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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

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