My legs are Ice cold from my knees down and im not shure if its Sinemet related or could it be the Baclofen im taking Background: Dopamine- or dopa-responsive dystonia (DRD), also known as hereditary progressive dystonia with diurnal variation (HPD), is an inherited dystonia typically presenting in the first decade of life. It is characterized by diurnal fluctuations, exquisite responsiveness to levodopa, and mild parkinsonian features. Segawa provided an early and detailed description (1976).
Nygard et al (1983) demonstrated linkage mapping of the autosomal-dominant DRD to chromosome 14q. In 1994, Ichinose et al identified the gene at the DRD locus in chromosome arm 14q to be responsible for the production of GTP cyclohydrolase I (GCH). Since the discovery of the gene mutation, many different mutations in the GCH 1 gene, TH gene (tyrosine hydroxylase), and SR (sepiapterin reductase) genes have been identified to cause levodopa responsive dystonic disorders, particularly of the autosomal recessive form of DRD.
Pathophysiology: DRD is characterized by striatal dopamine deficiency with preservation of nigrostriatal terminals. In healthy individuals, the enzyme activity in the nigrostriatal dopaminergic neurons shows variation with circadian rhythm and age. In DRD, these physiologic variations are preserved.
TH activity and therefore tetrahydrobiopterin (BH4) production is high in the postnatal period, decreasing after infancy. The activity peaks during the first decade and progressively declines with age. The rate of decline in TH activity is marked initially, and then progresses until it reaches a plateau in the third decade.
The activity of these dopaminergic neurons also has circadian variation. Dopamine production increases through the night with each cycle of rapid eye movement (REM) sleep. The activity at the nigrostriatal terminals is therefore maximal in the early morning; nocturnal variation is more marked in young children and decreases with age. Dopamine activity in nigrostriatal terminals, which already is reduced in patients with DRD, declines further during the course of the day (as well as with increasing age), exacerbating symptoms toward evening and with increasing age.
Dopamine is produced from tyrosine by the action of TH, which uses BH4 as a cofactor. BH4 is also a cofactor for tryptophan and serotonin synthesis, and also for the enzyme nitrous oxide synthetase.
The first rate-limiting step for BH4 synthesis is GCH. The gene for GCH has been cloned to 14q 22.1-22.2 and is the gene responsible for autosomal-dominant DRD/HPD. This gene in humans contains 6 exons, and various mutations (missense, frameshift, base insertions, base deletions) have been described. These mutations result in markedly reduced GCH values (2-20%), with a resultant decrease in dopamine content. Many cases of GCH 1 mutation negative have been discovered to harbor exon deletions in the GCH gene.
A point mutation in the gene for TH has been shown to result in autosomal-recessive DRD. This mutation at the Gln 381 Lys locus in the tyrosine gene results in TH activity that is only 15% of normal (L眉decke et al, 1995), with a resultant decrease in dopamine production.
Sepiapterin reductase deficiency, by point mutation, has also been shown to have a similar yet somewhat more severe picture of dopa-responsive dystonia.
Despite these advances, genetic testing is not definitive. Thirty to forty percent of patients with DRD do not show the common mutations. Some of these coding region mutation-negative cases may represent autosomal-recessive TH-deficient DRD, while others are apparently sporadic. These sporadic cases may be explained by either incomplete penetrance/expression of GCH1 gene mutations or de novo mutations or deletions in the gene (Furukawa and Kish, 1999). Asymptomatic carriers of mutated genes also have been described, suggesting that neurological function may be normal even when dopamine metabolism is altered (Takahashi et al, 1994).
Frequency:
In the US: Epidemiological studies are not available.
Internationally: Epidemiological studies are not available, but most cases have been reported from Japan and Southeast Asia. With increasing awareness of this condition, more cases are being reported from other parts of the world.
Mortality/Morbidity: Marked gait difficulty (not uncommonly misdiagnosed as spastic diplegia or cerebral palsy) requiring wheelchair ambulation has been reported. No data are available on mortality associated with DRD, but patients surviving beyond the fifth decade with treatment have been reported. Autosomal recessive forms of DRD from TH deficiency and sepiapetrin deficiency show considerable motor and mental developmental delay with early mortality.
Race: Most cases have been reported from Japan, but an increasing number of reports are coming from other parts of the world. No clear racial predilection has been noted in European studies.
Sex: Females are involved more frequently than males, with a ratio varying from 2:1 to 4.3:1. The penetrance of GCH gene mutations is reported to be 2.3 times higher in females than in males (Furukawa et al, 1998).
Age: Typically, the onset is in the first decade of life (Chen et al, 1996; Nygaard, 1995), although it may present in the second to early third decades. Late-onset DRD has been reported in a 67-year-old woman who presented with neck and trunk dystonia with diurnal fluctuations and no parkinsonian features (Maruta et al, 1993).
Numerous cases of patients with late-onset parkinsonian features who responded to very low doses of levodopa have been reported. Lately, cases of adult-onset focal dystonias have also been shown to be responsive to levodopa and identified to GCH 1 deficiency.
Likewise, family members of patients with DRD who have a parkinsonian syndrome in late life (like patients with DRD) have increased sensitivity to low doses of levodopa.
The late-onset forms are considered a forme fruste of DRD. |
