GTP-Cyclohydrolase 1 mutations in autosomal dominant dopamine responsive dystonia and autosomal recessive hyperphenylalaninemia. H.M. Bedford^1,2, C.A. Rupar^1,2,3, J.M. Gillett³, R. Casey⁴. 1) Biochemical Genetics Laboratory, CPRI; 2) Dept Paediatrics; 3) Dept Biochemistry, University of Western Ontario, London, Canada; 4) Dept Paediatrics, University of Saskatchewan, Saskatoon, Canada.

   Hereditary progressive dystonia with marked diurnal fluctuation (HPD) or dopa-responsive dystonia (DRD) is an autosomal dominant, childhood onset postural dystonia characterized by diurnal fluctuation and response to dopamine therapy. GTP-cyclohydrolase 1 (GCH1), maps to chromosome 14q and is the first and rate limiting step in the synthesis of tetrahydrobiopterin (BH4). Complete GCH1 deficiency, which is autosomal recessively inherited, results in a rare form of hyperphenylalaninemia. As an approach to understanding how these clinically and genetically disparate disorders could be due to mutations in the same gene, we have characterized causative mutations in a child with HPD/DRD and one with BH4 deficiency hyperphenylalaninemia. Analysis of sequences generated from PCR amplification of the GCH1 promoter and exons including exon/intron junctions revealed a novel point mutation in a sporadic case of HPD/DRD who presented with childhood-onset oromandibular dystonia. The G->A mutation in exon 6 at nucleotide 722 of the coding sequence results in an Arg to Gln substitution at amino acid 241 (Arg241Gln) and the loss of an AvaI restriction enzyme cleavage site. The child with hyperphenylalaninemia is a compound heterozygote for 2 novel mutations; C->T in exon 1 at position 276 resulting in a Leu92Phe substitution and C->G in exon 1 at nucleotide 312 resulting in a Phe104Leu substitution. The parents are heterozygous with no clinical evidence of neurologic sequelae. Neither mutation has been reported in patients with HPD/DRD. Mutations in the GCH1 gene in patients with HPD/DRD are scattered throughout the GCH1 gene with none prevalent. Mutations in the GCH1 gene which result in hyperphenylalaninemia have been described exons 1, 5, and 6 and located closely to DRD mutations. There are no mutations common to HPD/DRD and hyperphenylalaninemia. Establishing genotype/phenotype correlations between these two very distinct disorders will require further analysis of protein structure.