S66. Therapeutic effects of an AMPA receptor antagonist on fragile X syndrome and cerebellar coordination disorders/involuntary movements

Abstract

Introduction To examine the effectiveness of an AMPA receptor antagonist (perampanel: PER) for treating cerebellar coordination disorders/involuntary movements with the genetic loss of FMRP protein, which regulates AMPA receptor expression in Purkinje cells. Fragile X syndrome causes mental retardation and cerebellar motor disorders through CGG repeat expansion in the 5′-untranslated region of the FMR1 gene (chX 27.3). The FMRP protein encoded by the FMR1 gene is responsible for translational repression of the signaling of a metabotropic glutamate receptor, mGluR. In FMRP-protein knockout animals, abnormal phenotypes are caused by mGluR-dependent LTD, resulting in morphological abnormalities of the hippocampal neuronal dendrites, which were improved by mGluR antagonist administration ( Bear et al., 2004 ). In Japan, PER is covered by insurance as a combination therapy for epilepsy. Methods The present study was approved by the ethics committee of our hospital, with consent obtained from patients and their families. Two patients with fragile X syndrome (16-year-old male with FMR1-full mutation and 68-year-old female with FMRI-premutation) were included. One case of Usher syndrome and two cases of LCCA were included as disease controls. The administration of PER was started at 2 mg/day, and maintained at 4 mg/day in week 2 and later to examine effectiveness for 12 weeks. Motor symptoms and involuntary movements were evaluated using an international standard score, ICARS, and MDS-UPDRS part III-3, respectively 15–18. AMPA-R protein (130 m/kDa) expressed on the peripheral blood lymphocytes before drug administration was examined by Western blotting (MyBioSource, AMPA receptor (GluR4) rabbit polyclonal antibody). Results Motor and gait functions were markedly improved in the cases of fragile X syndrome (ICARS-motor; −9, gait; −3). Involuntary movement scores were improved in all cases (−12). AMPA-R protein on lymphocytes was detected in the cases of fragile X syndrome, but was not in the disease controls. Conclusion PER is effective for treating cerebellar involuntary movements in fragile X syndrome, and may have LTP/disinhibiting effects through AMPA-R blocking in Purkinje cells. Changes in lymphocyte AMPA-R expression level suggested that AMPA-R expression pattern might be changed in fragile X syndrome.