Masaya Segawa, MD, PhD,1 Yoshiko Nomura, MD, PhD,1 and Nobuyoshi Nishiyama, PhD2
Autosomal dominant guanosine triphosphate cyclohydrolase I (GCH-I) deficiency (Segawa disease) is a dopa-responsive dystonia caused by mutation of the GCH-I gene located on 14q22.1-q22.2. Neurohistochemical examination revealeda decrease of the tyrosine hydroxylase protein as well as its activity in the striatum and decrease of dopamine content, particularly in its ventral portion rich in D1 receptors (striatal direct pathways). Neuroimaging, clinical neurophysiological, and biochemical studies showed preservation of the structure and function of the terminal of the nigrostriatal DA neuron. Clinical neurophysiologicalstudies showed no progressive decrement of DA activities. As the enzymatic activity of pteridine metabolism is highest in the early developmental course, it may modulate dopamine receptors maturing early in the developmental course. Its product, tetrahydrobiopterin, has higher affinity to tyrosine hydroxylase among hydroxylases. Thus, partial deficiency of tetrahydrobiopterin caused byheterozygous mutation of the GCH-I gene decreases dopamine activity rather selectively. This affects the DA receptors that mature early and demonstrates characteristic symptoms age-dependently along with the developmental decrement of the tyrosine hydroxylase activities at the terminals and the maturational processes of the projecting neurons of the basal ganglia. A difference in the ratio ofmutant/wild-type GCH-I mRNA that depends on the locus of mutation may explain intrafamilial and interfamilial variation of phenotype. Ann Neurol 2003;54 (suppl 6):S32–S45
Autosomal dominant guanosine triphosphate cyclohydrolase I (GCH-I) deficiency (Segawa disease) is a dominantly inherited dystonia that responds markedly to L-dopa and is caused by heterozygous mutation of GCH-I gene located on14q22-q22.2. This disease was first described in 1971 as hereditary progressive basal ganglia disease with marked diurnal fluctuation.1 This was description was based on clinical evaluation of two children, cousins, each of whom had dystonic hypertonus that alleviated after sleep and responded markedly to L-dopa.1 However, observations of an adult patient with a clinical course of 43 years revealed thecharacteristic age-related clinical course and clarified this disease as a dystonia different from Parkinson’s disease. In 1976, we reported this disease as hereditary progressive dystonia with marked diurnal fluctuation.2 Later, it was called dopa-responsive dystonia by Nygaard and colleagues,3 and its criteria were defined by Calne.4 With correlation of the age-related clinical course to the agevariation of the activities of tyrosine hydroxylase (TH) in the caudate nucleus5 and marked sustained response to L-dopa, deficiency of TH at the terminal of the nigrostriatal dopamine (DA) neuron was suggested as the cause of this disease.6,7 This speculaFrom the 1Segawa Neurological Clinic for Children and the 2Graduate School of Pharmaceutical Sciences, University of Tokyo, Japan. Publishedonline Jul 25, 2003, in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ana.10630
tion was confirmed later by a neurohistochemical study,8 and it was revealed to be due to the partial deficiency of tetrahydrobiopterin (BH4) caused by abnormalities of the GCH-I gene.9 Although the presence of intrafamilial and interfamilial variation of symptoms had been shown,10 the discovery of thecausative gene further clarified heterogeneity of symptoms11,12 and also raised the question as to how a single gene mutation can cause this specific disorder age dependently.13,14 In this article, we demarcate characteristics of this disease by reviewing articles, including our recent investigations of our own patients, and we discuss the possible pathophysiology of this disorder. Clinical...