Hereditary progressive dystonia with marked diurnal fluctuation

Hereditary progressive dystonia with marked diurnal fluctuation or the strictly defined dopa-responsive dystonia (HPD/DRD) is an autosomally dominantly inherited dystonia caused by abnormalities of the gene of the GTP cyclohydrolase I (GCH 1) located on the 14q22.1-q22.2. The heterozygotic gene abnormality induces partial decrement of tetrahydrobiopterin (BH4) and affects synthesis of tyrosine hydroxylase (TH) rather selectively. The reduction of TH exists at the terminals of the nigrostriatal (NS) dopamine (DA) neuron, predominantly in the ventral area of the striatum and disfacilitates the D1 receptor-striatal direct pathway. This consequently disinhibit the inhibitory efferent pathways and develops postural dystonia via the particular descending pathways to the reticulospinal tract and postural tremor via the ascending pathways to the ventralis lateralis (VL) nucleus of the thalamus. This also inhibits the efferents to the superior colliculus, and affects voluntary saccade but spares that to the pedunculo-pontine nucleus (PPN) preserving locomotive movement clinically. The DA-D2 receptors, the striatal indirect pathways or the efferent connecting to these pathways are not involved in the pathophysiology of HPD/DRD. So parkinsonian plastic rigidity, parkinsonian resting tremor, cogwheel rigidity or levodopa induced dyskinesia are not observed. In some patients, particularly in compound hetereozygotes, there are symptoms suggesting the involvement of serotonergic neurons or those thought to be caused by exaggeration of DA-D2 receptors. Neuropathologically there is no degenerative changes. Clinical laboratory examinations suggest that levels of TH and DA activities are around 20% of the normal values throughout the course of illness. Therefore, the age-dependent clinical course, marked progression in the first one and one half decades, its subsiding in the third decade and almost stationary course from the fourth decade are just the reflection of age-related decremental variation of the TH activities at the terminal of the normal NS-DA neuron. The diurnal fluctuation is also the reflection of circadian oscillation of the TH activities at the terminal. Functional maturation of the striatal indirect pathways in the first one and one half decades and developmental decremental variation of the DA-D2 receptor in the first three decades also reflect in the age-dependent variation of symptoms by modulating the background tone of muscle. The later functional development of the ascending efferents of the basal ganglia to the thalamus, may cause the postural tremor which appears in the second decade and becomes predominant in the fourth decade. Early decrease of TH due to deficiency of BH4 in HPD/DRD also affects the DA-D4 receptor of the tuberoinfundibular DA neuron and cause stagnation of increase of body length in childhood. With normal preservation of the fundamental function of the NS-DA neuron, levodopa, by replacing the DA content at the terminal, alleviates the motor symptoms completely and the effects sustain without any side effects. Levodopa also improves the short body length, if it is administrated before puberty. Up to now 60 mutations have been detected in the GCH 1 gene. The locus of mutation differs among families except for two pare of families with different ethnic background which showed identical mutations. Experimentally, one abnormal heterozygotic gene decreased the production of the enzyme to less than 50%, e.g. some below 20% and others around 30–40%, which clinically as symptomatic patients and asymptomatic carriers, respectively. Other experiments show dominant negative effects which differ among families or the loci of mutation. These might be the background for developing the intra-familial variation, that is, in some there is anticipation, and in the other the symptoms and clinical course are identical or vary in a family without any relation to the generation. However, it is left unclarified why BH4 deficiency caused by GCH 1 deficiency affects predominantly DA-D1 receptors, and why there is female predominance in affected individuals, while male predominance in asymptomatic carrier.