title: Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis.
abstract: Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dopa.
authors.affiliation: Radboud University Nijmegen Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Paediatric Neurology (820 IKNC), PO Box 9101, 6500 HB Nijmegen, The Netherlands. m.willemsen@cukz.umcn.nl
authors.forename: Michèl A
authors.initials: MA
authors.lastname: Willemsen
authors.forename: Marcel M
authors.initials: MM
authors.lastname: Verbeek
authors.forename: Erik-Jan
authors.initials: EJ
authors.lastname: Kamsteeg
authors.forename: Johanneke F
authors.initials: JF
authors.lastname: de Rijk-van Andel
authors.forename: Alec
authors.initials: A
authors.lastname: Aeby
authors.forename: Nenad
authors.initials: N
authors.lastname: Blau
authors.forename: Alberto
authors.initials: A
authors.lastname: Burlina
authors.forename: Maria A
authors.initials: MA
authors.lastname: Donati
authors.forename: Ben
authors.initials: B
authors.lastname: Geurtz
authors.forename: Padraic J
authors.initials: PJ
authors.lastname: Grattan-Smith
authors.forename: Martin
authors.initials: M
authors.lastname: Haeussler
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.forename: Hans
authors.initials: H
authors.lastname: Jung
authors.forename: Johannis B
authors.initials: JB
authors.lastname: de Klerk
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.forename: Fernando
authors.initials: F
authors.lastname: Kok
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leuzzi
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Andre
authors.initials: A
authors.lastname: Megarbane
authors.forename: Hugh
authors.initials: H
authors.lastname: Monaghan
authors.forename: Willy O
authors.initials: WO
authors.lastname: Renier
authors.forename: Pierre
authors.initials: P
authors.lastname: Rondot
authors.forename: Monique M
authors.initials: MM
authors.lastname: Ryan
authors.forename: Jürgen
authors.initials: J
authors.lastname: Seeger
authors.forename: Jan A
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Gerry C
authors.initials: GC
authors.lastname: Steenbergen-Spanjers
authors.forename: Evangeline
authors.initials: E
authors.lastname: Wassmer
authors.forename: Bernhard
authors.initials: B
authors.lastname: Weschke
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
authors.forename: Bridget
authors.initials: B
authors.lastname: Wilcken
authors.forename: Dimitrios I
authors.initials: DI
authors.lastname: Zafeiriou
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
mesh_terms: D017668:Age of Onset; D000592:Amino Acid Metabolism, Inborn Errors / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D001927:Brain Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002395:Catecholamines / Q000096:biosynthesis*; D002675:Child, Preschool; D018450:Disease Progression; D015259:Dopamine Agents / Q000627:therapeutic use; D006719:Homovanillic Acid / Q000134:cerebrospinal fluid; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid; D018476:Hypokinesia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007223:Infant; D007980:Levodopa / Q000627:therapeutic use; D009127:Muscle Rigidity / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012720:Severity of Illness Index; D014446:Tyrosine 3-Monooxygenase / Q000172:deficiency* / Q000235:genetics
chemical_list: D002395:Catecholamines; D015259:Dopamine Agents; D007980:Levodopa; D006897:Hydroxyindoleacetic Acid; D014446:Tyrosine 3-Monooxygenase; D006719:Homovanillic Acid