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This is a presentation of PKU case and genetic counseling. Presented on April 2010 in Genetic Counseling master programme, FMDU, Semarang

This is a presentation of PKU case and genetic counseling. Presented on April 2010 in Genetic Counseling master programme, FMDU, Semarang

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  • 1. Genetic Counseling in Phenylketonuria
    Literature Review by
    Rahajeng N. Tunjungputri, MD
    Magister of Biomedical Science/ Genetic Counseling
    Faculty of Medicine Diponegoro University, 2010
  • 2. Case
    A married couple has their 2 year old daughter diagnosed with phenylketonuria. They are referred for genetic counseling. What are you going to do as their genetic counselor?
  • 3. What will be done?
    The girl was previously diagnosed with PKU, therefore the genetic counselor must:
    Confirm the diagnosis
    Look at the available medical records/laboratory examinations
    Establish the correct diagnosis before counseling
    Explain the genetic basis of phenylketonuria
    Explain the lifetime management of PKU and the need for monitoring
    Explain about recurrence risk and risk of carriers in the family
  • 4. Introduction
    Phenylketonuria (PKU) is an inborn error of protein metabolism that results from an impaired ability to metabolize the essential amino acid phenylalanine
    US 1/15000 births, Turkey 1/2600 births
    High frequency: northern and eastern Europe, Italy, China
    PKU counts for 1% of institutionalized MR patients.
    Untreated: severe mental retardation.
    Well-treated patients should have IQs within approximately 5-8 points of their siblings.
  • 5. Genetics of PKU
    Classical PKU is an autosomal recessive manner and is the result of mutations in the PAH gene, located in12q24.1
    The normal product of the PAH gene is the protein phenylalanine hydroxylase (PAH) which hydroxylates phenylalanine to tyrosine
    Deficiency of PAH leads to hyperphenylalaninemia
    Figure from : HoeksMP, den Heijer M, Janssen MC. Adult issues in phenylketonuria. Neth J Med. 2009 Jan;67(1):2-7
  • 6. Clinical manifestations
    Most appear normal at birth
    Progressive developmental delay
    Later infancy and childhood: vomiting, mousy odor, eczema, seizures, self-mutilation, and severe behavioral disorders
    Failure of dietary treatment may deteriorate:
    Motor function
    Cognitive ability
    Neuropsychological function
    Mental retardation
    Mousy odor
    Fair coloring as a result of tyrosine deficiency
  • 7. Diagnosis
    PAH deficiency can be diagnosed by newborn screening based upon detection of the presence of hyperphenylalaninemia using heelprick (<8 days)
    PKU is diagnosed in individuals with plasma phenylalanine (Phe) concentrations higher than 1000 µmol/L in the untreated state
  • 8. Management
    Dietary management:
    Goal: normalization of the concentrations of Phe and Tyr in the blood to prevent brain damage
    Phe: 120-360 µmol/L (2-6 mg/dL)
    Low Phe diet and amino acid supplementation except Phe (also: Phe-free medical formula)
    The diet, growth and nutritional status must be monitored
    The diet must be adjusted for growth, illness, activity, etc.
    Image available from
  • 9. Management
    Table adapted from various references. This table does not show complete classification of PKU
  • 10. Management
    Large Neutral Amino Acid (LNAA)
    Phenylalanine, tyrosine, tryptophan, leucine, isoleucinecompete with each other at the blood brain barrier
    Carrier saturation and competitive inhibition of Phe results in a decrease in Phe. A double blind RCT shows 39% decrease in plasma Phe
    Dose (number of tablets) is individualized by body weight (kg)X 0.4. For example, an individual who weighs 50 kg would receive 20 tab daily (ie, 50 kg X 0.4 = 20 tab). Divide daily dose into 3-4 doses administered with meals or snacks. For age >15 years.
  • 11. Malignant PKU
    A small percentage of children with elevated phenylalanine levels exhibit normal phenylalanine hydroxylase but have a deficiency in synthesis or recycling of the enzyme's cofactor, tetrahydrobiopterin. This condition is termed malignant phenylketonuria. 
    These patients benefit from treatment with synthetic form of tetrahydrobiopterin (BH4) for malignant PKU
    BH4 is cofactor for phenylalanine hydroxylase (PAH)
    BH4 can activate residual PAH enzyme, improve normal oxidative metabolism of phenylalanine, and decrease phenylalanine levels in some patients 10 mg/kg PO qd initially;
    Dosage ranges from 5-20 mg/kg/d (established for age >4 years old)
  • 12. Table from : HoeksMP, den Heijer M, Janssen MC. Adult issues in phenylketonuria. Neth J Med. 2009 Jan;67(1):2-7
  • 13. Counseling of recurrence risk
    Inherited in AR manner
    Risk to family members
    Unaffected parents of a child with PAH deficiency are obligate heterozygotes (asymptomatic carriers)
    At conception, each sibling of a proband has:
    25% chance of being affected (homozygous)
    50% chance of being an asymptomatic carrier of a disease-causing allele (heterozygous)
    25% chance of having two normal alleles
  • 14. Offspring of a proband
    Affected individuals who receive effective treatment can live physically and intellectually normal lives and have their own children
    Children born of one parent with PKU and one parent with two normal alleles are obligate heterozygotes.
    If one parent is affected and the other parent is a carrier:
    50% chance of being heterozygous (carrier)
    50% chance of being affected
    If the mother is the affected parent, maternal HPA/PKU becomes a critical issue
  • 15. Genetic testing
    Molecular genetic testing uses sequence analysis, targeted mutation analysis, or deletion/duplication analyses for:
    Confirmatory diagnostic testing
    Carrier testing
    Prenatal diagnosis
    Preimplantation genetic diagnosis
    Biochemical determination of carrier status if molecular genetic testing is not possible: analysis of the plasma Phe concentration and Phe/Tyr ratio
  • 16. Other related issues
    Carrier testing for at-risk family members is possible when mutations have been identified in the proband
    At-risk newborn of family members: 
    If prenatal diagnosis is not available/not done/not conclusive 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.
    Before pregnancy, the followings should be considered:
    Time for determination of genetic risk in child
    clarification of carrier status
    discussion of the availability of prenatal testing
  • 17. Prenatal diagnosis
    Available for pregnancies at increased risk with CVS or amniocentesis
    Prenatal diagnosis: ethical for early diagnosis rather than termination of pregnancy, as disease is treatable and associated with good prognosis with early treatment. 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.
  • 18. Adult and Maternal PKU
    Problems in adulthood: motor, cognitive and psychological problems, vitamin deficiencies, osteoporosis due to discontinuation of diet
    Women with PKU should receive information about the need of strict diet and monitoring before and during pregnancy
    Maternal PKU can be teratogenic unless strict dietary control is maintained (guidelines recommend blood Phe levels of 120 to 240 μmol/l) in pregnancy.
    Teratogenic effect: microcephaly, MR, CHD, IUGR, facial dysmorphism.
    PKU and HPA woman should be seen every three to four weeks and blood Phe levels must be monitored at least once a week.
  • 19. Take home message
    Adherence to treatment may be challenging due to acceptability of diet
    With good treatment and counseling PKU patients have excellent clinical outcomes
    Lifetime management is highly important
  • 20. References
    Cristine M. Trahms Program for Phenylketonuria. The Esssentials of PKU. [Online]. 2010 [cited 10 April 2010]. Available from: URL:
    Hoeks MP, den Heijer M, Janssen MC. Adult issues in phenylketonuria. Neth J Med. 2009 Jan;67(1):2-7.
    Hurst JA. Oxford Desk Reference Clinical Genetics. USA: Oxford University Press; 2005.
    Mitchell J. Phenylalanine Hydroxylase Deficiency. In: Gene Reviews. [Online]. 2007 [cited 11 April 2010]. Available from: URL:
    Muntau AC, Röschinger W, Habich M, Demmelmair H, Hoffman B, Sommerhoff CP, Roscher AA. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med. 2002 Dec 26;347(26):2122-32.
    OMIM. Phenylketonuria. [Online]. 2010 [cited 11 April 2010]. Available from: URL: