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Biosynthèse et remodelage des
Phospholipides:
Une nouvelle catégorie des EIM
Printemps de la SFEIM
Toulouse Juin 2013
C
HO C
C OH
H
H
H
H O
O
C OH
H C O
O
O
O-
P
O
OH H
Phospho-
glycerol
Fatty acid
(MU, PU)
Fatty acid
(saturated)
Structure des Phospholipides
O
C
O
O
C
O
C
O-
O
P O
OH
Lyso-PA
O
C
O
O
C
O
C
O-
O
P O
OH
PA
NH2
O
O
C
O
O
C
O
C
O-
O
P O
O
C
O
O
C
O
C
O-
O
P O
N+
H3C
H3C CH3
O
PC PE
O
O
C
O
O
C
O
C
O-
O
P O
CH2 CH
2HN
COOH
PS
variabilité Structurale
Remodelage permanent des structures
O
C
O
O
C
O
C
O-
O
P O
X
PA
O PLD
PLC
PLA1 PLA2
• Fatty acids release
• Fatty acids exchange
• Base exchange
Rôle Physiologique des PL
• Biological membranes
– Cell membranes
– Myelin
• Energy metabolism
• Cell signaling ( Archidonique Ac, Endocannabinoïds, PGN, LTN..)
– Inflammation
– Apopotosis
– Metabolic regulation (Acylation)
• Intracellular trafficking and cell adhesion
• Epidermal water barrier
• Mitochondrial function
• Visual cycle
Présentation Clinique
CNS presentation
Leukodystrophy and/or iron deposits in basal ganglia (NBIA)
(Neurodegeneration with Brain Iron Accumulation NBIA) : PLA2G6,
Spastic paraplegia (SPG 54:DDH2;SPG 28:DDH1;SPG 49: CYP2U1)
SPG with muscle wasting : Neuropathy target esterase deficiency (NTE: SPG 39).
Spastic quadriplegia with ichthyosis : ELOV4 deficiency and Sjogren-Larsson syndrome
Peripheral nerve presentation
PHARC syndrome: α-/β-hydrolase 12 deficiency
Muscular/cardiac presentations
Recurrent myoglobinuria : (Lipin1) deficiency
Barth syndrome : Cardiolipin deficiency ( Tafazzin mutations)
Sengers syndrome : mitochondrial acylglycerolkinase deficiency.
Congenital muscular dystrophy : choline-kinase deficiency
Glycerol-3-phosphate
Acyl CoA
CoA-SH
Lysophosphatidic Acid
Glycerol Dihydroxyacetone
3-phosphate
ABHD5
G3P-AT
Phosphatidic Acid
Acyl CoA
CoA-SH
AG-AT
-
• Erythrodermic Ichthyosis (congenital)
• Hepatomegaly with liver steatosis (70%)
• Nystagmus, cataracts, decreased hearing
• Mental, developmental retardation
• Myopathy
Non lysosomal lipid storage disease
Tissular accumulation of neutral lipids
(vacuolated PBC).
a/b Hydrolase domain containig 5 (ABHD5) Syndrome de Chanarin-Dorfman (AR)
Chanarin et al, 1974
Lefèvre et al,2001
Glycerol-3-phosphate
Acyl CoA
CoA-SH
Lysophosphatidic Acid
Glycerol Dihydroxyacetone
3-phosphate
ADP ATP
ABHD5
G3P-AT
Phosphatidic Acid
Acyl CoA
CoA-SH
AG-AT
-
CDP Diacylglycerol
CTP
PPi
Diacylglycerol
PAP CDP-DAG
Synthase
Lipin1 deficiency
Onset in infancy and childhood (2-7 y).
• Rhabdomyolysis, iduced by febrile illness, anaesthesia, fasting
• Episodic myoglobinuria with CK elevation
• Muscular Hypotonia
First cause of rhabdomyolysis after bêta-oxydation defects
Dual role :
• Biosynthesis of Triacylglycerol and phospholipids
• Regulation of the expression of genes encoding fatty acid oxidation and
respiratory chain enzymes: PPAR-a and PGC-1a
Déficit en Lipin 1 Phosphatidate phosphatase (AR)
Zeharia et al. 2008
Lpin2 deficiency : Majeed Syndrome
Onset in infancy and childhood.
• Multifocal osteomyelitis,
• Dyserythropoietic anemia
• Hepatosplenomagaly
Glycerol-3-phosphate
Acyl CoA
CoA-SH
Lysophosphatidic Acid
Glycerol Dihydroxyacetone
3-phosphate
ABHD5
G3P-AT
Phosphatidic Acid
Acyl CoA
CoA-SH
AG-AT
-
CDP Diacylglycerol
CTP
PPi
Diacylglycerol
PAP CDP-DAG
Synthase
choline
ADP ATP
Phospho-
choline
PC-Cytidylyl
transferase CHK
PS
PE PC
Ser Ser
Eth
Chol
PG
CDP-PChol
CMP
CDP-PEth
CMP
SAM SAH
PE-N-methyl
transferase
Early onset Muscular dystrophy (in infancy)
Mental retardation
Developmental delay (+/- epilepsy)
Dilated cardiomyopathy
Megaconial mitochondria
Decresed levels of PC and PC/PE ratio in muscle biopsy.
Déficit en CHKb Choline Kinase b (AR)
Mitsuhashi et al. 2011
Glycerol-3-phosphate
Acyl CoA
CoA-SH
Lysophosphatidic Acid
Glycerol Dihydroxyacetone
3-phosphate
ABHD5
G3P-AT
Phosphatidic Acid
Acyl CoA
CoA-SH
AG-AT
-
CDP Diacylglycerol
CTP
PPi
Diacylglycerol
PAP CDP-DAG
Synthase
choline
ADP ATP
Phospho-
choline
PC-Cytidylyl
transferase CHK
Triacylglycerol
DGAT
PS
PE PC
Ser Ser
Eth
Chol
PG
C18:0/C18:1
CDP-PChol
CMP
CDP-PEth
CMP
SAM SAH
PE-N-methyl
transferase
Déficit en DGAT 1
Congenital diarrhea disorder
Haas et al. 2012
Reported in a nonconsanguineous Ashkenazi Jewish family
• Early onset intractable diarrhea (few days after birth)
• Delayed fat absorption
• Fasting hypertriglyceridemia with normal cholesterol
• Resolution of symptoms at 10 to 12 months of age
Glycerol-3-phosphate
Acyl CoA
CoA-SH
Lysophosphatidic Acid
Glycerol Dihydroxyacetone
3-phosphate
ABHD5
G3P-AT
Phosphatidic Acid
Acyl CoA
CoA-SH
AG-AT
-
CDP Diacylglycerol
CTP
PPi
Diacylglycerol
PAP CDP-DAG
Synthase
choline
ADP ATP
Phospho-
choline
PC-Cytidylyl
transferase CHK
Triacylglycerol
DGAT
+
PS
PE PC
Ser Ser
Eth
Chol
PG
C18:0/C18:1
CDP-PChol
CMP
CDP-PEth
CMP
SAM SAH
PE-N-methyl
transferase
PNPLA2
Déficit en PNPLA2
Neutral lipid storage with myopathy (AR)
Fischer et al. 2007
• Adipose triglyceride lipase of lipid droplets
• Myopathy of proximal and distal muscles
• Assymetric Muscle Atrophy
•Hepatomegaly, liver steatosis (50%)
• Absence of ichthyosis
•Accumulation of Multisystem triglyceride storage :
• Lipid droplets in muscle, leucocytes (triglycerides)
Glycerol-3-phosphate
Acyl CoA
CoA-SH
Lysophosphatidic Acid
Glycerol Dihydroxyacetone
3-phosphate
ABHD5
G3P-AT
Phosphatidic Acid
Acyl CoA
CoA-SH
AG-AT
-
CDP Diacylglycerol
CTP
PPi
Diacylglycerol
PAP CDP-DAG
Synthase
choline
ADP ATP
Phospho-
choline
PC-Cytidylyl
transferase CHK
Triacylglycerol
DGAT
PNPLA2
+ DGKE
PS
PE PC
Ser Ser
Eth
Chol
PG
C18:0/C18:1
CDP-PChol
CMP
CDP-PEth
CMP
SAM SAH
PE-N-methyl
transferase
ADP
AGK Monoacylglycerol
ATP
Déficit en AGK2
Sengers Syndrome (AR)
• Congenital Cataract
• Hypertrophic cardiomyopathy (cause of death)
• Myopathy
• Lactique Acidosis
• Elevated 3-Methylglutaconic acid excretion
• Mitochondrial abnormalities :
• Decreased Adenine Nucleotide Translocator (ANT) expression
• Defective Cardiolipin and ATP synthesis
Mayr et al. 2012
Déficit en DGKE
Atypical HUS type 1 (AR)
• Early onset Hemolytic Uremic Syndrome (< 1 y)
• Persistent hypertension
• Hematuria and proteinuria
• Chronic renal failure with age
Lemaire et al. 2013
Glycerol-3-phosphate
Acyl CoA
CoA-SH
Lysophosphatidic Acid
Glycerol Dihydroxyacetone
3-phosphate
ABHD5
G3P-AT
Phosphatidic Acid
Acyl CoA
CoA-SH
AG-AT
-
CDP Diacylglycerol
CTP
PPi
Diacylglycerol
PAP CDP-DAG
Synthase
choline
ADP ATP
Phospho-
choline
PC-Cytidylyl
transferase CHK
Triacylglycerol
DGAT
PNPLA2
+ Phosphoglycero-
phosphate
Phosphatidyl-
Glycerol
Phse
CH2
O
P
O
CH2
CH
O
CO
CH2
O
CO
C
O. O. P
O
CH2
O.
CH2
CH
CH2
O
CO
CO
H H O O
Cardiolipin
- -
Taz
DGKE
PS
PE PC
Ser Ser
Eth
Chol
PG
C18:0/C18:1
CDP-PChol
CMP
CDP-PEth
CMP
SAM SAH
PE-N-methyl
transferase
ADP
AGK Monoacylglycerol
ATP
Déficit en Monolysocardiolipine acyl
transférase (Tafazzin)
Barth Syndrome (X-linked)
• Symptoms in infancy and childhood
• Dilated cardiomyopathy (bi or left ventricular dilatation)
• Muscle weaknesse, Neutropenia, Developmental delay
• Variability in age of onset and course
• No genotype/phenotype correlation
• 3-Methylglutaric aciduria (type III): inconstant
• Defective ATP synthesis
• Blood screening test
Bione et al. 1996
Glycerol-3-phosphate
Acyl CoA
CoA-SH
Lysophosphatidic Acid
Glycerol Dihydroxyacetone
3-phosphate
ABHD5
G3P-AT
Phosphatidic Acid
Acyl CoA
CoA-SH
AG-AT
-
CDP Diacylglycerol
CTP
PPi
Diacylglycerol
PAP CDP-DAG
Synthase
choline
ADP ATP
Phospho-
choline
PC-Cytidylyl
transferase CHK
Triacylglycerol
DGAT
PNPLA2
+ Phosphoglycero-
phosphate
Phosphatidyl-
Glycerol
Phse
CH2
O
P
O
CH2
CH
O
CO
CH2
O
CO
C
O. O. P
O
CH2
O.
CH2
CH
CH2
O
CO
CO
H H O O
Cardiolipin
- -
Taz
SERAC
DGKE
PS
PE PC
Ser Ser
Eth
Chol
PG
C18:0/C18:1
CDP-PChol
CMP
CDP-PEth
CMP
SAM SAH
PE-N-methyl
transferase
ADP
AGK Monoacylglycerol
ATP
Déficit en SERAC-1
MEGDEL Syndrome (AR)
• 3-METHYLGLUTACONIC ACIDURIA (Type III)
• DEAFNESS
• ENCEPHALOPATHY
• LEIGH-LIKE SYNDROME
•Lactic acidemia
• Psychomotor delay/regression in childhood
• Spasticity or dystonia
•MRI :
• Leigh syndrome
•Cerebral and cerebellar atrophy
Wortmann et al, 2012
COOH
Arachidonic
Acid
+
PLA2G6
DDHD1,2
Déficit en PLA2g calcium-independante
(PLA2G6) (AR)
INAD : Infantile Neuroaxonal dystrophie: Onset before 5y Motor and mental Retardation Cerebellar ataxie Trunc hypotonia and spastic paraplegia
Visual disturbances (Optic atrophy, nystagmus, strabism) MRI : cerebellar atrophy, Iron storage in globus pallidus and grey matter neuroaxonal spheroids
NBIA : Neurodegeneration with Brain Iron Accumulation Milder phenotype of INAD Variable age of onset (2-18 y) Encephalopathy in infancy to childhood , Neurodegeneration at adolescence
Dystonia/parkinson L-Dopa-responsive After 20 years Cerebellar atrophy, no iron deposits Pyramidal, psychiatric signs, cognitive decline
Cerebellar atrophy
3 years
NO iron deposition
3 years
Cerebellar atrophy with iron deposits in pallida
9 years
Mutations en DDHD1 et DDHD2
Paraplégie spastique 28 et 54 (AR)
Mixed spastic paraplegia :
• Early-onset (before 2y)
• Progressive spasticity upper limbs+++
• Strabismus, dysarthria +/- dysphagia
• Cognitive alterations
• Variable severity of symptoms,
independently from the nature of mutation
MRI : Thin corpus calosum and subtle
periventricular WM hyperintensities
Spinal syrinx
Basal ganglia
thalamus
Tesson et al. 2012
Schuurs-Hoeijmakers et al, 2012
COOH
Arachidonic
Acid
+
PLA2G6
DDHD1,2 Phospho-
glycerol
NTE +
Déficit en Neuropathy Target Esterase (NTE)
Paraplégie spastique 39 (AR)
Target for Organo-phosphorus induced delayed neuropathy (OPDN)
Onset in childhood or adulthood
• Progressive spastic paraplegia in childhood
• Motor axonopathy of lower and upper extremities
• Muscle weakness
• Motor nerve abnormalities / spared perepheral nerve
MRI : Spinal cord atrophy and spared CNS
Disturbance of vesicular transport a long the axons
Rainier et al. 2008
COOH
Arachidonic
Acid
Prostaglandins
Leukotriens
+
COOH
OH
COOH
OH
20-HETE
19-HETE
CYP2U1
PLA2G6
DDHD1,2 Phospho-
glycerol
NTE +
Mutations en Cytochrome P450 hydroxylase
(CYP2U1)
Paraplégie spastique 49 (AR)
Onset between birth to 8 Y
• Spastic paraplegia at upper limbs +/- dystonia
• Discrete axonal neuropathy at the lower limbs
• Cerebellar occulomotor disturbance (saccadic eye pursuit)
MRI : Thin corpus callosum
white matter lesions
Globus pallidus hypointensities (calcifications)-late
Normal spine
Tesson et al. 2012
COOH
Arachidonic
Acid
Fatty acid
Diacylglycerol
H2O
PLC
2-Arachidonoyl
Glycerol
H2O
Fatty
acid
DAGL Prostaglandins
Leukotriens
+
H2O Glycerol
ABDH12
COOH
OH
COOH
OH
20-HETE
19-HETE
CYP2U1
PLA2G6
DDHD1,2 Phospho-
glycerol
NTE +
Pseudo Refsum disease without phytanic acid elevation
- Polyneurpathy - Hearing loss - Ataxia - Retinitis pigmentosa - Cataract
MRI :Cerebellar atrophy
Déficit en a/b Hydrolase 12 (ABHD12) Syndrome de PHARC (AR)
Présentation hépatique des déficits de
biosynthèse et remodelage des PL (Saudubray)
Neutral Lipid storage with myopathy, PNPLA2 deficiency Myopathy of proximal and distal muscles Assymetric Muscle Atrophy Hepatomegaly, liver steatosis (50%) Absence of ichthyosis
Chanarin Dorfman (ABHD5)
Hepatomegaly with liver steatosis Cataract ,Deafness, Myopathy ,Developmental delay
Glycerol 3 phosphate dehydrogenase 1 deficiency : infantile hepatomegaly and hypertriglyceridemia Onset in the first months of life Asymptomatic soft hepatomegaly Transient hypertriglyceridemia, Normal with age liver dysfunction and progression of the fatty liver to fibrosis.
Conclusions
Déficits de biosynthèse des lipides complexes : un nouveau groupe
de MHM.
Les déficits de synthèse se situent à la frontière entre les MHM
classiques et les maladies génétiques impliquant le métabolisme
des protéines de structure.
Groupe de maladies en pleine expansion : nombreux gènes trés
récemment décrits et d’autres probablement à venir.
Peu de cas décrits pour chaque déficit : déscription clinique
temporaire
Le diagnostic repose principalement sur les analyses moléculaires
et l’analyse lipidomique (plasma/fibro).
Frédéric SEDEL Giovanni STEVANIN
Fanny MOCHEL Claude JARDEL
Jean Marie SAUDUBRAY Christelle DEPIENNE
Unité Neurométabolique bioclinique et génétique – Salpêtrière - Paris
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