Doenças Hereditárias do Metabolismo: de Garrod às Ciências Ómicas Isabel Tavares de Almeida Lab. Met & Gen. FFULisboa XIII Curso Básico de Doenças Hereditárias do Metabolismo Coimbra, 5 a 7 Dezembro 2016
Doenças Hereditárias do Metabolismo: de Garrod às Ciências Ómicas The Incidence of Alkaptonuria (AKU): A Study in Chemical Individuality (THE LANCET 1902) Sir Archibald Garrod
Alkaptonuria (AKU) Chemical Individuality Concept
Alkaptonuria (AKU) Chemical Individuality Concept
Doenças Hereditárias do Metabolismo: de Garrod às Ciências Ómicas Chemical Individuality (1902) Inborn Errors of Metabolism (1908)
Doenças Hereditárias do Metabolismo: de Garrod às Ciências Ómicas Chemical Individuality (1902) Inborn Factors in Disease Inborn Errors of Metabolism (1908)
Doenças Hereditárias do Metabolismo: de Garrod às Ciências Ómicas Inborn Errors of Metabolism (IEM): revived the laws of genetics and opened the way to interpretation of the molecular diseases with all their inherent practical modern implications: Neonatal Screening, Prenatal Diagnosis, and in perspective, Genetic Engineering.
Doenças Hereditárias do Metabolismo: de Garrod às Ciências Ómicas Year of 1909: ALBINISM PENTOSURIA CYSTINURIA TRANSPORT DEFECT urine
Inborn Errors of Metabolism 2 Function Structure Gene Protein 9
Inborn Errors of Metabolism Affected Indivídual Function Metabolic Abnormality Structure Gene Mutant Gene Protein Deficitary Protein 10
Inborn Errors of Intermediary Metabolism enzyme Cofactor A A B C MEMBRANE D E
Inborn Errors of Intermediary Metabolism Complex compound ( Glycogen) Intermediate substance ( tyrosine) Simple molecules ( propionic A) Energy ( Glucose ) Enzyme Co-Enzyme Enzyme Co-Enzyme Enzyme Co-Enzyme Accumulate Accumulate Accumulate Deficiency Organomegaly Storage diseases Toxic Toxic Energy defects
Inborn Errors of Metabolism
Inborn Errors of Metabolism
Inborn Errors of Metabolism How should we define or redefine inborn metabolic diseases (IMDs) in the era of genetic diagnostic revolution?? Until now, it was relatively easy: IMDs were mostly inherited, and occasionally de novo, genetic disorders of the biosynthesis or breakdown of substances within specific pathways that were recognized by specific biochemical tests and sometimes treatable by metabolic intervention. Quo vadis: the re-definition of inborn metabolic diseases Morava, E., Rahman, S., Peters, V. et al. J Inherit Metab Dis (2015) 38: 1003.
Inborn Errors of Metabolism This definition does not include disorders primarily affecting: Structural proteins and their modification Membrane channels or other membrane proteins as long as they do not have a primary function in a metabolic pathway Intra-or intercelular signal transduction as well as transcription factos Endocrine function or hormone biosynthesis Inherited Metabolic Diseases: A Clinical Approach. Eds.: G.F Hoffmann, J Zschocke ans W.L.Nyhan. Second Edition, 2016.
Inborn Errors of Metabolism From a pathophysiological perspective, metabolic disorders can be divided into the following three diagnostically useful groups. Group 1: Disorders which give rise to intoxication Group 2: Disorders involving energy metabolism Group 3: Disorders involving complex molecules
Main Categories of Metabolic Diseases Group I - Intoxication Syndromes Aminoacidophaties Organic acidurias Urea Cycle defects Amino acids transport Sugar intolerances Metal intoxication Porphyrias IE of Neurotransmitter synthesis and catabolism IE of Amino acid synthesis IE of intermediary metabolism - diagnosis relies on analysis of biomarkers in CSF (J. Marie Saudubray and F Sedel in Inborn Errors of Metabolism in Adults, 2013)
Main Categories of Metabolic Diseases Group I I Energy Metabolism Defects A - Mitochondrial energy defects B - Cytoplasmatic energy defects Congenital Lactic acidemias Respiratoty Chain Defects Fatty Acids Oxidation Defects Ketone Body defects. Some Organic acidurias Glycolysis Glycogen metabolism Gluconeogenesis Hyperinsulinisms. Creatine metabolism Pentose phosphate pathways (J. Marie Saudubray and F Sedel in Inborn Errors of Metabolism in Adults, 2013)
Main Categories of Metabolic Diseases Group I I I Involving Complex Molecules Lysosomal storage diseases Disorders of Intracellular trafficking CDG Cholesterol synthesis (J. Marie Saudubray and F Sedel in Inborn Errors of Metabolism in Adults, 2013)
SSIEM classification of Inborn Errors of Metabolism 1. Disorders of amino acid and peptide metabolism 1.1. Urea cycle disorders and inherited hyperammonaemias 1.2. Organic acidurias 1.3. Disorders of the metabolism of branched-chain amino acids not classified as organic acidurias 1.4. Disorders of phenylalanine or tyrosine metabolism 1.5. Disorders of the metabolism of sulphur amino acids 1.6. Disorders of histidine, tryptophan or lysine metabolism 1.7. Disorders of serine, glycine or glycerate metabolism 1.8. Disorders of ornithine or proline metabolism 1.9. Disorders of amino acid transport 1.10. Other disorders of amino acid metabolism 1.11. Disorders of the gamma-glutamyl cycle 1.12. Other disorders of peptide metabolism 1.13. Other disorders of amino acid and protein metabolism 2. Disorders of carbohydrate metabolism 2.1. Disorders of galactose metabolism 2.2. Disorders of fructose metabolism 2.3. Disorders of pentose metabolism 2.4. Disorders of glycerol metabolism 2.5. Disorders of glyoxylate metabolism 2.6. Disorders of glucose transport 2.7. Disorders of gluconeogenesis 2.8. Glycogen storage disorders 2.9. Other carbohydrate disorders http://www.ssiem.org/resources/iec.asp 3. Disorders of fatty acid and ketone body metabolism 3.1. Disorders of lipolysis 3.2. Disorders of carnitine transport and the carnitine cycle 3.3. Disorders of mitochondrial fatty acid oxidation 3.4. Disorders of ketone body metabolism 3.5. Other disorders of fatty acid and ketone body metabolism 4. Disorders of energy metabolism 4.1. Disorders of pyruvate metabolism 4.2. Disorders of the citric acid cycle 4.3. Mitochondrial respiratory chain disorders 4.4. Mitochondrial membrane transport disorders 4.5. Unspecified mitochondrial disorders 4.6. Disorders of creatine metabolism 4.7. Other disorders of energy metabolism 5. Disorders in the metabolism of purines, pyrimidines and nucleotides 5.1. Disorders of purine metabolism 5.2. Disorders of pyrimidine metabolism 5.3. Disorders of nucleotide metabolism
(cont.) 6. Disorders of the metabolism of sterols 6.1. Disorders of sterol biosynthesis 6.2. Disorders of bile acid biosynthesis 6.3. Disorders of bile acid metabolism and transport 6.4. Other disorders in the metabolism of sterols 7. Disorders of porphyrin and haem metabolism 9. Congenital disorders of glycosylation and other disorders of protein modification 9.1. Disorders of protein N-glycosylation 9.2. Disorders of protein O-glycosylation 9.3. Disorders of glycosphingolipid and glycosylphosphatidylinositol anchor glycosylation 9.4. Disorders of multiple glycosylation and other glycosylation pathways 9.5. Disorders of protein ubiquitinylation 9.6. Other disorders of protein modification 8. Disorders of lipid and lipoprotein metabolism 8.1. Inherited hypercholesterolaemias 8.2. Inherited hypertriglyceridaemias 8.3. Inherited mixed hyperlipidaemias 8.4. Disorders of high density lipoprotein metabolism 8.5. Inherited hypolipidaemias 8.6. Other disorders of lipid and lipoprotein metabolism 8.7. Unspecified disorders of lipid and lipoprotein metabolism 10. Lysosomal disorders 10.1. Mucopolysaccharidoses 10.2. Oligosaccharidoses 10.3. Sphingolipidoses 10.4. Ceroid lipfuscinoses, neuronal (CLN) 10.5. Lysosomal export disorders 10.6. Other lysosomal disorders
(cont.) 11. Peroxisomal disorders 11.1. Disorders of peroxisome biogenesis 11.2. Rhizomelic chondrodysplasia punctata 11.3. Disorders of peroxisomal alpha-, beta and omegaoxidation 11.4. Other peroxisomal disorders 12. Disorders of neurotransmitter metabolism 12.1. Disorders in the metabolism of biogenic amines 12.2. Disorders in the metabolism of gamma-aminobutyrate 12.3. Other disorders of neurotransmitter metabolism 13. Disorders in the metabolism of vitamins and (non-protein) cofactors 13.1. Disorders of folate metabolism and transport 13.2. Disorders of cobalamin absorption, transport and metabolism 13.3. Disorders of pterin metabolism 13.4. Disorders of vitamin D metabolism and transport 13.5. Disorders of biotin metabolism 13.6. Disorders of pyridoxine metabolism 13.7. Disorders of thiamine metabolism 13.8. Disorders of molybdenum cofactor metabolism 13.9. Other disorders of vitamins and cofactors 14. Disorders in the metabolism of trace elements and metals 14.1. Disorder of copper metabolism 14.2. Disorder of iron metabolism 14.3. Disorder of zinc metabolism 14.4. Disorder of phosphate, calcium and vitamin D metabolism 14.5. Disorder of magnesium metabolism 14.6. Disorders in the metabolism of other trace elements and metals 15. Disorders and variants in the metabolism of xenobiotics 15.1. Disorders and variants of cytochrome P450-mediated oxidation 15.2. Disorders and variants of other enzymes that oxidase xenobiotics 15.3. Disorders and variants of xenobiotics conjugation 15.4. Disorders and variants of xenobiotics transport
Inborn Errors of Metabolism patient metabolite protein (carrier / enzyme) cofactor DNA CLINICAL SYMPTOMS / SIGNS METABOLOMIC PROTEOMIC GENOMIC
Inborn Errors of Intermediary Metabolism FFA GLU NADH / NAD ATP / ADP HYPOKETOTIC HYPOGLYCEMIA ACETYL-COA HMG-CoA ACAC 3-HDA
Inborn Errors of Intermediary Metabolism Plasma ammonia concentrations by diagnosis. Concentrations have beenplotted on a logarithmic scale. IEM, inborn errors of metabolism; THAN, transient hyperammonaemia of the newborn. Chow, S L et al. Arch Dis Child 2004;89:585-586
INBORN ERRORS OF METABOLISM Homocystinuria Clinical heterogeneity! Both: premature cardiovascular disease
INBORN ERRORS OF METABOLISM β-oxid. IEM Cytosol Mitochondrion CENTRAL METABOLIC PATHWAYS AAs Carbohydrates Fatty Acids
INBORN ERRORS OF METABOLISM Amino Acid AMINOACIDOPATHIES NH 3 Glutamate Glutamine Keto acids Krebs Cycle Urea Cycle
BCAA METABOLISM MSUD
UREA CYCLE
Metabolic Profiling Amino acids
INBORN ERRORS OF METABOLISM Amino Acid Organic Acid O R C OH ORGANIC ACIDURIAS
Branched - Chain Amino Acids
Inborn Errors of Metabolism IEM CENTRAL METABOLIC PATHWAYS AAs Carbohydrates Fatty Acids OAs OAs Profiling
Metabolic Profiling Organic Acids 1000e3 147 1000e3 147 500e3 500e3 83 103113 133 172 203218 247 0e3 231 262 100 125 150 175 200 225 250 217 85 99 117 129 173 189 204 232 248 261 0e3 100 125 150 175 200 225 250 Methylmalonic acid Ethylmalonic acid IS
Metabolic Profiling Fatty acids and 3-OH-fatty acids 1 14 10 13 15 11 12 8 9 3 4 2 16 17 5 6 7 1- Ác. Hexanóico; 2- Ác. 3-OH-Butírico; 3- Ác. 3-OH-Hexanóico; 4- Ác. Octanóico; 5- Ác. 2-OH-Octanóico (PI); 6- Ác. Nonanóico (PI); 7- Ác. 3-OH-Octanóico; 8- Ác. Decanóico; C6 3OHC4 3OHC6 C8 3OHC8 C10 9- Ác. 3-OH-Decanóico; 10- Ác. Dodecanóico; 11- Ác. 3-OH-Dodecanóico; 12- Ác. Tetradecanóico; 13- Ác. 3-OH-Tetradecanóico; 14- Ác. Hexadecanóico; 15- Ác. 3-OH-Hexadecanóico; 16- Ác. Heptadecanóico (PI); 17- Ác. Esteárico. 3OHC10 C12 3OHC12 C14 3OHC14 C16 3OHC16 C18
Metabolic Profiling isobuvalerylglycine Isovalerilglicina Acylglycines Hexanoylglycine Hexanoilglicina 2.0e6 85 172 500e3 99 158 1.0e6 0.0e6 99 189 216 116 131 145 81 156 200 231 244 261 282 299 363 100 150 200 250 300 350 isobutirylglycine 250e3 0e3 189 230 172 130 87 104 173 202 216 245 287 299 314 100 150 200 250 300 Suberilglicina Suberylglycine 1000e3 500e3 0e3 158 202 145 173 88 102 116 131 81 189 217 239 260 274 299 341 100 150 200 250 300 350 1000e3 500e3 0e3 158 189 99 139 360 83 129 229 172 117 200 217 81 270285 303 342 362 393 418 447 100 150 200 250 300 350 400 450 P.I.
Metabolic Profiling Acylcarnitines
Metabolic Profiling Urinary Purines and Pirimidines Hypoxanthine Xanthine Uridine Thymine Adenine Thiols in tissue homogenates Creatine and Guanidinoacetate CYS IS Cys-Gly GSSG Cr *Cr G A A * G A A * C r C r * G A A G A A