Approach to phrnylketonuria.pptx chikdreb

Porphyrias are a group of inherited or acquired metabolic disorders resulting from a defect in the heme biosynthetic pathway, leading to accumulation of porphyrins or their precursors in tissues and body fluids.

Basic Concept:
• Heme is an essential component of hemoglobin, myoglobin, cytochromes, and various enzymes.
• It is synthesized mainly in the liver and bone marrow through a series of eight enzymatic steps.
• A deficiency or malfunction of any of these enzymes causes a build-up of intermediate compounds — these intermediates (porphyrins or their precursors) are toxic and lead to the clinical features of porphyria.

1. Phenylketonuria Presenter : Dr. Gowthami Moderator : Dr. VishnuVandana

2. PKU is discovered by a norwegian physician, Ivar Asbjørn Følling in 1934. In Norway, it is termed as Folling’s disease. HISTORY

3. Autosomal recessive disorder. Mutation in PAH gene located on 12 th chromosome . This enzyme is necessary to metabolize the amino acid phenylalanine ( PheA ) to the amino acid tyrosine. Etiology

4. The percentage of different types of mutation that can occur in the gene are as follows: Missense mutations : 62% Small or large deletions : 11% Splicing defects : 6% Nonsense mutations : 5% Insertions : 2%

5. The mean incidence of PKU varies widely in different human populations. More common in whites & Asians. India 1 in 18,300 incidence

6. The enzyme phenylalanine hydroxylase ( in the presence of co-factor tetrahydrobiopterin BH4) normally converts the aminoacid phenylalanine into the aminoacid tyrosine. Deficiency of the enzyme PAH or of its cofactor tetrahydrobiopterin (BH4) causes accumulation of phenylalanine in body fluids and in the brain. pathophysiology

7. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Excess phenylalanine is metabolized through the minor route, a  transaminase pathway with glutamate to phenyl ketones (phenyl pyruvate and phenyl acetate) that are excreted in the urine, giving rise to phenylketonuria (PKU).

8. Phenylalanine is a large, neutral amino acid (LNAA) . LNAAS compete for transport across the blood–brain barrier via the large neutral amino acid transporter . If phenylalanine is in excess in the blood, it will saturate the transporter, excessive levels of phenylalanine tend to decrease the levels of other LNAAS such as Tyrosine and Tryptophan in the brain.

9. It is the most severe form of PKU. Caused by complete or near-complete deficiency of phenylalanine hydroxylase activity. A normal plasma phenylalanine conc. is about 1mg/dl. In Classical PKU, plasma PheA concentration becomes greater than 20mg/dl. Classical pku

10. The affected infant is normal at birth. Symptoms only develop due to complications that arise if the condition is not treated properly. Profound mental retardation develops gradually if the infant remains untreated. Cognitive delay may not be evident for the 1st few months. In untreated patients, 50-70% will have an IQ below 35 , & 88-90% below 65 . Only 2-5% of untreated patients will have normal intelligence. Clinical features of classical pku

11. Microcephaly Seizures spasticity, hyperreflexia tremors Growth retardation Mousy odour Hair loss Prominent maxillae with widely spaced teeth Enamel Hypoplasia Albinism Light sensitivity eczema

12. Screening on blood samples during the first week of life. Usually a few drops of blood are obtained by a small prick on the heel, placed on a card and then sent for measurement. Newborn screening allows early identification and early implementation of treatment. Diagnosis

13. In places where such programs are not in effect, identification of phenyl ketones in the urine by ferric chloride may offer a simple test for diagnosis. Ferric chloride + urine of new born baby Green colour in the presence of ketone bodies.

14. Other tests include Guthrie test – Bacterial Inhibition Assay Fluorometric & Tandem Mass Spectrometry It is recommended that the blood for screening be obtained in the 1st 24-48 hr of life after feeding protein to reduce the possibility of false-negative results, especially in the milder forms of the condition.

15. The goal of therapy is to reduce phenylalanine levels in the plasma and brain. Treated with a phenylalanine-restricted diet. Formulas low in or free of phenylalanine are commercially available. The diet should be started as soon as diagnosis is established. T reatment

16. Because phenylalanine is not synthesized endogenously, small amounts of phenylalanine should be added to the diet to prevent phenylalanine deficiency. Moreover, Tyrosine becomes an essential amino acid in this disorder and its adequate intake must be ensured.

17. plasma phenylalanine levels to be maintained between 2 & 6 mg/dl in neonates through 12 yr of age and between 2 & 15 mg/dl in older individuals. The fact that brain development continues in adolescence and even in adulthood, lower plasma phenylalanine levels (2-10 mg/dl) have been encouraged strongly after 12 yr of age.

18. The duration of diet therapy is also controversial. Discontinuation of therapy, even in adulthood, may cause deterioration of IQ and Cognitive performance. The current recommendation from the National Institutes of Health consensus Development Panel is that all patients be kept on a phenylalanine-restricted diet for life.

19. Phenylalanine levels are monitored typically Twice a week in neonates, Weekly in infants, biweekly or every 3 weeks in toddlers & Monthly thereafter, even during adult life.

20. In patients with residual pah activity , Sapropterin , a synthetic form of BH4, which acts as a cofactor is approved by the food and drug administration (FDA) to reduce phenylalanine levels in PKU. At a dose of 10 mg/kg/day Used along with low phenylalanine diet

21. Pregnant women with hyper phenylalaninemia who are not on a phenylalanine-restricted diet have a Very high risk of having offspring with mental retardation, microcephaly, growth retardation & congenital heart disease. Maternal PKU

22. These complications are directly correlated with elevated maternal phenylalanine levels during pregnancy. Mothers who have been treated for hyper phenylalaninemia should be maintained on a Phenylalanine-restricted diet before & during pregnancy ; Blood phenylalanine levels below 6 mg/dl throughout pregnancy.

23. In 1-3% of infants with hyper phenylalaninemia , the defect resides in one of the enzymes necessary for production or recycling of the cofactor BH4. If these infants are misdiagnosed as having PKU, they may deteriorate neurologically despite adequate control of plasma phenylalanine. PKU due to co-factor bh4 deficiency:

24. In addition to acting as a cofactor for PAH, BH4 is also a cofactor for tyrosine hydroxylase & tryptophan hydroxylase , which are involved in the biosynthesis of Dopamine & Serotonin respectively. Therefore, patients with hyper phenylalaninemia due to BH4 deficiency also manifest neurologic findings related to deficiencies of the neurotransmitters dopamine and serotonin.

25. 4 enzyme deficiencies lead to defective bh4 formation which include: GTP CYCLOHYDROLASE deficiency, PTERIN-CARBINOLAMINE DEHYDRATASE deficiency, DIHYDROPTERIDINE REDUCTASE deficiency & 6 -PYRUVOYLTETRAHYDROPTERIN SYNTHASE deficiency.

26. the clinical manifestations of the neurotransmitter disorders differ greatly from those of pku. Neurologic symptoms of the neurotransmitter disorders often manifest in the 1st few months of life & include Extrapyramidal signs with Choreoathetotic or Dystonic limb movements, Axial & Truncal hypotonia, Hypokinesia, Feeding difficulties & Autonomic problems.

27. BH4 loading test: An oral dose of BH4 (20 mg/kg) normalizes plasma phenylalanine in patients with BH4 deficiency within 4 to 8 hrs The blood phenylalanine should be elevated (>20 mg/dl) to enable interpretation of the results. This may be achieved by discontinuing diet therapy for 2 days before the test or by administering a loading dose of phenylalanine (100 mg/kg) 3 hrs before the test. diagnosis

28. In BH4-responsive PKU due to PAH deficiency, phenylalanine levels may decrease during the BH4 loading test but increase later even with BH4 Supplementation. Patients who demonstrate phenylalanine levels within normal range over at least a week without a phenylalanine-restricted diet can be continued on BH4 supplementation as the sole treatment for the Hyper phenylalaninemia.

29. Enzyme assay : Activity of Dihydropteridine Reductase can be measured in the dry blood spots on the filter paper used for screening purposes. Activity of 6-Pyruvoyltetrahydropterin synthase can be measured in the liver, kidneys & erythrocytes .

30. Activity of Carbinolamine dehydratase can be measured in the liver & kidneys. Activity of GTP cyclohydrolase can be measured in the liver & in cytokine (interferon-γ) stimulated mononuclear cells or fibroblasts

31. The goals of therapy are; To correct hyper phenylalaninemia and to restore neurotransmitter deficiencies. The control of hyper phenylalaninemia is important in patients with cofactor deficiency, because high levels of phenylalanine interfere with the transport of neurotransmitter precursors (tyrosine, tryptophan) into the brain. Treatment

32. Plasma phenylalanine should be maintained as close to normal as possible (<6 mg/dl). This can be achieved by a combination of a low phenylalanine diet and oral supplementation of BH4. Infants with GTP cyclohydrolase or 6-PTS deficiencies respond more readily to BH4 therapy 5-10 mg/kg/day than those with DiHydropteridine Reductase deficiency require doses as high as 20 mg/kg/day .

33. Lifelong supplementation with neurotransmitter precursors such as L-dopa & 5-hydroxytryptophan, along with carbidopa. Neurotransmitter precursors usually does not fully resolve the neurologic symptoms due to the inability to attain normal levels of BH4 in the brain. Patients often demonstrate mental retardation, fluctuating abnormalities of tone, eye movement abnormalities, poor balance and coordination, decreased ability to ambulate, and seizures in spite of supplementation

34. Folinic acid supplementation is recommended in patients with Dihydropteridine Reductase deficiency. Some drugs such as Trimethoprim Sulfamethoxazole , Methotrexate & other antileukemic agents are known to inhibit Dihydropteridine Reductase enzyme activity & should be used with great caution in patients with BH4 deficiency.

35. The prognosis for normal intelligence is excellent when patients have been put on a diet low in phenylalanine in the first month of life, with careful monitoring. Patients with PKU who are treated early and continuously can have a normal health-related quality of life and course of life. PROGNOSIS

36. It is one of the preventable causes of Mental Retardation Psychological problems, including agoraphobia and other disorders, have been reported in individuals both on and off dietary treatment.

37. Nelson TextBook of Pediatrics IAP TextBook of Pediatrics Meherban Singh Care of NewBorn New strategies for the treatment of phenylketonuria nov /2014 references

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