Pyruvate - MeetOchondrie

Pathologies mitochondriales
de la clinique à la thérapie
Jean-Marie Saudubray, Paris
7e colloque "Meetochondrie »"
Evian 4-7 Mai 2014
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
The human cell
Peroxisomes
1. Synthesis of bile acids
2. Synthesis of some steroid hormones
3. Synthesis of plasmalogens
4. Transmission of glyoxylate to glycine
5. Catalase
6. Oxidation of D-amino acids
7. α-oxidation of branched chain fatty acids, e.g.,
phytanic acid
8. β-oxidation of long-chain and very-long-chain fatty
acids
9. Oxidation of pipecolic acid
10. Spermine and spermidine oxidation
Golgi complex
Post-translational modification of
N-linked oligosaccharides of
nascent glycoproteins, including
glycosaminoglycan biosynthesis
Plasma membrane
Rough endoplasmic
reticulum (ER)
1. Limiting loss of intracellular components of
the cell, ensuring concentration and preservation
of optimum local milieu
2, Regulating uptake of amino acids
3. Neurotransmitter binding and uptake (nervous
tissue)
4. Regulating uptake of metabolites, drugs,
chemicals, hormones, etc.
Translation (mRNA-directed synthesis
of polypeptides)
5. Uptake (endocytosis) and
intracellular trafficking of material
suspended in extracellular milieu
Smooth endoplasmic
reticulum (ER)
Mitochondria
1.
Oxidative phosphorylation
1. Post-translational modification of polypeptides,
2. Citric acid cycle
3. β-oxidation of fatty acids, with production of acetyl-CoA
4. Oxidative degradation of some amino acids
5. Proximal steps of urea biosynthesis
6. Biosynthesis of some amino acids
7. Proximal and distal steps of porphyrin biosynthesis
8. Mitochondrial transporters
Adapted from Dr. Joe Clarke
N- and O-glycosylation
2. Biosynthesis of cholesterol,
phospholipids, triglycerides,
glycosphingolipids
including
Lysosome
Localization of hydrolytic enzymes involved in the
degradation of large, complex substrates, such as
proteins, glycoconjugates, nucleic acids, complex lipids
Treatment: ERT;SRT,Chaperone
3. Steroid hormone biosynthesis (endocrine tissues)
4. Detoxifications (P450, liver)
5. Glucose-6-phosphate (liver)
6. Calcium sequestration (sarcoplasmic reticulum,
muscle)
7. Porphyrin degradation
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
The mitochondrion
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Mitochondrial Transporters
(yeast mitochondrial inner membrane)
Click to view animation >>
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Mitochondrial functions
  Energy production
•  Electron
transport chain (80% of cellular ATP)
•  Fatty
acid oxidation, ketogenesis, and ketolysis
•  Krebs
citric acid cycle
  Urea cycle (partial)
  Amino acid catabolism (branched chain, lysine,
glycine, ornithine, proline)
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Additional pathways
  Pyrimidine biosynthesis
  Heme and iron sulfur proteins synthesis
  Cholesterol metabolism
  Estrogen/testosterone synthesis
  Calcium homeostasis at synapse  neurotransmission
  Apoptosis
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
1960!
2001!
> 2001 On-line update !
continuous process…."
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Classification of IEMs
  1. Intoxication: IEM of intermediary metabolism (small
molecules)
•  Aminoacidopathies
•  Organic
•  Urea
(catabolism, synthesis*)
acidurias
cycle defects
•  Sugar
intolerances (polyols)
•  Metals,
porphyrias
•  Neurotransmitters
(catabolism, synthesis)
In synthesis defects amino acid levels are DECREASED
(*Serine,Glutamine,Proline)
Intoxication common characteristics
  Accumulation
  No
of small diffusible water soluble molecules
embryonic or fetal consequences
  Neonate
is typically normal and born at term
  Well
interval between birth and first symptoms
  Easy
to diagnose by plasma/urine chromatography
  Usually
  Most
  Many
present emergently with acute recurrent crisis
of them are treatable acutely and can be prevented
of them can be detected by neonatal screening
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
triglycerides glycogen free faDy acids G6P glucose pyruvate lactate faDy acyl-‐CoA acylcarniFnes galactose PDH amino acids organic acids NH4+ β-‐oxida6on Urea cycle TCA cycle ketones protein reducing equivalents Urea respiratory chain ATP Courtesy of Dr. John Walter
Courtesy of Dr John Walter © 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Classification of IEMs
  2. Energetic disorders: IEM of intermediary metabolism
Mitochondrial
•  Congenital
lactic acidemias (PC, PDH,CAC)
•  Respiratory
•  FAO
chain disorders
and ketone bodies disorders
Cytoplasmic
•  Gluconeogenesis,
•  Cerebral
•  Pentose
glycogenolysis, glycolysis defects
creatine disorders
phosphate pathway
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Energetic disorders: common
characteristics
  Disturbances of physiologic parameters including pH,
glucose, ketones, lactate, or carnitine
  Diagnosis relies on functional tests or metabolic
profiles
  Requires specific enzyme and/or DNA assays
  Can present with recurrent crisis triggered by
catabolism/food
  Progressive symptoms including antenatal/congenital
presentations (liver, brain, heart, and muscle)
  Presentation in any organ at any age
  Only a few are treatable
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
triglycerides glycogen free faDy acids G6P glucose pyruvate lactate faDy acyl-‐CoA acylcarniFnes galactose PDH protein amino acids organic acids NH4+ β-‐oxida6on Urea cycle TCA cycle ketones reducing equivalents Urea respiratory chain ATP Courtesy of Dr. John Walter
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
triglycerides free faDy acids faDy acyl-‐CoA acylcarniFnes glycogen galactose G6P glucose pyruvate lactate PDH protein amino acids organic acids NH4+ β-‐oxida6on Urea cycle ketones TCA cycle reducing equivalents Urea respiratory chain Courtesy of Dr. John Walter
ATP © 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Sources of lactate
GLYCOGEN
G.1.P
GALACTOSE
G.6.P
GLUCOSE
F.6.P
F.16.dP
FRUCTOSE
GLYCEROL
NAD
NADH
GA3P
1-3 DPG
XTP
PEP
XTP
LACTATE
PYRUVATE
ASPARTATE
NADH NAD
PYRUVATE
XTP
ALANINE
OXALO ACET
KREBS
ACETYL Co A
FATTY
ACIDS
NAD
KETONE
BODIES
CITRATE
α KETOGLU
NADH
GLUTAMATE
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Pyruvate flux
LACTATE
NAD
NADH
PYRUVATE
Pyruvate carrier
PYRUVATE
NAD
Alanine
PC
NADH
PDH
AcetylCoA
OAA
Aspartate
TCA Citrate
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
PDH enzymatic reaction:
NAD!
NADH + H !
CO2!
Pyruvate!
CoA!
Acetyl-CoA!
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
PDH enzymatic reaction:
New partners
Mito FAS II
Lipoic acid synthetase
NAD!
(J Mayr AJHG 2011)
Lipoic acid
Lipoyltransferase
NADH + H !
(Soreze Orphanet J.2013)
CO2!
Pyruvate!
SLC25A19
TPP
Mito carrier
(Science 2013) TPP kinase
(J Mayr AJHG 2007)
CoA!
Acetyl-CoA!
(J Mayr AJHG 2011)
Cytoplasmic
Pyruvate
Thiamine
SLC19A3!
Thiamine
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Branched chain !
ketoacid!
CoA-SH!
E3:Variant MSUD"
NAD!
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Insulin over secretion
3 IEM with gain of function
GK!
GDH!
SCHAD!
MCT1!
Adapted from P de Lonlay, Necker, Paris
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Inherited defects of Fe–S protein biosynthesis
and consequences on mitochondrial metabolism
LIAS!
ISCU!
NFS1!
NFU1!
IBA57!
LIPT1!
GCS!
PDH!
KGDH!
BCKDH!
Keto adipate!
NUBPL!
ISD11!
GLRX2!
BOLA3!
FXN!
After Lim S C et al. Hum. Mol. Genet. 2013;22:4460-4473
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Human sulfur dependent mitochondrial disorders
Complex I III IV!
subunits!
Acute Infantile "
Liver Failure"
and TRMU mut"
thio-modified mitochondrial tRNAs!
( tRNA-Lys, tRNAGln,and tRNA-Glu)!
TRMU!
NFU1!
NFS1!
ISD11!
NUBPL!
GLRX2!
Postnatal !
Development!
(1-4 months)!
LIPT1! GCS!
PDH!
KGDH!
BCKDH!
Keto adipate!
IBA57!
ISCU!
Cystathionine!
Metallothioneine!
LIAS!
BOLA3!
Metabolic !
profile!
FXN!
Mitochondrial Fe-S!
Assembly!
System!
After Lim S C et al. Hum. Mol. Genet. 2013;22:4460-4473
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Classification of IEMs
  3. Complex molecules: IEM of organelle metabolism
•  Lysosomes
•  Peroxisomes
•  CDG
(ER and Golgi)
•  Cholesterol (mito and ER)
•  Phospholipids (ER and mito)
•  Glycosphingolipids (ER ,Golgi and lysosome)
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Pyruvate
NAD+
Co A
PDH"
NADH
ATP
CoA synthase
Oxaloacetate
IDH"
Acetyl-CoA
Glucose 1-P
Isocitrate
phosphopantetheine
citrate
PANK2
-
Glucose 6-P
PFK
G6PD
CTP"
6-Pgluconolactone
F 1,6-BP
Vitamine B5
NADP+
citrate
NADPH
Citrate Lyase
G3P DHase
HMG-CoA
Synthase
Ribulose 5-P
Acetyl-CoA
AcetoAcetyl-CoA
Acetyl -CoA
Carboxylase
+
TPI
DHAP
Glycerol 3-P
Glyceraldehyde
3-P-DHase
Malonyl-CoA
NADPH
NADP+
HMG-CoA
HMG-CoA
Reductase
P-Glycerate
Kinase
3-PG
DHAPAT
G3-P Acyltransferase
Mevalonate
AGK
Cardiolipin
Diacylglycerol
Cholesterol"
Ubiquinone"
Dolichol "
1,3-DPG
FAS
Fatty acyl-CoA
Phosphatidate
Triglycerides"
Adapted from F Lamari
GA3-P
SERAC-1
Phospholipids"
Elongases
ELOV 1-6
Acyl-DHAP
ADHAPS
NADPH
NADP+
LCFA"
VLCFA"
Alkyl-DHAP
Plasmalogens
Serine
Serine Palmitoyl
transferase
Ceramide
Sphingolipids
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Phospho/sphingolipid structure
1 = Hydrophilic phosphate group head located at the surface of a bilayer
2 = Hydrophobic fatty acid chain tail located inside
Biosynthesis takes place mostly in the ER but also at the mitochondrial
membrane and in the Golgi
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Influence of structure on membranes
Vlis & Daum, Cold Spring Harb Perspect Biol 2013"
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Overview of mitochondrial membrane
phosphatidylethanolamine synthesis
2014 Nature Genetics Sousa et al
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Dihydroxyacetone
3-phosphate
Glycerol-3-phosphate
Glycerol
Acyl CoA
-
G3P-AT
CoA-SH
Lysophosphatidic acid
Acyl CoA
AG-AT
ABHD5
CoA-SH
AGK
Phosphatidic acid
+
PAP
PNPLA2
CDP-DAG
Synthase
DGKE
Diacylglycerol
Triacylglycerol
CTP
PPi
ADP
Monoacylglycerol
ATP
Phosphoglycerophosphate
CDP Diacylglycerol
DGAT
CHK
choline
ATP
ADP
Phse
PhosphatidylGlycerol
CDP-PEth
PC-Cytidylyl
transferase
PhosphoCDP-PChol
choline
CMP
PE-N-methyl
transferase
CMP
SAH
-
SAM
PG
PE
C16:0/C18:1
PC
Chol
Ser
PSS1
PS
O
CH2
C
P
O.
O.
SERAC1
O
Ser
CO
Eth
TAZ
CH2
O
H
O
H O.
CH2
CH
CH
CH2
CH2
CO
O
P
CH2
O
O
CO
O
CO
Cardiolipin remodeling"
Monolysocardiolipin Cardiolipin
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Mitochondrial cardiolipin synthesis"
ER
TAG
DAG
DAK PA
Ups1 (PRELID1)
Mdm35 (TRIAP1)
PL
TAG
DAG
X!
PA
AGK
Protein [µg]"
2.5
5.0 10
GPAT
AGPAT LPA
G3P
OMM
ADP
Mitochondrial intermembrane space
CDPPGP
PG CRLS1
DAG
Tam41
PGS1
PTPMT1
(TAMM41)
10 5.0
CL
ANT
IMM
ATP
2.5
Sengers syndrome"
Acylglycerol kinase deficiency:"
ANT is absent"
SDHA
ANT
Control
Sengerspatient
From J Mayr AJHG 2012
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Diagnostic approach to a symptomatic patient
1.  Clinical/radiology phenotype (clinical algorhytms)"
2.  Basic screening tests at the bedside (pH,glucose,
ketone,lactate,ammonia,)"
3.  Metabolic profiles (AA,OA….basal and function tests)"
4.  Therapeutic tests (Dopa,Vitamins ….)"
5. Ex vivo tests (whole fatty acid oxidation,respiratory chain)"
6.  Targeted enzymatic or molecular tests (in case of suggestive
phenotype)"
7.  DNA screening tests (targeted or general)"
In every situations search first for treatable disorders !
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Metabolic screening tests
  Urine tests
•  Organic
•  Orotic
acids, (Amino acids)
acid
•  Porphyrias
•  Glycosamine
glycans
•  Sulfatides,Oligosaccharides,Sialic
acid
•  Purines,Pyrimidines
•  Creatine
metabolites
•  Polyols
•  Neurotransmitters
(best in CSF)
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Metabolic screening tests
  Blood tests
•  Amino
•  Total
•  Acyl
acids
homocysteine
carnitine (OA,FAO)
•  VLCFA,Phytanic,Pristanic,Plasmalogens
•  Free
(PZO)
fatty acids profile
•  Copper,Ferritin,ceruloplasmin,transferrin
•  Fibroblast
•  IEF
growth factor 21?
and immunofixation of transferrin (CDG)
•  Thyroid
hormones (MCT 8)
•  Cholesterol,bile
acids
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Metabolic screening tests
  CSF tests
•  Amino
acids (Glycine,Serine,Threonine…)
•  Neurotransmitters
•  Glucose
(GABA,Monoamines,Pterins,Folates)
(plasma/CSF ratio in GLUT 1 deficiency)
•  Lactate,Pyruvate,L/P
ratio (when plasma lactate is < 2.5
mmol/l) (PDH,Pyruvate transporter)
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
 Although most identified by exome sequencing
thus far, lipidomics likely to revolutionize
discovery, treatment, and monitoring of
complex lipid synthesis and recycling diseases
and mitochondrial disorders
 Many new disorders likely to be defined
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Targeted enzyme/molecular tests
  Direct molecular analysis is deemed the most appropriate
diagnostic approach if
•  There
is a very specific phenotype to genotype correlation
•  The
biochemical marker is unavailable (many tissue specific
defects..) or unreliable (respiratory chain..)
•  The
test requires an invasive procedure (CSF,stress test,
biopsy)
•  The
test is difficult to access (complex lipids..)
•  The
molecular testing is easy compared to the enzyme assay
•  The
cost:effectiveness ratio is low
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Transporters defects of molecules involved in
energy metabolism: I. Cellular transporters
•  Glucose:GLUT1(SLC6A19),GLUTII(SLC2A2),GLUT10
•  Monocarboxylic
(SLC2A10)
acids:MCD8(AllanDudley),MCD1:EI/HI(SLC16A1)
(Otontoski T Am J Hum Genet 2007)
•  Creatine
cerebral transporter(SLC6A8)
•  Carnitine:Carnitine
uptake(OTCN 2)
•  Thiamine:BRBGD(SLC19A3)(Zeng Am J Hum Genet 2005)
•  Acetyl
CoA:Cataract,hearing loss,low copper(SLC33A)
(Huppke P, Am J Hum Genet 2012)
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Transporters defects of molecules involved in
energy metabolism: II. Mitochondrial transporters
•  Glutamate
•  Aspartate
•  Pyruvate
•  Citrate
(SLC25A22) :Neonatal Epilepsy
(F Molinari AJHG 2005)
(SLC25A13):Citrullinemia type II
(T Saheki MGM 2010)
(MPC1) :Lactic acidosis(DK Bricker Science 2012)
(SLC25A1):D-L-2-Hydroxyglutaric aciduria
•  Adenine
nucleotide translocator:mtDNA deletions
•  Phosphate
•  Thiamine
necrosis
(SLC25A3) :Neonatal cardiomyopathy
(B Nota AJHG 2013)
(L Palmieri HMG 2005)
(J Mayr AJHG 2007 )
pyrophosphate (SLC25A19):Amisch microcephaly,Striatal
(J Mayr AJHG 2007)
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Metabolic markers
  Some keys to interpret metabolic markers
•  Interorgan
metabolism (brain versus others)
•  Production
versus consumption (organs,organelles)
•  Physiological
state (fed,fasted,exercise,rest)
•  Development(foetus
•  Other
to adult)
(moon lighting proteins, transcription factors…)
•  Conformational
versus metabolic disease with characteristic
aggregation-prone protein (Ex:TPI)
  Most common markers
•  Lactate,
•  Organic
Ammonia
acids,amino acids ……
•  Profiles:
Metabolic signature (Metabolomics)
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Interorgan metabolism
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Interorgan metabolism:
Brain glycogen metabolism
Benarroch E. Neurology. 74:919-923 (2010)
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Production versus consumption:KB
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Development from fœtus to adult
% Basal metabolic rate !
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Regulation of enzymes by sirtuins
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Conformational versus metabolic disease!
Triose phosphate isomerase defect!
F. Orosz et al. BBA 1792 (2009) 1168–1174"
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Metabolic markers I!
Lactic acid!
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Lactate:a very common metabolic
marker
LACTATE
NAD
NADH
PYRUVATE
Pyruvate carrier
PYRUVATE
NAD
Alanine
PC
NADH
PDH
AcetylCoA
OAA
Aspartate
TCA Citrate
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
The cytoplasmic lactico deshydrogenase
O
||
LDH
CH3 — C — COOH
Pyruvate
NADH
|
H+
  Increased NADH/NAD+
•  Increased
}
lactate/pyruvate
•  Anoxia/ischemia
  Increased H+ (acidosis)
OH
|
CH3 — CH — COOH
NAD+
Lactate
Most common
Mostly not metabolic
  Increased pyruvate
•  Normal
•  Mostly
or low lactate/pyruvate
inborn errors
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Pyruvate metabolism:L/P ratio
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Clinical diagnostic issues in
lactic acidosis
  Timing of lactate elevation
•  Fasting
•  Postprandial
•  Permanent
  Hypoglycemia
  Hepatomegaly
  Neurologic signs
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Lactate utilization at fast
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Lactate elevation only with fasting
  Hypoglycemia
•  Gluconeogenesis
– Primary (FBPase, G6Pase)
– Secondary (FAOD,respiratory chain)
•  Glycogen
storage disorder type I (G6Pase defect)
  Probably not an oxidative disorder (but RC…)
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Lactate production in fed state
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Lactate increased postprandially
  In fasting ketotic hypoglycemia context:
Glycogenesis and glycogenolysis defects:Liver size ?
  In neurologic disease context:
Oxydative defect : L/P ratio?
•  Normal
lactate/pyruvate: Hyperpyruvicemia
– PDH,Pyruvate transporter
•  High
lactate/pyruvate: High NADH/NAD ration
– Pyruvate carboxylase ,Krebs cycle
– OXPHOS (primary and secondary)
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Diagnostic approach
Show
All
Hyperlactatemia
Permanent
with neuro signs
Only in postprandial phase
High
Respiratory
chain, PC
Normal
Or Low
PDH, Pyr carrier
L/P
Fasting ketotic
Hypoglycemia
GSD III
GSD 0
High RC, PC
Neuro signs
L/P
Low PDH
Only at fast
with hypoglycemia
Gluconeogenic
enzyme defects
G6Pase
FBPase
Energetic
defects
FAO, RC
Courtesy of JM Saudubray
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Metabolic markers II!
ammonia and amino acid profile!
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Urea cycle interactions:profile
UREA!
ORNITHINE!
AKG!
Orotic!
acid!
ACETYL!
GLUTAMATE!
NH3!
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
The central role of 2-ketoglutarate
Pyruvate!
Urea
Cycle!
PC!
2KG"
Aspartate"
GLU"
Oxaloacetate"
Citrate"
PCC!
PP-CoA
MMM!
MM-CoA!
Succinyl-CoA"
Urea!
Cycle!
Glutamine!
2-Ketoglutarate!
NH3! GDH!
Lys"
Saccharopine
AA"
ASAT!
2KA"
Glutamate!
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Hyperammonemia
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Urea cycle interactions: a new profile
Carbonic anhydrase VA
CO2
X!
CO3H!
X!
CO3H!
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
C van Karnebeeke Am J Hum Genet 2014 94:453-461 "
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Metabolic markers III!
organic acid profile!
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
BCAA catabolism defects:Profile
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Propionate metabolism:
specific profile
L-VALINE
LACTATE
L-ISOLEUCINE
THREONINE
METHIONINE
2-OXO-BUTYRYL-CoA
ACETO-ACETATE
3-OH-BUTYRATE
C15-C17 FA
CHOLESTEROL
3-OH-ISOVALERATE
PYRUVATE
ACETYL-CoA
CITRATE
PROPIONYL-CoA
Propionic acidemia
ETHYLMALONYL-CoA
MALONYL-CoA
ODD-NUMBERED FA
D-METHYLMALONYL-CoA
OXALOACETATE
CH3-CITRATE
L-METHYLMALONYL-CoA
PROPIONYLGLYCINE
PROPIONYLCARNITINE
3-OH-PROPIONATE SUCCINYL-CoA
Characteristic compounds accumulated in propionic acidemia and visible on urinary GCMS
Characteristic compounds accumulated in propionic acidemia and NOT visible on urinary GCMS
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Sources of propionate
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
3-CH3-Glutaconic acid
a marker of mitochondrial dysfunction
3-CH3-GLUTACONIC!
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
« Mitochondrial » disorders associated
with secondary 3-CH3-Glutaconic aciduria
1.Due to defective phospholipids remodeling
•  Tafazzin (Barth syndrome) (type 2)
•  Serac 1 (Megdhel syndrome)
•  Acylglycerol kinase (Sengers syndrome)
2. Due to mitochondrial membrane associated disorders
•  OPA3 (Costeff syndrome) (type 3)
•  DNJAC19 ( DCMA syndrome) (type 5)
•  TMEM70 ( with complex V deficiency)(type 4)
3. Due to ATP synthesis and ATP synthase assembly factors
•  ATP 5 E,ATP 12
4. Due to mitochondrial DNA dysfunction
•  mtDNA deletions and depletions
•  POLG1 mtDNA replication
•  tRNA leucine mtDNA translation
After S. Wortmann thesis 2013"
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
In vivo C13 metabolic fluxes quantifies mito dysfunction !
Mol Genet Metab 2014;111:331-341"
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Summary of diagnostic circumstances
« mitochondrial » disorders
1.  At any age from foetus to late adulthood
2.  Any symptoms (specific ,systemic)
3.  Any scenarios (acute,chronic,intermittent)
4.  Any mode of inheritance
5.  Neonatal screening (at-risk screening)
6.  Presymptomatic medicine
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
Take-home clinical messages
from a bedside clinical physician (retired….)
  Be very careful to the clinical phenotype
  START ALWAYS WITH SCREENING TESTS
  LOOK CAREFULLY AT THE METABOLIC PROFILES
  DO NOT MISS A TREATABLE DISORDER
  DON T BE SNOB (and/or limited minded!) nor NAIVE
  RARE DISEASES are often described first on only one or
a very few patients
  Understanding pathophysiology is crucial
  Molecular investigations are not the alpha and omega
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org
The End
© 2008-2013 Society for Inherited Metabolic Disorders www.simd.org

Download Report