Dopa-responsive dystonia. Delineation of the clinical syndrome and clues to pathogenesis.
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Adolescent↗
Biomedical subjects
T G Nygaard
Publications and source records attributed to T G Nygaard.
Clinical heterogeneity of dopa-responsive dystonia: PET observations.
Parkinsonism without dystonia has been reported in several older members of families with DRD. This raises the question whether such patients represent a variant in the clinical picture of DRD, or a separate disease, IP. We employed 6-FD PET to study the nigrostriatal dopaminergic function in a woman with typical DRD and two of her relatives with late-onset parkinsonism. These two had an excellent and prolonged therapeutic response to small doses of L-DOPA, without complications. We found that the dystonic patient and the women with "benign" parkinsonism had normal striatal 6-FD uptake. In conjunction with other clinical evidence, our PET study indicates that the biochemical lesion in these members may be "proximal" to dopa decarboxylase, as is suggested in DRD patients. We conclude that the adult-onset parkinsonism in DRD families is due to the same pathophysiological mechanism as the childhood-onset dystonia in the disease. DRD may display substantial clinical heterogeneity depending on the age of onset.
Adult↗
Long-term treatment response and fluorodopa positron emission tomographic scanning of parkinsonism in a family with dopa-responsive dystonia.
Dopa-responsive dystonia (DRD) is one form of childhood-onset idiopathic torsion dystonia. Adult-onset parkinsonism has appeared in several previously unaffected members in families with DRD suggesting that this may be an additional phenotypical expression of the disease. We report a family with DRD in which 2 women and 1 man, unaffected by dystonia, developed tremor-onset parkinsonism after age 50 years. The women continue on a low dosage of levodopa after 9 and 13 years of treatment, with a stable, nearly complete, symptomatic response. This contrasts to the typical long-term treatment complications observed in patients with Parkinson's disease. We assessed nigrostriatal dopaminergic function in the proband, with typical DRD, and the 2 women with parkinsonism using 6-[18F]fluoro-L-dopa positron emission tomography. All 3 had normal striatal 6-[18F]fluoro-L-dopa uptake. These observations provide compelling evidence that "benign" adult-onset parkinsonism may be an expression of the disease in some members of families with DRD and does not support consideration of the DRD gene as a risk factor for development of Parkinson's disease. There may be considerable clinical heterogeneity in DRD depending on the age at onset.
Adult↗
Genetic mapping of "Lubag" (X-linked dystonia-parkinsonism) in a Filipino kindred to the pericentromeric region of the X chromosome.
"Lubag" is an X-linked disorder causing dystonia and parkinsonism that has only been described in families from the Philippines, principally from the island of Panay. We have established linkage between the disease phenotype "lubag" and DNA markers which span the Xp11.22-Xq21.3 region by using a large Filipino family with 8 affected men in three generations. These DNA markers define an interval of about 20 centimorgans in the pericentromeric region of the X chromosome as the most likely site of the disease locus XDPD (X-linked dystonia-parkinsonism). XDPD has a maximum multipoint log likelihood ratio score (Zmax) of about 4.6 over the interval from Xq12 to Xq21.31 (DXS159-DXYS1X). The co-occurrence of dystonia and parkinsonism in lubag and in other known disorders suggests there may be a common pathogenetic mechanism. Identification of the genetic defect in this family may provide an important clue toward understanding the pathogenesis and pathophysiology of both dystonia and parkinsonism.
Adult↗
Dopa-responsive dystonia: long-term treatment response and prognosis.
We report observations on the treatment of 66 patients with presumed dopa-responsive dystonia (DRD). Forty-seven of these patients had hereditary disease; 19 had disease of sporadic occurrence. Initial diagnostic confusion with "cerebral palsy" or "spastic diplegia" existed in 16 patients. Several patients benefited from anticholinergic medications and a few from carbamazepine. Levodopa was the most effective treatment in all cases. In the majority, there was an excellent response, with continued long-term clinical stability on levodopa therapy for as long as 10 to 22 years. Four men with sporadic disease and 1 woman with a sister affected with adolescent-onset parkinsonism had similar initial treatment response, but developed "wearing-off" and a less satisfactory response to levodopa within the first few years of treatment. This indicates that some patients with clinical syndromes suggestive of DRD may not have an excellent prognosis on long-term levodopa treatment and may represent misclassified cases of childhood-onset parkinsonism.
Adolescent↗
Identification of a highly polymorphic microsatellite VNTR within the argininosuccinate synthetase locus: exclusion of the dystonia gene on 9q32-34 as the cause of dopa-responsive dystonia in a large kindred.
Dopa-responsive dystonia is a clinical variant of idiopathic torsion dystonia that is distinguished from other forms of dystonia by the frequent occurrence of parkinsonism, diurnal fluctuation of symptoms, and its dramatic therapeutic response to L-dopa. Linkage of a gene causing classic dystonia in a large non-Jewish kindred (DYT1) and in a group of Ashkenazi Jewish families, to the gelsolin (GSN) and arginino-succinate synthetase (ASS) loci on chromosome 9q32-34, respectively, was recently determined. Here we report the discovery of a highly informative (GT)n repeat VNTR polymorphism within the ASS locus. Analysis of a large kindred with dopa-responsive dystonia, using this new polymorphism and conventional RFLPs for the 9q32-34 region, excludes loci in this region as a cause of this form of dystonia. This provides proof of genetic heterogeneity between classic idiopathic torsion dystonia and dopa-responsive dystonia.
Argininosuccinate Synthase↗
Dopa-responsive dystonia: the spectrum of clinical manifestations in a large North American family.
We examined 106 members of a family affected with dopa-responsive dystonia (DRD), a subset of idiopathic dystonia. Ten members had unequivocal dystonia; 8 of these had generalized dystonia and the other 2 had focal dystonias (writer's cramp and spastic dysphonia). Twenty members had lesser dystonic signs and symptoms suggestive of a diagnosis of dystonia. Five members, including 1 with dystonia, had prominent parkinsonism that became symptomatic in late adulthood. All members affected with dystonia or parkinsonism had increased muscle tone (rigidity), which may represent the minimal clinical expression of DRD. Gene penetrance in families with DRD may be greater than previously suspected.
Adult↗
Parkinson's disease beginning before age 40.
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Adult↗
Tyrosine hydroxylase and levodopa responsive dystonia.
It has been suggested that a form of inherited dystonia responsive to levodopa might be due to an abnormality of tyrosine hydroxylase gene. This hypothesis has been tested using a cDNA tyrosine hydroxylase gene probe in three families with this disorder. No evidence for genetic linkage between the disease and tyrosine hydroxylase loci was found; it is possible that the disorder results from a post-transcriptional defect confined to the brain.
Chromosome Mapping↗
Seizures in progressive supranuclear palsy.
Among 62 patients with progressive supranuclear palsy (PSP) seen over a 9-year period, we encountered seven who had seizure phenomena. We suggest that PSP patients have seizures more frequently than has been appreciated.
Aged↗
Dopa-responsive dystonia.
DRD is a distinctive clinical entity and an unexpectedly common subgroup of torsion dystonia. Diurnal fluctuation is often but not always present and does not reliably distinguish the disorder from ITD. DRD must be considered in the differential diagnosis of the child or adolescent presenting with a dystonic gait disorder, diplegic cerebral palsy, sporadic spastic paraplegia, ataxic syndromes, and juvenile parkinsonism. The response to L-DOPA is so dramatic and occurs so quickly that a diagnostic therapeutic trial should be undertaken in all patients presenting with these syndromes.
Adolescent↗
Hereditary dystonia-parkinsonism syndrome of juvenile onset.
We studied a family with an extrapyramidal disorder characterized by childhood onset of lower-limb and axial dystonia, followed by parkinsonism. Dramatic response to levodopa therapy and minimal progression in adult life was seen. The family included five generations of affected members of both sexes in an autosomal dominant pattern.
Adult↗
Response of cells to hyperthermia under acute and chronic hypoxic conditions.
The lethal response of Chinese hamster cells heated to 42 degrees was determined following 0 to 30 hr culturing under hypoxic conditions. Oxygenated and acutely hypoxic cells were equally sensitive to hyperthermia; however, sensitivity increased with the time of culturing under hypoxic conditions prior to treatment. Three hr at 42 degrees resulted in a surviving fraction of approximately or equal to 0.1 under acute hypoxic conditions and less than 0.001 for cells cultured for 30 hr under oxygen-deprived conditions before the heat treatment. The increased sensitivity to hyperthermia was was due in part to a decrease in the pH of the medium which occurred as a result of cell metabolism; this could be reversed by increasing pH to 7.3 immediately prior to heat treatment. However, even under fully controlled pH conditions, prolonged oxygen deprivation increased hyperthermic cell killing by a factor of approximately or equal to 5. This effect was not reversed by returning the cells to normal oxygen tension prior to treatment. These data demonstrate that tumorlike microenvironmental conditions (reduced O2 tension and pH) substantially increase the sensitivity of cells to 42 degrees hyperthermia.
Animals↗