inborn errors of metabolism biochemical basis

Transcription

1 inborn errors of metabolism biochemical basis

2 What is an inborn error of metabolism (IEM)? Genetically determined biochemical disorders, that affect an individual s ability to convert nutrients or to use them for energy production.

3 Majority of IEMs are due to defect in a single gene that code for an : ENZYME COFACTOR TRANSPORTER Most of them are inherited in an autosomal recessive pattern

4 Fundamental design of the normal metabolic pathways and effects of metabolic aberrations Substrate accumulation METABOLIC BLOCK Product deficiency A B C D E F Accumulation of byproducts GARROD S HYPOTHESIS

5 IEMs affecting mother and fetus

6 diagnosis Prenatal diagnosis Newborn screening Evaluation of symptomatic patients Postmortem screening Analysis of 1) Metabolites 2) Enzymatic activity 3) Molecular structure

7 classification Three broad categories: Based on the effects of their metabolic derangement. 1. Intoxication type 2. Energy deficiency type 3. Disorders of complex molecules (storage type)

8 INTOXICATION EFFECT Disorders of amino acid metabolism

9 Disorders of amino acid metabolism Hartnup s disease Defects in aminoacid catabolism Defects in aminoacid membrane transport Cystinuria Urea cycle defects Glycine S containing aminoacids Branched chain a.a Aromatic a.a Nonketotic hyper glycinemia, Primary hyper oxaluria cystinuria, homo cystinuria, cysta thioninuria MSUD PKU, alkaptonuria, hyper tyrosinemias

10 Aromatic amino acids II Tyrosinaemia III Fumaryl acetoacetase Tyrosinaemia I

11 Classic Phenylketonuria And Other Hyperphenylalaninemias DHP reductase

12 phenylketonuria HYDROXY PHENYL LACTIC ACID, PHENYL PYRUVIC ACID PHENYL ALANINE* PHENYL ACETIC ACID* PHENYLALANINE HYDROXYLASE Blood phenylalanine (30-80mmol/L) Urine phenyllactic, phenylacetic Urine pterin profile - Neopterin and biopterin, primapterin Activity of dihydropteridine reductase in blood cells 5-HIAA and HVA in CSF

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14 3) DiNitroPhenylHydrazine

15 tyrosinaemias TYPE I Hepatorenal tyrosinaemia Fumaryl fumarate acetoacetate Fumaryl acetoacetate hydrolase acetoacetic acid ALA Succinyl acetone ALA dehydratase PBG Elevated conc. of tyrosine Urine succinylacetone ALA and succinylacetone in blood Alphafetoprotein

16 TYPE II Tyrosine transaminase Tyrosine P-hydroxy phenyl pyruvate Oculocutaneous tyrosinaemia painful corneal erosions and plaques, inflammation and keratosis of palmar surface

17 alkaptonuria Homogentisate Maleyl acetoacetate Ochronosis benzoquinone acetate (urine) black alkapton bodies Ferric cloride test- purple black Benedicts test- brown colour

18 ALBINISM Tyrosine Tyrosinase DOPA Tyrosinase Albinism DOPA quinone Dopachrome Melanine

19 Disorders of branched chain amino acid metabolism High plasma conc of branched chain aa s BC ketoacids, oxoacids and hydroxy acids urine Odor of maple syrup smelling ear wax alloisoleucine Positive DNPH test FeCl test- greenish grey color

20 Disorders of sulfur containing aa s

21 Biosynthesis of cysteine Homocystinuria α- KB dehydrogenase Propionyl Co A

22 Accumulation of homocysteine, Deposited in various tissues Binds copper and interferes with maturation of collagen and elastin Skeletal deformities, posterior dislocation of lens,mental retardation, increased susceptability to thrombosis.

23 Disulfide homocystine levels Total and free homocysteine levels (immunoassay, HPLC, tandem mass spectrometry) Methionine levels (B.U)

24 Urea cycle Hyperammonemia without metabolic acidosis defect of the UREA CYCLE

25 HYPERAMMONAEMIAS Acetyl CoA + glutamate Urine orotic acid NAG synthase OTC deficiency N-acetyl-glutamate Elevated citrulline citrullinaemia type I (ASA deficiency) CPS-I CO2 + NH3 - + type 2 ATP 2 (citrin deficiency) carbamoylphosphate carbamoylphosphate + MITOCHONDRION Ornithine Ornithine OTC ORC1 Aspartate Citrulline (HHH) Low conc of citrulline with elevated glutamine NAGS, CPS-1 and OTC deficiency Hyperammoniemias, abnormal liver functions, elevated CYTOSOL CITRIN ORC1 ORC1 transaminases, N abnormal Aspartate + Citrulline PT/PTT ratio, plasma aa s (glutamine ASA synthase and alanine), ASA urine lyase amino acids Arginosuccinic acid UREA UTP, CTP Orotic acid Arginase ORC1 deficiency HHH syndrome hyperammonaemia, hyperornithinaemia, homocitrullinuria fumarate + Arginine

26 Disorders of amino acid transport

27 Hartnups disease Results from defects in intestinal & renal transport of neutral aas like tryptophan (neutral AA transporter). Degradation of tryptophan indoleyl acetic acid and indolyl acetyl glutamine neurotoxic action neurological symptom Pellagra like symptoms Blood: plasma levels of tryptophan Urine shows amounts of IAA (Obermeyer test)

28 CYSTINURIA: renal and GIT transport of cystine and dibasic aa s defective Cystine insoluble Precipitates in the renal tubules Cystine calculi - nephrolithiasis. U- cystine, lysine, ornithine, arginine Lysinuric protein intolerance Cationic amino acid transporter Failure to thrive, alveolar proteinosis, hepatosplenomegaly, pancreatitis, diarrhea, osteoporesis, hypotonia, postprandial hyperamonemia Lysine, arginine, ornithine U Orotic acid - U

29 Organic acidaemias Hyperammonaemia with metabolic acidosis and ketosis ORGANIC ACIDAEMIAS

30 Accumulation of intermediates in the catabolic pathways of amino acids intermediates water soluble (carboxyl groups) Physiologic metabolites present in excessive amounts/ metabolites not normally present Metabolic acidosis 6.85 to 7.3 Low bicarbonate - <5-15 mmol/l Significant anion gap

31 Propionic aciduria Methyl malonic aciduria Propionyl CoA carboxylase Methyl malonyl CoA mutase Propiony l carnitine Methyl citric acid MMA Vitamin B12 lysosomal release

32 Biochemical effects in propionic acidaemia Increased organic acids Ketosis and metabolic acidosis with secondary Hyperammonaemia and Hyperglycinemia Increased glucose utilization Hypoglycemia and Ketosis

33 Severe metabolic acidosis Hyperammonaemia chracteristic odor of sweaty feet urine organic acid analysis -

34 3-OH glutaric acid Urine Glutary carnitine - plasma

35 Carbohydrate metabolism

36 SORBITOL/ GALACTOSE METABOLISM

37 Aldose reductase

38 Excess gal-1-p inhibits glycogen phosphorylase and phosphoglucomutase impede glycogenolysis accumulation of glycogen in the liver-jaundice; Feeding difficulties and vomitings poor weight gain Renal failure- albuminuria and aminoaciduria Galactitol accumulates in lens and causes cataracts Galactosaemia persistent stimulus for insulin secretion by pancreas - hypoglycaemia, Abnormal lethargy or irritability

39 Effect on erythrocytes: Galactose Inhibits glucose-6-phosphate dehydrogenase HMP Shunt Reduces the supply of NADPH haemolysis

40 FRUCTOSE METABOLISM

41 ENERGY DEFICIENCY Disorders of the carnitine cycle and fatty acid oxidation Hypoketotic hypoglycaemia with/witout hyperammonaemia FATTY ACID OXIDATION IMPAIRMENT

42 Fasting or high energy demand fatty acids main substrates for energy prodution in liver, cardiac and skeletal muscle Fasting or high energy demands Fatty acids are releaed from adipose tissue Impaired oxidation of fatty acids Accumulate in liver, heart, skeletal muscle Cardiomyopathy, myopathy, Fatal arrythmias

43 Lack of acetyl CoA Dec. Gluconeogenesis Excesssive utilization of glucose Hypoglycaemia Decreased availability of ketones Dec in energy supply to the brain LOC, seizures and coma

44 CARNITINE CYCLE Carnitine uptake defect Urinary carnitine wasting Low serum free, total and acylated carnitine conc(25-50µmol/l) CPT-I deficiency: Elevated Carnitine-acyl FFA carnitine levels translocase Low long-chain carnitine Elevated Elevated conc free of carnitine/(c16+c18) long chain acylcarnitine Elevated levels long chain acyl carnitine ratio Low levels free with carnitine no carnitine levels deficiency OCTN2 carnitine transporter CPT-1 carnitine palmitoyl transferase 1 CACT- carnitine-acyl carnitine translocase Hypoglycaemia deficiency CPT-2 - carnitine palmitoyl transferase 1 CPT 2 deficiciency No ketone bodies Hyperammonaemia Carnitine essential Elevated role in the liver transport transaminase of LCFA inside mitochondria Occasionally for -oxidation Creatine kinase activity Medium and short chain fatty acid - independent

45 -Oxidation defects VLC acyl-coa dehydrogenase deficiency Trifunctional protein deficiency Hypoketotic hypoglycaemia Elevated CK and transaminase Elevated acyl carnitine Specific enzyme assay Medium chain acyl-coa dehydrogenase deficiency urine acyl glycine, dicarboxylic acids Short chain acyl Co-A dehydrogenase deficiency butyryl CoA ethyl malonic acid, butyryl glycine and butyryl carnitine levels

46 Glycogen storage disorders

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48 COMPLEX MOLECULES

49 Lipid storage disorders

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51 Thank you

52 references Teitz textbook of clinical chemistry and molecular diagnostics fifth edition Clinical biochemistry- metabolic and clinical aspects churchill livingstone Indian journal of Practical pediatrics. Vol.12 No.2 APR.-JUN.2010