Clinical Diagnosis

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

Testing

For laboratories offering biochemical testing, see .

Plasma phenylalanine concentration. The main route for phenylalanine metabolism is hydroxylation of phenylalanine to tyrosine by phenylalanine hydroxylase (PAH). The diagnosis of primary phenylalanine hydroxylase deficiency (PAH deficiency) is based on the detection of an elevated plasma phenylalanine (Phe) concentration and evidence of normal BH₄ cofactor metabolism. 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 2004].

For a description of two different systems of nomenclature, see Clinical Description.

Newborn screening. PAH deficiency is most commonly diagnosed upon 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. 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.

• Initial test. The initial test yields a significant number of false positive test results (imperfect specificity of the test) leading to follow-up tests and sometimes stressful experiences for parents. A false positive elevated Phe concentration (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 (in newborns who are fed cow's milk), and possible heterozygosity for phenylalanine hydroxylase deficiency in premature babies [Hennermann et al 2004].
  
  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, further tests are performed to distinguish those infants with 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, Donlon et al 2004]. Molecular genetic testing of the PAH gene in these infants can be used to confirm PAH deficiency [Guttler & Guldberg 2000].

A concern is the reliability of current tests to accurately measure Phe concentrations in infants less than 24 hours old, since hyperphenylalaninemia (HPA) manifests itself as a time-dependent increase of Phe concentration in the blood .

Three methods of newborn screening are currently in use:

• Guthrie card bacterial inhibition assay (BIA), a time-tested, inexpensive, simple, and reliable test

• Fluorometric analysis, a reliable quantitative and automated test which produces fewer false positive test results than the BIA

• Tandem mass spectrometry (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]. Cost-effectiveness analysis, with economic modeling, suggests that to replace existing methods of newborn screening for PKU with tandem MS would not be justified, unless the intent is to capture additional metabolic disorders, notably MCAD deficiency [Pandor et al 2004].

Determination of carrier status. 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. Of 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 .

Molecular Genetic Testing

Gene. PAH is the only gene associated with phenylalanine hydroxylase deficiency [Scriver & Kaufman 2001].

Clinical testing

• Targeted mutation analysis. A panel of one to 15 common point mutations and very small deletions has a detection rate of approximately 30%-50%. Alleles may be population related.

• Mutation scanning. Mutation scanning detects virtually all point mutations in the PAH gene. Mutation scanning by denaturing high-performance liquid chromatography, a fast and very efficient method to detect locus-specific point mutations, has shown its relevance for detection of PKU-causing alleles [Brautigam et al 2003].

• Sequence analysis. Sequencing of all 13 exons has a mutation detection rate of about 99%.

• Duplication/deletion analysis. Comparative multiplex dosage analysis may be useful in detecting large duplications or deletions when no mutations have been identified by mutation scanning or sequence analysis. 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 mutations [Kozak et al 2006].

• Linkage analysis. For families in which only one or neither PAH mutation 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.

Table 1. Summary of Molecular Genetic Testing Used in Phenylalanine Hydroxylase Deficiency

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
PAH	Targeted mutation analysis	1-15 common mutations (alleles may be population related)	30%-50%	Clinical
	Mutation scanning	Common and private sequence variants	99%
	Sequence analysis	Common and private sequence variants	99% 2
	Duplication/deletion analysis 3	Exonic or whole-gene deletions/duplications	Rare

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

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

3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To establish the diagnosis in a proband. Once the initial screen is positive, diagnostic tests must be performed:

• Blood for amino acid analysis permits confirmation of hyperphenylalaninemia and the exclusion of the diagnoses of hepatic insufficiency or other aminoacidopathies.

• To exclude hyperphenylalaninemia as a secondary consequence of an inborn error of biopterin metabolism, a urine sample to measure pterins and a blood sample to assay dihydropteridine reductase activity are collected (see Differential Diagnosis). Once these blood samples have been collected, a low phenylalanine diet is started.

• Although molecular genetic testing is not necessary for diagnosis or treatment in the immediate newborn period, it is often performed for genotype/phenotype correlation. See Genotype-Phenotype Correlations.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. If molecular analysis via mutation testing or linkage analysis is not possible, biochemical testing may be a possibility.

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 disease-causing mutations in the family.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in the PAH gene.

Natural History

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 have a much lower risk of 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 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].

The changes that occur in adolescence and adulthood as a result of high plasma Phe concentrations are both chronic and acute. 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, our 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 a 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]. Although adolescence is an important time to accrue bone mass, adolescents with PKU are often not compliant with diets. However, 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 of 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 the PAH gene) are necessary causal components of disease [Scriver & Waters 1999]. Because each individual has a personal genome, even those with similar mutant PAH genotypes may not have similar 'PKU' phenotypes. As explained elsewhere [Scriver 2002], PAH genotype may not be a robust predictor of phenotype, and to evaluate and treat the individual (the actual phenotype), rather than the phenotype predicted from genotype, is the correct approach.

Variability of metabolic phenotypes in PAH deficiency is caused primarily by different mutations within the PAH gene [Kayaalp et al 1997, Guldberg et al 1998]. DiSilvestre et al [1991] found that genotype does predict biochemical phenotype (i.e., by Phe loading tests) but does not predict clinical phenotype (i.e., occurrence of intellectual disability). PAH deficiency is therefore a 'complex' disorder at the cognitive and metabolic levels [Scriver & Waters 1999]. It is becoming more difficult to assess clinical phenotypes given that most individuals with PAH deficiency in developed countries are treated successfully.

Some untreated individuals with PAH deficiency and PAH mutations that usually confer classic PKU have elevated plasma Phe concentration but normal intelligence. Some 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. These atypical individuals have significantly lower brain Phe concentrations than do individuals with similar blood Phe concentrations. Moller 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 these 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.

An emerging theory that attempts to explain the variations in plasma Phe concentrations in individuals with the same genotypes [Scriver & Waters 1999, Waters et al 2000, Waters et al 2001] suggests that some missense mutations affect protein folding, thus altering the oligomerization of the nascent PAH protein. This process is likely influenced by an individual's genetic background, including, potentially, differences in the quality and quantity of chaperones and proteases.

Despite all the different factors influencing phenylalanine hydroxylase deficiency phenotypes, the specific PAH genotype is the main determinant of metabolic phenotype in most cases. In compound heterozygotes with functional hemizygosity (null/missense paired alleles), the less severe of the two PAH mutations determines disease severity. When two mutations with similar severity are present, the phenotype may be milder than predicted by either of the mutations [Kayaalp et al 1997, Guldberg et al 1998, Waters et al 1998].

Many physicians are now advocating genotyping all newborns identified with hyperphenylalaninemia to better anticipate dietary needs [Guttler & Guldberg 2000, National Institutes of Health Consensus Development Panel 2001, Zschocke & Hoffmann 2000]. Zschocke & Hoffmann [2000] even suggest that individuals identified as having mild hyperphenylalaninemia associated with known 'mild' mutations be treated as such with relaxation of their follow-up control analyses at a relatively early stage. Greeves et al [2000] suggest that genotype can help predict the likelihood of intellectual change if or when individuals relax their dietary restrictions later in life.

Genotype-phenotype correlation is also seen with a large number of mutations that are BH₄ responsive. Therefore, genotyping may help to predict which individuals will respond to BH₄ supplementation and what the response will be. Mutations that are found 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)

Prevalence

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.

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, a microbial inhibition assay was used for mass screening of newborns, providing early diagnosis and access to successful treatment.

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 mutations 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).

Evaluations Following Initial Diagnosis

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

Infants with hyperphenylalaninemia are classified at the time of diagnosis based on blood phenylalanine concentration and phenylalanine tolerance [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 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. BH₄ responsiveness is determined based on response to a pharmacologic dose of BH₄ (10-20 mg/kg per day).

• The majority of BH₄ responders belong to the mild PKU and hyperphenylalaninemia group [Bernegger & Blau 2002, Pérez-Dueñas et al 2004, Mitchell et al 2005].

• A small number of BH₄ responders have classic disease [Pérez-Dueñas et al 2004, Zurflüh et al 2006].

Note: Although the genotype/phenotype relationship for BH₄ responsiveness is also fairly robust, discrepancies have been described; see Mutations (pdf).

Treatment of Manifestations

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].

Currently, there are no recommendations for surveillance for osteopenia, but baseline bone scans 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.

Testing 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 their 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.

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 k_m 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. Clinical trials are needed before conclusions on the effectiveness of these treatments can be made.

BH₄ supplementation. BH₄ may have important implications for treatment of maternal PKU [Trefz & Blau 2003]. By increasing the phenylalanine tolerance, BH₄ supplementation may allow for a more complete diet, thus minimizing risk of nutritional deficiencies associated with a low-protein diet. 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 [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 ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 normal 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, Pregnant Women with PAH Deficiency).

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations have been identified in a family member.

Reproductive partners of carriers can now access such carrier testing on a limited basis. Three methods can be used:

• Carrier testing using molecular genetic testing for at-risk family members; such testing is possible if the disease-causing mutations have been identified in a family member.

• Linkage analysis, for the few families in which the disease-causing mutations have not been identified, if the family is informative for markers within the PAH gene

• Biochemical analysis for determination of carrier status if molecular genetic testing is not possible

Related Genetic Counseling Issues

At-risk newborn family members. If prenatal diagnosis yields no definitive results, is not available, or was not performed, at-risk children should be monitored with measurement of plasma Phe concentration after two to three days of feeds that include unrestricted amounts of protein.

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.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified or linkage established in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member. For laboratories offering PGD, see .

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Published Statements and Policies Regarding Genetic Testing

1. Canadian Task Force on Preventive Health Care (1994; reaffirmed 1998) Screening for Phenylketonuria.
2. US Preventive Services Task Force (2008) Screening for Phenylketonuria (PKU). Available at www.ahrq.gov. Accessed 4-30-10.

Suggested Reading

1. Scriver CR, Levy H, Donlon J (Revised 2008) Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 77. Available at www.ommbid.com. Accessed 4-30-10.

Author History

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

Acknowledgments

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

• 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