AMINOACIDURIAS types causes and diagnosis.pptx

Types
Causes
Diagnosis and
Management

1. AMINOACIDURIAS

2. OBJECTIVES DISORDERS OF Aromatic aminoacids Branched chain aminoacids Sulphur containing aminoacids

3. CLASSIFICATION OVER FLOW AMINOACIDURIA - Due to metabolic defects - May affect a single / few amino acids - Increased plasma level of amino acids

4. RENAL AMINOACIDURIA - Normal plasma concentration - Defective renal tubular reabsorption

5. COMMON SIGNS & SYMPTOMS Early neonatal period Persistent vomiting Failure to thrive, Developmental delay Elevated blood or urinary levels of a particular metabolite Peculiar odour Physical changes – Hepatomegaly Mental retardation

6. AROMATIC AMINOACID METABOLISM

7. DISORDERS OF AROMATIC AMINO ACID METABOLISM PKU Tyrosinemia Albinism Alkaptonuria Hartnup’s disease

8. PHENYLKETONURIA (PKU) Deficiency of phenylalanine hydroxylase Recessive condition Frequency -1 in 10,000 births 5 types

9. DEFECT IN PHY HYDROXYLASE

10. SUBTYPES SUBTYPE ENZYME DEFECT Classical phenylketonuria Phenylalanine hydroxylase Defect of biopterin cofactor biosynthesis GTP cyclohydrolase I Defect of biopterin cofactor biosynthesis 6-Pyruvoyltetrahydropterin synthase Defect of biopterin cofactor regeneration Dihydropterin reductase Defect of biopterin cofactor regeneration Pterin-4a-carbinolamine dehydratase

11. ALTERNATE PATHWAY

12. CLINICAL MANIFESTATIONS Mentally retarded with an IQ of 50 Agitation, hyperactivity, tremors and convulsions because phenylalanine interferes with neurotransmitter synthesis Hypopigmentation - the inhibition of tyrosinase Mousy body odor

13. Laboratory Diagnosis Blood phenylalanine: normal level is 1 mg/dl. In PKU, the level is >20 mg/dl. Demonstrated by chromatography Guthrie test - rapid screening test

14. Ferric chloride test: transient blue-green color DNA probes - diagnose the defects in phenylalanine hydroxylase and dihydrobiopterin reductase Tandem mass spectroscopy - most reliable test

15. ALKAPTONURIA Autosomal recessive condition Incidence of 1 in 250,000 births Deficiency of homogentisate oxidase , excretion of homogentisic acid in urine

16. The homogentisic acid is oxidized by polyphenol oxidase to benzoquinone acetate, polymerized to black alkaptone bodies

17. ALKAPTONURIA - OCHRONOSIS Deposition of Alkaptone bodies in intervertebral discs, cartilages of nose, pinna of ear Deposition of black pigments in joint cavities – arthritis 3 rd or 4 th decade of life

18. ALKAPTONURIA

19. Diagnosis of Alkaptonuria Urine becomes black on standing when it becomes alkaline

20. Ferric chloride test - positive for urine Benedict’s test - strongly positive Silver nitrate reduction test Detection of elevated homogentisic acid by GC/MS (gas chromatography/mass spectrometry)

21. TREATMENT No specific treatment Low protein diet – low phenylalanine < 500 mg/day Treatment - pHPPA oxidase inhibitors on trial

22. TYROSINEMIA 3 types Tyrosinemia type I ( Hepatorenal Tyrosinemia ) Tyrosinemia type II Tyrosinemia type III

23. Hepatorenal Tyrosinemia ( Tyrosinemia Type I) Def of Fumaryl Acetoacetate Hydrolase(FAH) Can lead to liver & kidney failure Affects nervous system Increased risk of cirrhosis & cancer later Treatment: nitisinone with low phenylalanine, tyrosine Succinyl acetone –specific marker in newborn screening

24. TYPE II ( OCULO CUTANEOUS TYROSINOSIS) RICHNER HANHART SYNDROME ) - def .of tyrosine transminase - ocular & skin manifestations - ocular lesion- corneal damage - skin lesions develop later -marked hypertyrosinemia Treatment : low phenyalanine & tyrosine diet

25. Type III def.of Hydroxy Phenyl Pyuruvate Dioxygenase (HPPD) developmental delay, seizures, self destructive behaviour elevated tyrosine levels

26. Transient tyrosinemia of newborn : -delayed maturity of HPPD enzyme -most common in preterm infants Hawkinsinuria – dysfunction of pHPPA oxidase Autosomal dominant

27. ALBINISM Greek word albino - white Autosomal recessive disease Incidence of 1 in 20,000 population Tyrosinase -completely absent, leading to defective synthesis of melanin One of Garrod’s tetrad – Albinism, Pentosuria , Cystinuria & Alkaptonuria

28. Melanin synthesis Tyrosinase defect

29. Features - albinism The ocular fundus is hypopigmented iris may be gray or red photophobia, nystagmus and decreased visual acuity The skin - low pigmentation, sensitive to UV rays nevi and melanomas Hair - white

30. Hartnup’s Disease inherited autosomal recessive disease Absorption of aromatic amino acids from intestine as well as reabsorption from renal tubules are defective.

31. Features – Hartnup’s disease The pellagra like symptoms - deficiency of niacin derived from tryptophan photodermatitis and ataxia Increased excretion of indole compounds - Obermeyer test .

32. BRANCHED CHAIN AMINOACIDIDURIA

33. Maple Syrup Urine Disease (MSUD) branched chain ketonuria incidence is 1 per 1 lakh births Branched-chain ketoacid dehydrogenase complex Hypotonia , lethargy, seizures, coma, vomiting, ketosis, pancreatitis, brain edema

34. Maple Syrup urine disease- MSUD Valine , leucine , isoleucine, alloisoleucine Detected by Tandem mass spectrometry

35. Urine – burnt sugar/ maple syrup Urine – Br. Chain keto acids + Rothera’s test + Tt : Diet low in branched chain aa , thiamine, liver transplantation

36. ISOVALERIC ACIDURIA leucine catabolism is affected Severe metabolic acidosis and neurological deficit fatal in early childhood offensive odor of urine - first sign

37. SULPHUR CONTAINING AMINOACID METABOLISM

38. DISORDERS OF SULPHUR CONTAINING AMINOACIDS Methionine metabolism: 1. Hypermethioninemia 2. Homocystinurias 3. Cystathioninuria Cysteine metabolism 1. Cystinuria 2. Cystinosis

39. HYPERMETHIONINEMIA Autosomal recessive Liver methionine adenosyl transferase def. CAUSES Impaired utilisation of methionine Excessive remethylation of Homocysteine Secondary to hepatic function

40. HYPERMETHIONINEMIA

41. Oasthouse syndrome – malabsorption of methionine Blood - ↑ methionine; Urine - ↑ met, phe , tyrosine, Br.chain keto acids

42. HOMOCYSTINURIA Disorder Absence of Clinical manifestation Treatment Type I Cystathionine B synthase MR, Ectopia lentis , charlie chaplin gait, homocysteine , Methionine Cysteine Methionine Type II Methyl transferase MR Homocyteine Folate Type III Methylene THFA reductase MR Homocyteine Folate

43. CHARLEY CHAPLIN GAIT ECTOPIA LENTIS

44. CYSTATHIONINURIA Due to deficiency of cystathionase Autosomal Recessive Mental retardation, Anaemia , thrombocytopenia, endocrinopathies

45. Diagnosis – Cyanide NP test – negative Cystathionine present in urine Treatment – Large quantities of pyridoxine – 200 to 400 mg

46. CYSTINOSIS AR - Lysosomal storage disease Rare – Deposition of Cysteine crystals in lysosomes – RES – spleen, liver, BM, WBC Kidney, & lymph nodes Due to - Defective carrier mediated transport Urine & plasma – Cysteine –N

47. CYSTINURIA AR – 1: 7000 - common Defective renal transport of Cys , Lys, Ornithine & arginine- COAL Excretion of cystine – 25 to 40 times normal

48. Cysteine – insoluble - Crystalluria – acidic pH – cysteine crystals Calculi – Obstructive uropathy – Stasis & infection – Renal failure Treatment – Increase fluid intake - ↑ urine – alkalinisation – sodium bicarbonate Cyanide nitroprusside test & Chromatography

49. CYSTINURIA – RENAL STONES

50. SUMMARY

51. DISORDERS OF Aromatic aminoacids Branched chain aminoacids Sulphur containing aminoacids

52. Peculiar odour Inborn error Urine odour Phenylketonuria Mousy or musty Tyrosinemia Boiled cabbage, Rancid butter Hawkinsinuria Swimming pool Isovaleric acidemia Sweaty feet MSUD Maple syrup Hypermethioninemia Boiled cabbage

53. Newborn Screening

54. Dried blood spot (DBS) – Sample collection Full term infants – 48-72 hrs after birth. If collected before 24hrs repeat sample within 5 days Premature (<33 wks gestational age)/ Low birth weight infants (<1800gms) Second sample 2 weeks of age Specimen should be collected before blood transfusion and TPN 60

55. Expanded Newborn screening panel 61

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