-O-MethyDopa (3-OMD) is a metabolite of the Dopaminergic pathway that accumulates in case of
a default in the neurotransmitter biosynthesis due to a key enzyme deficiency: Aromatic
L-Amino Acid Decarboxylase (AADC) deficiency. 3-OMD is a validated biomarker specific for
this AADC enzyme defect. (Chen et al., 2014, Chien et al., 2016, Brennenstuhl et al., 2019).
To date, the prevalence of the elevation of 3-OMD has been studied in neonatal screening of
healthy newborns and in patients with a previously proven AADC deficiency but not in a target
population. (Chen et al., 2014, Chien et al., 2016, Brennenstuhl et al., 2019, Kubaski et
al., 2021). The prevalence of elevated plasma 3-OMD, a biomarker of cerebral monoamine
neurotransmitters deficiency, has never been evaluated in a targeted population.
The AADC enzyme is encoded by the DDC (Dopa-Decarboxylase) gene. Pathogenic bi-allelic
variations of the DDC gene are responsible for a dysfunction of the AADC enzyme, leading to a
decrease in the synthesis of biogenic amine neurotransmitters (Dopamine, Serotonin).
AADC deficiency is a rare recessive genetic disease, with less than 200 cases published in
the literature. The clinical signs begin in childhood are varied, with a broad phenotypic
spectrum, reflecting the deficiency in biogenic amine neurotransmitters: motor impairment,
neurodevelopmental abnormalities (delay in acquisitions, cognitive disorders and / or
disorders of social interactions), dysautonomia, epileptic seizures. However, there are no
specific clinical symptoms and evoking this diagnosis is tricky (Pearson et al., 2020).
A confirmation of the diagnosis requires at least 2 positive tests among: (i) analysis of the
profile of cerebrospinal fluid (CSF) neurotransmitters by lumbar puncture (ii) enzymatic
study of AADC (iii) genetic study of the DDC gene (Wassenberg et al. al., 2017). The
cerebrospinal fluid (CSF) analysis is an invasive examination and the enzymatic study is
performed in only a few laboratories. Therefore, it is largely admitted that this pathology
is underdiagnosed (Brun et al, 2010, Brennenstuhl et al, 2019, Hyland et al. 2019).
The purpose of this study is to assess the prevalence of the elevation of 3-OMD in a
predominantly pediatric targeted population with symptoms compatible with AADC deficiency;
that will allow investigators to specify the indications for this screening test according to
the clinical symptoms of the patients with the aim, ultimately, of optimizing the diagnosis
of AADC deficiency.
Targeted screening of the disease via the measuring of the level of 3-OMD would allow for :
an early diagnosis
an adequate and pertinent therapeutic strategy, while avoiding inappropriate treatment
due to lack of diagnosis, which can go as far as targeted treatment by gene therapy
genetic counseling to families since there is a 25% risk of recurrence
Although the level of 3-OMD is a validated and specific biomarker of AADC deficiency, the
blood assay is performed in very few laboratories in Europe. This assay was recently
developed in the Biochemistry laboratory of the Montpellier University Hospital (Pr Cristol,
Dr Badiou).