Inborn Errors of Metabolism PDF

INBORN ERRORS OF METABOLISM Dr RB Khan Discipline of Medical Biochemistry School of Laboratory Medicine & Medical Sciences Room 331, George Campbell (south), Howard College X 4597 [email protected]  Inborn Errors of Metab...

INBORN ERRORS OF METABOLISM Dr RB Khan Discipline of Medical Biochemistry School of Laboratory Medicine & Medical Sciences Room 331, George Campbell (south), Howard College X 4597 [email protected]  Inborn Errors of Metabolism  Metabolic disease – aka enzymopathy, genotropic disease arises due to an inborn error of metabolism  Inherited  Mutation  Metabolism  Catabolism  Anabolism  Enzymes play an important role in facilitating this process  Catalysts  Definition  A genetically determined biochemical disorder in which a specific enzyme defect produces a metabolic block that may have pathological consequences:  at birth (e.g. phenylketonuria)  in later life (e.g. diabetes mellitus) Enzyme AB Enzyme BC Precursor Intermediate End-product A B C Toxic metabolite  About inborn errors of metabolism? Genetic deficiencies in the production of:  Enzymes  Transport proteins  Receptor proteins  Subcellular organelles Lysosomes, mitochondria, peroxisomes  Structural, assembly and chaperone proteins Macromolecule disease  Carbohydrates, lipids, proteins and nucleic acids  Types of Inborn Errors CHO disorders Protein disorders  Galactose  Amino acid  Glucose  Organic acid  Glycogen  Urea cycle  Fructose  Haemoglobin  Connective Tissue Lipid disorders  Synthesis Nucleic acids  Degradation  Purines  Storage  Pyrimidines  Transport  Genetic basis of disease Alkaptonuria  X Ingestion of phenylalanine or tyrosine  homogentisic acid  maleylacetoacetic acid  CO2 + H2O  Biochemistry: liver lacks the enzyme homogentisic acid oxidase  Homogentisic acid accumulates and is excreted in urine  Urine turns black & in later life there is arthritis Phenylketonuria  Ingestion of phenylalanine  accumulation of phenylpyruvate in urine (phenylalanine hydroxylase OR tetrahydrobiopterin)  Tyrosine is metabolised normally NB. We cannot rely solely on metabolic blocks because minor pathways become significant when blockages occur  Patterns of inheritance Mendelian inheritance  New mutations in germ cells are passed onto succeeding generations  New somatic cell mutations are not but may be important (eg. in the development of cancer) Different patterns of inheritance will be seen (mutant gene is recessive or dominant and whether it is on an autosome or a sex chromosome)  Autosomal recessive disorders  Autosomal dominant disorders  X-linked recessive disorders  X-linked dominant disorders  Codominant Autosomal dominant One mutated copy  disease Only one affected parent Males & females equally affected 50% chance of passing the defect Incomplete penetrance Mutation in egg/sperm eg. acute intermittent porphyria Examples: Huntington’s chorea, Tuberous sclerosis, familial hypercholesterolaemia Autosomal recessive Two mutated copies of the gene are present in each cell Carrier parents Both sexes equally affected 25% chance Examples: alkaptonuria, cystic fibrosis, Tay-Sachs disease, Friedreich’s ataxia & phenylketonuria What if she marries an affected person? What if she marries an unaffected person?  X-linked dominant Females are more frequently affected No male-to male transmission Example: Coffin-Lowry syndrome  males and females are both affected  An affected female will have a 50% chance of passing the disorder on to both her sons and her daughters  An affected male will pass the condition on to all his daughters, but not to his sons. X-linked recessive Sons: 50% inheritance Daughters: 50% chance of inheritance, but usually not affected. WHY? NB. A father cannot pass X-linked traits to his son.Daughters will be carriers. WHY? Examples: Duchenne muscular dystrophy, haemophilia, hunters disease Fragile X syndrome Codominant single gene has more than one dominant allele 2 different versions of a gene can be expressed Eg. AB blood types  Mechanisms of disease A  Accumulation of substrate A  Reduced product D B  Accumulation of B STOP C intermediates C X X  Diversion of intermediates through Y X minor side-pathways D Y  Failure of feedback mechanisms C Example: Possible consequences of a defect in  Failure of transport mechanisms the enzyme catalysing CD  Accumulation of substrate Example : Fructose intolerance  Reduced product Example : Albinism L-tyrosine tyrosinase DihyrOxy PhenylAlanine quinone ocular melanin oculaocutaneous  Accumulation of intermediates The storage diseases Types:  Sphingolipidoses  lysosomes  Mucopolysaccharidoses  Mucolipidoses  Glycogen storage disease  liver, skeletal muscle Causes:  Lack of synthesis of an enzyme  Synthesis of abnormal enzyme  Inability to transport the enzyme the lysosome  Synthesis of enzymes which are inactive in the lysosome  Absence or inactivity of activator enzymes  Loss of feedback mechanism Example : Lesch-Nyhann Syndrome Hypoxanthine-guanine phosphoribosyl transferase Gout and overproduction of uric acid Choreoasthetosis, spasticity,variable degrees of mental retardation & compulsive self-mutilation Prenatal detection  Use of minor pathways Example: Phenylketonuria Essential amino acid  Used in protein synthesis  Degraded via tyrosine pathway Deficiencies  Phenylalanine hydroxylase  Tetrahydrobiopterin Accumulation of phenylalanine and phenylpyruvate in body fluids Value of early detection  Diagnosis Clinical  Symptoms usually nonspecific  Useful clues: Consanguinuity History of unexplained premature death in older sibling Onset of symptoms follow a change in feeding regimen Dysmorphic features, coarse facies Hepatomegaly Cherry red spots Abnormal kinky hair Decreased pigmentation Cataracts Retinitis pigmentosa  Diagnosis Clinical Unusual smell  Maple syrup  Maple Syrup Urine Disease  Mousy/Musty  Phenylketonuria  Sweaty feet or cheese  Isovaleric acidaemia, Type II Glutaric acidaemia  Rotting fish  Trimethylaminuria  Boiled cabbage  Hypermethioninaemia, Tyrosinaemia  ??  Diabetes  Diagnosis Laboratory  Must be guided by clinical presentation eg. cataracts  suspect galactosaemia  test for Galactose-1-phosphate uridyl transferase in red blood cells  Routine investigations should include: Plasma ammonia Organic acids (urine) and amino acids (urine & plasma) Plasma lactate Galactose-1-phosphate uridyl transferase  Other biochemical investigations …  Laboratory diagnosis Urinalysis  Reducing substances  Ketones  pH Blood  Anion gap  Metabolic acidosis  Hypoglycaemia  Hyponatraemia  Respiratory alkalosis  Abnormal liver function tests  Hyperammonaemia  Role of nutrition Protein metabolism  Phenylketonuria - diet low in phenylalanine – no milk, eggs, nutrasweet  Maple syrup urine disease – diet low in branched chain amino acids Carbohydrate metabolism  Fructose intolerance – no fruit, fruit juices, sucrose, honey, starch etc.  Galactosaemia – milk and milk products should be avoided Co-factor replacement  Some enzyme deficiencies are vitamin responsive  Eg biotin, vitamin B12, thiamine, vitamin B6  Treatment 1st line – restore child to health Dietary modification Enzyme replacement therapy Co-factor replacement Aim  To decrease formation of toxic metabolites  To produce adequate calories  To enhance excretion of toxic metabolites Screening the newborn for disease Factors that determine if screening will occur:  Does the disease have a relatively high incidence?  Can the disease be detected within days of birth?  Can the disease be identified by a biochemical marker which can easily be measured?  Will the disease be missed clinically, and would this cause irreversible damage to the baby?  Is the disease treatable, and will the results be available before irreversible damage has occurred? Will not be the same in all countries  Hypothyroidism (1:3500) and phenylketonuria (1:10000) mental retardation - not carried out in Finland  Congenital adrenal hyperplasia 1:500  Alaska