wendel U, Ullrich K, Harms E. Normal clinical outcome in untreated subjects with mild hyperphenylalaninemia. Pediatr Res. 2001;49:532–6. [PubMed: 11264437]
  59. Weglage J, Wiedermann D, Denecke J, Feldmann R, Koch HG, Ullrich K, Möller HE. Individual blood-brain barrier phenylalanine transport in siblings with classical phenylketonuria. J Inherit Metab Dis. 2002;25:431–6. [PubMed: 12555936]
  60. Zeman J, Bayer M, Stepán J. Bone mineral density in patients with phenylketonuria. Acta Paediatr. 1999;88:1348–51. [PubMed: 10626520]
  61. Zschocke J, Haverkamp T, Møller LB. Clinical utility gene card for: Phenylketonuria. Eur J Hum Genet. 2012;20(2) [PMC free article: PMC3260912] [PubMed: 21915151]
  62. Zschocke J, Hoffmann GF. PAH gene mutation analysis in clinical practice--comments on mutation analysis anticipates dietary requirements in phenylketonuria. Eur J Pediatr. 2000;159 Suppl 2:S154–5. [PubMed: 11043163]
  63. Zurflüh MR, Fiori L, Fiege B, Ozen I, Demirkol M, Gärtner KH, Thöny B, Giovannini M, Blau N. Pharmacokinetics of orally administered tetrahydrobiopterin in patients with phenylalanine hydroxylase deficiency. J Inherit Metab Dis. 2006;29:725–31. [PubMed: 17091341]

Suggested Reading

  1. Berry SA, Brown C, Grant M, Greene CL, Jurecki E, Koch J, Moseley K, Suter R, van Calcar SC, Wiles J, Cederbaum S. Newborn screening 50 years later: access issues faced by adults with PKU. Genet Med. 2013;15:591–9. [PMC free article: PMC3938172] [PubMed: 23470838]
  2. Brosco JP, Paul DB. The political history of PKU: reflections on 50 years of newborn screening. Pediatrics. 2013;132:987–9. [PMC free article: PMC3838532] [PubMed: 24276841]
  3. Groselj U, Tansek MZ, Battelino T. Fifty years of phenylketonuria newborn screening - A great success for many, but what about the rest? Mol Genet Metab. 2014;113:8–10. [PubMed: 25174964]
  4. Matern D, Greene CL. Newborn screening for inborn errors of metabolism. In: Thöny B, Duran M, Gibson KM, Dionisi-Visi C, eds. Physician’s guide to the Diagnosis, Treatment, and Follow-up of Metabolic Diseases. Springer; 2014:719-35.
  5. Pollitt RJ. Commentary: What degree of hyperphenylalaninemia requires treatment? J Inherit Metab Dis. 2012;35:927–30. [PubMed: 22718276]

Chapter Notes

Author History

Carol L Greene, MD, FAAP, FACMG (2016-present)
John J Mitchell, MD; McGill University, Montreal (2005-2016)
Debra S Regier, MD, PhD, FAAP, FACMG (2016-present)
Shannon Ryan, MSc; Montreal Children's Hospital (2000-2005)
Charles R Scriver, MD; Montreal Children’s Hospital (2000-2013)

Revision History

  • 20 October 2016 (ma) Comprehensive update posted live
  • 31 January 2013 (me) Comprehensive update posted live
  • 4 May 2010 (me) Comprehensive update posted live
  • 29 March 2007 (me) Comprehensive update posted to live Web site
  • 19 July 2005 (jm) Revision: duplication/deletion testing clinically available
  • 8 July 2004 (me) Comprehensive update posted to live Web site
  • 13 August 2002 (me) Comprehensive update posted to live Web site
  • 10 January 2000 (me) Review posted to live Web site
  • 16 July 1999 (sr) Original submission
Copyright © 1993-2016, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2016 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1504PMID: 20301677

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...