in born errors of protein metabolism

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This presentation gives entire metabolic disorders of protein metabolism

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INBORN ERRORS OF PROTEIN METABOLISM : 

INBORN ERRORS OF PROTEIN METABOLISM Dr Ramakrishna Dept. of Biochemistry

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What is a metabolic disease? Garrod’s hypothesis (Inherited Metabolic Disorders, 1908) product deficiency substrate excess toxic metabolite congenital metabolic diseases/ inherited metabolic diseases. A D B C

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Introduction a genetic disease also known as biochemical genetics Gene-level Gene mutation Protein-level Abnormal protein Transport Other Enzyme protein protein Metabolic-level Abnormal metabolites

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Unique sequence of DNA Specific sequence of RNA (mRNA) Specific AA sequence of polypeptide Specific Biochemical function

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AMINOACIDURIAS Primary – Inborn errors of metabolism Secondary – Hepatic,Renal,PEM

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CLINICAL MANIFESTATIONS CNS Dysfunction – mental retardation seizure disorder behavioral disturbances Metabolic Ketoacidosis Occasionally – liver disease, renal failure, cutaneous abnormalities, ocular lesions

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AMINOACIDURIAS Neurological Phenylketonuria Hypertyrosinemia Homocystinuria Maple-syrup urine disease Hyperglycenemia Methyl melonic aciduria Carnosinemia Citrullinemia Argininemia Hypopigmentation Brown syndrome Chediak–Higashi Syn. Hermansky Pudlak Syn.

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Phenyl Ketonuria

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Metabolic Pathways for Phe and Tyr

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The PAH gene is located on chromosome 12 . Several hundred DNA mutations in the phenylalanine hydroxylase gene can cause PKU (98% of cases), as well as mutations in other genes necessary for tetrahydrobiopterin production (2% of cases). All newborns with PKU should be tested for tetrahydrobiopterin defects. Mutations in the GCH1, PCBD1, PTS and QDPR genes cause THB deficiency.

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Phenylketonuria is inherited in an autosomal recessive fashion All genetic diseases, genetic counseling may be appropriate to help families understand recurrence risks and ensure that they receive proper evaluation and care.

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Detection of Phe – Ferric chloride test Guthrie test Automated method Plasma level estimation of Phe – Chromatography Fluorometry

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The Heel Test Guthrie test

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Hypopigmentation-Biochemical basis Competitive inhibition of Tyrosinase by Phenyl alanine Impaired Melanin synthesis Hypopigmentation of hair and skin

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Diet low in phenylalanine Treatment

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Alkaptonuria is an inherited disorder first described by Garrod (1902) and Willliam Bateson. Infants have black urine, darkened ears and nose due to homogentisic acid deposits. Garrod increased the amino acids phenylalanine and tyrosine in the diet and saw increased deposits in affected individuals only. Alkaptonuria

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Metabolic Pathways for Phe and Tyr

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Inheritance The gene encoding the HGD enzyme is located on chromosome 3

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Alcaptonuria Absence of homogentisate oxidase activity urine sclera

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Dark urine Ochronosis Arthritis Musculoskeletal (muscle and ligament tears) Cardiovascular (valvulitis, fibrosis, calcification) Genitourinary (renal and prostatic calculi, renal failure) Hearing loss Clinical Features of AKU

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Albinism Albinism Autosomal recessive Results from loss of tyrosinase enzyme in skin, which converts Tyr to DOPA and DOPA to Melanin pigments Loss of tyrosinase in brain causes Parkinson’s Disease (loss of DOPA+ neurons). Tyrosinemia Results from loss of tyrosine transaminase

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Types of albinism Ocular albinism : eyes X-linked ocular: This type of albinism occurs mostly in males, who inherit the gene from their mothers. It causes visual disabilities. Oculocutaneous: Hair, skin, and eyes. Tyrosinase-negative oculocutaneous: Also known as Type 1A, this is the most severe form of albinism, marked by a total absence of pigment in hair, skin, and eyes. People with this type of albinism have vision problems and sensitivity to sunlight. They also are extremely susceptible to sunburn. Tyrosinase-positive oculocutaneous: People with this type of albinism have light hair, skin, and eye coloration and fewer visual impairments.

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Hermansky-Pudlak syndrome (HPS): This rare type of albinism is common in the Puerto Rican community. Approximately one person in every 1,800 people in Puerto Rico will be affected by it. Chediak-Higashi syndrome: A rare type of albinism that interferes with white blood cells and the body’s ability to fight infection. mutation in the lysosomal trafficking regulator gene, LYST.

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Maple syrup urine disease (MSUD) Branched-chain ketoaciduria Autosomal recessive Branched-chain alpha-ketoacid dehydrogenase (BCKADH). Chromosome 1, 6, 7, 19

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Maple syrup urine disease

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Maple Syrup Urine Dz Maple syrup Isovaleric acidemia Sweaty feet Tyrosinemia Rancid butter Beta-methylcrotonyl- coenzyme A def. Tomcat’s urine Phenylketonuria Mousy/Musty Methionine malabsorption Cabbage Trimethylaminuria Rotting fish Inborn Errors of Metabolism The Smell Test

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Homocystinuria Autosomal recessive condition Incidence is one in 200,000 births Cystathionine synthase deficiency Cobalamin deficiency N5, N10-Methylene THFA Reductase deficiency Urinary excretion of homocystine > 300 mg/24 h

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Methionine synthesis

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Homocystinuria

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Symptoms Mental retardation Flat foot Charley Chaplin gait Skeletal deformities Ectopia lentis Myopia Glaucoma

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Tests Cyanide-nitroprusside test positive in urine Chromatography

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Treatment Diet low in methionine and rich in cysteine

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Purine Metabolism Disorders

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Gout Leshnyhan syndrome

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Gout 40 Gout is a systemic disease deficient purine metabolism deposition of uric acid in soft tissue as monosodium urate crystals.

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Purine nucleotides hypoxanthine xanthine Uric acid Xanthine oxidase Alimentary excretion Urinary excretion Tissue deposition in excess Urate crystal microtophi Phagocytosis with acute inflammation and arthritis uricosurics colchicine NSAID Allopurinol Oxypurinol

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Classification Primary Gout: Abnormal PRPP synthetase Abnormal 5-phosphoribosyl amido transferase Deficiency of enzymes of salvage pathway Glucose 6-phosphate deficiency Glutathione reductase variant Secondary Gout: 1. Leukemia, lymphomas, polycythemia 2. Increased tissue breakdown after treatment of large malignant tumors 3. Increased tissue damage due to trauma and raised rate of catabolism as in starvation

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Serum urate levels vary with age and sex. Children: 3 to 4 mg/dL Adult men : 3.5 to 7 mg/dL Adult women: 2 to 5 mg/dL

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Hyperuricemia Defined as a plasma urate concentration > 7.0 mg/dl

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Hyperuricemia Can result from: Increased production of uric acid Decreased excretion of uric acid Combination of the two processes.

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Sites Can occur in other joints, bursa & tendons

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Silent tissue deposition & Hidden Damage

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TOPHI In severe hyperuricemia, crystals of sodium urate get deposited in the soft tissues, particularly in the joints. Such deposits commonly known as Tophi.

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SYNOVIAL FLUID

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Treatment Reduce dietary purine intake and restrict alchohol Increase renal excretion of urate by uricosuric drugs Allopurinol : Blocks conversion of hypoxanthine to uric acid Effective in overproducers May be effective in underexcretors Can work in pt.s with renal insufficiency

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X-linked recessive disorder Deficiency of HGPRT Males affected,female carriers Cerebellar dysfunction,MR,self-mutilation Genetic Counselling-study of females in affected families Lesch-Nyhan Syndrome

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Salvage pathway of purine PRPP Purine ribonucleotide purine PPi Adenine + PRPP Adenylate + PPi (AMP) Mg 2+ APRTase Catalyzed by adenine phosphoribosyl transferase (APRTase)

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IMP and GMP interconversion Hypoxanthine + PRPP Inosinate + PPi ( IMP) Mg 2+ HGPRTase Guanine + PRPP Guanylate + PPi (GMP) Mg 2+ HGPRTase HGPRTase = Hypoxanthine-guanine phosphoribosyl transferase

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PURINE & PYRIMIDINE METABOLISM –INBORN ERRORS

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Carbohydrate metabolic disorders

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Glycolysis

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Glycolisis

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