Researchers Develop Guidelines for Diagnosing, Managing, and Treating AADC Deficiency

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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urine analysis, diagnosis


The International Working Group on Neurotransmitter Related Disorders (iNTD) has created guidelines for the care of patients with aromatic L-amino acid decarboxylase (AADC) deficiency.

Titled, “Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency,” the guidelines were published in Orphanet Journal of Rare Diseases.

As an extremely rare genetic disease, with only about 100 cases reported, care for AADC deficiency is often inconsistent between individual expert centers. Some patients are given only one or two therapies, whereas others receive many, and results are difficult to predict.

The iNTD was founded in 2013 to help improve care for patients with diseases related to neurotransmitters, including AADC deficiency. To help guide the care of patients with AADC deficiency, an expert committee of iNTD-affiliated neurologists and researchers with expertise in the disorder was formed.

Using their expertise and an extensive review of the available scientific literature, the committee drafted guidelines for AADC deficiency treatment. These guidelines were then reviewed by outside academics and laypeople and were tested in practice by non-expert neurologists prior to publication.

The committee used Scottish Intercollegiate Guideline Network (SIGN) methodology to rate the available data, from low (expert opinion) to high (conclusion of a high-quality meta-analysis with low risk of bias). They also used the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach to qualify their recommendations, rating them as strong, either for or against implementation; conditional, for or against; or recommendations for further research or restricted trials.

First, they summarized the clinical presentation of AADC deficiency, as well as the techniques by which it can be diagnosed. They strongly recommended that there be increased awareness of AADC deficiency among patients of Chinese, Japanese, or Taiwanese descent, as there is a higher prevalence of a disease-causing mutation in this population.

They similarly recommended that AADC deficiency be considered in children exhibiting movement disorders and developmental delay. They also suggested further research to define the changes in behavior and sleep that occur in these patients.

According to the guidelines, the presentation of AADC deficiency “is broad and can range from very severe to relatively mild.” However, they also note that a deteriorating clinical course is not expected in the condition, so symptoms such as these should lead to further diagnostic tests for other diseases.

Strong support was found for tests on both cerebrospinal fluid (CSF) — the liquid surrounding the brain and spinal cord — and plasma for the diagnosis of the disease, although the guidelines stress that proper lab procedures must be followed.

Although most patients can be diagnosed genetically — AADC deficiency is characterized by mutations in the DDC gene — there are no clear correlations between specific genotypes and disease courses.

The guidelines summarize three diagnostic “keys” for the condition: mutation(s) in the DDC gene; decreased plasma AADC enzyme activity; and abnormal levels of neurotransmitters in CSF. They suggest that genetic testing always be performed and that at least two of the three diagnostic keys be positive to diagnose AADC deficiency.

Other tests, such as certain urine analyses, that have been tried were found to be poor predictors of AADC deficiency and were not recommended for use or were suggested as avenues for possible further research.

The guidelines recommend selective dopamine agonists, MAO-inhibitors, and pyridoxine as first-line treatments. They also suggest that other compounds could be used in conjunction to treat symptoms; for example, melatonin can be given to help patients with difficulty sleeping.

They strongly suggest that combinations of therapies will generally be needed, that doses “start low and go slow,” that unhelpful treatments be promptly discontinued, and that treatment be coordinated by a multifaceted team of healthcare professionals.

Some proposed treatments were found to be less effective; selective serotonin reuptake inhibitors (generally used as antidepressants), for example, have not shown much promise, and centrally acting dopamine antagonists were strongly discouraged because they could worsen disease symptoms. Other experimental therapies, such as gene therapies, may be on the way, but will require a great deal more research.

The guidelines also note the importance of monitoring for AADC deficiency patients, who can be at an increased risk of cardiac events and may respond poorly to infections. It is also recommended that patients be given access to social support, such as therapy and genetic counseling for their relatives.

Researchers also acknowledge that, although guidelines are created with the best intentions, they are by no means infallible.

“AADCD being a very rare disorder, the body of evidence encompasses mainly non-analytical studies and case reports. Therefore, many recommendations reflect expert opinion,” they said. “This guideline is meant to give a solid foundation to caregivers who look after AADCD patients, but should never replace sensible, well-informed clinical care.”