The ADCY5 gene provides instructions for creating an enzyme called adenylate cyclase 5 (AC5). The ADCY5 gene is located on chromosome 3 in humans. Mutations within this gene can lead to a condition known as ADCY5-related dyskinesia, a rare movement disorder.
How ADCY5 Functions
This enzyme is a membrane protein that converts adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). cAMP acts as a signaling molecule involved in many cellular functions. AC5 catalyzes the production of cAMP under the regulation of G proteins. Cellular cAMP levels influence the activity of protein kinase A (PKA), which enables cellular responses to G protein-coupled receptor stimulation.
The ADCY5 gene is expressed in many tissues, including the brain, heart, and pancreas. It is highly expressed in the striatum, a brain region involved in modulating movement, as well as in cardiomyocytes and pancreatic islets. ADCY5 is also involved in balancing and maintaining coordination and locomotion, and in responding to dopamine neurotransmitters.
Understanding ADCY5-Related Dyskinesia
The term “dyskinesia” refers to abnormal involuntary movements, which are a defining characteristic of this condition. These movements typically manifest as sudden jerks, twitches, tremors, muscle tensing (dystonia), or writhing (choreiform) movements.
The involuntary movements can affect various parts of the body, including the limbs, neck, and face, with facial and orofacial dyskinesia being commonly observed. The onset of these abnormal movements typically occurs between infancy and late adolescence, though cases of late adult onset have also been reported. These movements can be continuous during waking hours and often persist or worsen during sleep, particularly during transitions between sleep stages.
The severity of ADCY5-related dyskinesia can vary significantly among affected individuals, even within the same family. Some infants with severe forms may experience weak muscle tone (hypotonia) and delays in motor skill development, such as crawling and walking. These individuals may eventually require assistive devices for mobility. In contrast, those with milder forms might experience clumsiness or social difficulties due to the movements, but their walking and other motor skills are less impacted.
Anxiety, fatigue, and other forms of stress can temporarily increase the severity of symptoms. Some individuals may also experience periods of remission, where they have days or weeks without abnormal movements. The condition is typically inherited in an autosomal dominant pattern, meaning that only one copy of the altered gene is sufficient to cause the disorder. In some instances, the mutation arises spontaneously in the affected individual and is not inherited from a parent.
Identifying ADCY5-Related Dyskinesia
Diagnosis involves a clinical evaluation, including observing movement patterns and reviewing medical history. The varied presentation of symptoms can sometimes lead to misdiagnosis, as the features may resemble other conditions such as cerebral palsy, epilepsy, or other paroxysmal movement disorders.
Genetic testing directly confirms a mutation in the ADCY5 gene. This can involve sequence analysis, deletion/duplication analysis, or targeted variant analysis, often through whole exome sequencing or specific gene panels. Brain MRI typically shows no evidence of structural abnormalities in individuals with this condition, which helps distinguish it from other neurological disorders.
Approaches to Managing ADCY5-Related Dyskinesia
There is currently no cure for ADCY5-related dyskinesia, so treatment focuses on managing symptoms and improving quality of life. Management often requires a multidisciplinary team, including neurologists, physical, occupational, and speech therapists, to address movement control, daily living activities, and communication.
Medications are a primary component of symptomatic treatment, though their effectiveness can vary among individuals and may decrease over time. Common medications that have been explored include trihexyphenidyl, tetrabenazine, and clonazepam. Adenosine-2A receptor antagonists, such as caffeine and theophylline, have also shown promise in reducing involuntary movements in some patients by influencing cAMP levels in neurons.
Deep brain stimulation (DBS) is a surgical option considered for some individuals with severe, drug-refractory movement disorders. DBS involves implanting electrodes in specific brain areas to deliver electrical pulses that can help reduce involuntary movements, including nocturnal exacerbations. While DBS can lead to significant improvements in movement control, it may not always translate to a complete resolution of functional impairments. Ongoing research continues to explore new therapeutic avenues and improve understanding of the disorder’s mechanisms.