Tyrosine hydroxylase (TH) deficiency is an inborn error of dopamine synthesis. Two clinical phenotypes have been described. The THD “B” phenotype produces a severe encephalopathy of early-onset with sub-optimal L-Dopa response, whereas the “A” phenotype has a better L-Dopa response and outcome. The objective of the study is to describe the expression of key synaptic proteins and neurodevelopmental markers in a fetal brain of THD “B” phenotype. The brain of a 16-week-old miscarried human fetus was dissected in different brain areas and frozen until the analysis. TH gene study revealed the p.R328W/p.T399M mutations, the same mutations that produced a B phenotype in her sister. After protein extraction, western blot analyses were performed to assess protein expression. The results were compared to an age-matched control. We observed a decreased expression in TH and in other dopaminergic proteins, such as VMAT 1 and 2 and dopamine receptors, especially D2DR. GABAergic and glutamatergic proteins such as GABA VT, NMDAR1 and calbindin were also altered. Developmental markers for synapses, axons and dendrites were decreased whereas markers of neuronal volume were preserved. Although this is an isolated case, this brain sample is unique and corresponds to the first reported study of a THD brain. It provides interesting information about the influence of dopamine as a regulator of other neurotransmitter systems, brain development and movement disorders with origin at the embryological state. This study could also contribute to a better understanding of the pathophysiology of THD at early fetal stages.
Tyrosine hydroxylase deficiency Infantile parkinsonism Human fetal brain Neurodevelopmental markers Neurotransmitter systems markers
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Dr. AGC is funded by the project PS09/01132 ISCIII-FEDER. ATN was initially funded by a grant from the “Fundación Godía” and later on by PFIS grant.
We thank the participating family for their collaboration with this study. We thank Carles Lerín and Núria Villamanzo for their generously supplying of the Bullet Blender System and their assistance.
This study was funded by the project PS09/01132 ISCIII-FEDER.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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