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Phenylalanine Hydroxylase Deficiency

Synonym: PAH Deficiency
, MD
Department of Pediatrics
Division of Endocrinology and Metabolism
McGill University
Montreal, Quebec

Initial Posting: ; Last Update: January 31, 2013.


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 including phenylketonuria (PKU), non-PKU hyperphenylalaninemia (non-PKU HPA), and variant PKU. Classic PKU is caused by a complete or near-complete deficiency of phenylalanine hydroxylase activity; without dietary restriction of phenylalanine, most children with PKU develop profound and irreversible intellectual disability. Non-PKU HPA is associated with a much lower risk of impaired cognitive development in the absence of treatment.


PAH deficiency can be diagnosed by newborn screening in virtually 100% of cases based on detection of the presence of hyperphenylalaninemia using the Guthrie microbial or other assays on a blood spot obtained from a heel prick. PKU is diagnosed in individuals with plasma phenylalanine (Phe) concentrations higher than 1000 µmol/L in the untreated state; non-PKU HPA is diagnosed in individuals with plasma Phe concentrations consistently above normal (i.e., >120 µmol/L), but lower than 1000 µmol/L when on a normal diet. Molecular genetic testing of PAH is used primarily for genetic counseling purposes to determine carrier status of at-risk relatives and for prenatal testing.


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 significant proportion of individuals with PKU may benefit from adjuvant therapy with 6R-BH4 stereoisomer. Non-PKU HPA: It is debated whether those with plasma Phe concentrations consistently below 600 µmol/L (10 mg/dL) require dietary treatment.

Prevention of primary manifestations: Same as Treatment of manifestations.

Surveillance: Regular monitoring of plasma Phe and Tyr concentrations in individuals with classic PKU.

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

Evaluation of relatives at risk: Newborn sibs of an individual with PKU 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: 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.

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 pathogenic variants have been identified in an affected family member.

GeneReview Scope

Phenylalanine Hydroxylase Deficiency: Included Phenotypes
  • Phenylketonuria (PKU)
  • Hyperphenylalaninemia (HPA)
  • Variant PKU


Clinical Diagnosis

Neonates with phenylalanine hydroxylase (PAH) deficiency show no physical signs of hyperphenylalaninemia (HPA).

When untreated, older children can show the following clinical manifestations: microcephaly, epilepsy, a musty body odor, decreased skin and hair pigmentation, eczema, severe intellectual disability, and behavior problems, as well as structural brain changes visible on MRI.


The main route for phenylalanine metabolism is hydroxylation of phenylalanine to tyrosine by phenylalanine hydroxylase (PAH).

Biochemical testing. The diagnosis of primary phenylalanine hydroxylase deficiency (PAH deficiency) is based on:

  • An elevated plasma phenylalanine (Phe) concentration, most commonly identified by quantitative plasma amino acid analysis. Individuals with PAH deficiency show plasma phenylalanine (Phe) concentrations that are persistently higher than 120 µmol/L (2 mg/dL) in the untreated state [Scriver & Kaufman 2001, Donlon et al 2014].
  • Evidence of normal BH4 (tetrahydrobiopterin) cofactor metabolism, which can be confirmed by urine pterin studies by liquid chromatography and dihydropterin reductase measurement. Some centers also use a neonatal BH4 load to evaluate for BH4 metabolism disorders.

Note: Enzyme analysis is not usually indicated because PAH is a hepatic enzyme.

For the nomenclature used to describe PAH deficiency, see Clinical Description.

PAH deficiency is most frequently diagnosed through newborn screening programs using dried blood spots.

  • Guthrie card bacterial inhibition assay (BIA) is a time-tested, inexpensive, simple, and reliable test. However, many if not all states within the US have replaced this method with tandem mass spectrometry (MS/MS).
  • Fluorometric analysis is a reliable quantitative and automated test which produces fewer false positive test results than the BIA
  • Tandem mass spectrometry (MS/MS), which has the same benefits as fluorometric analysis, can also measure tyrosine concentration, and can be useful in interpreting Phe concentration. Tandem mass spectrometry can be used to identify numerous other metabolic disorders on the same sample [National Institutes of Health Consensus Development Panel 2001]. This method is used in most if not all states in the USA for newborn screening.

Molecular Genetic Testing

Gene. PAH is the only gene in which mutation is known to cause phenylalanine hydroxylase deficiency [Scriver & Kaufman 2001].

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in Phenylalanine Hydroxylase Deficiency

Gene 1Test MethodAllelic Variants Detected 2Mutation Detection Frequency by Test Method 3
PAHTargeted mutation analysis1-15 common variants (alleles may be population-related)30%-50%
Sequence analysis 4 of select exons 5Exons 7, 8, 11, 12 6100% for variants in the select exons
Sequence analysis 4 / mutation scanning 7Common and private sequence variants99% 4
Duplication/deletion analysis 8Exon or whole-gene deletions/duplications~3% 9
Linkage analysis 10Not applicableNot applicable

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


Examples of pathogenic variants detected by sequence analysis 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.


The mutation detection frequency may be lower than 99% if not all of the PAH exons are included in the sequence analysis.


Select exons may vary by laboratory.


Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used. See Bräutigam et al [2003].


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


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 [Kozak et al 2006].


For families in which only one or neither PAH mutant allele has been identified, linkage analysis may be an option for carrier testing and prenatal diagnosis. Linkage studies are based on accurate clinical diagnosis of PAH deficiency in the affected family member(s) and accurate understanding of the genetic relationships in the family. Samples from multiple family members, including a sample from at least one affected individual, are required to perform linkage analysis. The markers used for linkage are highly informative and are both intragenic and flanking to the PAH locus; thus, they can be used with greater than 99% accuracy in families with PAH deficiency.

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

Testing Strategy

To confirm/establish the diagnosis in a proband in the four following clinical scenarios:

  • Newborn who is positive on newborn screening (NBS) for elevated phenylalanine with normal or reduced tyrosine (ACMG ACT Sheet). PAH deficiency is most commonly diagnosed in routine screening of newborns. PAH deficiency can be detected in virtually 100% of cases by newborn screening utilizing the Guthrie card bloodspot obtained from a heel prick.
    • Initial test. The initial test yields a significant number of false positive test results. Such falsely positive hyperphenylalaninemia may result from a blood spot that is too thick, a sample that is improperly prepared, or combinations of the following: liver immaturity, protein overload (e.g. in newborns who are fed cow's milk), and possible heterozygosity for PAH deficiency in premature babies [Hennermann et al 2004]. Use of phenylalanine-to-tyrosine ratios can reduce the number of false positives [Chace et al 1998].

      Infants whose initial test results exceed the threshold concentration of Phe must be tested a second time.
    • Second test. If the second test confirms hyperphenylalaninemia, a presumptive diagnosis of PAH deficiency can be made. However, to distinguish infants with true PAH deficiency from the approximately 2% of infants with hyperphenylalaninemia who have impaired synthesis or recycling of tetrahydrobiopterin (BH4) (see Differential Diagnosis) [Scriver & Kaufman 2001, Blau et al 2011, Donlon et al 2014], a urine pterins profile needs to be done in addition to red blood cell measurement of dihydropterin reductase. Some centers will also do a newborn tetrahydrobiopterin load to detect rare cases of inborn errors of tetrahydrobiopterin metabolism. Molecular genetic testing of PAH in these infants can also be used to confirm PAH deficiency [Güttler & Guldberg 2000]. It is important that a low phenylalanine diet be initiated prior to receiving the results of the pterins study.

      Note: 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.
    • Molecular genetic testing. Many physicians now advocate genotyping all newborns identified with hyperphenylalaninemia to better anticipate dietary needs and response to BH4 cofactor therapy [Zschocke & Hoffmann 2000, National Institutes of Health Consensus Development Panel 2001, Güttler & Guldberg 2006, Santos et al 2010]. Although current recommendations include a low phenylalanine diet for life, some investigators have proposed that individuals identified as having mild hyperphenylalaninemia associated with known 'mild' pathogenic variants be treated as such with relaxation of their dietary restrictions at a relatively early stage [Zschocke & Hoffmann 2000].

      Genotype analysis may also help to determine the likelihood of BH4 responsiveness. There are certain pathogenic variants that correlate with BH4 responsiveness and non-responsiveness [Bernegger & Blau 2002, Trefz et al 2009].
  • Newborn with a previously affected sib. Allow ad libitum protein intake after birth and obtain quantitative plasma amino acid analysis between 18 and 24 hours of life.
  • Older child or adult with signs and symptoms suggestive of PKU, or a woman who has a child with signs and symptoms suggestive of maternal PKU embryopathy. Obtain quantitative plasma amino acid while on a normal diet.
  • Individuals with hyperphenylalanemia to whom any of the following apply. Molecular genetic testing may be beneficial:
    • A non-diagnostic urine pterins profile
    • A complicated diagnostic picture and uncertainty about dietary treatment
    • Interest in more precise prognostication
    • Interest in participation in a clinical trial

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Characteristics

Clinical Description

Hyperphenylalaninemia classification schemes. Phenylalanine in excess can be toxic to brain and cognitive development; thus any degree of hyperphenylalaninemia could be called a 'phenylketonuric' phenotype and would be a risk factor to be managed accordingly. However, because the risk also appears to vary relative to the degree of hyperphenylalaninemia, various classification schemes have emerged.

The initial classification scheme proposed by Kayaalp et al [1997] was meant to keep the nomenclature simple. This system uses the following terms:

  • Phenylketonuria (PKU) is the most severe of the three types and in an untreated state is associated with plasma Phe concentrations greater than 1000 µmol/L and a dietary Phe tolerance of less than 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.

The 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 no more than 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 lower than 600 µmol/L (10 mg/dL) on a normal diet.

Untreated children with persistent severe hyperphenylalaninemia (i.e., PKU) show impaired brain development. Signs and symptoms include microcephaly, epilepsy, severe intellectual disability, and behavior problems. 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 is responsible for decreased skin and hair pigmentation. Affected individuals also have decreased myelin formation and decreased dopamine, norepinephrine, and serotonin production. Further problems can emerge later in life and include exaggerated deep tendon reflexes, tremor, and paraplegia or hemiplegia [Pietz et al 1998, Williams 1998, Pérez-Dueñas et al 2005]. Individuals for whom treatment was initiated after the first months of life, or those who were never treated may develop severe behavioral or psychiatric problems (depression, anxiety, phobias) in the third or fourth decade [Hanley 2004].

Children with persistent severe hyperphenylalaninemia identified and treated from birth

  • Neuropsychological issues. A growing body of evidence suggests that individuals with strict adherence to diet (see Management) may still have some underlying sequelae and suboptimal cognitive outcome [Moyle et al 2007, Waisbren et al 2007, Burton et al 2013]. In treated individuals, psychological problems are increased as compared to sibs or children with other chronic diseases.

    Adults who have abandoned the 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]. Early treated (treated from the first weeks of life) adults who discontinue diet are also at risk for minor neurologic abnormalities such as tremor and brisk reflexes [Pietz et al 1998]. There is also a higher incidence of anxiety and depression, phobias and panic attacks in early treated individuals who discontinued therapy in the second decade of life [Koch et al 2002]. They develop changes in the frequency distribution of brain electrical activity [Pietz et al 1998], increased muscle tone, and tremor as well as lowered bone mineral content.

    The important chronic effects of non-compliance are neuropsychological and include a decrease in cognitive function as well as structural changes visible on MRI. The acute toxic effects are initially neurophysiologic. They affect neurotransmitter production and can be reflected in electroencephalographic changes. These changes are reversible. However, current understanding of these issues is not complete. In a few case reports untreated individuals with PKU with normal intelligence were diagnosed in adulthood as a result of sudden and severe psychiatric deterioration [Weglage et al 2000]
  • Osteopenia. Numerous studies indicate that individuals with PKU have a high incidence of osteopenia (as measured by DEXA) [Zeman et al 1999, Pérez-Dueñas et al 2002, Modan-Moses et al 2007]. It is not clear if this is a problem inherent to PKU or if it is secondary to dietary deficiencies. The low-phenylalanine diet has been adjusted for many years to try to mimic a natural protein diet. However, deficiencies in micronutrients important for bone metabolism may remain. This may be complicated by non-compliance during adolescence (an important time to accrue bone mass). However, de Groot et al [2012] has found a lower Z-score in affected individuals of all ages, including young children. Schwahn et al [1998] found osteopenia in an individual diagnosed late who had not received an artificial diet, suggesting that a component of abnormal bone metabolism may be a result of the disease itself.
  • 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 patients decrease their amino acid supplement, they often still choose low-protein foods and are therefore at risk for vitamin B12 deficiency.

Genotype-Phenotype Correlations

Phenylalanine hydroxylase deficiency is a 'multifactorial disorder' in that both environment (dietary intake of Phe) and genotype (mutation of both PAH alleles) are necessary causal components of disease [Scriver & Waters 1999]. PAH deficiency is also a 'complex' disorder at the cognitive and metabolic levels, because each individual has a personal genome, even those with similar mutant PAH genotypes may not have similar 'PKU' phenotypes. As explained by Scriver [2002], PAH genotype may correlate with phenylalanine tolerance and BH4 responsiveness but is not always a robust predictor of phenotype; thus, evaluating and treating the individual (i.e., the actual phenotype), rather than the phenotype predicted from genotype, is the correct approach.

The genotype-phenotype correlation in PAH deficiency is not absolute. On the one hand, variability of metabolic phenotypes in PAH deficiency is caused primarily by different pathogenic variants in PAH [Kayaalp et al 1997, Guldberg et al 1998]. The specific PAH genotype significantly determines the metabolic phenotype in most cases. For example, 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 mutant alleles 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].

Genotype-phenotype correlation is also seen with a large number of mutant alleles that are BH4 responsive. Therefore, genotyping may help to predict which individuals will respond to BH4 supplementation and the level of the response. Pathogenic variants in the regulatory domain of PAH are more likely to show inconsistency in BH4 responsiveness from person to person [Trefz et al 2009] (see BH4 Databatases)

However, the 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 confer classic PKU have elevated plasma Phe concentration but normal intelligence. In other instances, sibs with the same genotype have different clinical and metabolic phenotypes. The mechanisms that cause dissimilarities in pathogenesis at the level of the brain in spite of comparable plasma Phe concentrations are still unclear [Scriver & Waters 1999].

These individuals with an atypical phenotype have significantly lower brain Phe concentrations than do individuals with similar blood Phe concentrations.

  • Möller et al [1998] suggest that different brain Phe concentrations in individuals with similar blood Phe concentrations are the result of individual variations in the kinetics of Phe uptake and distribution at the blood-brain barrier.
  • Trefz et al [2000] speculate that individuals with atypical manifestations may be protected by a second catalytic variant affecting an amino acid transporter.
  • Pietz et al [1999] have demonstrated that loading individuals who have classic PKU with large neutral amino acids decreases Phe uptake into the brain at the transporter and improves neurophysiologic parameters.
  • Bik-Multanowski & Pietrzyk [2006] have suggested that polymorphisms in the large neutral amino acid transporter (LAT1) may account for some protection of the harmful effects of phenylalanine in some individuals. This hypothesis is not supported by a study by Møller et al [2005].


Since the appearance of universal newborn screening, symptomatic classic PKU is infrequently seen. Its predicted incidence in screened populations of fewer than one in a million live births reflects those children not detected by newborn screening. See Table 2.

Table 2.

Prevalence of PAH Deficiency by Population

PopulationPAH Deficiency in Live BirthsCarrier RateCitation
Turks1:2,6001/26Ozalp et al [1986]
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]

Historical Perspective

Hyperphenylalaninemia (HPA) has been called the epitome of human biochemical genetics. In 1934, Asjbørn Følling recognized that a certain type of intellectual disability was caused by elevated levels of phenylalanine in body fluids. He identified the disease as an autosomal recessive condition. In the 1940s, Lionel Penrose, who had recognized 'phenylketonuria' (PKU) to be the first form of intellectual disability with a chemical explanation, introduced the idea that PKU was not randomly distributed in human populations and could be treatable. In the mid-1950s, it was demonstrated that individuals with PKU had a deficiency of hepatic cytosolic phenylalanine hydroxylase (PAH) enzyme activity.

Next it was shown that affected individuals responded to dietary restriction of the essential nutrient phenylalanine. By the 1960s, the Guthrie microbial inhibition assay was used for mass screening of newborns, providing early diagnosis and access to successful treatment. Newborn screening for HPA has been routine throughout North America [National Newborn Screening Status Report (pdf)] and the UK since the mid-1960s and in most other developed countries since the early 1970s [Scriver 1998, Levy 1999]. The test became routine because of the excellent prognosis for children with PAH deficiency who are treated early and the high risk for severe and irreversible brain damage for children who are not treated. In most countries a parental right of refusal for this test exists; however, this right is exercised only in rare circumstances.

In the 1970s, it was discovered that not all HPA was PKU. Some forms of HPA were caused by disorders of synthesis and recycling of the cofactor (tetrahydrobiopterin, or BH4) involved in the Phe hydroxylation reaction. During the 1980s, the human PAH gene was mapped and cloned, and the first pathogenic variants identified. In the 1990s, in vitro expression analysis was being used to study the effects of different PAH alleles on enzyme function and the crystal structure of PAH was elucidated.

HPA is treatable. Affected individuals can lead normal lives. Continuous efforts are made to improve the taste and convenience of the current synthetic dietary supplements [Rohr et al 2001]. Research to improve the current treatment with restrictive phenylalanine diets, supplemented by medical formula, is ongoing (see Management, Therapies Under Investigation).

Differential Diagnosis

Hyperphenylalaninemia (HPA) 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 HPA. BH4 is also involved in catecholamine, serotonin, and nitric oxide biosynthesis (see

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

Blau et al [2001] and Scriver & Kaufman [2001] 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:

  • Analysis of pterins in the urine which will aid in diagnosis of PTPS deficiency, DHPR, and pyruvate carboxylase deficiency (PCD). The pterin profile may be normal for DHPR, and enzyme activity should be measured in erythrocytes or from a dried blood spot.
  • Other disorders of BH4 metabolism including dopamine-responsive dystonia (DRD) and sepiapterin reductase (SR) deficiency do not have elevations in phenylalanine but abnormalities in pterins can be detected in cerebrospinal fluid (CSF).
  • Some centers will also perform a loading test with BH4 on babies with a positive newborn screen. This test can rapidly differentiate BH4 deficiencies from PKU.

If screening test results show abnormal pterins, the following confirmatory tests are recommended:

  • Analysis of folates and neurotransmitter metabolites in CSF. This analysis will help to determine the severity of the BH4 defect [Blau 2006].
  • Enzyme activity measurements
  • Molecular genetic testing. Mutation testing for each of the genes involved in BH4 synthesis and recycling is available for confirmatory diagnosis and is useful for prenatal diagnosis. The genotype/phenotype relationships have not been determined and the above biochemical tests are still important for prognostic classification.

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


Evaluations Following Initial Diagnosis

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

  • Blood phenylalanine concentration and phenylalanine tolerance at the time of diagnosis to classify infants with hyperphenylalaninemia [Kayaalp et al 1997, Guldberg et al 1998]. Because the PAH genotype may not be a robust predictor of phenotype (see Genotype-Phenotype Correlations), the individual's diet should be tailored to calculate phenylalanine tolerance irrespective of genotype.
  • BH4 loading tests to determine which persons are BH4 responsive and which are not in order to relax or discontinue restriction of dietary phenylalanine in those who are responsive. An ever-growing body of evidence indicates that many individuals with primary phenylalanine hydroxylase deficiency are responsive to the 6R-BH4 stereoisomer in pharmacologic doses (≤20 mg/kg daily in divided oral doses) [Kure et al 1999, Bernegger & Blau 2002, Matalon et al 2004]. A review by Blau et al [2009] discusses some of controversial issues of how, whom, and when to test for BH4 responsiveness.

    BH4 responsiveness is determined based on response to a pharmacologic dose of BH4 (10-20 mg/kg per day):

Note: Although the genotype/phenotype relationship for BH4 responsiveness is also fairly robust, discrepancies have been described; see PAH mutation database.

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.

Classic PKU

Restriction of dietary phenylalanine. The generally accepted goal of treatment for the hyperphenylalaninemias 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]; Phe concentrations of 120-360 µmol/L (2-6 mg/dL) [Koch et al 1996] or 40-240 µmol/L (1-4 mg/dL) [Burgard et al 1999] are generally regarded as safe.

A diet restricted in Phe should be initiated as soon as possible after birth and continued at least into adolescence [Pietz et al 1998], perhaps for life [National Institutes of Health Consensus Development Panel 2001].

It is clear that if the diet is not followed closely (especially during childhood) and if plasma Phe concentration is allowed to rise frequently above the recommended concentration, some impairment is inevitable. A meta-analysis by Waisbren et al [2007] showed a reduction of IQ of 1.9 to 3.8 points for every 100 μmol/L increase in lifetime blood phenylalanine level. In addition, despite normal IQ, children and adolescents treated early have a higher frequency of ADHD, decreased autonomy, and school problems compared to either healthy controls or chronically ill peers [Simon et al 2008, Antshel 2010, Brumm et al 2010]. There is some evidence that childhood metabolic control correlates with development of these problems; this relationship needs to be clarified by well-designed prospective studies.

The restricted phenylalanine diet is adapted to individual tolerance for phenylalanine and includes appropriate protein and energy for age.

Plasma concentrations of Phe within the effective treatment range and normal nutritional status cannot be achieved by a low-protein diet alone, but rather require the use of a Phe-free medical formula.

The diet must be carefully monitored so that growth and nutritional status are unaffected and deficiency of phenylalanine or tyrosine is not created. The diet must be adjusted for all relevant factors including growth, illness, and activity. Adequate calcium and vitamin D intake as assessed by the metabolic dietician is an important component of care.

Supplementation with BH4. Individuality in BH4 pharmacokinetics implies the need for patient-specific dosage schedules [Blau & Erlandsen 2004]. For patients who have a positive BH4 loading test, 6R-BH4 should be given (≤20 mg/kg daily in divided oral doses). Long-term treatment in a small number of persons responsive to BH4 has documented the maintenance of the phenylalanine-lowering effect and the absence of major side effects [Trefz et al 2005].

In the majority of individuals, the BH4 response is likely a result of correction of PAH mutant kinetic effects and/or a chaperone-like effect of BH4 [Erlandsen et al 2004]. Whatever the mechanism of the therapeutic effect, the 6R-BH4 enhances in vivo phenylalanine hydroxylation and the corresponding oxidative flux and lowers plasma phenylalanine concentration with improved tolerance of dietary phenylalanine [Muntau et al 2002].

Treatment in infancy. A Phe-restricted diet and a Phe-free medical formula must be started as soon as possible after birth under the direction of a nutritionist. The consumption of Phe-free formula should be spread out evenly over the 24 hours of the day to minimize fluctuations in blood amino acid concentrations.

Breastfeeding is encouraged along with Phe-free formula [National Institutes of Health Consensus Development Panel 2001].

Intake of tyrosine and total amino acids must be monitored. Children under age two years should maintain a total amino acid intake of at least 3 g/kg/day including 25 mg tyrosine/kg/day.

Care must be taken to avoid long periods of low blood Phe concentration, which is also harmful to brain development. Blood Phe concentration should be monitored weekly or biweekly to evaluate control [Burgard et al 1999].

Treatment in childhood. Children older than age two years should maintain a total amino acid consumption of 2 g/kg/day including 25 mg tyrosine/kg/day.

Practices in blood Phe concentration monitoring vary widely [Blau et al 2010]. 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 [National Institutes of Health Consensus Development Panel 2001].

Treatment in adolescence and adulthood. Recommendations for treatment of adolescents and adults vary [Linder 2006, Lachmann & Murphy 2013].

In general, support for 'diet therapy for life' is increasing [National Institutes of Health Consensus Development Panel 2001, McPheeters et al 2012].

  • Some recommendations are more liberal than others and indicate that relaxation (not elimination) of the strict diet in adolescence does not affect non-executive functions when plasma Phe concentration remains below 1200 µmol/L [Griffiths 2000].
  • Other studies indicate that if the diet is relaxed after age 12 years, IQ can remain stable but other functions deteriorate. Controversy remains over the plasma Phe concentration to be achieved for individuals older than age 12 years [Linder 2006]. The general consensus is that the closer the Phe concentration is to the recommended normal value, the better the individual's general state of well-being.


Individuals with non-PKU HPA who have plasma Phe concentrations consistently below 600 µmol/L (10 mg/dL) are not at higher risk of developing intellectual, neurologic, and neuropsychological impairment than are individuals without PAH deficiency. While some specialists debate the advisability of non-treatment, others believe that dietary treatment is unnecessary for the individuals in this class. A study by Weglage et al [2001] confirmed the hypothesis of Levy et al [1971] that such individuals may not need dietary treatment. Thirty-one individuals with HPA who were never treated and whose plasma Phe concentrations did not exceed 600 µmol/L had normal cognitive neuropsychological development. Two recent review articles on this debate have been published and it is still unclear whether these individuals need treatment or not [Hanley 2011, van Spronsen 2011].

Care should be taken so that girls in this group receive proper counseling about 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).

Prevention of Primary Manifestations

See Treatment of Manifestations.


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

Lower bone mineral density has been found in both affected individuals on dietary therapy and those who have relaxed their dietary management [Schwahn et al 1998, Porta et al 2011]. The clinical significance of this finding is unclear and currently, there are no recommendations for surveillance for osteopenia. This will likely change as the treated cohort of affected individuals age. A baseline bone mineral density scan may be of value for long-term follow up.

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

Newborn sibs of an individual with PKU who have not been tested prenatally should have blood concentration of phenylalanine measured shortly after birth, in addition to the newborn screen. This will allow earlier detection than by newborn screening alone and thus, treatment as soon as possible after birth.

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 been properly treated throughout childhood and adolescence have normal physical and intellectual development. However, if the woman has high plasma Phe concentrations, her intrauterine environment will be hostile to a developing fetus as phenylalanine is a potent teratogen.

Preconception. It is strongly recommended that women with PAH deficiency use reliable methods of contraception to prevent unplanned pregnancies.

Women with PAH deficiency who are off diet and are planning a pregnancy should start a Phe-restricted diet prior to conception and should maintain plasma Phe concentrations between 120 and 360 µmol/L (2-6 mg/dL), ideally over several months, before attempting conception [Maillot et al 2008, American College of Obstetricians and Gynecologists Committee on Genetics 2009]. Furthermore, avoidance of variability in phenylalanine control is important [Maillot et al 2008].

Pregnancy management. After conception, women with PAH deficiency should be offered continuous nutritional guidance and weekly or biweekly measurement of plasma Phe concentration, as dietary Phe and protein requirements change considerably during pregnancy. It is important that pregnant women with PAH deficiency have an adequate energy intake with the proper proportion of protein, fat, and carbohydrates. They should try to attain normal weight gain patterns to provide the most favorable conditions for fetal growth [Koch et al 2000, Maillot et al 2008].

Proper prenatal care should include serial ultrasonography to: (1) identify nonviable pregnancies in the first trimester; (2) monitor fetal growth; and (3) identify congenital abnormalities (e.g., congenital heart disease) that are relatively common in babies whose mothers have PAH deficiency. This information can be useful in anticipating the postnatal needs of the infant.

Support for women with PAH deficiency. Waisbren et al [1998] contend that suboptimal home environments can have as much of an adverse effect on offspring as a delay in control of maternal plasma Phe concentration. Of concern, the limited intellectual abilities, the reduced social resources, and the emotional difficulties of many women with HPA may complicate adherence to the diet, prenatal care, and the care of their infant [Koch et al 2000]. Support for women with HPA/PKU starting before conception and continuing after delivery is essential for optimal outcome. A successful pilot project involving mothers serving as resources for their daughters with PKU when they reached childbearing age resulted in better dietary control during pregnancy and better outcome for the children [Waisbren et al 2000].

Children Born to Women with PAH Deficiency

Risk for maternal HPA/PKU. The abnormalities that result from exposure of a fetus to high maternal plasma Phe concentration are the result of 'maternal HPA/PKU'. The likelihood that the fetus will have congenital heart disease, intrauterine and postnatal growth retardation, microcephaly, and intellectual disability depends upon the severity of the maternal HPA and the effectiveness of the mother's dietary management.

  • Although studies have shown that women with non-PKU HPA who have plasma Phe concentrations lower than 400 µmol/L (7 mg/dL) when untreated can give birth to offspring who seem to be normal, the Maternal PKU Collaborative Study reports that even at maternal plasma Phe concentrations of 120-360 µmol/L (2-6 mg/dL), 6% of infants are born with microcephaly and 4% with postnatal growth retardation.
  • If maternal plasma Phe concentrations are greater than 900 µmol/L (15 mg/dL), the risk is 85% for microcephaly, 51% for postnatal growth retardation, and 26% for intrauterine growth retardation.

The risk for these abnormalities is both dose dependent and time dependent. Thus, optimal plasma Phe concentrations must be strictly maintained throughout pregnancy to reduce the risk for each individual abnormality; continuing studies corroborate this position [Rouse & Azen 2004, Prick et al 2012].

Unfortunately, many pregnancies are unplanned:

  • Women with HPA who conceive while off the Phe-restricted diet and who manage to bring their plasma Phe concentrations into the recommended range (120 to 360 µmol/L) as early as possible after conception and no later than eight weeks of pregnancy can be encouraged by the existing data. Though the risks of congenital abnormalities, especially for congenital heart disease, are greater than if plasma Phe concentration is controlled preconceptually, the possibility for a normal child still exists.
  • If plasma Phe concentrations are not controlled until the second or third trimester, the risks are the same as if the plasma Phe concentration were never brought under control [Koch et al 2000].

Other risks. Too little published data exist on children born to mothers with PKU. One interesting observation of this cohort of children is a decline in the scores achieved on developmental tests at age four years from those achieved on similar tests taken at age two years [Waisbren et al 2000]. Longitudinal studies of these children are necessary to interpret the significance of these findings.

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.

Large neutral amino acids (LNAA) transporters. At the blood-brain barrier, phenylalanine shares a transporter with other large neutral amino acids (LNAA). Some individuals exclude excess phenylalanine, more or less efficiently, because they show evidence of variation in the high-capacity/high km component of phenylalanine transport across the blood-brain barrier [Weglage et al 2002]. LNAA supplementation has reduced brain phenylalanine concentration despite consistently high serum concentrations of phenylalanine by competition at this transporter [Pietz et al 1999, Moats et al 2003]. In non-compliant adults, this may help to protect the brain from acute toxic effects of phenylalanine.

Significant improvement in ability to concentrate and decreased self-injurious behavior were seen with trial of LNAA supplements in a small number of untreated adults with PKU [Kalkanoğlu et al 2005].

A similar transporter for LNAA also exists in the intestine, and supplementation with a different formulation of LNAA reduced the blood Phe concentration by 40%-50% in a small number of individuals with PKU [Matalon et al 2006]. These supplements will not replace the phenylalanine-restricted diet but may help relax dietary restriction of treated individuals or may aid in management of adults who are not treated. LNAA supplementation had a specific impact on executive function but was of limited use in individuals who were already complying with dietary restriction [Schindeler et al 2007]. Larger clinical trials are needed before conclusions on the effectiveness of these treatments can be made.

BH4 supplementation. As an adjunct to dietary therapy, BH4 therapy may become the standard of care for PKU in a subset of affected individuals [Vernon et al 2010]. By increasing the phenylalanine tolerance, BH4 supplementation may allow for a more complete diet, thus minimizing risks of nutritional deficiencies associated with a low-protein diet. Long-term treatment in BH4-responsive persons has documented the maintenance of the Phe-lowering effect and the absence of major side effects [Trefz et al 2005]. There is some anecdotal evidence, including positive behavioral improvements, in severely affected individuals with untreated PKU [Vernon et al 2010]. Burton et al [2011] has shown that this treatment is safe and effective in children younger than age four years. One limitation to this therapy may be its high cost.

BH4 may have important implications for the treatment of maternal PKU [Trefz & Blau 2003]. In one case report, pregnancies were successfully managed with BH4 supplementation; however, more data are needed to prove the safety and efficacy of this alternative treatment in pregnancy [Koch et al 2005].

Enzyme substitution. Under investigation is the administration of the enzyme phenylalanine ammonia lyase (PAL) by oral routes to degrade Phe to trans-cinnamic acid and ammonia [Sarkissian et al 1999, Gámez et al 2004]. The oral route is complicated by proteolytic degradation, while injected PAL is complicated by increased immunogenicity [Gámez et al 2005, Sarkissian & Gámez 2005]. PEGylation (conjugation with polyethylene glycol) of PAL has been found to decrease the immune response [Gámez et al 2005, Sarkissian & Gámez 2005]. Clinical trials with this protected form of injectable enzyme are currently underway. Modification of oral PAL to prevent degradation by digestive enzymes is also being investigated [Kang et al 2010].

Somatic gene therapy is also being explored in animal models and holds some promise for possible future treatment [Eisensmith et al 1999, National Institutes of Health Consensus Development Panel 2001, Ding et al 2004, Ding et al 2006].

Search 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

  • Unaffected parents of a child with PAH deficiency are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic and do not have PAH deficiency.

Sibs of a proband

  • At conception, each sib of a proband has a 25% chance of being affected (homozygous), a 50% chance of being an asymptomatic carrier of a disease-causing allele (heterozygous), and a 25% chance of having two benign alleles.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

Offspring of a proband

  • Because PAH deficiency is treatable, affected individuals who have the benefit of effective treatment can live physically and intellectually normal lives and have children of their own.
  • Children born of one parent with PAH deficiency and one parent with two normal alleles are obligate heterozygotes.
  • If one parent is affected and the other parent is a carrier, the offspring have a 50% chance of being heterozygous and a 50% chance of being affected.
  • If the father is the affected parent, no additional risks exist. If the mother is the affected parent, maternal HPA/PKU becomes a critical issue (see Management, Children Born to Women with PAH Deficiency).

Carrier Detection

Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in a family member. Three methods can be used:

  • Carrier testing using molecular genetic testing for at-risk family members; such testing is possible if the pathogenic variants have been identified in a family member.
  • Linkage analysis, for the few families in which the pathogenic variants have not been identified, if the family is informative for markers within PAH
  • Biochemical analysis; can be used to determine carrier status if molecular genetic testing is not possible. Biochemical analysis relies on analysis of the plasma Phe concentration and Phe/Tyr ratio. Note: This test must take into account circadian variation (i.e., it must be performed before noon after a normal breakfast) and variations in a woman's menstrual cycle; it is not accurate during pregnancy. When these variations are taken into account, the probability of heterozygote misclassification is 0.01 or less.

Reproductive partners of carriers can now access carrier testing on a limited basis.

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

  • 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

If both PAH pathogenic variants have been identified in an affected family member or linkage has been established in the family, prenatal diagnosis for pregnancies at increased risk may be available from a clinical laboratory offering either testing of this gene or custom prenatal testing.

Other issues to consider. Prenatal diagnosis of a treatable condition associated with a good prognosis with early treatment may be controversial if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider this to be the choice of the parents, discussion of these issues is appropriate. Prenatal diagnosis may be a consideration in countries where treatment is expensive or unavailable.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified in an affected family member.


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

GeneChromosome LocusProteinLocus SpecificHGMD
PAH12q23​.2Phenylalanine-4-hydroxylasePhenylalanine Hydroxylase Locus Knowledgebase
PAH database

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)


Gene structure. PAH contains 13 exons and spans 90 kb [Scriver & Kaufman 2001, Donlon et al 2014]; the genomic sequence is known to code for a 2.6-kb mature messenger RNA (NM_000277.1). For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. Thirty-one different benign variants causing minor changes in the gene sequence have been identified (see Table A, PAH Locus Knowledgebase); all are presumed to be neutral in their effect on protein product [Waters et al 1998].

Pathogenic allelic variants. More than 500 different pathogenic variants have been identified to date in PAH (see Table A, PAH Locus Knowledgebase and HGMD). This database provides information on pathogenic variants, associated phenotypes, gene structure, enzyme structure, clinical guidance, and much else [Scriver et al 2003].

Pathogenic variants observed in PAH (see Table 3) include missense, splice site, and nonsense variants and small deletions and insertions.

Table 3.

Classes of Pathogenic Variants Observed in PAH

% of Pathogenic VariantsGenetic Mechanism
13%Deletion (mainly small) 1
<1%Deletion or duplication of exon(s) or whole gene

From PAHdb Knowledgebase


Large deletions account for 2%-3% of pathogenic variants [Kozak et al 2006].

Normal gene product. The normal product of PAH is the protein phenylalanine hydroxylase (PAH), containing 452 amino acids (NP_000268.1; see Table A, PAH Locus Knowledgebase). 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 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].


Published Guidelines/Consensus Statements

  1. Canadian Task Force on the Preventive Health Care. Screening for phenylketonuria. In: The Canadian Guide to Clinical Preventive Health Care. Ch 17. Available online. 1994. Accessed 7-2-15.
  2. US Preventive Services Task Force. Screening for phenylketonuria (PKU). Available online. 2008. Accessed 7-2-15.

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Suggested Reading

  1. Haack TB, Makowski C, Yao Y, Graf E, Hempel M, Wieland T, Tauer U, Ahting U, Mayr JA, Freisinger P, Yoshimatsu H, Inui K, Strom TM, Meitinger T, Yonezawa A, Prokisch H. Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome. J Inherit Metab Dis. 2012;35:943–8. [PMC free article: PMC3470687] [PubMed: 22864630]

Chapter Notes

Author History

John J Mitchell, MD (2005-present)
Shannon Ryan, MSc; Montreal Children's Hospital (2000-2005)
Charles R Scriver, MD; Montreal Children’s Hospital (2000-2013)


This work was supported in part by the Canadian Genetic Diseases Network and by the Fonds de la Recherche en Santé du Québec du Réseau de médecine génétique appliquée.

Revision History

  • 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
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