An alternative option to treat ADCY5-related dyskinesia in patients

The asthma medication theophylline can be used to treat the movement disorder ADCY5-related dyskinesia. A recent study conducted by Martin Luther University Halle-Wittenberg (MLU), University Medicine Halle, and the University of Leipzig Medical Center demonstrated this.

The researchers reported a case of a child with this disease whose symptoms massively improved after receiving the drug in the journal PLOS ONE. ADCY5-related dyskinesia is a very rare condition that causes dyskinesia and unregulated movements in those who suffer from it. There is currently no cure for this disease.

Deformities in the ADCY5 gene cause ADCY5-related dyskinesia.

Just one error in the genetic code of this gene can have devastating consequences.”

Andrea Sinz, Professor, Institute of Pharmacy, Martin Luther University Halle-Wittenberg

The genetic defect in ADCY5-related dyskinesia induces a specific enzyme in the cells to become overly active. This enzyme is engaged in the production of cAMP, the second messenger.

Too much “cAMP” in those affected causes uncontrolled movements, dyskinesia, and a variety of other symptoms, including speech deficiencies, beginning in infancy. The disease is thought to be extremely rare. The disease affects between one and 300 people in the United States, according to estimates from the National Institutes of Health; however, more precise data is not available.

“Rare diseases like ADCY5-related dyskinesia are often not recognized and accurately diagnosed,” notes Sinz.

The symptoms are commonly mistaken for those of other medical conditions.

There is currently no established therapy for ADCY5-related dyskinesia. Symptoms were previously treated with muscle relaxants, but these have serious side effects. By chance, a case came to light in which a family in the United States treated their child’s symptoms with coffee. Caffeine treatment helped almost all the children in a small study of 30.

“Caffeine reduces the uncontrolled movements. The treatment also has drawbacks and the children often have trouble sleeping,” elucidates Sinz.

The investigators from Halle and Leipzig searched for existing drugs with structures like caffeine. The concept was that such drugs would be more effective and have fewer side effects. Off-label use is a term used in medicine to describe when a drug that was originally approved for one purpose is used for another.

The researchers discovered what they were seeking in the asthma drug theophylline and the Parkinson’s drug istradefylline; however, the latter is not approved in Europe.

Cell experiments were carried out in collaboration with Professor Stefan Hüttelmaier of the University Medicine Halle’s Institute of Molecular Medicine. The experiments demonstrated how the substances function in the case of ADCY5-related dyskinesia: They reduce the production of cAMP, the second messenger.

Following that, the researchers provided theophylline to a child with ADCY5-related dyskinesia, as directed by the parents and the family’s neurologist, Professor Andreas Merkenschlager of the University of Leipzig Medical Center.

“The drug is approved for use in children and therefore can be safely applied,” elaborates pharmacist Andrea Sinz. It was initially given in low doses that were steadily increased. The child's health was monitored closely during this time.

“The results were phenomenal: the child straightened up, the dyskinesia and uncontrolled movements decreased, and even disappeared completely during sleep,” Andrea Sinz adds. The kid was able to get out of the wheelchair, walk, and speak more clearly after a few months. Simultaneously, no side effects have been observed.

Theophylline was able to alleviate symptoms in a controlled manner and increase the child’s quality of life in an impressive way. Our work is initially only a case study, but it already provides new hope for families affected around the world. Larger studies with more children across the globe started recently, and all of them are showing early success, especially in walking and talking. We hope that the results will lead to a regular therapy as soon as possible.”

Andrea Sinz, Professor, Institute of Pharmacy, Martin Luther University Halle-Wittenberg