Doenças Hereditárias do Metabolismo: de Garrod às Ciências Ómicas

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1 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

2 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

3 Alkaptonuria (AKU) Chemical Individuality Concept

4 Alkaptonuria (AKU) Chemical Individuality Concept

5 Doenças Hereditárias do Metabolismo: de Garrod às Ciências Ómicas Chemical Individuality (1902) Inborn Errors of Metabolism (1908)

6 Doenças Hereditárias do Metabolismo: de Garrod às Ciências Ómicas Chemical Individuality (1902) Inborn Factors in Disease Inborn Errors of Metabolism (1908)

7 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.

8 Doenças Hereditárias do Metabolismo: de Garrod às Ciências Ómicas Year of 1909: ALBINISM PENTOSURIA CYSTINURIA TRANSPORT DEFECT urine

9 Inborn Errors of Metabolism 2 Function Structure Gene Protein 9

10 Inborn Errors of Metabolism Affected Indivídual Function Metabolic Abnormality Structure Gene Mutant Gene Protein Deficitary Protein 10

11 Inborn Errors of Intermediary Metabolism enzyme Cofactor A A B C MEMBRANE D E

Glucose ) Enzyme Co-Enzyme Enzyme Co-Enzyme Enzyme Co-Enzyme Accumulate

12 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

13 Inborn Errors of Metabolism

14 Inborn Errors of Metabolism

15 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.

16 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.

17 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

18 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)

19 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)

20 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)

21 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 Other disorders of amino acid metabolism Disorders of the gamma-glutamyl cycle Other disorders of peptide metabolism 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 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

22 (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 Mucopolysaccharidoses Oligosaccharidoses Sphingolipidoses Ceroid lipfuscinoses, neuronal (CLN) Lysosomal export disorders Other lysosomal disorders

23 (cont.) 11. Peroxisomal disorders Disorders of peroxisome biogenesis Rhizomelic chondrodysplasia punctata Disorders of peroxisomal alpha-, beta and omegaoxidation Other peroxisomal disorders 12. Disorders of neurotransmitter metabolism Disorders in the metabolism of biogenic amines Disorders in the metabolism of gamma-aminobutyrate Other disorders of neurotransmitter metabolism 13. Disorders in the metabolism of vitamins and (non-protein) cofactors Disorders of folate metabolism and transport Disorders of cobalamin absorption, transport and metabolism Disorders of pterin metabolism Disorders of vitamin D metabolism and transport Disorders of biotin metabolism Disorders of pyridoxine metabolism Disorders of thiamine metabolism Disorders of molybdenum cofactor metabolism Other disorders of vitamins and cofactors 14. Disorders in the metabolism of trace elements and metals Disorder of copper metabolism Disorder of iron metabolism Disorder of zinc metabolism Disorder of phosphate, calcium and vitamin D metabolism Disorder of magnesium metabolism Disorders in the metabolism of other trace elements and metals 15. Disorders and variants in the metabolism of xenobiotics Disorders and variants of cytochrome P450-mediated oxidation Disorders and variants of other enzymes that oxidase xenobiotics Disorders and variants of xenobiotics conjugation Disorders and variants of xenobiotics transport

24 Inborn Errors of Metabolism patient metabolite protein (carrier / enzyme) cofactor DNA CLINICAL SYMPTOMS / SIGNS METABOLOMIC PROTEOMIC GENOMIC

25 Inborn Errors of Intermediary Metabolism FFA GLU NADH / NAD ATP / ADP HYPOKETOTIC HYPOGLYCEMIA ACETYL-COA HMG-CoA ACAC 3-HDA

26 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:

27 INBORN ERRORS OF METABOLISM Homocystinuria Clinical heterogeneity! Both: premature cardiovascular disease

28 INBORN ERRORS OF METABOLISM β-oxid. IEM Cytosol Mitochondrion CENTRAL METABOLIC PATHWAYS AAs Carbohydrates Fatty Acids

29 INBORN ERRORS OF METABOLISM Amino Acid AMINOACIDOPATHIES NH 3 Glutamate Glutamine Keto acids Krebs Cycle Urea Cycle

30 BCAA METABOLISM MSUD

31 UREA CYCLE

32 Metabolic Profiling Amino acids

33 INBORN ERRORS OF METABOLISM Amino Acid Organic Acid O R C OH ORGANIC ACIDURIAS

34 Branched - Chain Amino Acids

35 Inborn Errors of Metabolism IEM CENTRAL METABOLIC PATHWAYS AAs Carbohydrates Fatty Acids OAs OAs Profiling

36 Metabolic Profiling Organic Acids 1000e e e3 500e e e 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.

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.

37 Metabolic Profiling Fatty acids and 3-OH-fatty acids 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.

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

38 Metabolic Profiling isobuvalerylglycine Isovalerilglicina Acylglycines Hexanoylglycine Hexanoilglicina 2.0e e e6 0.0e isobutirylglycine 250e3 0e Suberilglicina Suberylglycine 1000e3 500e3 0e e3 500e3 0e P.I.

39 Metabolic Profiling Acylcarnitines

40 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

Training Syllabus CLINICAL SYLLABUS

Training Syllabus CLINICAL SYLLABUS SYLLABUS FOR TRAINING IN CLINICAL PAEDIATRIC METABOLIC MEDICINE Updated July 2006 This syllabus is intended as a guide. Whilst the training should be comprehensive,