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New research suggests AADCd is less ultra-rare than previously thought. Records in 2019 established 82 variants, however that figure has grown exponentially, and current records show 420 variants ...

"The last systematic collection of genetic and clinical data was published in 2019 and is based on 123 confirmed patients and 82 variants (71% missense, 11% splice, 11% insertions/deletions/duplications, 7% others) in 58 genotypes (33% in homozygosis and 67% in compound heterozygosis), and no clear genotype-to-phenotype correlation has been established [3].

In the last three years, there has been a marked increase in the number of identified variants, as shown by the locus-specific database PNDdb (http://biopku.org/home/pndbdb.asp accessed on 30 August 2022) that currently (August 2022) reports 420 variants, highlighting that the number of variants has exponentially increased (Figure 1), with the compound heterozygous genotype contributing over 70% of genotypes [4]."

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This important research by Professor Mita Bertoldi and Giovanni Bisello at the University of Verona in Italy, is part of a larger study to establish correlation between genotype and phenotype.

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Long-term neurological and psychiatric outcomes in patients with aromatic L-amino acid decarboxylase deficiency (Manti et. al 2022)

"As for other ultrarare diseases, understanding the natural history of AADCD is an important prerequisite for designing interventional studies aimed at improving or preventing severe outcomes of this condition [25]. A more systematic approach to AADCD outcome has recently been adopted [3,7], with acceleration after the development of a preclinical murine model of the disease and the demonstration of the effectiveness of adeno-associated virus 2 (AAV2)-delivered gene therapy in improving or reversing the disease phenotype, first in mice and later in affected children [26,27]. Despite huge efforts toward clinical data systematization, several aspects of this disease remain to be explored, including the full characterization of neurocognitive and emotional functioning and the potential impact of brain neurotransmitter depletion and genotype on clinical outcome ...

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In conclusion, our study provides further evidence that AADCD requires specific neurological and neuropsychological assessments to monitor the disease. Attention, language, memory, visuospatial, and motor impairments significantly determine the quality of life in AADCD. Moreover, cognitive functioning should be specifically examined to avoid its underestimation based on movement disorder severity. The present study expands the clinical characterization of the AADCD phenotype by providing possible cognitive and behavioural correlates to early and continuous depletion of biogenic amines in the brain."

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Long term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency (Tai C-H et. al 2022)

This is an extensive review of the eladocagene exuparvovec gene therapy trials. The paper has been used as supporting evidence in the applications for license approval, providing data on efficacy and safety, with promising results. 

"These analyses provide two important advancements in understanding the use of gene therapy in patients with AADC deficiency. The first is the ability to look at results in a total population of 26 patients with AADC deficiency who have completed 1-year evaluations, allowing for a better understanding of the potential relationship between patient characteristics and dosage on outcomes. The second is the evaluation of long-term efficacy and safety in 11 of the 26 patients, who have been followed for >5 years."

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Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons (Pearson et. al 2021)

This comprehensive study analysing the data of participants in the AAV2-AADC gene therapy trials to the Substansia Nigra Pars Compacta & Ventral Tegmental area of the brain. The publication covers an age range of 4 -26 years old and various mutation combinations. The outcomes are clearly positive including a cessation of oculogyric crise, by far the most common and distressing symptom of this disease.

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"Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function."

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