ADCY5

ADCY5 is a human gene that encodes adenylyl cyclase 5, a membrane-bound enzyme that catalyzes the conversion of ATP to cyclic AMP (cAMP). As one of several mammalian adenylyl cyclase isoforms, ADCY5 participates in cAMP signaling pathways that translate extracellular cues into intracellular responses. The enzyme is highly expressed in the central nervous system, with prominent presence in regions such as the basal ganglia, which play a key role in motor control. Its activity is regulated by G proteins, calcium/calmodulin, and other signaling factors, linking neurotransmitter signaling to cAMP production.

Variants in ADCY5 cause a group of movement disorders known as ADCY5-related dyskinesias. The clinical presentation is often infancy- or early childhood-onset and includes hyperkinetic movements such as chorea and dystonia, sometimes with axial hypotonia or developmental delay. Some individuals experience paroxysmal episodes of dyskinesia that fluctuate in frequency and severity. The phenotypic spectrum is broad, and seizures have been reported in a minority of cases. Most cases show autosomal dominant inheritance, although many arise from de novo variants.

Diagnosis is based on clinical features and confirmation by molecular genetic testing identifying pathogenic or likely pathogenic ADCY5 variants. Management is supportive and symptom-driven, with treatment choices drawn from those used for chorea and dystonia (for example benzodiazepines, anticholinergics, tetrabenazine, or antipsychotics), though responses vary. In some patients, deep brain stimulation of the internal segment of the globus pallidus (GPi DBS) has provided meaningful improvement of disabling movements. Ongoing research aims to elucidate how specific ADCY5 variants alter cAMP signaling and neuronal excitability to inform targeted therapies.