ADCY5-related movement disorder: broader spectrum and genotype/phenotype correlations including new cases (P2.140)

OBJECTIVE: To investigate the clinical spectrum of adenylate cyclase-5 (ADCY5)-related movement disorders and the relationship of phenotype to genotype. BACKGROUND: We recently identified mutations in ADCY5 as the cause of the autosomal dominant disorder previously called familial dyskinesia with facial myokymia (FDFM, OMIM #600293) in one multigenerational family and a choreiform/myoclonic movement disorder in two sporadic cases. DESIGN/METHODS: Two new families and a new sporadic case with choreiform and/or dystonic movement disorders were examined for mutations in ADCY5 by exome sequencing and/or PCR-Sanger sequencing. Clinical features were evaluated in these new cases and those previously reported, comprising 23 affected individuals from six families. The associations of phenotypes to the mutations were analyzed. RESULTS: Heterozygous mutations in ADCY5 cause a mixed movement disorder with dystonia, hypotonia, chorea, myoclonus and rarely seizures. In two unrelated families, a p.A726T mutation in the first cytoplasmic domain causes a relatively mild disorder that manifests as facial twitches and dystonic/choreiform hand movements. A p.R418W mutation in the first membrane-spanning domain that arose de novo in three unrelated individuals produces a moderately severe disorder with axial hypotonia, limb hypertonia, and dystonia and myoclonus. One subject with milder and episodic manifestations is likely mosaic. In a three-generation family, a p.M1029K mutation in the second cytoplasmic domain causes a severe disorder with dystonia, hypotonia and chorea. The progenitor who had childhood onset episodic dystonia, which essentially disappeared in adulthood, was shown to be mosaic. CONCLUSIONS: Mutations in ADCY5 cause a range of movement disorders with apparent genotype/phenotype correlation. The observation of the same inherited mutation in two unrelated families and a recurrent de novo mutation in three sporadic patients suggests that there may be a limited spectrum of pathogenic mutations that cause ADCY5-related dyskinesias. Disclosure: Dr. Chen has received license fee payments from Athena Diagnostics. Dr. Bonkowski has nothing to disclose. Dr. Korvatska has nothing to disclose. Dr. Hisama has received personal compensation for activities with Familion, Inc. Dr. Friedman has nothing to disclose. Dr. Davis has nothing to disclose. Dr. Swanson has nothing to disclose. Dr. Gad has nothing to disclose. Dr. Amendola has nothing to disclose. Dr. Guo has nothing to disclose. Dr. Weiss has received personal compensation for activities with Walgreens, Grifols, and Nufactor. Dr. Weiss has received research support from Clinical Trials Research Unit/Northeast ALS Consortium and the ALS Therapy Alliance. Dr. Torkamani has received personal compensation for activities with Cypher Genomics as a consultant. Dr. Bird has received licensing fees payments from Athena Diagnostics Inc. Dr. Raskind has received license fee payments from Athena Diagnostics.