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