Dantrolene Can Prevent Severe Muscle Problems in Children With AADC Deficiency, Case Report Shows

Dantrolene can prevent the destruction of damaged muscle tissue associated with crises of widespread involuntary muscle contractions in children with aromatic l-amino acid decarboxylase (AADC) deficiency, according to a recent case report.

The case report study, “Recurrent Dystonic Crisis and Rhabdomyolysis Treated with Dantrolene in Two Patients with Aromatic L-Amino Acid Decarboxylase Deficiency,” was published in the journal Neuropediatrics.

AADC deficiency is caused by mutations in the DDC gene, which provides instructions for making an enzyme that is essential for the production of dopamine and serotonin, two types of neurotransmitters (chemical substances that allow communication between nerve cells).

Involuntary muscle contractions, also known as dystonia, is one of the hallmarks of AADC deficiency. Some patients may also develop a complication of dystonia, known as a dystonic storm, in which all muscles of the body start to contract involuntarily.

These crises, which can be triggered by infections or medication adjustments, can lead to life-threatening complications, including respiratory failure and rhabdomyolysis, a medical condition characterized by the rapid destruction of damaged muscle tissue.

Investigators from the BC Children’s Hospital in Vancouver and their colleagues described the cases of two girls, ages 16 months and 4.5 years, with AADC deficiency who were admitted to different hospitals due to oculogyric crises (involuntary eye movements) and dystonic storms that evolved to rhabdomyolysis.

To assess the degree of muscle damage, doctors measured the levels of creatine kinase (CK), an enzyme normally found in muscles but is released into the bloodstream when muscle cells are destroyed. Once in the bloodstream, CK can reach the kidneys and cause kidney failure, a life-threatening condition.

Normal CK levels range from 22 to 198 U/L (units per liter). In one of the girls, CK levels rose to 50,000 U/L, sending her into kidney failure, while in the other, they rose to 10,722 U/L.

Both girls received standard-of-care dopamine agonists and monoamine oxidase inhibitors to prevent the breakdown of dopamine and serotonin associated with AADC deficiency, as part of their treatment regimens. Additionally, they were both started on dantrolene to control their high CK levels.

Dantrolene is a muscle relaxant that is often used to treat spasticity (involuntary muscle contractions). The medication works by blocking the release of calcium from muscle cells, reducing the amount of free calcium available in the body and the chances of having dystonic storms and rhabdomyolysis.

In the toddler, treatment with dantrolene helped manage her symptoms and prevented significant rises in CK levels in subsequent hospital admissions over the next decade. She is now 11 and has not experienced another episode of rhabdomyolysis.

In the 4.5-year-old girl, dantrolene prevented serious complications and kept her CK levels from reaching sustained extremes. Once her CK levels dropped to 238 U/L, she was discharged from the hospital.

Because dantrolene does not affect the dopamine signaling pathway that is the root cause of many issues associated with AADC deficiency, the authors believe that a separate biological process is contributing to the development of dystonic storms and rhabdomyolysis in these patients.

In fact, the researchers suspect that the dopamine loss in AADC patients may induce the continuous release of another neurotransmitter called acetylcholine — which in normal circumstances is released intermittently — leading to a subsequent rise in calcium levels and the severe muscle symptoms of dystonia and rhabdomyolysis. 

If replicated in other patients, the researchers said, dantrolene could be added to the toolkit of medications currently used to treat AADC deficiency.

“Although our numbers are small, we suggest that a trial of dantrolene in cases of sustained dystonic crisis is warranted in AADC deficiency patients,” the investigators wrote.