Long-term effects of L-dopa on hereditary progressive dystonia with marked diurnal fluctuation

Segawa, Masaya; Nomura, Yasuo; Yamashita, Shinji; Kase, M; Nishiyama, Nobuyoshi; Yukishita, Shoko; Ohta, Hiroyuki; Nagata, K; Hosaka, Ai

doi:10.1016/b978-0-12-089445-1.50030-8

Cited by 17 publications

(14 citation statements)

References 12 publications

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“…30 The beneficial effect of levodopa remained complete after more than 7 years, in agreement with previous reports. 21 This suggests that levodopa treatment may prevent worsening of motor impairment, and underscores the importance of evaluating clinical improvement with levodopa in every dystonic patient.…”

Section: Discussionsupporting

confidence: 81%

Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1

Wider¹,

Melquist²,

Hauf³

et al. 2008

Neurology

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Objective-To repor the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD).Methods-Clinical investigation was made of available family members, including historical and chart reviews. Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis.Results-We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset doparesponsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy.Conclusions-This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis. Dopa-responsive dystonia (DRD) is a rare disorder characterized by childhood-onset fluctuating foot dystonia, which later generalizes and becomes associated with tremor and parkinsonism. 1-3 Response to small doses of levodopa is dramatic. In its classic form, also Although close to 100 mutations have been described in GCH1, 6 comprehensive screening fails to identify the responsible mutation in 40 to 50% of the families. 7 Recently, families have been described with heterozygous exonic deletions in GCH1, which were not detected by conventional screening techniques. 8-11In this study, we report more comprehensive clinical and genetic investigations of a multigenerational DRD family, in which a previous study had found linkage to a novel locus nominated DYT14 on chromosome 14q13, adjacent to the DYT5 locus. 12 Expanded data allowed us to exclude DYT14, and to identify a novel deletion in GCH1 as the disease-causing mutation in this family. METHODS Genealogy and clinical evaluationsInformation on the pedigree was collected by means of historical material, family records, and medical charts review, along with interviews with elderly family members.The project was approved by the local ethics committee. After signing an informed consent, subjects underwent a detailed videotaped neurologic evaluation. A clinical diagnosis of definite DRD was established in pa...

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Section: Discussionsupporting

confidence: 81%

Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1

Wider¹,

Melquist²,

Hauf³

et al. 2008

Neurology

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“…In the literature, the latter had generally subsided with or without dose reduction (in 2 cases) and had not reappeared with later dose increases (11,19). Apart from this the characteristics coincided.…”

Section: Discussionmentioning

confidence: 67%

“…Hereditary Progressive Dystonia with Diurnal Fluctuation effects of treatment were obtained only within 14 months compared to 4, mean 1.8 months (19) and chorea persisted with long-term levodopa medication. In the literature, the latter had generally subsided with or without dose reduction (in 2 cases) and had not reappeared with later dose increases (11,19).…”

Section: Discussionmentioning

confidence: 89%

“…HPD is suggested to be distinct from ITD and juvenile parkinsonism (JP) (17,19). The distinction from JP in sporadic cases may be difficult and may require aperiod of follow-up (11).…”

mentioning

confidence: 99%

“…The region containing the gene loci for classic idiopathic torsion dystonia (ITD) on chromosome 9q 32-34 (8,13) is not linked to dopa-responsive dystonia (11 ). The pathophysiological mechanism is supposed to be a decrease of function in the terminals of the nigrostriatal dopaminergic (DA) neurons; it is not due to an enzyme deficiency or degenerative process but due to the lowering of the level of DA contents, probably a low level of tyrosine hydroxylase (TH) (9,18,19). Furthermore, a deficiency of central biopterin as a cofactor of TH in the catecholamine biosynthetic pathway has been suggested to play a role in the pathogenesis (3).…”

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confidence: 99%

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Hereditary Progressive Dystonia with Diurnal Fluctuation (Segawa's Syndrome) - An Unusual Case

Kaiser

Ziegler²

1992

Neuropediatrics

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A young girl with hereditary progressive dystonia with diurnal fluctuation or Segawa's syndrome, completely handicapped and confined to a wheelchair between the age of 5 and 9, revealed an unusually slow response to levodopa. The ability to walk returned only after 12 to 14 months of treatment. Apart from peculiarities of behaviour due to longstanding immobility and ensuing parental overprotection, there were no psychological or mental abnormalities. Other organic diseases were ruled out. A series of regular follow-ups over the course of 7 years was performed. While residual and irregular day-to-day variation of functional capacities almost disappeared after conversion to a preparation with a decarboxylase inhibitor, some mild neurological abnormalities and a slight choreic hyperkinesia persisted with doses providing functional results. The patient today leads an almost normal teenage life and has performed well in school.

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Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease)

2003

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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 revealed a 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 neurophysiological studies 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 by heterozygous 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 of mutant/wild-type GCH-I mRNA that depends on the locus of mutation may explain intrafamilial and interfamilial variation of phenotype.

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Long-term effects of L-dopa on hereditary progressive dystonia with marked diurnal fluctuation

Cited by 17 publications

References 12 publications

Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1

Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1

Hereditary Progressive Dystonia with Diurnal Fluctuation (Segawa's Syndrome) - An Unusual Case

Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease)

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