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Clinical Chemistry 44: 1897-1904, 1998;
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(Clinical Chemistry. 1998;44:1897-1904.)
© 1998 American Association for Clinical Chemistry, Inc.

Molecular Diagnostics and Genetics

Biochemical hallmarks of tyrosine hydroxylase deficiency

Christa Bräutigam1, Ron A. Wevers2,a, Riet J. T. Jansen2, Jan A. M. Smeitink2, Johanneke F. de Rijk-van Andel3, Fons J. M. Gabreëls2, and Georg F. Hoffmann1

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

2 Department of Neurology, University Hospital Nijmegen, 6525 GC Nijmegen, The Netherlands.

3 Department of Neurology, Ignatius Hospital, 4800RK Breda, The Netherlands.
a Address correspondence to this author at: University Hospital Nijmegen, Laboratory of Pediatrics and Neurology, Reinier Postlaan 4, 6525 GC Nijmegen, The Netherlands. Fax 31 24 3540297; e-mail R.Wevers{at}ckslkn.azn.nl.

We report the biochemical hallmarks of tyrosine hydroxylase deficiency with emphasis on reliable diagnostic strategies of four new cases of an inborn error of tyrosine hydroxylase (TH). Three of our patients from different parts of the Netherlands were found homozygous for a mutation in exon 6 (G698A) of the TH gene, and one patient was found compound heterozygous for the same mutation and an additional mutation in exon 3. The first clinical symptoms of hypokinesia, rigidity of arms and legs and axial hypotonia, developed between 3 and 7 months of age. Cerebrospinal fluid investigations revealed a characteristic metabolite constellation in every case: low homovanillic acid (HVA) and 3-methoxy-4-hydroxy-phenylethyleneglycol concentrations in the presence of normal reference range 5-hydroxyindolacetic acid concentrations. Strict adherence to a standardized lumbar puncture protocol and adequate age-related reference values are essential for diagnosis of this "new" treatable neurometabolic disorder. Urinary measurements of HVA, vanillylmandelic acid, and catecholamines can lead to false-negative conclusions. All patients showed a remarkable clinical improvement on a low dose of L-dihydroxyphenylalanine/(S)-2-(3,4-dihydroxybenzyl)-2-hydrazinpropionic acid. During treatment, cerebrospinal fluid HVA, and 3-methoxy-4-hydroxy-phenylethyleneglycol increased substantially.


Key Words: L-dopa, L-dihydroxyphenylalanine • TH, tyrosine hydroxylase • HVA, homovanillic acid • CNS, central nervous system • VMA, vanillylmandelic acid • CSF, cerebrospinal fluid • MHPG, 3-methoxy-4-hydroxyphenylethyleneglycol • 5-HIAA, 5-hydroxyindolacetic acid • DRD, dopa-responsive dystonia • 3-OMD, 3-o-methyldopa • carbidopa, (S)-2-(3,4-dihydroxybenzyl)-2-hydrazinpropionic acid.




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