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.

Testing

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, Scriver et al 2008].
• 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.

Testing Strategy

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

1. Newborn who is positive on newborn screening (NBS) for elevated phenylalanine with normal or reduced tyrosine ().

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, Scriver et al 2008, Blau et al 2011], 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' mutations 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 mutations that correlate with BH₄ responsiveness and non-responsiveness [Bernegger & Blau 2002, Trefz et al 2009].

2. 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.

3. 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.

4. Individuals with hyperphenylalanemia to whom any of the following apply may benefit from molecular genetic testing:

• 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 disease-causing mutations 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 disease-causing mutations in the family.

Genetically Related (Allelic) Disorders

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

Natural History

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 2012]. 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 mutations 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 mutations 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. Mutations 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 mutations 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].

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, 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 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 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):
  • The majority of individuals with mild or moderate PKU may be responsive to BH₄ while up to 10% of individuals with classic PKU can show a response [Bernegger & Blau 2002, Pérez-Dueñas et al 2004, Zurflüh et al 2006].
  • Most responders can be detected with a standard 24-hour load, but some slow responders escape detection unless a more prolonged protocol is used [Shintaku et al 2004, Fiege et al 2005, Mitchell et al 2005].

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.

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].

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

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

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, Children Born to 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. 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 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

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 ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 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. 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 disease-causing mutations have been identified in an affected family member.

Published Guidelines/Consensus Statements

1. Canadian Task Force on the Preventive Health Care. Screening for phenylketonuria. Available online. 1994. Accessed 1-24-13.
2. US Preventive Services Task Force. Screening for phenylketonuria (PKU). Available online. 2008. Accessed 1-24-13.

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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]

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)

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

• 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