An Italian panel of experts recommends using vitamin B6, dopamine agonists, and monoamine oxidase inhibitors (MAOIs) as first-line therapies for the treatment of people with rare aromatic l-amino acid decarboxylase (AADC) deficiency. Further, the expert panel called for an across-the-board, multidisciplinary approach for follow-up management of patients with the neurometabolic disease.
On diagnostic procedures, the experts fully agree on the use of genetic analysis to diagnose adult-onset cases of AADC deficiency with mild symptoms.
And, all 13 panel members — medical doctors with experience in managing AADC patients — say greater efforts need to be made with clinical networking and advocacy groups to raise awareness of the rare disease throughout the country.
Those are some of the highlights of a first-ever consensus, using the Delphi method, on treatment and management approaches for AADC deficiency by an expert panel in Italy.
These recommendations and others are included in a study, titled “Aromatic L-amino Acid Decarboxylase (AADC) deficiency: results from an Italian modified Delphi consensus,” which was published in the Italian Journal of Pediatrics.
“This research aimed to set out critical lines of intervention to achieve increased scientific knowledge and empowered diagnostic suspicion, intending to deliver better care to Italian patients with AADC deficiency,” the scientists wrote.
Given the limited research and treatment options for people with AADC deficiency, a team of experts from various institutes across Italy formed a Delphi consensus panel to promote discussion among doctors with experience with the disease. The Delphi method is an investigational technique designed to define standards, find the best consensus regarding treatment and management approaches, and provide recommendations.
A steering committee included one neurologist, three child neurologists, and one pediatrician, all with special expertise in AADC deficiency. The voting panel was comprised of 13 doctors who sought to improve knowledge about the condition, provide support for research, raise awareness, and reach a consensus on key care interventions.
Based on a literature review, the steering committee selected six topics for discussion: clinical manifestations, clinical phenotypes (characteristics), diagnostic work-up, treatments, patients’ associations, and follow-up.
Panel members were then asked to anonymously fill out an online questionnaire to express their level of agreement or disagreement with each statement, using a 5-point scale that ranged from strongly disagree (score of 1) to strongly agree (score of 5). Consensus was reached when the sum for disagreement or agreement was 66% or higher. From those scores, all items were ranked and summarized; then, the steering committee finalized the recommendations.
Together, the expert panel found that most patients with AADC deficiency are severely affected, starting in early childhood, with developmental delays, feeding problems, weak muscle tone and movement disorders, and sleep disturbances. Milder disease, involving spontaneous improvement later in life, with independent feeding and walking, also has been reported, the scientists noted.
However, there is a lack of approved disease-modifying therapies, and steps need to be taken to improve diagnosis and deliver the best care to patients, the expert panel said.
On clinical manifestations, there was a 100% consensus on the high degree of variability in AADC manifestations, in part related to the age of onset, and the presentation of deficiencies associated with movement disorders and developmental delay.
There was an 85% consensus, with two experts disagreeing, that early onset and adult-onset cases exhibit differences in clinical characteristics. With a 92% consensus, with one disagreement, the expert panel determined that the disease’s first symptoms usually appear within the first year of life, regardless of clinical severity.
Regarding clinical phenotypes, there was a complete consensus on all statements. These included an increased awareness of underestimated symptoms — such as oculogyric crises, characterized by the involuntary upward movement of the eyes, as well as involuntary movements and non-diabetic low glucose (hypoglycemia).
In addition, the panel agreed on the usefulness of common symptoms associated with hypoglycemia for early diagnosis, as well as other manifestations, including diarrhea, feeding difficulties, acid reflux, and nasal congestion. Epilepsy was agreed to be a rare, uncommon symptom.
On diagnostic procedures, the experts fully agreed on the use of genetic analysis to diagnose adult-onset cases with mild symptoms, and the need to measure AADC activity in patients in which a diagnosis is uncertain. One agreed-upon measure was examining the fluid around the brain and spinal cord, called cerebrospinal fluid, or CSF, for neurotransmitters — nerve cell signaling molecules that are low in AADC patients.
There was a 92% consensus, with one disagreement, on the need to measure CSF neurotransmitters as the first diagnostic step in suspected patients. The expert panel reached an 85% consensus — with one disagreement and one strong disagreement — on the usefulness of measuring 3-OMD, which is elevated in AADC. 3-OMD is considered a potential biomarker for diagnosing AADC before symptoms appear in newborn screening programs.
The expert panel reached a 100% consensus on therapies. The doctors agreed on using vitamin B6, dopamine agonists, and monoamine oxidase inhibitors (MAOIs) as first-line therapies. Also, they agreed on the use of other medications for movement disorders and oculogyric crises.
Furthermore, all agreed that a multidisciplinary approach is needed for follow-up management. Additionally, early diagnosis was considered necessary by all panel members to achieve efficacy from investigational gene therapies, even if patients are not eligible for such treatments.
On clinical networking and support or advocacy groups, all members agreed on raising awareness of the disease by involving scientific societies and rare disease groups, particularly those dedicated to AADC, throughout Italy. There was a 92% agreement, with one disagreement, on creating an association of patients.
Among the panel members, there was a 100% agreement that cognitive and psychological functions should be evaluated using age-appropriate tests, not only to correctly characterize movement problems experienced by patients, but also to assess response to therapies.
Finally, the experts fully agreed that cognitive and motor improvements associated with development and treatment must be evaluated.
“We showed high rates of agreement on a series of statements paving the way to the dissemination of clear clinical messages concerning disease presentation, diagnosis and treatment and strategic interventions to disseminate knowledge at different levels,” the investigators concluded. “Future lines of research were also identified.”
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