Objective: To expand and determine the clinical spectrum associated with mutations in the Adenylate Cyclase 5 gene (ADCY5).

Background: Recently, mutations in the ADCY5 gene have been identified as the cause of a childhood-onset movement disorder with variable persistent or paroxysmal choreic, myoclonic, and/or dystonic movements involving the limbs, neck, and/or face.

Methods: In a group of 108 patients affected with an unexplained hyperkinetic movement disorder, all 21 coding exons of the ADCY5 gene including intron/exon boundaries were sequenced by Sanger method. This was followed by in-silico analysis of detected nonsynonymous coding variants.

Results: Two novel mutations in the ADCY5 gene (c.3045C>A; p.Asp1015Glu and c.3074A>T; p.Glu1025Val) were found in a heterozygous state, one in each of two male patients. Both changes are evolutionarily conserved, predicted to be pathogenic, and absent from more than 60,000 exomes in the Exome Aggregation Consortium (ExAC) Browser. Moreover, these mutations affect the same functionally important cytoplasmic domain that creates a catalytic adenosine-5′-triphosphate (ATP)-binding pocket of the ADCY5 protein. In addition to generalized chorea, our ADCY5 mutation carriers presented with attacks of paroxysmal weakness/paralysis, which had led to a clinical assessment of alternating hemiplegia of childhood (AHC).

Conclusions: The two ADCY5 mutation carriers that we identified have a comparable clinical presentation that includes AHC-like symptoms. Thus, the phenotypic spectrum of ADCY5 mutations encompasses paroxysmal weakness in addition to paroxysmal dyskinesia and persistent hyperkinesia. Given this new phenotype of ADCY5-mutation-associated disease, genetic analysis of ADCY5 should be considered in patients with unexplained AHC.

« Back to 2016 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/alternating-hemiplegia-of-childhood-ahc-as-a-new-presentation-of-adenylate-cyclase-5-adcy5-mutation-associated-disease/