Long-term course of L-dopa-responsive dystonia caused by tyrosine hydroxylase deficiency

Department of Neurology, University Hospital Zürich, Zürich, Switzerland.
Neurology (Impact Factor: 8.29). 11/2004; 63(8):1524-6. DOI: 10.1212/01.WNL.0000142083.47927.0A
Source: PubMed


The authors report the long-term course of two siblings with L-dopa responsive dystonia (DRD) associated with a compound heterozygous mutation in the tyrosine hydroxylase (TH) gene. Both siblings manifested with lower-limb onset generalized DRD and had a sustained response to low-dose L-dopa therapy for over 35 years. Although the l-dopa therapy was delayed up to 20 years after disease onset, there were no cognitive or neurologic sequelae of the long-term catecholamine deficit.

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    • "To date, 29 patients with TH mutations have been reported in the literature. The clinical presentations of patients with TH deficiency ranged from typical DRD (Ludecke et al., 1995; Furukawa et al, 2001; Shiller et al., 2004) to L-Dopa-responsive infantile parkinsonism (Ludecke et al., 1996, Swaans et al., 2000) or severe progressive encephalopathy (Hoffmann et al., 2004, Ribasé s et al., 2007). All of our patients, one of whom was mentally retarded, had infantile parkinsonism with a rather good response to L-Dopa therapy which was limited by the occurrence of dyskinesia. "
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    ABSTRACT: Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of L-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after L-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of L-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with L-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later.
    Brain 08/2009; 132(Pt 7):1753-63. DOI:10.1093/brain/awp084 · 9.20 Impact Factor
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    • "GCH I deWciency leads to a decreased production of tetrahydrobiopterin (BH 4 ), the cofactor for a number of hydroxylases converting phenylalanine to tyrosine, tyrosine to DOPA, and tryptophan to 5-hydroxytryptophan (5-HTP), and for nitric oxide synthase [2], (Fig. 1A). Mutations in the tyrosine hydroxylase (TH) gene, resulting in a defective TH and hence a shortage of DOPA, cause autosomal recessive DRD [3]. Sepiapterin reductase (SR) deWciency is the most recently discovered inherited defect in the biosynthesis of BH 4 . "
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    ABSTRACT: The diagnosis of a 14-year-old girl with a new homoallelic mutation in the sepiapterin reductase (SR) gene is reported. Initially she presented at the age of 2 with hypotonia and mild cognitive developmental delay, and was diagnosed as having mild methylmalonic aciduria, which was recently identified as methylmalonylCoA racemase deficiency, a new defect in valine-isoleucine metabolism. After a 12-year progression of her neurologic condition, which had made her wheelchair-bound at the age of 6, dystonia with diurnal variation had become apparent. At the age of 14 this finding led to rapid diagnosis of SR deficiency. The diagnostic approach with CSF neurotransmitter and pterins analysis and combined phenylalanine/BH(4) loading test, and finally measurement of sepiapterin in CSF is illustrative for the diagnosis of SR deficiency. As in all other patients with this new defect, very low levels of homovanillic acid and 5-hydroxyindoleacetic acid and high levels of biopterin and sepiapterin in the CSF are the diagnostic hallmark. The girl improved dramatically on treatment with L-DOPA and 5-hydroxytryptophan. The initial diagnosis of methylmalonic aciduria may afterwards be considered to have not significantly contributed to her clinical condition and only has led to a long delay of the clinically relevant diagnosis of SR deficiency. Although the clinical condition of this recently recognized autosomal recessive defect in pterin metabolism is complex and many symptoms can occur in variable severity and time of onset, dystonia with diurnal variation is a characteristic finding, as shown in nearly all patients described so far. The rapid and favourable response on treatment with L-DOPA warrants the classification of SR deficiency as another autosomal recessive type of DOPA-responsive dystonia (DRD). This classification is important to improve the awareness of clinicians that more than one metabolic defect can underlie the phenotype of a DOPA-responsive dystonic disorder and that dystonia should always trigger a rapid diagnosis of the underlying neurotransmitter synthesis defect, in view of the excellent treatability of a DRD.
    Molecular Genetics and Metabolism 09/2006; 89(1-2):116-20. DOI:10.1016/j.ymgme.2006.03.010 · 2.63 Impact Factor
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    ABSTRACT: Two siblings from a Hong Kong Chinese family are diagnosed to have heterozygous mutation in tyrosine hydroxylase gene-a novel mutation R169X and the common Dutch mutation R233H. Presented with developmental delay and dystonia before 6 months of age, both had hyperprolactinemia with persistent galactorrhea present in the elder brother since birth. Serum prolactin level is a good screening test for those suspected of underlying neurotransmitter diseases. To our knowledge, this is the first Chinese family diagnosed with such condition. Clinicians must be aware of this rare disease especially in those unexplained 'cerebral palsy' like children.
    Brain and Development 08/2006; 28(6):389-91. DOI:10.1016/j.braindev.2005.10.012 · 1.88 Impact Factor
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