title: Study of a fetal brain affected by a severe form of tyrosine hydroxylase deficiency, a rare cause of early parkinsonism.
abstract: 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.
authors.affiliation: Laboratory of Synaptic Metabolism, Fundació Sant Joan de Déu (FSJD), Barcelona, Spain.|Department of Neurology, Hospital Sant Joan de Déu (HSJD), Passeig Sant Joan de Déu, 2, Esplugues, 08950,, Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Tristán-Noguero
authors.affiliation: Laboratory of Synaptic Metabolism, Fundació Sant Joan de Déu (FSJD), Barcelona, Spain.|Department of Neurology, Hospital Sant Joan de Déu (HSJD), Passeig Sant Joan de Déu, 2, Esplugues, 08950,, Barcelona, Spain.
authors.forename: Héctor
authors.initials: H
authors.lastname: Díez
authors.affiliation: Department of Pathology, Hospital Sant Joan de Déu (HSJD), Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Jou
authors.affiliation: Department of Neurology, Hospital Sant Joan de Déu (HSJD), Passeig Sant Joan de Déu, 2, Esplugues, 08950,, Barcelona, Spain.|CIBERER (Biomedical Network Research Centre on Rare Diseases), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Department of Clinical Biochemistry, Hospital Sant Joan de Déu (HSJD), Barcelona, Spain.|CIBERER (Biomedical Network Research Centre on Rare Diseases), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Aida
authors.initials: A
authors.lastname: Ormazábal
authors.affiliation: CIBERER (Biomedical Network Research Centre on Rare Diseases), Instituto de Salud Carlos III, Madrid, Spain.|Servei de Bioquímica i Genètica Molecular and IDIBAPS, Hospital Clínic, Barcelona, Spain.
authors.forename: Aurora
authors.initials: A
authors.lastname: Sánchez
authors.affiliation: Department of Clinical Biochemistry, Hospital Sant Joan de Déu (HSJD), Barcelona, Spain.|CIBERER (Biomedical Network Research Centre on Rare Diseases), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Artuch
authors.affiliation: Laboratory of Synaptic Metabolism, Fundació Sant Joan de Déu (FSJD), Barcelona, Spain. agarcia@hsjdbcn.org.|Department of Neurology, Hospital Sant Joan de Déu (HSJD), Passeig Sant Joan de Déu, 2, Esplugues, 08950,, Barcelona, Spain. agarcia@hsjdbcn.org.|CIBERER (Biomedical Network Research Centre on Rare Diseases), Instituto de Salud Carlos III, Madrid, Spain. agarcia@hsjdbcn.org.
authors.forename: Àngels
authors.initials: À
authors.lastname: Garcia-Cazorla
mesh_terms: D000022:Abortion, Spontaneous; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D020821:Dystonic Disorders / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005333:Fetus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009154:Mutation; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics* / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C493449:SLC18A1 protein, human; C493452:SLC18A2 protein, human; D050493:Vesicular Monoamine Transport Proteins; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: Human fetal brain; Infantile parkinsonism; Neurodevelopmental markers; Neurotransmitter systems markers; Tyrosine hydroxylase deficiency