Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis.
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.
Willemsen
Michèl A
MA
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
Verbeek
Marcel M
MM
Kamsteeg
Erik-Jan
EJ
de Rijk-van Andel
Johanneke F
JF
Aeby
Alec
A
Blau
Nenad
N
Burlina
Alberto
A
Donati
Maria A
MA
Geurtz
Ben
B
Grattan-Smith
Padraic J
PJ
Haeussler
Martin
M
Hoffmann
Georg F
GF
Jung
Hans
H
de Klerk
Johannis B
JB
van der Knaap
Marjo S
MS
Kok
Fernando
F
Leuzzi
Vincenzo
V
de Lonlay
Pascale
P
Megarbane
Andre
A
Monaghan
Hugh
H
Renier
Willy O
WO
Rondot
Pierre
P
Ryan
Monique M
MM
Seeger
Jürgen
J
Smeitink
Jan A
JA
Steenbergen-Spanjers
Gerry C
GC
Wassmer
Evangeline
E
Weschke
Bernhard
B
Wijburg
Frits A
FA
Wilcken
Bridget
B
Zafeiriou
Dimitrios I
DI
Wevers
Ron A
RA
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
D002395:Catecholamines; D015259:Dopamine Agents; D007980:Levodopa; D006897:Hydroxyindoleacetic Acid; D014446:Tyrosine 3-Monooxygenase; D006719:Homovanillic Acid