Dados do Trabalho

Título

ADCY5 related dyskinesia presenting as dystonia-plus responsive to caffeine

RESUMO

Case Presentation

We present a case of a 40 years old male with early childhood onset dystonia, paroxysmal worsening of varying frequency triggered by fasting and improved by coffee consumption, important orofacial dyskinesia and normal cognitive function, neuroimaging and laboratory screenings. This suggestive story brought up the suspicion of a ADCY5 related dyskinesia, confirmed by genetic testing and with excellent response to caffeine with clonazepam.

Discussion
ADCY5 related dyskinesia is a newly recognised heterogeneous entity with various phenotypes caused by many different pathogenic variants in the ADCY5 gene in chromosome 3q21-3p21.
Clinically it is characterized by hyperkinetic movement disorder of early childhood onset including choreoathetosis, myoclonus and dystonia with paroxysmal worsening related to sleep, waking up, fatigue, physiological or psychological stresses, little to no progression and important facial dyskinesia. The majority of cases have normal neuroimaging, normal cognitive function and unrevealing laboratory finds.
Some cases are associated with axial hypotonia, painful dystonias, hyperreflexia and proeminent nocturnal paroxysms. This phenotype suggests the R418W mutation as the cause.
The two most frequent variants (first the R418W and second the A726T) both occur at conserved residues in the catalytic pocket of the protein, probably resulting in gain of function.
Many therapies have been tried in those patients, with conflicting data on response.
Treatment with caffeine has been proposed by many authors. The rationale behind this relies on the antagonism of the A2A adenosine receptor by caffeine counterbalancing the theoretical gain of function of ADCY5.
There are reports in literature of autosomal dominant heritage, autosomal recessive cases with a more severe phenotype, de novo mutations, mosaicisms and even possible dual diagnosis. The most prevalent seems to be the de novo mutation in R418W.

Final comments
This report helps to consolidate the phenotype of ADCY5-related-dyskinesia, to describe a new case of R418W as a causative variant and adds evidence to the safety and efficacy of caffeine in association use with benzodiazepines.