Biochemical and Molecular Genetic Characteristics of the Severe Form of Tyrosine Hydroxylase Deficiency

Author:

Bräutigam Christa1,Steenbergen-Spanjers Gerry CH2,Hoffmann Georg F1,Dionisi-Vici Carlo3,van den Heuvel Lambert PWJ2,Smeitink Jan AM2,Wevers Ron A2

Affiliation:

1. University Hospital, Department of Neuropediatrics and Metabolic Diseases, D-35037 Marburg, Germany

2. University Hospital Nijmegen, Laboratory of Paediatrics and Neurology, NL-6500 HB Nijmegen, The Netherlands

3. Bambino Gesù Hospital, Department of Metabolism, I-00165 Rome, Italy

Abstract

AbstractBackground: 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.

Publisher

Oxford University Press (OUP)

Subject

Biochemistry, medical,Clinical Biochemistry

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