Aromatic L-amino Acid Decarboxylase (AADC) deficiency: results from an Italian modified Delphi consensus

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurometabolic disorder characterized by a severe impairment of serotonin, dopamine, norepinephrine and epinephrine biosynthesis. Since its first description in 1990 [1], approximately 135 cases have been described worldwide [2]. Global prevalence is unknown, although estimates report predicted birth rates of 1:90,000 in the USA, 1:118,000 in Europe and 1:182,000 in Japan [3], while in an at-risk population with neurological deficits of unknown origin, an estimated prevalence of 1:9000 was documented [4].

The majority of patients are severely affected, with early-onset hypotonia (within the first year of life), severe/profound developmental delay (with no or limited motor attainments) and oculogyric crises. Additional common findings include dystonia, hypokinesia, and autonomic dysfunction (excessive sweating, nasal congestion, hypersalivation, temperature instability, ptosis, pupillary dysfunction, hypotension). Sleep disturbances, irritability, feeding and swallowing difficulties, vomiting can also represent prominent non-motor symptoms [2, 5, 6].

However, a milder phenotype, including spontaneous improvement during the second decade of life [7], with independent walking and feeding [8] and syndromic intellectual disability with autonomic dysfunction but no dystonia or oculogyric crises [9] has also been described.

Even though long-term outcome data are scanty, a significant childhood mortality risk has been suggested [2, 10], secondary to complications of pneumonia or acute events, at times in the context of oculogyric crises [2].

In the current lack of any approved therapy, clinicians’ priority is to identify the critical steps to take to improve the diagnostic rate and deliver the best care to AADC deficiency patients. To address potential lines of intervention enabling to achieve this goal, a Delphi consensus panel was organized by a group of Italian experts in AADC deficiency. The aims of this project were: a) to promote discussion between experts to improve knowledge on AADC deficiency; b) to give support to research, dissemination and actions to be undertaken locally to raise awareness on this rare disease; c) to reach a consensus between experts on the key interventions to set up to deliver better care and management to patients with AADC deficiency.

Six main areas of discussion were selected: AADC clinical manifestations and phenotypes, diagnostic work-up, therapy, clinical network and advocacy groups, and follow-up.

As the first round of the survey, 13 participants completed the questionnaire for all 6 statements. The consensus was achieved for all statements at first round (view the Additional documentation 1 for Delphi Consensus Results and Statements).

By using a modified Delphi method, a panel of experts reached consensus on clinical, diagnostic and therapeutic cornerstones of AADC deficiency management, and clinically-relevant research gaps. Key lines of intervention to sensitize referring clinicians and the general audience at a national and local level were also identified. This initiative of national experts has identified a series of clinical features possibly promoting AADC diagnosis even among non-specialist physicians and provided relevant expert insights into the main barriers to early diagnosis.

Full agreement was reached on the high phenotypic variability and on the typical association of neurological and extra-neurological symptoms, which can make diagnosis challenging. The panel agreed that despite the presence of significant differences in clinical characteristics between early-onset and adult-onset cases, true clinical onset always occurs in infancy, regardless of severity. However, some of the symptoms and signs might be overlooked or not attributed to AADC deficiency, resulting in significant diagnostic delay [15]. Especially in early-onset forms, unspecific neurological symptoms and signs such as developmental delay and hypotonia/hypokinesia can be either underestimated or interpreted as of neuromuscular origin (with a misdiagnosis of myasthenia [2, 16]).

The panel acknowledged an urgent need to raise awareness on underestimated neurological symptoms such as oculogyric crises, dystonia or dyskinesia, and on non-neurological symptoms, such as non-diabetic hypoglycemic crises, often not correctly attributed to metabolic dysfunction in AADC deficiency [6, 17], or vegetative symptoms (diarrhea, gastroesophageal reflux, feeding difficulties, nasal congestion). These latter are often poorly described in the literature, even though they can become prominent and disabling since childhood [18], likely resulting in referral to specialists unfamiliar with inherited neurotransmitters disorders, and – consequently— in diagnostic delay.

Regarding diagnostic tests, while the consensus was unanimous in considering whole-exome sequencing in the diagnostic work-up of patients with mild, adult-onset (less specific) phenotypes, and on the need to consider dosing plasma enzymatic AADC activity if CSF neurotransmitters show non-significant abnormalities (100% consensus), the agreement was still high, although not complete, on the need to analyze CSF neurotransmitters as the first diagnostic step in suspected cases (one expert disagreed) and on dosing blood 3-OMD as a valid screening tool at the beginning of the diagnostic work-up (one expert disagreed and one strongly disagreed). Based on the literature review and the recent consensus guidelines [17], lumbar puncture (showing a typical profile with low levels of 5-HIAA, HVA and MHPG, increased levels of 3-OMD, L-dopa and 5-HTP, and normal pterins), molecular diagnosis and AADC activity in plasma is strongly recommended, and two out of three criteria are required to confirm the diagnosis [17]. Additionally, recent studies applying dried blood spot 3-OMD dosing have shown a positive predictive value of 100% in newborns [19] and a > 15-fold increase in neonates and children with AADC deficiency compared to controls [20], thus making this test a suitable and readily available screening tool to start the diagnostic workup [4].

Although the quality of the available evidence is poor and no specific therapy has yet been approved, there was full agreement on therapeutic aspects, as the clinical management of AADC deficiency is based on symptomatic treatment for which recommendations have been provided in 2017 [17]. However, it must be emphasized that the efficacy of symptomatic therapy is disappointing in the majority of cases [15], although some researches have suggested clinical improvement in milder forms [6, 7]. Finally, early diagnosis is considered necessary by all experts to expect the best improvements from AAV vector-based gene therapy even if it is not required to be eligible for AAV vector-based gene therapy (currently seeking approval by regulatory agencies).

Identified cardinal interventions to raise awareness on this disorder in Italy include involvement of multidisciplinary scientific societies; involvement of working groups focusing on rare diseases; creation of an AADC working group; creation of a patients’ association through a clinical network. Although government-based policies on rare diseases have been promoted worldwide, and especially in Europe [21], actively involving patients’ communities and clinicians at a local level would be a primary target to increase knowledge on presentation and correct diagnostic and therapeutic management. Comparing the estimated prevalence of AADC deficiency with the number of reported patients makes evident that the majority of affected individuals are still undiagnosed [3]. Recent research focusing on the information needs of physicians in Belgium documented perceived lack of academic education on rare diseases [22]. Lack of awareness among physicians working in the community services might result in the clinical suspicion of a rare disorder never being raised, or in the family being referred to a high number of different specialists before the correct diagnosis is formulated.

The creation of an AADC deficiency patients association has been identified as a strategy to promote awareness on this disorder, based on a body of evidence documenting a positive role of advocacy groups in addressing difficulties in accessing timely diagnosis and appropriate treatment in rare diseases [21]. Patient advocacy groups can also facilitate research, helping with patient recruitment, research funding, patient assistance programs, and facilitation of communication [23].

Finally, the experts identified an important knowledge gap in the lack of follow-up data on cognition and motor function examined with standardized scales [17]. These are necessary to identify specific profiles (if present), to gain deeper insight into the natural history of the disorder, to assess the effectiveness of therapeutic interventions and to increase the reproducibility of results in clinical research.

In this study, we utilized a modified Delphi technique to establish consensus from an expert panel. The use of expert opinion was necessary since data from randomized clinical trials are lacking due to the small number of patients. Research into rare diseases faces unique challenges, including difficulties in establishing diagnoses, in recruiting subjects into research studies, the paucity of expert centres, and lack of awareness among treating physicians [24].

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. Potential future lines of research were also identified. 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.