Handbook of Genetic Counseling/Phenylketonuria (PKU)

Phenylketonuria (PKU)


  • What is your understanding about why you are here?
  • When were you first told about the abnormal test?
  • Do you have any specific questions or concerns?
  • Outline the visit
    • We will be taking a family history
    • We will discuss the genetic basis of PKU
    • The medical geneticist will obtain some medical history and discuss medical management
    • The dietitian will also be visiting with you to discuss the specifics about diet

Family historyEdit

  • Get basic 3 generation pedigree
  • Ask about mental retardation, pregnancy losses, birth defects, learning difficulties, chronic health problems, children that died young, and PKU specifically

Basic Info to review with family

  • PKU is one of the disorders that is part of the newborn screening for in every state using a heel prick to get a blood sample
  • PKU can be successfully treated to prevent symptoms by maintaining a strict diet
  • There can be serious effects if the diet is not maintained especially during childhood
  • Mental retardation
  • Microcephaly
  • Delayed speech
  • Seizures
  • Eczema
  • Behavioral abnormalities
  • This is a diet that should be maintained throughout life.
  • The goal is to maintain phe levels below 6 mg/dl during childhood(some metabolic geneticists prefer to keep them below 5 mg/dl)
  • It is especially important that a woman with PKU maintain the diet before and during a pregnancy because high phe can harm the development of the baby.
  • Phe is an essential amino acid and is one of the building blocks of protein
  • When a baby has an excess amount of phe there are a couple of potential explanations as follows:
    • Phenyalanine hydroxylase (PAH) deficiency -- (most common cause, 98% of the time this is explanation)
  • (show diagram) This liver enzyme usually converts phenylalanine to another amino acid tyrosine
  • Sometimes the gene that tells the body how to make the PAH is changed and so it doesn't work as well or doesn't work at all
  • When this happens the path can be blocked and some by products will build up and cause the effects that can be seen in patients that are not on a well controlled diet
    • Inability to make or recycle a cofactor that is required to help PAH do its job.
  • This is rare and is found in about 2% of those with high phe.
  • HOWEVER it can't be ruled out completely until results of the test for this come back which will indicate if this is the explanation.
  • Because this cofactor also helps out in other important reactions in our bodies this can often be more severe sometimes referred to as atypical PKU

Details for ReferenceEdit

  • tetrahydrobiopterine (BH4), the cofactor in the phenylalanine, tyrosine, and tryptophan hydroxylation reactions.
  • Defects in BH4 synthesis result from guanosine triphosphate cyclohydrolase (GTPCH) deficiency or 6-pyruvoyl tetrahydropterine synthase (PTPS) deficiency.
  • Impaired recycling of BH4 is caused by deficient dihydropteridine reductase (DHPR) or deficient pterin-4a carbinolamine dehydratase (PCD).
  • All of the HPAs caused by BH4 deficiency are inherited in an autosomal recessive manner.
  • They account for approximately 2% of patients with HPA. BH4 is also involved in catecholamine and serotonin biosynthesis.
  • The typical (severe) forms of GTPCH, PTPS, and DHPR deficiencies have the following variable, but common, symptoms:
    • mental retardation
    • Convulsions
    • disturbance of tone and posture
    • drowsiness
    • irritability
    • abnormal movements
    • recurrent hyperthermia without infections
    • hypersalivation
    • swallowing difficulties
    • Microcephaly is common in PTPS and DHPR deficiencies
  • Plasma phenylalanine levels can vary
  • Mild forms of BH4 deficiency have no clinical signs
  • PCD deficiency, sometimes referred to as "primapterinuria" is associated with benign transient hyperphenylalaninemia.
  • Treatment requires the normalization of blood phe concentration and restoration of the BH4-dependent hydroxylation of tyrosine and tryptophan by BH4 supplementation or by dietary modification, neurotransmitter precursor replacement therapy, and supplements of folic acid in DHPR deficiency

Three category classificationEdit

(when due to altered PAH) based on levels of phe when untreated

  • Classic PKU
    • due to a complete or near-complete deficiency of PAH activity
    • plasma phe concentrations above 20 mg/dl in the untreated state
    • must be treated by diet or brain damage will develop
  • Non-PKU Hyperphenylalinemia (also referred to as benign hyperphenylalinemia)
    • characterized by plasma phe concentrations consistently above normal when the patient is on a normal diet, but not high enough to cause impaired cognitive development
    • does not need to be treated by diet
  • Variant PKU (intermediate levels and requires some treatment)
    • intermediate levels between PKU and benign hyperphenylalinemia
    • many metabolic geneticists choose to treat these patients with a modified diet that may not be as restrictive as for those with classical PKU


(regardless of whether it is due to PAH gene or to a problem with the cofactor BH4, it is inherited in an AR fashion)

  • Autosomal means that the gene for PAH is on a chromosome other than the sex chromosomes
  • Recessive means that for a person to have clinical symptoms they must have inherited two copies of the altered gene one from each parent
  • We assume that you and your partner (husband) are carriers and don't have symptoms because you each have one functional copy
  • Two carriers have a one in four (or 25%) chance for each pregnancy that the baby will have PKU (draw out AR inheritance) and a 50 % chance of having a child that is a carrier just like the parents, a 25% chance of having a child with both functional copies


  • one in 15,000 live births in Caucasian populations and in Utah (carrier frequency in this population is approximately one in sixty)
  • Most literature still quotes one in 10,000 live births in Caucasian and East Asian pop. (one in 60 carrier rate)
  • Highly variable among populations
  • Turks one in 2600
  • Irish one in 4500
  • Japanese population one in 143,000
  • Finn and Ashkenazi Jewish populations one in 200,000

Psychosocial considerationsEdit

  • It can feel overwhelming to get a diagnosis and so much information
  • Reassure that we don't expect them to remember everything and that is why we'll be sending out a letter that will explain much of what we discuss
  • It is common for parents not to even know the test was done or what it means initially
  • Concerns about their ability to carry out the diet restrictions
  • Scared of the unknown
  • Provide information about the PKU picnic and potential to meet other families and see how children with PKU who are on diet since birth don't look or act any different than other children
  • Reassure them that it is possible to manage, but don't give the impression that it is super easy because it does take some special planning, time and effort
  • Reassure that we all carry genes that don't function properly, but we don't always know what they are unless we happen to find a partner that has one of the same altered genes (estimates are 4-6)
  • Explain that we are here to help them and they can call the dietician (Sharon) about diet questions or concerns and us about questions concerning the genetics of PKU

Molecular Genetic Testing

  • used primarily for genetic counseling purposes to determine carrier status of at-risk relatives and for prenatal testing
  • Over 380 different disease-causing mutations have been identified in the PAH gene
  • Molecular diagnosis for these mutations is possible but is only available on a limited clinical basis in the US and Canada
  • Mutations are identified and confirmed by DNA analysis using various methods
  • When mutation analysis is not available or disease-causing mutations are not identified in a family, linkage analysis can be considered for couples who have a child affected with PAH deficiency
  • No other phenotypes are known to be associated with mutations in the PAH gene

Determination of carrier statusEdit

  • Molecular testing used to be offered only to at-risk family members with a positive history
  • Now molecular testing can be offered to unrelated spouses and detects carriers with a rate of 98%
  • Not recommended for population screening to detect carriers
  • Three methods can be used
    • analysis of the plasma phe concentration and phe/tyr ratio (this test must take into account circadian variation and variations in a woman's menstrual cycle; it is not accurate during pregnancy.) When these variations are taken into account there is a 0.01 probability or less of heterozygote misclassification
    • DNA analysis if the disease-causing PAH mutation in the family is known
    • Linkage analysis with markers in the PAH gene

Prenatal TestingEdit

  • Prenatal testing (once the genotype of the proband has been established) is possible for fetuses at 25% risk for PAH deficiency by amnio and CVS
  • Has also been done with linkage studies


THE REST OF THE OUTLINE IS ONLY IF QUESTIONS ARISE, but much of it will be talked about by other members of the team


  • Each person with PKU is affected differently and at varying levels of severity
  • Appear to have some other factors that may modify the phenotype (modifier genes and definitely environment)
  • Variations in severity correlate somewhat with the type of over 500 mutations in the phenylalanine hydroxylase gene located at chromosomal locus 12q22-q24
  • If diet is adhered to intelligence is usually in normal range, but still tends to be slightly lower than expected based on sibling and parent IQ's, but it mostly tends to correlate with levels of phe that are maintained and age at which treatment begun
  • Untreated patients often have:
    • abnormal electroencephalograms (EEGs)
    • seizures
    • neurologic disorders
    • a musty odor
    • varying degrees of mental retardation
  • Other possible symptoms include:
    • increased occurrences of eczema
    • tremor in the hands and eyelids
    • memory problems
    • raised levels of anxiety and depression
    • social disorders, i.e. agoraphobia
    • decreased motor functions, i.e. hand-eye coordination
    • on average, a loss of one IQ point per year off diet
  • Behavior problems of untreated or late-treated patients with PKU include:
    • Hyperactivity
    • aggressiveness
    • negative moods
    • motor and attention disturbances
    • self-inflicted injury


  • carried out in every state in the US and in many other countries with a heel-prick blood test
  • screening started in the mid-1960's however this could be earlier or later depending on which state and hospital
  • Utah statewide screening for PKU began in 1965 and galactosemia screening was added in 1979
  • PKU detected in virtually 100% of cases
  • Used to be done with Guthrie test that detected the presence of high phe by whether or not bacteria that were auxotrophic for phe would grow
  • Utah uses the Delphia method which is a fluormetric assay and is semi-quantitative
  • Mass spectrometry is now being used by some states (better accuracy and less false positives then Guthrie test)
  • In the US there are several hundred babies diagnosed and put on diet each year
  • An initial positive test does not necessarily mean that the child will have PKU
  • A false positive elevated phe concentration (hyperphenylalaninemia) may result from:
    • a blood spot that is too thick (when using Guthrie test)
    • a sample that is improperly prepared
    • combinations of the following: liver immaturity, protein overload (in newborns who are fed cow's milk), and heterozygosity for phenylalanine hydroxylase deficiency.
  • A second screening will be performed if the first is failed
  • If the second test is positive, than further quantitative testing will be performed to confirm the levels of phe
  • After hyperphe has been established, further tests must be done to distinguish those infants with PAH deficiency from the ~2% of infants with hyperphenylalaninemia who have impaired tetrahydrobiopterin (BH4) synthesis or recycling)
  • After diagnosis, the infant is treated without delay

Diet for PKUEdit

  • Medical management is a low phe diet maintained throughout life
  • Just the right amount of phe is required because some is necessary for the body to make proteins
  • Adults with PKU who were not diagnosed at birth and have suffered irreversible brain damage can still benefit significantly from being placed on a phenylalanine-restricted diet (improved behavior noted)
  • not a typical vegetarian or vegan diet
  • protein replaced by low phe formula, usually taken in powdered form mixed with water
  • excludes all meat, fish, poultry, dairy, eggs, legumes chickpeas), nuts and seeds
  • diet includes starchy foods, fruits, vegetables, special low-protein products, and foods that contain no protein
  • starchy foods in the PKU diet contribute enough phenylanine
  • diet sweeteners such as Nutrasweet®, Sweetmate®, Canderal®, or aspartame® are made from phenylalanine and aspartic acid and should be avoided
  • diet must be carefully monitored so that growth and nutritional status are unaffected and deficiency of phenylalanine or tyrosine is not created.
  • must be adjusted for growth, illness, activity, etc.

Treatment in infancy and childhoodEdit

  • 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
  • Intake of tyrosine and total amino acids must be monitored
  • 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
  • avoid long periods of low blood phe concentration, which is also harmful to brain development
  • blood phe concentration should be monitored periodically to evaluate control
  • Recommendations for monitoring may vary, but levels should be maintained below 6 mg/dl according to NIH consensus
  • Levels are usually taken weekly or bi-weekly in infancy and less frequently as a child gets older

Treatment in adolescence and adulthoodEdit

  • Recommendations for treatment of adolescents and adults vary
  • In general, support for "diet therapy for life" is increasing
  • Adults who have abandoned the phe-restricted diet tend to have a reduced attention span, slow information processing abilities, and slow motor reaction time
  • They also develop changes in the frequency distribution of brain electrical activity, increased muscle tone and tremor, lowered bone mineral content and mental health disorders
  • Controversy remains over the plasma phe concentration to be achieved for patients older than 12 years of age
  • General consensus is that the closer the phe concentration is to the recommended normal value, the better is the individual's general state of well being

Treatment for patients with levels below that of classical PKUEdit

  • Patients with non-PKU HPA who have plasma phe concentrations consistently below (10mg/dl) have been shown to not be at higher risk of developing intellectual, neurological, and neuropsychological impairment than individuals without PAH deficiency
  • Some specialists believe that dietary treatment is unnecessary for the individuals in this class
  • However, others debate the advisability of non-treatment and will treat if level is above 5-6mg/dl

Maternal PKU risksEdit

  • fetus can be severely damaged in the womb before birth by the effects of the mother's high PHE levels
  • Blood PHE levels of a pregnant woman transferred at a 1:3 ratio to fetus
  • very possible to have normal, healthy children if the mother follows the low-phenylalanine diet strictly before conception and throughout the pregnancy
  • women with PAH deficiency who are planning a pregnancy should start a phe-restricted diet prior to conception and should maintain plasma phe concentrations between 2 to 6mg/dl (ideally over several months) before attempting conception, but the exact preferred level depends on the clinic. (At the U of U Nichola prefers that they are kept between 2-4 mg/dl)
  • after conception, they should be offered continuous nutritional guidance and weekly or bi-weekly measurement of plasma phe concentration because dietary phe and protein requirements change considerably during pregnancy
  • the likelihood that the fetus will have congenital heart disease, intrauterine and post-natal growth retardation, microcephaly, and mental retardation depends upon the severity of the maternal HPA and the effectiveness of her dietary restriction
  • Potential consequences to the fetus if diet is not maintained
    • mental retardation
  • slowness in learning ability and growth
  • affect on short term memory
  • low birth size
  • microcephaly
  • congenital heart disease

Resources and ReferencesEdit

  • Children's PKU Network
1520 State St., Suite 111
San Diego, CA 92101-2930
Phone: (619) 233-3202
Fax: (619) 233 0838
Email: pkunetwork@aol.com
  • National PKU News
Virginia Schuett, editor/dietician
6869 Woodlawn Avenue NE #116
Seattle, Washington 98115-5469
Phone: (206) 525-8140
Fax: (206) 525-5023
Email: schuett@pkunews.org
URL: http://www.pkunews.org
  • National Food Distribution Center
Roman Bhattacharya, Manager
995 Wellington, Suite 220
Montreal, Quebec, Canada H3C 1V3
Email: roman@nfdc.info
URL: http://www.nfdc.info
  • Association for Neuro-Metabolic Disorders (ANMD)
PO Box 0202/L3220 Women's
1500 Medical Center Drive
Ann Arbor, MI 48109-0202
Phone: 313-763-4697 (clinic)
Fax: 313-764-7502 (clinic)
  • Children's PKU Network
1520 State St, Suite 111
San Diego, CA 92101-2930
Phone: 619-233-3202
Fax: 619-233-0838
Email: pkunetwork@aol.com
  • NCBI Genes and Disease Webpage
Web: www.ncbi.nlm.nih.gov/disease/Phenylketo.html
  • PAH/PKU Knowledgebase
Web: www.mcgill.ca/pahdb


The information in this outline was last updated in 2002.