PRENATAL DIAGNOSIS Prenat Diagn 2005; 25: 671–675. Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/pd.1193 Pre- and postnatal diagnosis of tyrosine hydroxylase deficiency Lisbeth Birk Møller 1 *, Anne Romstad 1 , Marianne Paulsen 1 , Pia Hougaard 1 , Aida Ormazabal 2 , Merc´ e Pineda 2 , Nenad Blau 3 , Flemming G¨ uttler 1 and Rafael Artuch 2 1 The John F. Kennedy Institute, Glostrup, Denmark 2 Serveis de Bioqu´ımica y Neuropediatr´ıa, Hospital Sant Joan de D´ eu, Esplugues, Barcelona, Spain 3 University Children’s Hospital, Zurich, Switzerland Objectives Tyrosine hydroxylase (TH) is a key enzyme in the biosynthesis of dopamine, epinephrine and norepinephrine. The primary diagnosis of TH deficiency is based on the measurement of neurotransmitter metabolites and pterins in the cerebrospinal fluid, and the final diagnosis is made by detection of mutations in the TH gene. The clinical expression varies with presentations as infantile parkinsonism, L-dopa responsive spastic paraplegia, or as a progressive severe encephalopathy. Treatment with L-dopa is not always sufficient and a number of patients with poor or no response to L-dopa have recently been described. Methods TH is not expressed in amniotic fluid cells or in chorionic villus, so prenatal diagnosis by measurement of the enzyme activity is not possible. The only possibility of a prenatal diagnosis is by analyzing the TH gene for mutations. Results Here we describe a case of severe TH deficiency, identification of two novel mutations (p.R328W and p.T399M) and most importantly, the first prenatal diagnosis of this disease. Conclusions The availability of prenatal diagnosis offers the parents new options. They may use the result as preparation for the birth of a child with TH deficiency, or they may decide termination of an affected pregnancy. Copyright  2005 John Wiley & Sons, Ltd. KEY WORDS: tyrosine hydroxylase; L-dopa responsive dystonia; prenatal diagnosis INTRODUCTION Tyrosine hydroxylase (TH, EC 1.14.16.2) is the rate- limiting enzyme in the biosynthesis of catecholamines, and it catalyses the conversion of tyrosine to 3,4- dihydroxyphenylalanine (L-dopa) (Nagatsu et al., 1964; Blau et al., 2002). An autosomal recessive form of pri- mary L-dopa responsive dystonia in early childhood (Knappskog et al., 1995; L¨ udecke et al., 1995) and L-dopa responsive parkinsonism occurring in infancy (L¨ udecke et al., 1996) were the first descriptions associ- ated with mutations in the TH gene. TH deficiency leads to a deficit of the neurotransmitters dopamine, nore- pinephrine, and epinephrine, which may cause develop- mental delay, central and peripheral hypotonia, temper- ature instability, chorea, ptosis, miosis, and oculogyric crises as the main clinical characteristics (Wevers et al., 1999). However, the clinical phenotype is variable and other clinical forms have been reported (L¨ udecke et al., 1996; Furukawa et al., 2001; Hoffmann et al., 2003). The diagnosis of TH deficiency is based on the mea- surement of neurotransmitter metabolites and pterins in the cerebral spinal fluid (CSF). The disease is biochem- ically characterized by low concentrations of homovanil- lic acid (HVA) and 3  methoxy-4-hydroxyphenyl- *Correspondence to: Lisbeth Birk Møller, The John F. Kennedy Institute, Gl. Landevej 7, 2600 Glostrup, Denmark. E-mail: lbm@kennedy.dk glycol (MHPG), but normal levels of 5-hydroxyindole- acetic acid (5-HIAA) (Bra¨ utigam et al., 1999). The final diagnosis is only possible by mutation analysis of the TH gene (Blau et al., 2002; Scriver, 2000). To date, 13 dif- ferent mutations have been identified in the TH gene (Knappskog et al., 1995; L¨ udecke et al., 1995, 1996; Van den Heuvel et al., 1998; Bra¨ utigam et al., 1999; Wevers et al., 1999; De Lonlay et al., 2000; Janssen et al., 2000; Swaans et al., 2000; Furukawa et al., 2001). Treatment with oral L-dopa plus carbidopa administered orally improves the clinical manifestations, although more recently patients with poor or no response have been described (De Lonlay et al., 2000; Hoffmann et al., 2003). Prenatal diagnosis is therefore an important issue in affected families. Since TH is not expressed in amni- otic fluid cells or in chorionic villus samples, prenatal diagnosis cannot be performed biochemically, but only by mutation analysis. In the present study, we describe a new case of the severe form of TH deficiency caused by two novel mutations in the TH gene and the first prenatal diagnosis of TH deficiency. The clinical, biochemical and genetic aspects will be discussed, as well as the options given by the availability of prenatal diagnosis. PATIENT AND METHODS The index patient, a girl, was born as the first child of healthy unrelated parents of Caucasian origin. The Copyright  2005 John Wiley & Sons, Ltd. Received: 20 December 2004 Revised: 14 April 2005 Accepted: 14 April 2005