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Delphi consensus development


Aromatic L-amino acid decarboxylase (AADC) deficiency: Results from an Italian modified Delphi consensus

Fusco C, Leuzzi V, Strian P, et al. Ital J Pediatr. 2021;47:13.

Publication Date | Jan 2021
Authors | Fusco C, Leuzzi V, Strian P, Battini R, Burlina A, the Delphi panel experts’ group and Spagnoli C.
Citation | Ital J Pediatr. 2021;47:13.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare neurometabolic disorder which may be underdiagnosed. Arising from an autosomal recessive genetic mutation, it is characterised by severe impairment of serotonin, dopamine, norepinephrine and epinephrine biosynthesis.1

The majority of patients with AADC deficiency are severely affected with profound developmental delay, early-onset hypotonia and oculogyric crises. There is currently no licensed therapy available for AADC deficiency, so the priority must be to improve the diagnostic rate and ensure that the critical steps required to deliver the best care to these patients are followed.1 In order to move closer to this goal, a Delphi consensus panel was assembled by a group of Italian experts in AADC deficiency with the following aims:1

  1. To promote discussion between experts to improve knowledge
  2. To provide support to research, dissemination and actions to be undertaken locally to raise awareness of this rare disease
  3. To reach consensus between experts on the key interventions required to deliver improved care and management to patients with AADC deficiency

The Delphi method is a process involving repeated rounds of discussion aimed at reaching a consensus. For this study, a modified Delphi technique was used, involving carefully selected statements drawn from literature reviews rather than open-ended questions.1

Six topics were selected for discussion by the Steering Committee: clinical manifestations, clinical phenotypes, diagnostic work-up, treatments, patients’ associations and follow-up. Statements on these topics were then sent to 13 clinicians, who expressed their level of agreement of disagreement using a 5-point scale (1 = strongly disagree, 2 = disagree, 3 = somewhat agree, 4 = agree and 5 = strongly agree). The percentage of participants who scored each item as 1 or 2 (disagreement) or as 3, 4 or 5 (agreement) were calculated and consensus was reached when the sum for agreement or disagreement was ≥66%.1

Consensus was achieved on the following statements:1

Statement 1: Clinical manifestations
The consensus was reached when the sum for disagreement or agreement was ≥66%. Complete consensus was reached on:

  • The high phenotypic variability of AADC deficiency
  • The predominant presentation of autonomic dysfunction associated with movement disorders (such as hypotonia, hypokinesia and or dyskinesias) and developmental delay (100% consensus)

Almost full consensus was reached:

  • That clinical characteristics differ between early-onset and adult-onset cases (85% consensus)
  • The onset of symptoms occurs within first year of life (92% consensus)

Statement 2: Clinical phenotype
100% agreement was reached on:

  • The need to raise awareness of symptoms which may be under-recognised (i.e. oculogyric crises, dystonia or dyskinesia)
  • Non-diabetic hypoglycaemic crises not always being recognised as a sign of metabolic dysfunction in AADC deficiency
  • The usefulness of recognising common AADC deficiency symptoms in association with hypoglycaemic crises and non-neurological symptoms (diarrhoea, gastro-oesophageal reflux, feeding difficulties, nasal congestion) for early diagnosis
  • Epileptic encephalopathy being a rare and atypical presentation

Statement 3: Diagnostic work-up
With regards to the following, almost 100% consensus was achieved:

  • The usefulness of whole-exome sequencing in patients with adult-onset and mild phenotypes (100% consensus)
  • Analysing plasma enzymatic AADC activity in cases with doubtful diagnosis if cerebrospinal fluid neurotransmitters show non-significant abnormalities (100% consensus)
  • Analysis of venous 3-O-methyldopa (3-OMD) levels is a valid, cheap and readily available screening tool to decide whether to further the diagnostic work-up (100% consensus)
  • Analysis of the CSF neurotransmitters profile as the first diagnostic step (92% consensus)

Statement 4: Pharmacological and non-pharmacological therapies
Complete consensus was reached on:

  • Considering dopamine agonists, MAO inhibitors and vitamin B6 as the first therapeutic choice
  • Anticholinergic drug therapy for symptomatic treatment
  • Treatment with benzodiazepines in specific cases
  • The need for a multidisciplinary approach to follow-up
  • Early diagnosis is necessary to enable the best improvements from gene therapy
    • Statement 5: Clinical network and support/advocacy groups
      • All experts agreed on the need to raise awareness of AADC deficiency by involving scientific societies operating in the paediatric, child neurology and neurometabolic fields, by involving working groups dedicated to rare diseases and by creating a dedicated AADC deficiency working group (100% consensus)
      • There was almost complete agreement on the need to consider creating an association of patients through a clinical network (92% consensus)

Statement 6: Follow-up
Almost complete consensus was reached on:

      • The need to evaluate cognitive and neuropsychological functions with standardised, age-appropriate scales (100% consensus)
      • The need to characterise correctly the movement disorder phenotype using these scales (100% consensus)
      • These scales being constantly applied in patients’ follow-up (100% consensus)
      • The need to evaluate symptomatic improvements following therapy (100% consensus)

The use of a modified Delphi method enabled this panel of experts to identify a set of clinical features that could facilitate diagnosis of AADC deficiency. An urgent need to raise awareness of under-recognised neurological and non-neurological symptoms of AADC deficiency was highlighted, as well as the importance of patient associations for support and advocacy of patients and in raising awareness of the disease.1


  1. Fusco C, et al. Ital J Pediatr. 2021;47:13.



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