Journal Article

99 Opportunities to improve screening programmes identifying patients with aromatic L-amino acid decarboxylase deficiency (AADCd) in the UK

Fox, Emily, Eugen-Matthias, Strehle, Monaghan, Marie, Amin, Sam, Taylor, Micheal, Gowda Vasantha, De Goede Christian

2023

Overview

ObjectiveAromatic L-amino acid decarboxylase deficiency (AADCd) is a rare neurometabolic disorder resulting from variants in the dopa decarboxylase (DDC) gene. Diagnosis of AADCd is often delayed because of variable clinical presentation. Patients are frequently misdiagnosed with more common conditions, such as cerebral palsy (CP) owing to a lack of AADCd awareness. REVEAL-CP is a prospective, multicentre, multinational, interventional, non-registrational study designed to investigate the prevalence of AADCd in patients presenting with symptoms of CP and to characterise genotypes associated with high 3-O-methyldopa (3-OMD) levels in dried blood spot samples. Following the study, UK paediatric neurologist investigators completed a survey on learning opportunities to improve the early identification of patients with AADCd who may be eligible for treatment.MethodsThe REVEAL-CP study screened patient records. After exclusion of patients with genetic and/or CSF neurotransmitter analysis, 49 UK patients were identified as being suitable for 3-OMD testing. Following the study, UK investigators completed a survey developed in collaboration with PharmaGenesis London, a third-party agency, including questions requiring yes/no, Likert scale (strongly agree; somewhat agree; neither agree nor disagree; somewhat disagree; strongly disagree; don’t know) and/or qualitative responses. Consensus was reached if the majority of investigator respondents somewhat or strongly agreed to individual questions.ResultsSix investigators completed the survey and reached consensus on the following recommendations to improve AADCd patient identification in the UK: adoption of a more centralised record system between NHS trusts, particularly between community and secondary paediatric practices; implementing genetic testing as the primary diagnostic tool for patients with CP-like symptoms of unknown aetiology; increasing awareness among clinicians of the differential diagnosis of neurotransmitter disorders in patients with CP-like symptoms; and earlier use of 3-OMD testing in the diagnostic workup of patients presenting with unexplained movement disorders or CP-like symptoms, alongside testing for serum prolactin and urinary organic acids including vanillactate, through the establishment of a nationally accredited 3-OMD service.ConclusionsA greater number of patients with CP-like symptoms of unknown aetiology could be screened for AADCd, taking into consideration the investigators’ suggestions. For rare diseases like AADCd, the provision of additional resources will be key for targeted patient screening. Given the recent EMA and MHRA marketing authorisation approvals for the first licensed gene therapy for AADCd, these improved efforts for early diagnosis could prove critical to the timely and effective management of patients with AADCd.ReferencesRizzi S, et al. Behav Neurol 2022;2022:2210555.Opladen T, et al. Mol Genet Metab Rep 2016;9:61–6.Burlina A, et al. Mol Genet Metab 2021;133:56–62.Chien YH, et al. Mol Genet Metab 2016;118:259–63.

• Publisher: BMJ Publishing Group LTD
• Subject: Amino acids / Aromatic-L-amino-acid decarboxylase / Cerebral palsy / Cerebrospinal fluid / Differential diagnosis / Etiology / Gene therapy / Genetic analysis / Genetic screening / Genotypes / Likert Scales / Medical diagnosis / Metabolic disorders / Methyldopa / Movement disorders / Organic acids / Paralysis / Patients / Pediatrics / Prolactin / Surveys