ASL-HSP France & RESEARCH a rear overview (1992-2012) Jean BENARD, Scientific Advisor, ASL-HSP France & EURO-HSP May 26, 2012 Louis Lumière International Center, 75020 Paris, France
How to fight HSP? 1992: Strumpell-Lorrain Association, the ASL-HSP France Founder: Phil GRAMMONT (Besançon, France) Helping each other among patients, meetings & sharing Being recognized by society and obtain legal rights Improving quality of life: Finding means enabling - reduction of fatigue - decrease of spasticity - control of sphincters dysfunction - improvement of speaking Helping research in funding scientific projects
A rare disease A familial disease An orphan disease for treatment For Neurologist A spinal tract degenerescence For Geneticist In1992, a HSP was A disease with autosomic transmission (dominante & récessive), orphan of genes
French mousquetaires against HSP Paris, AFM, May 1993
Sus to guilty gene(s)
HSP: transmission mode Dominant autosomic 70% Recessive autosomic 25%
Type Locus, Chromosome Gene Protéine HSP1 SPG1, Xq L1CAM NCAM HSP2 SPG2, Xq PLP1 MPLP HSP3A SPG3, 14q ATL1 Atlastine-1 1995-2012 Neurologists HSP4 SPG4, 2p SPAST Spastin HSP5A SPG5, 8q CYP7B1 OAH1 HSP6 SPG6, 15q NIPA1 NIPA1 HSP7 SPG7, 16q SPG7 Paraplégine HSP8 SPG8, 8q KIAA0196 Strumpelline HSP10 SPG10, 12q KIF5A Kinesine HC5A HSP11 SPG11, 15q KIAA1840 Spatacsine HSP12 SPG12, 19q RTN2 Reticulon 2 HSP13 SPG13, 2q HSPD1 HSP60 Jean de Recondo Alexis Brice Alexandra DÜRR HSP15 SPG15, 14q ZFYVE26 Spastizine HSP17 SPG17, 11q BSCL2 Seipine HSP18 SPG18, 8p12 8q11 ERLIN2 SPFH2 have enabled researchers identifying 30 genes HSP20 SPG20, 13q SPG20 Spartine HSP21 SPG21, 15q ACP33 Maspardin HSP22 SPG22, Xq SLC16A2 MCT8 HSP28 SPG28, 14q DDHD1 DDHD1 HSP30 SPG30, 2q KIF1A kinesin 3 HSP31 SPG31, 9p REEP1 REEP1 HSP35 SPG35, 16q FA2H FAAH HSP39 SPG39, 19p NTE Esterase HSP43 SPG43, 19p13-q12 C19orf12 C19orf12 HSP44 SPG44, 1q GJA12/GJC 2 HSP47 SPG47, 1p AP4B1 AP4B1 Connexine 47 HSP48 SPG48, 7p KIAA0415 KIAA0415 J. Weisenbach & J.Hazan G. Casari G. Stevanin Locus SPG3A, gene SPG4 Gène SPG7 Gène SPG11
Mutated genes responsible for HSP : Frequency unknown SPG 4 40 48% SPG 11 21% unknown SPG3A(3 20%) SPG 8 (<1%) SPG10 (2 3%) SPG 6 (<1%) SPG31 (2 3%) SPG 17/Silver syndrome (0 1%) SPG 13, SPG 42 (rare) SPG 15 (4%) SPG 5 (7%) SPG 7, ARSACS (~7%) SPG 20, SPG21 (rare) Autosomic Dominant Forms Recessive Autosomic Forms Data obtained from Salpêtrière, Dr Giovanni Stevanin (May 2012)
Star physiopathological studies of French teams s 2006: A transgenic knock-out SPG4 mouse model: Dr Judith Melki s team, Evry, France. Degenerescence of a specific part of cortico-spinal neurones and defect of axonal transport 2010: Mitochondrial dysfunction (SPG31) and lipidic metabolism (SPG5 & SPG47): Pr Cyril Goizet s team, Bordeaux) SPG5 phenotype shows altered cholesterol metabolites (accumulation of 25-0HC & 27- OHC) 2011: Zebra fish SPG3A model: Involvement of the Bone Morphogenic Pathway: Dr Jamilé Hazan s team, Paris.
Each of these 30 genes is mandatory for maintenance of cortico-spinal function Experimental models, «On/off», to study function of cortico-spinal neuron Neuron Organism : zebra fish pour SPG3, SPG4, mice for SPG4, SPG11 BMP pathway Trafic REendosomes Anomalies du transport axonal Dysfonctions de la mitochondrie Paraplegine Reep1 Hsp60 Atlastine, Kinesine NIPA1 spastine spartine, spastizine, spastine PLP1 L1CAM, Anomalies NTE, de développement GJC2 et de la myélinisation Dr Cyril Goizet, CHU Bordeaux (May2012)
Fundings of ASL-HSP France for research On-going standard process Grant Calls from ASL twice a year Scientific evaluation by 2 independent reviewers committed by the Scientific Committee (common to 3 associations, French Ataxia Friedreich Association, French Cerebellum Syndrom Association, & Strümpell-Lorrain-HSP France Association) Upon favorable recommendation of the Scientific Committee, funding of the recipient research team. Fundings :2007-2011= 90kE Genetics Physiopathogy at both cellular & molecular levels
SPATAX Group CHU, Salpétrière, Paris (June 2009)
For patients In 2012, la HSP is A rare disease A familial disease A disease orphan of treatment For Neurologist A spinal tract degenerescence For geneticist A monogenic but heterogenous disease About 50% of families have nt got yet a genetic status and still wait
Helping research in funding high-ranked projects meeting the patients expectation Genetics & biology Genetics: for families still waiting molecular diagnosis (near 50%), picking up the guilty gene via high-troughput technology Genes function: exhaustive functional study of SPG3, SPG4, SPG11 to finding cellular pathways of therapeutic value. Quality of life Measurement of fatigue to test candidate therapeutic Scientificaly investigating potential interest of alternative therapies (chinese approaches, sophrology )
How to fight HSP? Helping each other among patients, meetings & sharing Being recognized by society and obtaining legal rights Improving quality of life: Finding means enabling: - reduction of fatigue - decrease of spasticity - control of sphincters problems - improvement of speaking Helping research in boosting scientific projects