title: Cerebrospinal fluid synaptic proteins as useful biomarkers in tyrosine hydroxylase deficiency.
abstract: Tyrosine hydroxylase (TH) deficiency is an inborn error of dopamine biosynthesis and a cause of early parkinsonism. Two clinical phenotypes have been described. Type "B": early onset severe encephalopathy; type "A": later onset, less severe and better response to L-dopa. We aimed to study the expression of several key dopaminergic and gabaergic synaptic proteins in the cerebrospinal fluid (CSF) of a series of patients with TH deficiency and their possible relation with the clinical phenotype and response to L-DOPA. Dopamine transporter (DAT), D2-receptor and vesicular monoamine transporter (VMAT2) were measured in the CSF of 10 subjects with TH deficiency by Western blot analysis. In 3 patients, data of pre- and post-treatment with L-DOPA were available, and in one of them, GABA vesicular transporter was determined. Results were compared to an age-matched control population. The concentration of D2-receptors in CSF was significantly higher in patients with TH deficiency than in controls. Similarly, DAT and vesicular monoamine transporter type 2 were up-regulated. Studies performed before L-DOPA, and on L-DOPA therapy showed a paradoxical response with D2 receptor expression increase as L-Dopa doses and homovanillic concentration gradually raised in a B phenotype patient. The opposite results were found in two patients with A phenotype. However, this is a very small sample, and further studies are needed to conclude robust differences between phenotypes. Synaptic proteins are detectable in the CSF and their quantification can be useful for understanding the pathophysiology of neurotransmitter defects and potentially to adjust and personalize treatments in the future.
authors.affiliation: Department of Neurology, CIBER-ER Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain; Hospital Sant Joan de Déu (HSJD), CIBER-ER Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Ortez
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal; Hospital Dona Estefânia, CHLC, Lisbon, Portugal.
authors.forename: S T
authors.initials: ST
authors.lastname: Duarte
authors.affiliation: Department of Biochemistry, CIBER-ER Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain; Hospital Sant Joan de Déu (HSJD), CIBER-ER Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Ormazábal
authors.affiliation: Hospital Sant Joan de Déu (HSJD), CIBER-ER Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Serrano
authors.affiliation: Department of Neurology, CIBER-ER Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Pérez
authors.affiliation: Department of Pediatrics, University of Athens, Aghia Sofia Hospital, Athens, Greece.
authors.forename: R
authors.initials: R
authors.lastname: Pons
authors.affiliation: Department of Neurology, CIBER-ER Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain; Hospital Sant Joan de Déu (HSJD), CIBER-ER Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Istanbul Faculty of Medicine, Department of Child Neurology, Istanbul, Turkey.
authors.forename: Z
authors.initials: Z
authors.lastname: Yapici
authors.affiliation: Department of Neurology, CIBER-ER Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Fernández-Álvarez
authors.affiliation: Departament of Pediatric Neurology, Hospital V. Arrixaca, Murcia, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Domingo-Jiménez
authors.affiliation: Department of Pediatric Neurology, Hospital Gregorio Marañón, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: De Castro
authors.affiliation: Department of Biochemistry, CIBER-ER Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain; Hospital Sant Joan de Déu (HSJD), CIBER-ER Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Artuch
authors.affiliation: Department of Neurology, CIBER-ER Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain; Department of Biochemistry, CIBER-ER Biomedical Network Research Centre on Rare Diseases, Instituto de Salud Carlos III, Barcelona, Spain. Electronic address: agarcia@hsjdbcn.org.
authors.forename: A
authors.initials: A
authors.lastname: García-Cazorla
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002648:Child; D002675:Child, Preschool; D050483:Dopamine Plasma Membrane Transport Proteins / Q000134:cerebrospinal fluid*; D020821:Dystonic Disorders / Q000134:cerebrospinal fluid / Q000151:congenital* / Q000188:drug therapy; D005260:Female; D015870:Gene Expression; D006801:Humans; D007231:Infant, Newborn; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D010641:Phenotype; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000172:deficiency; D050493:Vesicular Monoamine Transport Proteins / Q000134:cerebrospinal fluid*; D055815:Young Adult
chemical_list: D015415:Biomarkers; C581293:DRD2 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; C493452:SLC18A2 protein, human; D050493:Vesicular Monoamine Transport Proteins; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase
keywords: Cerebrospinal fluid; Dopaminergic receptor type 2; Infantile parkinsonism; Synaptic proteins; Tyrosine hydroxylase deficiency