inborn errors of protein metabolism

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  • Tapeshwar Yadav (Lecturer) BMLT, DNHE, M.Sc. Medical Biochemistry

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  • Inborn errors of metabolismDefinition:- Inborn errors of metabolism occur from a group of rare genetic disorders in which the body cannot metabolize food components normally. These disorders are usually caused by defects in the enzymes involved in the biochemical pathways that break down food components.

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  • Introduction:-Protein contains carbon, hydrogen, oxygen and nitrogen as the major components while sulfur and phosphorus are minor components.Nitrogen is characteristics of proteins. On an average, the nitrogen content of ordinary proteins is 16% by weight. All proteins are polymers of amino acids. Amino acids are linked by protein.A moderately active man consuming about 300g carbohydrates, 100g fats and 100g proteins daily must excrete about 16.5g of nitrogen daily.95% is eliminated by the kidneys and the remaining 5% for the most part as nitrogen in the feces.

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  • Normal values of urea:-The normal concentration in blood plasma is 20-40mg.Indians take less proteins, hence normal level in Indians varies from 15-40 mg/dl.

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  • Inborn errors of urea cycle :- These are divided in to five type.Hyperammonemia type-IHyperammonemia type-IICitrullinemia.Argininosuccinic aciduria.Hyper argininemia.

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  • Hyperammonemia type-I :-A familiar disorder, enzyme deficiency carbamoyl phosphate synthase 1, produces Hyperammonemia and symptoms of ammonia toxicity.CO2+ NH3 Carbamoyl-(P)

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  • Hyperammonemia type-II :-X-linked inheritance.Enzyme deficiency ornithine transcarbamoylase, produces Hyperammonemia and symptoms of ammonia toxicity.OrnithineCitrulline

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  • Citrullinemia :-It is an autosomal recessive disorder.Enzyme deficiency is Argininosuccinate synthatase.Citrulline+AspartateArginosuccinateClinically :- Presents with, produces Hyperammonemia and symptoms of ammonia toxicity, and mental retardation.Urine:- large quantities of citrulline are excreted in urine (1-2g/dl).Feeding arginine in the patients enhance citrulline excretion.

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  • Argininosuccinic aciduria :- Autosomal recessive disorder.Enzyme deficiency Argininosuccinase.ArgininosuccinateArginine + Fumarate.Clinically :- Hyperammonemia, ammonia toxicity and mental retardation.The enzyme deficiency has been identified in brain, liver, kidney and RBC.

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  • Hyper Argininemia :-Enzyme deficiency is Arginase.ArginineOrnithine + UreaDefect in liver and RBC.Clinically:- Hyperammonemia.Urine :- increased urinary excretion of lysine, cystine, ornithine and Arginine.Low protein diet result in lowering of plasma ammonia levels and disappearance of urinary lysinecystinuria pattern.

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  • Disorders of Aromatic amino acids { Phe, Tyr & Trp } :-Phenylketonuria.Alkaptonuria.Tyrosinemia.Albinism.Hartnups disease.

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  • Phenylketonuria :-Deficiency of the enzyme phenylalanine hydroxylase.In some patients dihydrobiopterin reductase deficiency, neurological symptoms appear.Frequency is 1 in10,000 births.Introduction of better diagnostic facilities showed that the incidence is as high as 1 in 1,500 births (WHO-2003).

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  • Biochemical abnormalities :-Phenyl alanine could not be converted to tyrosine.So phenylalanine accumulates in blood.So alternate minor pathways are opened, phenyl ketone, phenyl lactate, phenyl acetate are excreted in urine.Clinical conditions :- Mental retardationFailure to walk/talk.Failure of growth.

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  • This maybe because phenyalanine interferes with neurotransmitter synthesis.The child often has hypopigmentation explained by the inhibition of tyrosinase.Phenyllactic acid in sweet may lead to moucy body odur.

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  • Laboratory diagnosis :-Blood phenyl alanine normal level is 1mg/dl.In PKU the level is >20mg/dl.This is identified by chromatography.

    Ferric chloride test :-Urine of the patient contains phenyl ketones, about 500-3000mg/dl.

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  • ALKAPTONURIA :- Alkaptonuria is an autosomal recessive condition with an incidece of 1 in 2,50,000 births.The metabolic defect is the deficiency of homogentisate oxidase. This results in excretion of homogentisic acid in urine.Homogentisic acid4-maleyl aceto acetateThe only abnormality is the blackening of urine on standing.The homogensic acid is oxidised by polypheyl oxidase to bezoquinine acetate.

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  • Homogentisic acidBenzoquinone acetateIt is then polymerized to black colored alkapton bodies.Black pigments are depositd over the connective tissue including joint cavities to produce arthrities.No specific treatment is required.But low protein with phenylalanine less than 500mg/day.

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  • Diagnosis of alkaptonuria :-Ferric choloride test :- It is positive for urineBenedicts test :- It is strongly positve.Therefore alkaptonuria comes under the differential diagnosis of reducing substance in urine.

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  • Albinism :- It is an autosomal recessive disease with an incidence of 1 in 20,000 births.Defect is tyrosinase enzyme leads complete absence of melanin synthesis.The ocular fundus is hypopigmented and iris may be grey or red. They will be associated photophobia and decreased visual acuity.The skin has low pigmentation and so skin is sensitive to UV rays.The hair is also white.TyrosineDOPA

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  • Hypertyrosinemias :- It is due to deficiency of phenylacetoacetate hydrolase.Symptoms :- the first six months of life and death occurs rapidly.Cabbage like odor and hypoglycemia are seen.Urine contains tyrosine, p-hydroxy phenyl pyruvic acid and phenyl latic acid; and serum shows tyrosine and methionine.

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  • Hypertyrosinemia-2 :-It is due to deficiency of tyrosine amino transferase.Symptoms :- Mental retardation, keratosis of palmar surface and photophobia are seen.There is increased excretion of tyrosine, tyramine in urine.

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  • Hartnups disease :- It is a hereditary disorder of tryptophan metabolism the clinical symptoms include dermatitis and ataxia.The pellagra like symptoms are due to the deficiency of niacin derived from tryptophan.The diagnosis is based on aminoaciduria and increased excretion of indole compounds detected by the Obermeyer test.Hartnups is characterized by low plasma level of tryptophan and other neutral amino acids and their elevated urinary excretion.

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  • GlycineGlycine is a non-essential optically inactive and glycogenic amino acids.Glycine is actively involved in the synthesis of many specialized products in the body(Heme, purins, creatinine).

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  • Metabolic disorders of Glycine :- Glycinuria :- This is rare disorder, due to defect in the glycine cleavage system.Glycine level is increased in blood and CSF.Very high amount of it is excreted in urine.Glycinuria characterized by increased tendency for the formation of oxalate stones.

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  • Primary hyperoxaluria :- Increased excretion of oxalates observed upto 600mg/day compared to a normal of 50mg/day.Primary hyperoxaluria is due to defect in glycine transaminase coupled with impairment in glyoxalate oxidation to formate.GlycineGlyoxalate

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  • In vit-B6 deficiency, urinary oxalate is elevated it can be corrected by B6 supplementation.However B6 administration has no effect on endogenous hyperoxaluria.

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  • Sulphur containing Amino acidsSulfur containing amino acids :- Methionine, Cystein and Cystine.The other sources of sulfur in the body are sulfur containing vitamins are the thiamin, biotin and lipoic acid.Disorders :- Cystinuria, Cystanosis, Homocysteinurias(I, II, III), Hyper methioninemias.

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  • Cystinuria :- It is one of the most inhereted disease with a frequency of 1 in 7,000 births.It is primarily characterized by increased excretion of cystine in urine.Defect :- it is considered to be due to a renal transport defect in that re-absorption of the four amino acids, lysine, arginine, and ornithine and diabasic amino acids donot occur.A single re-absorptive site is involved.Complications :- Cystine is relatively insoluble amino acids which may precipitate in renal tubules uterus and bladder to form cystine calculi.

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  • Cystine stones account for 1-2 % of all urinary tract calculi.It forms a major complication of the disease.Cyanide nitroprusside test :- It is a screening test urine is made alkaline with ammonium hydroxide and sodium cyanide is added cystine if present reduced to cysteine. Then added sodium nitroprusside to get a megenta red colored complex.Specific amino aciduria may be conformed by chromatography.

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  • Cystinosis:-Defect in the enzyme cystine reductase. It is a familial disorder characterised by the wide spread deposition of cystine crystals in the lysomes.Cystine accumulates in liver,spleen,bone marrow, WBCs, kidneys and lymphnodes.Microscopy of blood shows cystine crystals in WBCs.Treatment policies are to give adquate fluid intake so as to increased urine output,alkalinasation of urine by sodium-bi-carbonate as well as administration of D-penicillamine.

    Cystinosis:-Defect in the enzyme cystine reductase. It is a familial disorder characterised by the wide spread deposition of cystine crystals in the lysomes.Cystine accumulates in liver,spleen,bone marrow, WBCs, kidneys and lymphnodes.Microscopy of blood shows cystine crystals in WBCs.Treatment policies are to give adquate fluid intake so as to increased urine output,alkalinasation of urine by sodium-bi-carbonate as well as administration of D-penicillamine.

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  • Hypermethioninemias :CAUSESImpaired utilizationExcessive remethylation of homocysteineOasthous syndrome is due to malabsorption of methionine, in such children excrete methi

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