Hereditary progressive dystonia with marked diurnal fluctuation

Hereditary progressive dystonia with marked diurnal fluctuation (HPD) is a dopa-responsive dystonia, now called autosomal dominant GTP cyclohydrolase I deficiency or Segawa disease, caused by mutation of the GCH-1 gene located on 14q22.1 to q22.2. Because of heterozygous mutation, partial deficiency of tetrahydrobiopterin affects tyrosine hydroxylase (TH) rather selectively and causes decrease of TH in the terminals of the nigrostriatal dopamine (NS DA) neurons, projecting to the D1 receptors on the striosome, the striatal direct pathways and the subthalamic nucleus (STN) and the D4 receptors of the tuberoinfundibular tract. The activities of TH in the terminal are high in early childhood decrease exponentially to the stational level around early twenties, and show circadian oscillatron. TH. in HPD follows these variations with around 20% of normal levels and with development of the downstream structures show appears characteristic clinical symptoms age dependently. In late fetus period to early infancy, through the striosome-substantia nigra pars compacta pathway failure in morphogenesis of the DA neurons in substantia nigra, in childhood around 6 years postural dystonia through the D1 direct pathways and the descending output of the basal ganglia. Diurnal fluctuation is apparent in childhood but decrease its grade with age. TH deficiency at the terminal on the STN causes action dystonia from around 8 years and postural tremor from around 10 years, focal dystonia in adulthood. Adult onset cases in the family with action dystonia start with writer's cramp, torticollis or generalized rigid hypertonus with tremor but do not show postural dystonia. TH deficiency on the D4 receptors causes stagnation of the body length in childhood. With or without action dystonia depends on the locus of mutation. Postural dystonia is inhibitory disorder, while action dystonia is excitatory disorder. The TH deficiency at the terminal does not cause morphological changes or degenerative process. Thus, levodopa shows favorable effects without any relation to the duration of illness. (C) 2010 Published by Elsevier B.V. on behalf of the Japanese Society of Child Neurology.