Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the genetic spectrum of ADCY5-Related movement disorders

Abstract Introduction ADCY5-related hyperkinesiaencompasses a heterogeneous group of phenotypes, including paroxysmal chorea, myoclonus, and dystonia. The disease is attributed to mutations of ADCY5, which encodes an adenylate cyclase enzyme. The disease can occur in a sporadic or familial pattern. With exception of one study, all reports on familial ADCY5-related hyperkinesiawere associated with an autosomaldominant inheritance. Herein, we describe a native Arabian Bedouin family with an autosomalrecessive ADCY5- related disorderand expand the genotypic and phenotypic spectrum of this disorder. Methods The pedigree included 4 generations of a family with 6 affected individuals. The patients were examined clinically and radiologically. Homozygosity mapping and Whole Exome Sequencing(WES) were used to identify a variant, predicted to be pathogenic, which segregated with disease in this family. Results All patients presented with early-onset dystoniaand myoclonus. The patients had delayed motor and language milestones, axial hypotonia, severe anxiety, social phobia, and isolation. One patient had dilated cardiomyopathy. WES of one affected individual revealed a novel homozygous missense mutation (c.1762G > A, p.D588N) of ADCY5, that segregated with disease in an autosomalrecessive manner, and was absent in more than 1000 ethnically-matched chromosomes. The mutation replaces a highly conserved nucleotide and is predicted to be deleterious. Conclusion This study reports the second family with autosomalrecessive childhood-onset ADCY5- related disorderand expands our understanding of phenotype/genotype correlations of this disorder.