Gli individui affetti dalla sindrome FRAX mostrano fenotipi clinici e risposte al trattamento farmacologici di tipo eterogeneo. Una possibile spiegazione potrebbe essere la variazione nella regolazione epigenetica del gene FMR1 e differenze nei livelli residui della proteina FMRP (mosaicismo). Non è del tutto chiaro come queste differenze a livello molecolare riflettano il fenotipo clinico globale.
Le cure attuali per la sindrome FRAX si focalizzano in modo particolare sul trattamento dei sintomi, per questo è necessario sviluppare trattamenti farmacologici terapeutici. L’identificazione di un ruolo chiave del mGluR5 nella fisiopatologia della sindrome FRAX è stato fondamentale. La ricerca delle terapie farmacologiche per la sindrome dell’ X fragile si è concentrata sugli antagonisti del recettore mGluR5.
Studi preclinici, con gli antagonisti del recettore mGluR5, suggeriscono che queste terapie potrebbero avere la capacità di curare i pazienti affetti dalla sindrome FRAX.
Allo scopo di rivelare le potenziali modifiche dei trattamenti terapeutici, negli esperimenti clinici sulla sindrome FRAX, sono necessarie scale di valutazione appropriate.
Nonostante la scala ABC-C e le sue sottoscale siano storicamente state selezionate come indicatori di rilevanza, negli esperimenti sulla FRAX, la validità clinica è stata messa in discussione. La nuova scala sviluppata per la FRAX sembra essere efficace come la scala ABC-C. Studi ulteriori saranno necessari per convalidare la correttezza della nuova scala ABC-C per la FRAX.
I dati clinici, in pazienti affetti da FRAX, mostrano risultati incoraggianti in seguito al trattamento con antagonisti mGluR5.
Attualmente sono attesi i risultati dalla fase III degli esperimenti clinici con Mavoglurant, se questi risultati confermeranno le ipotesi sviluppate a livello preclinico, in poco tempo avverrà la registrazione della prima terapia specifica per la sindrome del X fragile.
7.GLOSSARIO
ABC-C Aberrant Behavior Checklist-Community edition
ADHD Disturbo dell’attenzione e dell’iperattività
AMPA Acido α-amino-3-idrossi-5-metil-4-isossazolproprionico
ASD Autism spectrum disorder
ATP Adenosin trifosfato
BDNF Brain-derived neurotrophic factor
CaM Calmodulina
CaMKIV Calmodulina chinasi IV
CGG Citosina Guanina Guanina
cGMP Guanosin-monofosfato ciclico
cNOS Ossido nitrico sintetasi costitutiva
CRE Nuclear cAMP response element
CREB cAMP responsive element binding protein (proteina associata a CRE)
CSF Fluidi cerebro-spinali
EAA Amminoacido eccitatorio
ECT Terapia elettroconvulsiva
FDA Food and drug administration
FMR1 Fragile X mental retardation 1
FMRP Proteina espressa dal gene FMR1
FXTAS Fragile X associated tremor/ataxia syndrome
GABA Acido γ-ammino butirrico
GAD-65/67 Acido glutammico decarbossilasi 65/67 GLX Glutammato e glutammina
HAM-D Hamilton depression rating scale
KO Knockout
LTD Depressione a lungo termine
MAO Mono ammino ossidasi
MAPK Proteina chinasi mitocondriale
MDD Disordini di depressione maggiore
MMP-9 Matrix metallo-proteinase-9
MPEP 2-metil-6-feniletinil-piridina
MTEP 3-[(2-metil-1,3-tiazol-4-enil)etilenil]-piridina
mRNA RNA messaggero
NAA N-acetil aspartato
NE Noradrenalina
NMDA N- metil D aspartato
NO Ossido nitrico
NOS Enzima ossido nitrico sintetasi
nNOS Enzima neuronale N-ossido sintetasi calcio-calmodulina dipendente
nPGi Nucleus paragiganto cellularis
REM Rapid eye movement
RSK Chinasi ribosomiale S
SLA Sclerosi laterale amiotrofica
SNC Sistema nervoso centrale
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