Doenças Hereditárias do Metabolismo: de Garrodàs … · Doenças Hereditárias do Metabolismo: de Garrodàs Ciências Ómicas. ... novo, genetic disorders of the biosynthesis or

XIII Curso Básico de Doenças Hereditárias do Metabolismo

Coimbra, 5 a 7 Dezembro 2016

Isabel Tavares de AlmeidaLab. Met & Gen . FFULisboa

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

¾ Chemical Individuality (1902)

¾ Inborn Errors of Metabolism (1908)


¾ Chemical Individuality (1902)

¾ Inborn Errors of Metabolism (1908)

Inborn Factors in Disease


¾ Inborn Errors of Metabolism (IEM):

revived the laws of genetics and opened the way tointerpretation of the molecular diseases with all theirinherent practical modern implications:

Neonatal Screening, Prenatal Diagnosis, and inperspective, Genetic Engineering.


Year of 1909:

Î ALBINISM

Î PENTOSURIA

Î CYSTINURIA

TRANSPORT DEFECT

urine


9

2

Function

Gene

Protein

Structure

Inborn Errors of Metabolism

AffectedIndivídual

10

Function

Gene

Protein

StructureMetabolic

Abnormality

DeficitaryProtein

MutantGene


MEMBRANE

A B CD

Inborn Errors of Intermediary Metabolism

AE

enzyme Cofactor

Complex compound ( Glycogen)

Intermediate substance ( tyrosine)

Simple molecules( propionic A)

Energy ( Glucose )

Accumulate Accumulate Accumulate Deficiency

EnzymeCo-Enzyme

EnzymeCo-Enzyme

EnzymeCo-Enzyme

OrganomegalyStorage diseases Energy defects

Toxic Toxic




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 diseasesMorava, E., Rahman, S., Peters, V. et al. J Inherit Metab Dis (2015) 38: 1003.


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.


From a pathophysiological perspective, metabolicdisorders can be divided into the following threediagnostically 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)

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



Group I I I– Involving Complex Molecules


• Lysosomal storage diseases• Disorders of Intracellular trafficking• CDG • Cholesterol synthesis


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

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

SSIEM classification of Inborn Errors of Metabolism

http://www.ssiem.org/resources/IEC.asp

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

8. Disorders of lipid and lipoprotein metabolism

8.1. Inherited hypercholesterolaemias8.2. Inherited hypertriglyceridaemias8.3. Inherited mixed hyperlipidaemias8.4. Disorders of high density lipoprotein metabolism 8.5. Inherited hypolipidaemias8.6. Other disorders of lipid and lipoprotein metabolism 8.7. Unspecified disorders of lipid and lipoprotein 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 ubiquitinylation9.6. Other disorders of protein modification

10. Lysosomal disorders

10.1. Mucopolysaccharidoses10.2. Oligosaccharidoses10.3. Sphingolipidoses10.4. 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 punctata11.3. Disorders of peroxisomal alpha-, beta and omega-oxidation 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-aminobutyrate12.3. 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

(cont.)


metabolite protein(carrier / enzyme)

DNApatient cofactor

METABOLOMIC PROTEOMIC GENOMICCLINICALSYMPTOMS /

SIGNS

FFA

ACETYL-COA

NADH / NAD

HMG-CoA

3-HDAACAC

GLU

ATP / ADP

HYPOKETOTIC

HYPOGLYCEMIA



Chow, S L et al. Arch Dis Child 2004;89:585-586

Plasma ammonia concentrations by diagnosis. Concentrations have been plottedon a logarithmic scale. IEM, inborn errors of metabolism; THAN, transienthyperammonaemia of the newborn.

Homocystinuria

� Clinical heterogeneity!

� Both: premature cardio-vascular disease

INBORN ERRORS OF METABOLISM

IEM

CENTRAL METABOLIC PATHWAYS

AAs Carbohydrates Fatty Acids

CytosolMitochondrion

β-Oxid.


Amino Acid

NH3 Ketoacids

Glutamate

Glutamine

UreaCycle

KrebsCycle

AMINOACIDOPATHIES


MSUD

BCAA METABOLISM

UREA CYCLE

Metabolic Profiling

Amino acids

Amino Acid

R C OHO

Organic Acid

ORGANIC ACIDURIAS


Branched - Chain Amino Acids

IEM

CENTRAL METABOLIC PATHWAYS

AAs

OAs

Carbohydrates Fatty Acids

OAs Profiling


Methylmalonic acid

Ethylmalonic acid

100 125 150 175 200 225 2500e3

500e3

1000e3147

24721813383 103 203113 172 262231

100 125 150 175 200 225 2500e3

500e3

1000e3147

217 26112911799 232173 24820485 189

Organic Acids

Metabolic Profiling

IS

12

13

4

65

7

89

10

1115

14

13

17

2 16

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;

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.

3OHC103OHC43OHC6

3OHC8

3OHC12

3OHC14

3OHC16

C12C6

C8

C10

C14

C16

C18

Metabolic Profiling

Fatty acids and3-OH-fatty acids

Hexanoilglicina

Suberilglicina100 150 200 250 300

0e3

250e3

500e3 15899

189 23017213010487 173 202 287216 245 299 314

100 150 200 250 300 3500e3

500e3

1000e3 158

202173145102 116 13188

18981 217 299274239 260 341

Isovalerilglicina

100 150 200 250 300 3500.0e6

1.0e6

2.0e6 17285

189 21699 145131116156 231 26181 200 244 299 363282

100 150 200 250 300 350 400 4500e3

500e3

1000e3158

189 3601399922912983 172 200 217117 285 30327081 362342 393 418 447

P.I.

isobuvalerylglycine

isobutirylglycine

Hexanoylglycine

Suberylglycine

Metabolic Profiling

Acylglycines

Metabolic Profiling

Acylcarnitines

Urinary Purines and Pirimidines

HypoxanthineXanthine

Uridine

Thymine

Adenine

Thiols in tissue homogenates

GAA

*GAACr

*Cr Cr

*Cr

GAA

*GAA

Creatine and Guanidinoacetate

ISCYS Cys-GlyGSSG

Metabolic Profiling

Documents

Doenças Hereditárias do Metabolismo: de Garrodàs … · Doenças Hereditárias do Metabolismo: de Garrodàs Ciências Ómicas. ... novo, genetic disorders of the biosynthesis or