PMID- 10585338
OWN - NLM
STAT- MEDLINE
DCOM- 19991217
LR  - 20190722
IS  - 0009-9147 (Print)
IS  - 0009-9147 (Linking)
VI  - 45
IP  - 12
DP  - 1999 Dec
TI  - Biochemical and molecular genetic characteristics of the severe form of tyrosine 
      hydroxylase deficiency.
PG  - 2073-8
AB  - BACKGROUND: Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the
      biosynthesis of the catecholamines dopamine, norepinephrine, and epinephrine.
      Recently, mutations were identified in cases of autosomal recessive
      dopa-responsive dystonia and infantile parkinsonism. We describe a patient with
      severe symptoms and a new missense mutation in TH. METHODS: Relevant metabolites 
      in urine and cerebrospinal fluid were measured by HPLC with fluorometric and
      electrochemical detection. All exons of the TH gene were amplified by PCR and
      subjected to single-strand conformation polymorphism analysis. Amplimers
      displaying aberrant migration patterns were analyzed by DNA sequence analysis.
      RESULTS: The patient presented with severe axial hypotonia, hypokinesia, reduced 
      facial mimicry, ptosis, and oculogyric crises from infancy. The major metabolite 
      of dopamine, homovanillic acid, was undetectable in the patient's cerebrospinal
      fluid. A low dose of L-dopa produced substantial biochemical but limited clinical
      improvement. DNA sequencing revealed a homozygous 1076G-->T missense mutation in 
      exon 10 of the TH gene. The mutation was confirmed with restriction enzyme
      analysis. It was not present in 100 control alleles. Secondary structure
      prediction based on Chou-Fasman calculations showed an abnormal secondary
      structure of the mutant protein. CONCLUSIONS: We describe a new missense mutation
      (1076G-->T, C359F) in the TH gene. The transversion is present in all known
      splice variants of the enzyme. It produces more severe clinical and biochemical
      manifestations than previously described in TH-deficient cases. Our findings
      extend the clinical and the biochemical phenotype of genetically demonstrated TH 
      deficiency.
FAU - Brautigam, C
AU  - Brautigam C
AD  - University Hospital, Department of Neuropediatrics and Metabolic Diseases,
      D-35037 Marburg, Germany.
FAU - Steenbergen-Spanjers, G C
AU  - Steenbergen-Spanjers GC
FAU - Hoffmann, G F
AU  - Hoffmann GF
FAU - Dionisi-Vici, C
AU  - Dionisi-Vici C
FAU - van den Heuvel, L P
AU  - van den Heuvel LP
FAU - Smeitink, J A
AU  - Smeitink JA
FAU - Wevers, R A
AU  - Wevers RA
LA  - eng
PT  - Case Reports
PT  - Journal Article
PL  - England
TA  - Clin Chem
JT  - Clinical chemistry
JID - 9421549
RN  - 0 (Catecholamines)
RN  - EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
SB  - IM
MH  - Amino Acid Sequence
MH  - Brain/pathology
MH  - Catecholamines/biosynthesis
MH  - Consanguinity
MH  - Humans
MH  - Hypokinesia/etiology
MH  - Infant
MH  - Infant, Newborn
MH  - Infant, Premature, Diseases/cerebrospinal fluid/*enzymology/urine
MH  - Magnetic Resonance Imaging
MH  - Molecular Sequence Data
MH  - *Mutation, Missense
MH  - Tyrosine 3-Monooxygenase/*deficiency/genetics/metabolism
EDAT- 1999/12/10 00:00
MHDA- 1999/12/10 00:01
CRDT- 1999/12/10 00:00
PHST- 1999/12/10 00:00 [pubmed]
PHST- 1999/12/10 00:01 [medline]
PHST- 1999/12/10 00:00 [entrez]
PST - ppublish
SO  - Clin Chem. 1999 Dec;45(12):2073-8.