INBORN ERRORS OF SOME AMINO ACID.pptx

Inborn errors of metabolism of some amino acids Dr. Akande J.O.  Introduction Inborn error metabolic disorders (IEM) are a class of genetic diseases involving disorders of metabolism. Inborn errors mean birth defects in newborn infants which are passed down from the family and...

Inborn errors of metabolism of some amino acids Dr. Akande J.O.  Introduction Inborn error metabolic disorders (IEM) are a class of genetic diseases involving disorders of metabolism. Inborn errors mean birth defects in newborn infants which are passed down from the family and affect metabolism. It is called Inborn errors of metabolism or inherited metabolic disorders. These diseases are caused by mutations/ defects in single genes that encode enzymes, membrane transporters, and other functional proteins related to various metabolic pathways Leading to the synthesis of defective enzyme activity or deficiency of an enzyme that affects the normal function of a metabolic pathway that facilitates the conversion of various substrates into products. Mostly inherited in an autosomal recessive manner, and rarely in autosomal dominant and X-linked manners.  Cont’d IEM can appear at birth or later in life such as phenylketonuria, albinism, lactose intolerance, Gaucher disease, Fabry disease etc. The main indication of IEM is excess storage or accumulation of specific metabolites in tissues, organs and blood which further manifest to health diseases. Individual inborn error of metabolism is very rare, collectively they are very common, affecting 1 in 2500 infants at birth. These disorders can be identified through newborn screening tests. Most IEM are rare but some are life-threatening. The early and specific diagnosis and prompt initiation of appropriate therapy are still the best determinants of outcomes for these patients.  PATHOGENESIS Substrates are converted to products and its alternative pathway yields other product(s). Metabolism facilitated by enzymes, cofactors and transporters whose failure lead to disorder(s): Decrease of the products immediately after the blockage causes deficiency Accumulated substrate could be toxic, Accumulated alternative product could be toxic Cont’d Metabolic consequences The gene is mutated that codes an enzyme leads to the formation of a defective enzyme. As a result, a metabolic blockage occurs in a specific metabolic pathway resulting in elevation of substrate concentration and product shortage in cells. The possible metabolic consequences of IEM are: I. Accumulation of a substrate, II. Accumulation of intermediate Metabolites, III. Lack of an essential product, IV. Interfere with normal metabolic function. CLASSIFICATION OF IEM Disorders of Amino acid metabolism Urea cycle defects Disorders of carbohydrate metabolism Disorders of lipid, fatty acid oxidation and organic acidurias Lysosomal storage defects Mitochondrial disorders Peroxisomal Disorders Defects of drug metabolism Miscellaneous CLINICAL PRESENTATION Symptoms usually first appear in infancy but in IEM, appearance is in adulthood. Severity of symptoms vary from very severe, mild or absent Neonate without genetic defect may be symptomatic in poorly controlled maternal disease. Feeding difficulties, failure to thrive, seizures , mental retardation, organ failure and death  PHENYLKETONURIA Definition It is an error of amino acid metabolism caused by deficiency of the enzyme phenylalanine hydroxylase leading to hyperphenylallaninemia Causes sustained exposure of a fetus to phenylalanine – Phenylalanine hydroxylase or – tetrahydrobiopterine synthesis or its recycling defect Incidence 1:10000 to 1:20000  Pathogenesis Phenylalanine hydroxylase inactivity Accumulation of phenylalanine in the blood Interference of phenylalanine with synthesis and uptake of neurotransmitters Alternative pathway of metabolism of phenylalanine produces excess phenyllactate, phenylpyruvate  Clinical features Asymptomatic No symptoms Symptomatic – GIT gastroesophageal reflux – SKIN Chronic eczema, – HEAD pale skin, fair hair and blue eyed, microcephaly, – NEUROMUSCULAR Delays in development, intellectual disability – MATERNAL adverse pregnancy outcome,  Diagnosis Elevated Phenylalanine in blood, Pterine deficiency Dihydropteridine reductase deficiency DNA analysis  Treatment Phenylalanine free diet. Monitor and keep within 60-360 µmol/l. Council couples intending to be pregnant and manage phenylalanine in the pregnancy.  ALKAPTONURIA Alkaptonuria is the first inborn errors of metabolism discovered by Garrod. Estimated incident of alkaptonuria is about 2-5 per million live births.  Cause Affected people with alkaptonuria have a deficient enzyme activity of the homogentisate 1,2-dioxigenase. This enzyme metabolizes homogentisic acid to maleylacetoacetic acid Deficient enzyme leads to abnormal accumulation of homogentisic acid in blood and tissues. High level of homogentisic acid in tissues cause a syndrome is called ochronosis. Recent findings reported that alkaptonuria is now considered a multisystemic disease starting from the third decade of life and classified as a secondary amyloidosis. On exposure to atmospheric oxygen, urine homogentisic acid is converted into coloured compound  Clinical symptoms Affected person show an abnormal level of homogentisic acid in cartilage tissue caused inflammation and arthritis in older people Oxidation and polymerization of HGA produces alkapton that causes, darkening urine, ochronosis and arthritis. HGA reacts with clinitest.  Diagnosis/Treatment The urine level of homogentisic acid is primarily measured to the diagnosis of alkaptonuria. The excretion level of HGA is usually about 1-8 grams per day in alkaptonuria’s patients.  Vitamin C and low proteins diet are recommended to control of the ochronosis by reducing the level of homogentisic acid in tissues.  Newborn screening and oral nitisinone therapy may also helpful for the treatment of this disease Nails and dorsum of hands showing bluish-colored discolorationin affected people with alkaptonuria  Tyrosinemia Tyrosinemia is also metabolic genetic disorders of phenylalanine catabolism, occur usually in newborns. This disorder results due to the absence or deficiency of enzymes involved in the multiple steps of phenylalanine and tyrosine catabolism. Untreated tyrosinemia can be fatal for life. There are three subtypes of Tyrosinemia:  Tyrosinemia I Lack of fumarylacetoacetate hydrolase (FAH) enzyme with inherited genetic defect results in tyrosinemia disease. This enzyme involves in tyrosine metabolism which converts fumaryl acetoacetic acid into fumaric and acetoacetic acids. Deficiency of this enzyme, fumaryl acetoacetic acid and other intermediate precursors accumulate in the tissue and organ cause liver and renal diseases. It is also called hepatorenal tyrosinemia.  Cont’d Clinical symptoms Diarrhoea, Vomiting, Renal tubular dysfunction, Vitamin D-resistant rickets, Acute intermittent porphyria- like symptoms (abdominal pain, neuropsychiatric findings and sensitive to light), hypertension, Progressive liver and renal failure.  Tyrosinemia II Caused by the deficiency of tyrosine aminotransferase enzyme, which catalyzes the first step in the catabolism of tyrosine forming the corresponding keto acid, p- hydroxyphenyl pyruvic acid. Deficiency of this enzyme leads to accumulation of the tyrosine in cells and blood.  Clinical symptoms Accumulation of tyrosine can affect on eyes, skin, and mental development. This disease begins in early childhood. Persistent keratitis and hyperkeratosis occur on the fingers, palms of hands and soles of feet, moderate mental retardation.  Tyrosinemia Type III(Neonatal tyrosinemia) This disorder occurs due to the defective enzyme, p- hydroxyphenyl pyruvic hydroxylase which normally involved in catalyzing of p- hydroxyphenyl pyruvic acid into homogentisic acid. The condition is more common in premature infants.  Treatment The dietary restriction of tyrosine and phenylalanine with low protein diet may useful to control clinical symptoms of all three types of tyrosinemias. The drug, nitisinone known as NTBC has shown to be effective for the treatment of Tyrosinemia I.  Albinism Congenital hereditary disorder of amino acid metabolism in which biosynthesis of melanin is defective. Melanin is a color pigment absent in certain parts of the body such as eyes, patches of skin and areas of hair. Normally, melanin is polymers of the amino acid tyrosine which gives color to skin, hair and eyes.  Alb. Cont’d Cause Clinical symptoms Caused by the mutation in a gene Albinism can affect eye and skin coding tyrosine hydroxylase enzyme. in infants or people. This enzyme converts tyrosine to 3,4- dihydroxy phenylalanine (DOPA) This condition refers to Deficient activity of this enzyme leads oculocutaneous albinism (OCA) to albinism in which melanin formation resulting in hypopigmentation of is missing. the hair, skin and eyes. This condition is referred to Extremely pale skin, poor vision hypomelanosis The pale skin, pinkish eyes and visual and white hair. abnormalities are primary symptoms of this disease.  Alb Cont’d Diagnosis Treatment Diagnosis is based on biochemical There is no treatment for albinism. finding of hypopigmentation of the skin Albino people require visual rehabilitation and hair. such as wear prescription lenses for Molecular genetic testing of OCA gene correction of refractive errors, use hats with brims and dark glasses or is available for the albinism diagnosis. transition lenses to reduce discomfort from bright light wear protective clothing to protect skin from sun exposure  Homocystinuria Definition Clinical symptoms Homocystinuria is a rare High level of homocysteine in inherited disorder of cells causing lipid peroxidation, metabolism of the methionine. fibrosis, and atherogenesis and affecting muscles, cardiovascular system and nervous system.  Cause This disorder results due to the deficit activity or absence of cystathionine β-synthase enzyme involved in methionine degradation. In normal metabolism, methionine converts into homocysteine which further form cystathionine in presence of cystathionine β-synthase. This defect leads to accumulation of homocysteine in tissues.  Management Diagnosis Treatment Estimation of the level of Vitamin B6 (Pyridoxine) therapy, homocysteine, total betaine, folate and vitamin B12 homocysteine, homocysteine- supplementation are used to cysteine mixed disulfide, and control the biochemical methioninein plasma. abnormalities, especially to management the plasma homocysteine and homocysteine concentrations and prevent thrombosis.  MARPLE SYRUP URINE DISEASE (MSUD) Cause – Inactivity of branched chain decarboxylase – Inactivity of thiamine pyrophosphate (TPP) Accumulation of branched chain amino acids Patients present with – poor feeding and vomiting, lethargy and coma. Urine Ketones and Amino acids appear Enzyme defects demonstrated in leuckocytes  TREATMENT OF MSUD Branched chain free diet, Thiamine supplement, Treat brain edema with IV manitol. Supplement sodium. Dialysis may be needed. Genetic disorders affecting amino acid catabolism Conclusion The inborn errors of Metabolism (IEM) are significantly interrelated with genetic abnormalities. The inheritance pattern of genes may be either dominant or recessive, from carrier parents to their children. In other words, defective genes lead to synthesis of defective enzymes. The basis of EMI is the gene mutation in single genes that code for an enzyme resulting in synthesis of deficiency of a specific enzyme involved in metabolic pathway of amino acids, carbohydrates, lipids, urines, and pyrimidines. Absence or deficiency of enzymes in metabolism lead to blockage in individual steps of normal metabolic pathway resulting in biochemical abnormalities. As a result, intermediate metabolites accumulate in tissues and bold system, consequently affecting the biochemical and physiological functions of the cells and vital organs of the body and its consequences progressive Health problems arise. Clinical symptoms of IEM may appear with few days in affected people or newborns resulting in physical and mental abnormalities in human beings. Early diagnosis, genetic analysis of newborns, screening of future parents and nutritional treatment may help in reducing the chance to develop clinical symptoms and to management of the inherited metabolic disorders