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Phenyl ketonuria Slide 1 Phenyl ketonuria Slide 2 Phenyl ketonuria Slide 3 Phenyl ketonuria Slide 4 Phenyl ketonuria Slide 5 Phenyl ketonuria Slide 6 Phenyl ketonuria Slide 7 Phenyl ketonuria Slide 8 Phenyl ketonuria Slide 9 Phenyl ketonuria Slide 10 Phenyl ketonuria Slide 11 Phenyl ketonuria Slide 12 Phenyl ketonuria Slide 13 Phenyl ketonuria Slide 14 Phenyl ketonuria Slide 15 Phenyl ketonuria Slide 16 Phenyl ketonuria Slide 17 Phenyl ketonuria Slide 18 Phenyl ketonuria Slide 19 Phenyl ketonuria Slide 20 Phenyl ketonuria Slide 21 Phenyl ketonuria Slide 22 Phenyl ketonuria Slide 23 Phenyl ketonuria Slide 24 Phenyl ketonuria Slide 25 Phenyl ketonuria Slide 26 Phenyl ketonuria Slide 27 Phenyl ketonuria Slide 28 Phenyl ketonuria Slide 29 Phenyl ketonuria Slide 30 Phenyl ketonuria Slide 31
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Phenyl ketonuria

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INBORN ERRORS OF METABOLISM, PKU, PHENYLKETONURIA, BY: MR. DINABANDHU BARAD, MSC TUTOR, SUM NURSING COLLEGE, SIKSHA O ANUSANDHAN DEEMED TO BE UNIVERSITY, BHUBANESWAR, ODISHA

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Phenyl ketonuria

  1. 1. PHENYL KETONURIA PRESENTED BY: MR. DINABANDHU BARAD MSC TUTOR, SNC, SOA,DTU
  2. 2. METABOLIC DISORDER • Metabolism is the aggregate of the chemical reactions that are continuously occurring in the living organisms to keep them alive. • The principal function of the metabolism are the production of energy, elimination of the nitrogen wastes, making building blocks for carbohydrate, protein and fat.
  3. 3. METABOLIC DISORDER • Numerous chemical reactions are occurring at the subcellular level at the same time that are controlled by specific proteins or enzymes. • Any defect in these proteins or enzymes may lead to defect in the metabolic process and in turn leads to the disorders.
  4. 4. METABOLIC DISORDER • The metabolic disorders or the inborn errors of metabolism are the group of rare genetic disorders most of which are autosomal recessive, some are x-linked recessive and few are autosomal dominant. • Although these are very rare kind of genetic defects till now more than 500 in born errors of metabolism diseases are identified.
  5. 5. CLASSIFICATION The common groups of in born errors of metabolism with example are listed below AMINO ACID METABOLISM DEFECT A) Defective metabolism (Phenylketonuria, Maple Syrup Urine Disease (MSUD), alkaptonuria, tyrosinemia, albinism) B) Defective transport (Cystinosis, Cysturia, Hartnup disease, Lysinuric protein intolerance)
  6. 6. CLASSIFICATION CARBOHYDRATE METABOLISM DEFECT A. Galactosemia B. Glucose 6 phosphate dehydrogenase(G6PD) deficiency C. Pyruvate dehydrogenase deficiency D. Carbohydrate intolerance disorders (Lactose intolerance, Heriditary fructose intolerance) E. Fructosuria F. Pentosuria G. Mucopolysachharidosis and oligosacharidosis H. Glycogen storage disorders Type-I (Von Gierke’s disease), Type-II (Pompe’s disease), Type-III (Cori’s disease), Type-IV (Anderson’s disease), Type-V (Mc Ardle’s disease), Type-VI (Her’s disease), Type-VII (Tauri’s disease)
  7. 7. CLASSIFICATION LIPID METABOLISM DEFECT A. Fatty acid oxidation defects (Zellweger’s syndrome, Carnitine deficiency, refsum’s disease) B. Lipid storage defects (Tay-Sachs disease, Gaucher’s disease, Niemann pick disease, farber’s disease, fabry’s disease, Krabbe’s disease) C. Lipoprotein metabolism defects Hyperlipoproteinaemias, Hypolipoproteinaemias (Tangier’s disease, A- beta Lipoproteinaemia)
  8. 8. CLASSIFICATION MINERAL METABOLISM DEFECT (Wilson disease, Menkes Kinky hair disease, hemochromatosis) PURINE AND PYRIMIDINE METABOLISM DEFECT (Lesch-Nyhan disease) MITOCHONDRIAL DISEASES (Leigh disease, myoclonic epilepsy ragged red fibers (MERRF), Leber hereditary optic neuropathy)
  9. 9. PHENYLKETONURIA • It is an autosomal recessive disorder caused by defective metabolism of the amino acid phenylalanine. • Normally phenylalanine converts to tyrosine by the enzyme called phenylalanine hydroxylase. • This enzyme is encoded by the gene PAH located in the q arm of chromosome 12 (Chr. 12q23.2).
  10. 10. PHENYLKETONURIA • Therefore mutation in this locus causes the deficiency of the enzyme which leads to failure of conversion and finally there is accumulation of phenylalanine in the blood, CSF and other tissues. • The severity of the hyperpheynylalaninemia depends on the degree of enzyme deficiency which may differ from very high plasma concentrations >20mg/dl (Classic PKU) to mild elevation 2-6mg/dl.
  11. 11. PHENYLKETONURIA • The excess amount of phenylalanine is metabolized and converted to phenyl ketones (phenyl pyruvate and phenyl acetate) that are excreted through urine thus justifies the name Phenylketonuria.
  12. 12. H2O O2 METABOLIC PATHWAY OF PHENYLALANINE
  13. 13. TYPES OF PKU Based on the defect of the enzymes PKU can be classified as follows: • TYPE-I (Classical) : complete deficiency of the enzyme Phenylalanine hydroxylase (PAH) • TYPE-II (Variant) : Partial deficiency of enzyme PAH • TYPE-III (Transient): Delayed maturation of PAH • TYPE-IV : Deficiency of Dihydrobiopterin reductase • TYPE-V : Deficiency of Dihydrobiopterin synthetase lead to defective biosynthesis Of Dihydrobiopterin
  14. 14. ETIOLOGY • Approximately 97% of the cases are affected with the phenylalanine hydroxylase deficient PKU in which the enzyme PAH is partially or completely deficient and in few cases there is immature phenylalanine hydroxylase which has altered function. • The deficiency of PAH is due to the mutation in the gene PAH which provides instructions to make the enzyme Phenylalanine hydroxylase.
  15. 15. ETIOLOGY • PAH gene is located in the q arm of the chromosome 12 at the locus 12q23.2 between 102,836,889bp-102,958,410 bp. • There are more than 500 mutations identified till now in the PAH gene which leads to PKU.
  16. 16. ETIOLOGY • Most of the mutations are the point mutation which replaces single codon on the DNA sequence thereby change the corresponding amino acid. • The most common point mutation is the replacement of the amino acid arginine with tryptophan at the position 408 (written as Arg408Trp or R408W).
  17. 17. CLASSIC PHENYLKETONURIA When severe hyperphenylalaninemia (>20mg/dl in plasma) remain untreated it shows sign symptoms of classic PKU except rare cases. Clinical Features: • The infants affected with classic PKU do not show sign symptoms at birth but gradually begin to develop neurological manifestations due to accumulation of excess phenylalanine in the brain which causes destruction of myelin sheath.
  18. 18. CLASSIC PHENYLKETONURIA When severe hyperphenylalaninemia (>20mg/dl in plasma) remain untreated it shows sign symptoms of classic PKU except rare cases. Clinical Features: • The neurological features can be intellectual disability, seizure, behavioural problems, delayed development etc. • Excess phenylalanine also interfere with the neurotransmitters like dopamine and serotonin causing depression.
  19. 19. CLASSIC PHENYLKETONURIA When severe hyperphenylalaninemia (>20mg/dl in plasma) remain untreated it shows sign symptoms of classic PKU except rare cases. Clinical Features: • High level of phenylalanine also impede the melanin production that leads to light colour of the eye, skin and hair. • Excretion of the phenyl acetic acid (phenyl ketone) in urine and sweat causes musty or mousy odour of the body.
  20. 20. MILD HYPERPHENYLALANINEMIA When the plasma concentration of phenylalanine is between 2-20 mg/dl is called mild hyperphenylalaninemia or non-PKU hyperphenylalaninemia. • The infants suffering from mild hyperphenylalaninemia have partial deficiency of the phenylalanine hydroxylase enzyme or Tetrahydrobiopterin (BH4) Clinical features: • Clinically these infants don’t reveal any sign symptoms but progressive brain damage may occur with age.
  21. 21. DIAGNOSIS PHYSICAL EXAMINATION FOR CLASSICAL PKU • The affected infants have lighter eye, skin and hair colour as compare to the normal infants. • They may have Musty or mousy body odour. Microcephaly, Growth retardation, wide gap between the teeth also can be seen.
  22. 22. DIAGNOSIS LAB INVESTIGATIONS According to the recommendation of American academy of pediatric PKU screening should be repeated by two weeks of age if it is performed before the newborn was 24h of age. PKU screening can be performed by the following methods: • Guthrie Bacterial Inhibition Assay • McCamon Robins Flurometric test • Tandem mass spectrometry
  23. 23. DIAGNOSIS DNA analysis: It is useful to detect specific mutation in the affected gene for which following methods are used: • Sanger sequencing • Next Generation sequencing (NGS) • Multiplex ligation dependent probe amplification (MLPA) • Whole exome sequencing • PCR based technique
  24. 24. DIAGNOSIS IMAGING STUDY: • In research studies cranial CT scan on patients with 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency revealed calcification in the lentiform nuclei and in patients with Dihydropteridine reductase (DHPR) deficiency there was severe cortical and subcortical atrophy.
  25. 25. DIAGNOSIS IMAGING STUDY: • MRI studies on patients with BH4 deficiency showed white matter changes and on patients with PTPS deficiency showed delayed myelination and abnormal high intensity signals in cerebral white matter. • So imaging study can be used to understand and monitor the neurophysiological changes of the affected patients but this may not be appropriate for a newborn.
  26. 26. TREATMENT Diet therapy: • The aim of the treatment is to lower and maintain the plasma phenylalanine level between 2-6 mg/dl at least till 12 years of age. • The infant with persistent plasma phenyl alanine level >6mg/dl are treated with phenylalanine restricted diet. • But infant having plasma phenylalanine level between 2-6mg/dl are not required any diet restriction.
  27. 27. TREATMENT Diet therapy: • The foods that contains high amount of phenylalanine are fish, meat, eggs, nuts, legumes, wheat, milk, beans etc. therefore should be avoided. • As the body do not produce phenylalanine the infant should not be over treated when the infant is under diet restriction otherwise it may leads to phenylalanine deficiency.
  28. 28. TREATMENT Diet therapy: • There is a controversy regarding the duration of the diet restriction as discontinuation of the therapy leads to IQ deterioration and cognitive impairment. Current recommendation says diet restriction should be continued lifelong.
  29. 29. TREATMENT Pharmacological therapy: • In case of mild form of hyperphenylalanine oral administration of Sapropterin dihydrochloride (Tetrahydrobiopterin) is effective in reducing plasma phenylalanine level. It is also effective in case of BH4 deficient PKU. • Phenylalanine ammonia lyase (PAL) is currently under clinical trial which is used as an alternative to the PAH enzyme therefore can be used in case of classic form of phenylketonuria
  30. 30. TREATMENT NURSING MANAGEMENT: • Educate the family members about the diet containing phenylalanine, need and duration of the restriction. • Care givers of the infant need to be counselled regarding the process and transmission of the disease from one generation to another. • Emotional support should be provided to the parents so that they can cope with the stress and adverse situation. • Educate the caregivers regarding safety measures during seizure.
  31. 31. THANK YOU
  • AmlHassan7

    Nov. 25, 2020

INBORN ERRORS OF METABOLISM, PKU, PHENYLKETONURIA, BY: MR. DINABANDHU BARAD, MSC TUTOR, SUM NURSING COLLEGE, SIKSHA O ANUSANDHAN DEEMED TO BE UNIVERSITY, BHUBANESWAR, ODISHA

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