Phenotypic insights into ADCY5-associated disease.

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Adenylyl cyclase 5 (ADCY5) gene mutations are linked to various neurological syndromes, including familial dyskinesia, chorea, and dystonia.
• The phenotypic spectrum associated with ADCY5 mutations requires further definition.

Purpose of the Study:

• To expand and define the phenotypic spectrum of ADCY5 mutations.
• To provide detailed clinical data on 7 patients from six new kindreds with ADCY5 mutations.

Main Methods:

• Sanger sequencing was used for 5 patients with long-term follow-up (9-32 years).
• Whole-exome sequencing was performed on 2 unrelated pediatric patients with hyperkinetic movement disorders.

Main Results:

• Five patients harbored the known p.R418W ADCY5 mutation; two novel mutations (p.R418G, p.R418Q) were identified.
• All patients exhibited motor milestone delay and infantile-onset, action-induced choreoathetosis, dystonia, or myoclonus, often exacerbated during drowsiness.
• Milder phenotypes were observed with p.R418G and p.R418Q mutations. Six patients showed mild improvement with clonazepam or clobazam; one patient benefited from bilateral pallidal deep brain stimulation (DBS).

Conclusions:

• This study further delineates the clinical features and wide phenotypic expression of ADCY5 gene mutations.
• Mild functional improvement was noted with clonazepam, clobazam, and bilateral pallidal DBS.
• ADCY5-associated dyskinesia may be under-recognized, highlighting the diagnostic, prognostic, and therapeutic importance of identifying these mutations.