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Aromatic L-amino acid decarboxylase (AADC) is crucial for brain development and motor functions.

ABSTRACT: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare pediatric neuro-metabolic disease in children. Due to the lack of an animal model, its pathogenetic mechanism is poorly understood. To study the role of AADC in brain development, a zebrafish model of AADC deficiency was generated. We identified an aadc gene homolog, dopa decarboxylase (ddc), in the zebrafish genome. Whole-mount in situ hybridization analysis showed that the ddc gene is expressed in the epiphysis, locus caeruleus, diencephalic catecholaminergic clusters, and raphe nuclei of 36-h post-fertilization (hpf) zebrafish embryos. Inhibition of Ddc by AADC inhibitor NSD-1015 or anti-sense morpholino oligonucleotides (MO) reduced brain volume and body length. We observed increased brain cell apoptosis and loss of dipencephalic catecholaminergic cluster neurons in ddc morphants (ddc MO-injected embryos). Seizure-like activity was also detected in ddc morphants in a dose-dependent manner. ddc morphants had less sensitive touch response and impaired swimming activity that could be rescued by injection of ddc plasmids. In addition, eye movement was also significantly impaired in ddc morphants. Collectively, loss of Ddc appears to result in similar phenotypes as that of ADCC deficiency, thus zebrafish could be a good model for investigating pathogenetic mechanisms of AADC deficiency in children.

SUBMITTER: Shih DF

PROVIDER: S-EPMC3734303 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Aromatic L-amino acid decarboxylase (AADC) is crucial for brain development and motor functions.

Shih De-Fen DF Hsiao Chung-Der CD Min Ming-Yuan MY Lai Wen-Sung WS Yang Chianne-Wen CW Lee Wang-Tso WT Lee Shyh-Jye SJ

PloS one 20130805 8

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare pediatric neuro-metabolic disease in children. Due to the lack of an animal model, its pathogenetic mechanism is poorly understood. To study the role of AADC in brain development, a zebrafish model of AADC deficiency was generated. We identified an aadc gene homolog, dopa decarboxylase (ddc), in the zebrafish genome. Whole-mount in situ hybridization analysis showed that the ddc gene is expressed in the epiphysis, locus caeruleus, d ...[more]

PMID: 23940784

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Project description:PurposeDeriving health utilities for rare medical conditions such as aromatic L-amino acid decarboxylase (AADC) deficiency poses challenges. The rarity of AADC deficiency and the fact that this genetic condition often presents in very young children means that robust utility values cannot be derived from the child or their parent/caregiver. Alternative approaches, eg, discrete choice experiments (DCE), are required in order to provide health utilities. The aim of the study was to generate health utilities for AADC deficiency using a DCE.MethodsThe DCE was completed online by panel participants from a UK representative sample. The DCE comprised 6 AADC deficiency attributes (2-6 levels): mobility, muscle weakness, oculogyric crises, feeding ability, cognitive impairment and screaming. These were identified from published literature, clinician input, parent interviews and expert opinion. Participants were presented with 10 choice sets specified using an orthogonal design, including a repeat task to evaluate choice consistency. Participants were presented with 5 health state vignettes prior to the DCE. These were used to elicit time trade-off (TTO) utilities. Multinomial logit models were estimated for the DCE data. The TTO utilities for the worst/best health states were used as anchors to convert indirect DCE part-worth utilities to health utilities.ResultsA total of 1596 participants completed the DCE. The majority (70.7%) gave consistent responses to the repeated choice task; only 1.7% (27) always chose the same alternative for every choice set. Five models were evaluated. There was one preference reversal ("sitting unaided"/"standing with assistance") occurring in all models; these two mobility level coefficients were set to be equal in the final model. Rescaled utilities ranged from 0.494 to 0.7279, corresponding to the worst (633233) and best (111111) health states.ConclusionHealth utilities were derived for AADC deficiency through a DCE. These will be used for a cost-effectiveness model of an AADC deficiency treatment.

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Aromatic L-amino acid decarboxylase (AADC) is crucial for brain development and motor functions.

Publications

Aromatic L-amino acid decarboxylase (AADC) is crucial for brain development and motor functions.

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