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Metabolic Brain Disease

, Volume 31, Issue 3, pp 705–709 | Cite as

Study of a fetal brain affected by a severe form of tyrosine hydroxylase deficiency, a rare cause of early parkinsonism

  • Alba Tristán-Noguero
  • Héctor Díez
  • Cristina Jou
  • Mercè Pineda
  • Aida Ormazábal
  • Aurora Sánchez
  • Rafael Artuch
  • Àngels Garcia-Cazorla
Short Communication

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.

Keywords

Tyrosine hydroxylase deficiency Infantile parkinsonism Human fetal brain Neurodevelopmental markers Neurotransmitter systems markers 

Notes

Acknowledgments

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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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Alba Tristán-Noguero
    • 1
    • 2
  • Héctor Díez
    • 1
    • 2
  • Cristina Jou
    • 4
  • Mercè Pineda
    • 2
    • 5
  • Aida Ormazábal
    • 3
    • 5
  • Aurora Sánchez
    • 5
    • 6
  • Rafael Artuch
    • 3
    • 5
  • Àngels Garcia-Cazorla
    • 1
    • 2
    • 5
  1. 1.Laboratory of Synaptic Metabolism, Fundació Sant Joan de Déu (FSJD)BarcelonaSpain
  2. 2.Department of Neurology, Hospital Sant Joan de Déu (HSJD)BarcelonaSpain
  3. 3.Department of Clinical Biochemistry, Hospital Sant Joan de Déu (HSJD)BarcelonaSpain
  4. 4.Department of Pathology, Hospital Sant Joan de Déu (HSJD)BarcelonaSpain
  5. 5.CIBERER (Biomedical Network Research Centre on Rare Diseases), Instituto de Salud Carlos IIIMadridSpain
  6. 6.Servei de Bioquímica i Genètica Molecular and IDIBAPS, Hospital ClínicBarcelonaSpain

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