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PubMed2004

Validity of family history data on primary adult-onset dystonia.

BACKGROUND: To our knowledge, no study has assessed the validity of family history data provided by probands with adult-onset dystonia. OBJECTIVE: To measure the sensitivity and specificity of interviewing patients with primary adult-onset dystonia as a method for obtaining information on dystonia in first-degree relatives. PARTICIPANTS: Seventy probands with primary adult-onset dystonia were asked to identify first-degree relatives who had dystonia. Available relatives were then directly examined by a trained neurologist. The validity of the probands' reports was tested against the neurologists' diagnoses. RESULTS: Among 300 first-degree relatives who were examined, 26 received a diagnosis of dystonia. Only 7 of the 26 were identified by the probands' reports. Among the 274 relatives free of dystonia, the probands reported 5 as having dystonia. The probands' reports therefore yielded a sensitivity of 27.0% and a specificity of 98.2%. CONCLUSIONS: Because the family history method yields low sensitivity and incurs a risk of misclassification, it is of limited use in family studies of adult-onset dystonia. The only valid means of ascertaining dystonia among relatives remains neurological examination of at-risk subjects.

Adult↗
PubMed2002

Intrafamilial phenotypic variability of the DYT1 dystonia: from asymptomatic TOR1A gene carrier status to dystonic storm.

When primary torsion dystonia is caused by a GAG deletion in the TOR1A gene (DYT1 dystonia), it typically presents with an early-onset dystonia involving distal limbs, subsequently spreading to a generalized dystonia. We describe a large family with an unusually broad variability in the clinical features of their dystonia both with regard to severity and age of onset. The proband of this family succumbed in his second decade to malignant generalized dystonia, whereas other family members carrying the same mutation are either asymptomatic or display dystonia that may be focal, segmental, multifocal, or generalized in distribution. One family member had onset of her dystonia at age 64 years, probably the oldest reported in genetically confirmed DYT1 dystonia. We conclude that marked phenotypic heterogeneity characterizes some families with DYT1 dystonia, suggesting a role for genetic, environmental, or other modifiers. These findings have implications for genetic testing and counseling.

Adolescent↗
PubMed2005

Homocysteine and serum markers of immune activation in primary dystonia.

The cause of primary dystonia remains unknown. Several reports point to immune system disturbances in primary dystonia and a recent study demonstrated hyperhomocysteinemia in cervical dystonia. Homocysteine (HCY) is an amino acid and elevated HCY concentrations were shown to be associated with immune system activation and increased neopterin serum concentrations. We examined HCY serum concentrations together with serum markers of immune activation in patients with different types of primary dystonia. Eighty-three patients with different types of primary dystonia were included and investigated at least 3 months following botulinum toxin treatment. Thirty-six healthy volunteers with similar age and sex distribution served as controls. Total serum HCY, kynurenine, and tryptophan concentrations were determined by high-performance liquid chromatography; neopterin, folate, and vitamin B12 concentrations were measured by immunoassays. Routine blood analysis, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and white blood count (WBC), was performed. Patients with primary dystonia had significantly higher HCY concentrations compared to controls. Among the dystonia subtypes, no significant difference of HCY serum concentrations was observed. CRP and ESR were within the normal range in >90% of the patients and all had normal WBC. Neopterin, kynurenine, and tryptophan serum concentrations were similar in patients and controls and not correlated with HCY serum concentrations. The results provide evidence against enhanced cellular immune activation in patients with primary dystonia. However, hyperhomocysteinemia was present in all dystonia subtypes and unrelated to immune activation in this study. HCY is a neuronal excitotoxic amino acid and hyperhomocysteinemia is considered an independent vascular risk factor. Further studies are required to define the background of hyperhomocysteinemia in primary dystonia.

Adult↗
PubMed2004

Timing of tactile and visuo-tactile events is impaired in patients with cervical dystonia.

Psychophysical studies show alterations of cross-modal integration and timing processes in patients with generalized and focal hand dystonia. Here we assess the capability of 10 cervical dystonia patients, 5 patients with cervical pain but no dystonia, and 10 healthy controls to determine whether pairs of visual, tactile or visuo-tactile stimuli were simultaneous or sequential (TD threshold) and which stimulus preceded the other (temporal order judgement, TOJ). Visual stimuli consisted of light emitting diodes and tactile stimuli of non-noxious electrical shocks delivered to the hands. Intervals between stimuli were increased from 0 to 400 ms in steps of 10 ms. Cervical dystonia patients had a clear impairment of tactile and visuo-tactile temporal discrimination compared with patients with cervical pain but no dystonia who performed as well as healthy subjects. This suggests that deficits of temporal discrimination in cervical dystonia patients are not due to the possible distracting effect of unpleasant sensations or pain. Comparisons with previous studies show that deficits in cervical dystonia were more severe than in focal hand dystonia and less severe than in generalized dystonia. Thus, impairment of sensory timing may be a marker of disease, which varies along a continuum in the different forms of dystonia.

Adult↗
PubMed2003

Frequency of familial aggregation in primary adult-onset cranial cervical dystonia.

Family history of definite/probable dystonia was studied in 36 probands with primary adult-onset cranial/cervical dystonia. Of the 157 relatives who were examined, 8 from 7 families and 11 from 10 families were diagnosed as having definite or probable dystonia, respectively. The frequency of familial occurrence of definite dystonia was 19.4%, 33% when considering both definite and probable dystonia. There was a tendency for relatives affected by either definite or probable dystonia to have the same type of dystonia as the index patient. Similar segregation ratios were found for parents, siblings, and children with either definite or probable dystonia. These observations raise the possibility that probable dystonia represents formes frustes/mild phenotypes of dystonia rather than another movement disorder.

Adult↗
PubMed1999

Dystonia: recent advances.

Dystonia may be primary or symptomatic. Most, if not all, primary torsion dystonias are genetic diseases and manifest as 'pure dystonia', without consistent biochemical or neuropathological changes. Symptomatic dystonias may be (a) secondary to drugs or other environmental factors, (b) part of a 'dystonia plus' syndrome or (c) part of several heredodegenerative diseases. In the last few years, there have been rapid advances in the genetic classification of primary torsion dystonia. The gene for one form (DYT1dystonia), particularly common in Ashkenazi Jews, has been isolated. In this review, I present a basic clinical overview of dystonia and focus on the recent advances in molecular genetics of primary torsion dystonia (PTD). Treatment of dystonia is a large subject, worthy of a review in itself, and is not covered here. Several of the paroxysmal movement disorders may manifest with dystonia, but these are usually considered separately, as I have done in this review. Copyright 1999 Harcourt Publishers Ltd.

Journal Article↗
PubMed2004

Orthopedic and neurological complications of cervical dystonia--review of the literature.

Cervical dystonia is the most frequent form of focal dystonia. Further, cervical dystonia can occur as a feature of segmental or generalized dystonias and cerebral palsy. Treatment with botulinum toxin to relieve pain and improve functional and psychological outcome is effective, but expensive. However, pharmacoeconomic studies evaluating treatment and disease costs have not taken into consideration the long-term complications of cervical dystonia. Here we present a review of the medical literature on orthopedic and neurological complications arising from cervical dystonia, including cervical spine degeneration, spondylosis, disk herniation, vertebral subluxations and fractures, radiculopathies and myelopathies. In summary, complications are more often reported in generalized dystonia and cerebral palsy than in focal dystonia. The prevalence is not well established, published estimations go from 18 to 41% in selected populations. Awareness of the frequent occurrence of complications and screening for symptoms of radiculomyelopathy in patients with dystonia is essential to avoid irreversible spinal cord damage. Complications of cervical dystonia need to be taken into consideration when weighting risks and calculating costs of the disease and its treatment.

Humans↗
PubMed2003

Does sex influence age at onset in cranial-cervical and upper limb dystonia?

The relation between age at dystonia onset and sex was investigated in 264 patients with cranial-cervical dystonia and 56 patients with upper limb dystonia. In cranial-cervical dystonia, women had a significantly greater age at the onset of dystonia than men. The association was independent of duration of disease and distance of referral, but it was no longer detectable after adjustment for educational level. In upper limb dystonia, men and women did not differ for age at dystonia onset, duration of disease, education level, or distance of referral. A significant inverse association between age at the onset of dystonia and education was observed in both cranial-cervical dystonia and upper limb dystonia series.

Adult↗
PubMed2003

[Epidemiological analysis of primary dystonia in Szczecin and Gdańsk regions].

The aim of the study was to determine the prevalence of primary dystonia in Szczecin Region (total population of 995,000 individuals) and Gdansk Region (total population of 149,000 individuals). We identified on the prevalence day 31.12.2000--98 patients with primary dystonia in Szczecin Region (SR) and 130 in Gdansk Region (GR) and crude rate of 98 per million (CI 81-121) in SR and 87(CI--71-108) in GR. The rates per million for the main types of dystonia were as follows: focal: in SR (n = 84) 84 (CI--69-105), in GR (n = 125) 84 (CI--68-104), segmental: in SR (n = 8) 8 (CI--4-16), in GR (n = 5) 3 (CI--1-9) and multi-focal: in SR (n = 6) (CI--3-13). The prevalence rates per million for the more common types of dystonia were: cervical dystonia: in SR 44 (CI--33-66), in GR 50 (CI--38-69), blepharospasm: in SR 22 (CI-15-34), in GR 27 (CI--18-39) writer's cramp: in SR 10 (CI--5-19), in GR-4 (CI--2-10) laryngeal: in SR-8 (CI--4-16), in GR-3 (CI--1-8). The female predominance was been noted for all subtypes of focal dystonia in both regions. In focal dystonia mean patient's age at onset was: for cervical dystonia in SR--37.86, in GR--39.53, for blepharospasm in SR--54.00, in GR--57.44, for laryngeal dystonia in SR--53.12, in GR--66.25 and for writer's cramp in SR--24.50, in GR--34.75. Our study provide the first data on the prevalence of primary dystonia and its subtypes in two similar Regions in Poland.

Adult↗
PubMed1977

Patterns of dystonia ("I-D-I" and "D-I-D-") in response to l-dopa therapy for Parkinson's disease.

The clinical, biochemical, and pharmacologic responses to L-dopa were studied in 87 patients with Parkinson's disease. Eleven of the 87 patients had a long-duration response, 39 had a short-duration response, and 37 had a combination of both. Thirty-four of the 39 patients with short-duration response to L-dopa experienced a consistent and reproducible sequence of clinical and biochemical events after each dose, characterized by improvement of parkinsonism and a single phase of dystonia occurring during or shortly after the peak of dopa concentration in plasma and during maximal clinical improvement. We have called this the I-D-I- response, for Parkinsonism-Improvement-Dystonia-Improvement-Parkinsonism. The remaining five patients all had the onset of the disease at an unusually young age and showed a distinctly different response pattern consisting of a first phase of dystonia, before there was any improvement, followed by a phase of improvement without dystonia and then by a second phase of dystonia before the abrupt return of parkinsonism. We have called this the D-I-D response, for Parkinsonism-Dystonia-Improvement-Dystonia-Parkinsonsim. Dystonia occurs in the D-I-D- response when the concentration of dopa in plasma passes through a critical but relatively low level, whereas it remains absent as long as the concentration of dopa remains above that level. In the I-D-I- response, dystonia is avoided by keeping the plasma concentration of dopa low, in the D-I-D- response by keeping it high. It is postulated that in the D-I-D response postsynaptic depolarization blockade due to supramaximal stimulation of the neuronal system mediating dystonia occurs, whereas in the I-D-I response the postsynaptic members of the same neuronal population respond with excitation but not with depolarization blockade.

Dose-Response Relationship, Drug↗
PubMed2000

A prevalence study of primary dystonia in eight European countries.

There have been few epidemiological studies of dystonia. Most previous studies have provided estimates based on few cases. A European prevalence study was undertaken to provide more precise rates of dystonia by pooling data from eight European countries. Diagnosed cases were ascertained by adult neurologists with specialist movement disorder (and botulinum toxin) clinics. The crude annual period prevalence rate (1996-1997) for primary dystonia was 152 per million (95% confidence interval 142-162), with focal dystonia having the highest rate of 117 per million (108-126). Prevalence rates for cervical dystonia, blepharospasm and writer's cramp were as follows: 57 (95% confidence interval 51-63), 36 (31-41), and 14 (11-17). The age-adjusted relative rates were significantly higher in women than in men for segmental and focal dystonias with the exception of writer's cramp. Comparing rates between centres demonstrated significant variations for cervical dystonia, blepharospasm and writer's cramp, probably due to methodological differences. Our results provide the first data on the prevalence of primary dystonia and its subtypes across several European countries. Due to under-ascertainment of cases, our rates should be seen as conservative and an under-estimate of the true prevalence of dystonia.

Adult↗
PubMed1990

X-linked recessive torsion dystonia in the Philippines.

The occurrence of an X-linked form of torsion dystonia in the Philippines was demonstrated by the genetic and biochemical analysis of affected males and their relatives. Thirty-six affected males were ascertained in 21 families by clinical neurologic evaluation. The mean age-of-onset of dystonia was 37.9 years with a range from 12 to 52 years. Neurologic symptoms began focally and progressed to either segmental or generalized involvement in all cases. Generalized dystonia developed in 78% of the patients after a mean duration of 6.8 years from the onset of symptoms. A family history of dystonia was elicited in 17 of the 21 kindreds, accounting for a total of 64 males and one possibly affected female, distributed among 224 individuals in 33 sibships. In 18 of the 33 sibships, 2 or more brothers reportedly had dystonia. There were 12 kindreds with a history of multigenerational dystonia. In those, only males of maternal ancestry were affected, and in 7 of these families, maternal grandfathers reportedly had dystonia. There were no instances of male-to-male transmission. Cytogenetic analysis did not show any X chromosome abnormalities in 4 affected propositi. Several secondary causes of torsion dystonia were excluded, including Wilson disease, aminoacidopathies, organic acidurias, oligosaccharidoses, and chronic hexosaminidase A and B deficiency. These findings substantiate the existence of an X-linked recessive form of primary torsion dystonia.

Adolescent↗
PubMed1995

Gonadal sex hormones and dystonia: experimental studies in genetically dystonic hamsters.

In some kinds of idiopathic dystonia, including paroxysmal dystonia, a role of sex hormones has been suggested because of female predominance and onset, recurrence, or exacerbation of dystonic symptoms with pregnancy. Similar effects of pregnancy have recently been reported in a model of paroxysmal dystonia, the genetically dystonic hamster. Dystonia in mutant hamsters of both genders is transient, i.e., exhibits spontaneous remission at around puberty, strongly suggesting involvement of gonadal sex hormones. For exploration of the role of sex hormones in dystonia, we undertook a series of ontogenetic experiments in male and female dystonic hamsters. Mutant animals of both genders exhibited the same postnatal development of dystonia with maximum severity of dystonic attacks between weaning and approximately 40 days of age and spontaneous remission thereafter. As shown by plasma sex hormone determinations and, in females, vaginal cytology, spontaneous improvement of the movement disorder coincided with puberty in both genders. Male and female hamsters had about the same plasma levels of progesterone. Compared with nondystonic hamsters, onset of puberty was significantly retarded in both male and female dystonic hamsters. Furthermore, body weight gain was lower in dystonic animals, indicating retarded postnatal development. Gonadectomy at time of weaning did not alter the age-dependent development and remission of dystonia, suggesting that gonadal sex hormones are not critically involved in the disease in hamsters. We propose that transient paroxysmal dystonia in mutant hamsters is caused by postnatal retardation of brain development resulting in a temporary impairment of brain functions with spontaneous remission independent of gonadal sex hormones. In view of the fact that the brain can synthesize steroids such as progesterone independent of peripheral glands in both genders, such neurosteroids might be involved in the postnatal brain maturation that leads to remission of dystonia at around puberty in mutant hamsters.

Age Factors↗
PubMed1991

Dopamine beta-hydroxylase gene excluded in four subtypes of hereditary dystonia.

The hereditary dystonias include a clinically heterogeneous group of movement disorders varying in symptoms, age of onset, and drug responsiveness. Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, has been implicated in dystonia because of increased serum levels of DBH in some patients, the influence of catecholaminergic drugs on the human phenotypes, and altered norepinephrine levels in several brain regions in dystonia patients and in genetically dystonic rodents. In addition, markers linked to the dystonia gene in two ethnic groups map close to the DBH locus on human chromosome 9q34. Here we evaluate the inheritance of restriction fragment length polymorphisms near the DBH gene in families with four subtypes of hereditary dystonia: Jewish and non-Jewish, early onset, generalized idiopathic torsion dystonia (ITD); dopa-responsive dystonia; and myoclonic dystonia. In all families, obligate recombination events were observed between the DBH and dystonia genes, thus excluding the DBH gene as the primary defect.

Adolescent↗
PubMed1995

Alterations in the brain GABAA/benzodiazepine receptor-chloride ionophore complex in a genetic model of paroxysmal dystonia: a quantitative autoradiographic analysis.

Dystonia is a relatively common syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The most frequent type of dystonia is idiopathic generalized dystonia, whose pathophysiology is largely unknown. In this respect, mutant animal strains with inborn dystonia may be helpful to elucidate the pathophysiological defects involved in idiopathic dystonia. The genetically dystonic (dtsz) hamster is an animal model of paroxysmal dystonia that displays attacks of generalized dystonia either spontaneously or in response to mild environmental stimuli. In the present study, a quantitative autoradiographic analysis of ligand binding to different sites of the GABAA/benzodiazepine receptor-chloride ionophore complex was carried out in 123 brain areas from genetically dystonic mutant hamsters and age-matched control hamsters. Animals were killed 2 weeks after their last dystonic attack. Analysis of the GABA-binding site of the receptor complex, using the ligand [3H]muscimol, and the benzodiazepine site labelled with [3H]flunitrazepam revealed no significant alterations in the binding of either ligand in any of the brain regions examined. In contrast, widespread changes were observed in binding densities of [35S]t-butylbicyclophosphorothionate ([35S]t-butylbicyclophosphorothionate), which labels the picrotoxinin site of the GABAA receptor-chloride ionophore complex. Significantly increased [35S]t-butylbicyclophosphorothionate binding was found in several parts of the thalamus, cortex, and hippocampus as well as in the red nucleus, the subthalamic nucleus, and the granular layer of the cerebellum. Since high-affinity [35S]TBPS binding is thought to represent the closed conformation of the GABA-gated chloride ionophore, increased TBPS binding would indicate an impaired GABAergic function. The study is consistent with the concept that dystonia is caused by impaired connections between the basal ganglia, the thalamus, and frontal association areas. The data on increased [35S]TBPS binding are the first evidence implicating alterations in the GABA-gated chloride ion channel function in a movement disorder, i.e. idiopathic generalized dystonia.

Animals↗
PubMed2000

Evidence for striatal dopaminergic overactivity in paroxysmal dystonia indicated by microinjections in a genetic rodent model.

Mutant dystonic hamsters (dt(sz)), a model of primary paroxysmal dystonia, display attacks of generalized dystonia in response to mild stress in an age-dependent manner. Recent studies in dystonic hamsters have revealed decreased densities of dopamine D(1) and D(2) in the dorsal striatum. This finding has been interpreted as a down-regulation in response to enhanced dopamine release because systemic treatments with neuroleptics reduced the severity of dystonia while levodopa exerted prodystonic effects. Therefore, in the present study we investigated the effects of amphetamine as well as of selective D(1) or D(2) receptor agonists and antagonists on the severity of dystonia after systemic administrations and after microinjections into the dorsal striatum. Amphetamine and the dopamine D(2) agonist quinpirole increased the severity of dystonia after systemic and striatal injections, while the dopamine D(1) agonist SKF 38393 exerted only moderate prodystonic effects after systemic administration of a high dose but not after striatal injections. These results suggest that a predominant overstimulation of D(2) receptors is pathogenetically involved in the dystonic syndrome. Combined systemic or striatal administrations of the D(1) and D(2) receptor agonists did not reveal synergistic prodystonic effects at the examined doses. The selective D(1) antagonist SCH 23390 as well as the D(2) antagonist raclopride tended to decrease the severity of dystonia after systemic administration but failed to exert significant effects after striatal injection. The coadministration of ineffective doses of the antagonists SCH 23390 and raclopride, however, exerted an enormous antidystonic efficacy after both systemic and striatal injections. Since striatal injections of compounds which enhance dopaminergic activity aggravated dystonia, while coinjections of dopamine D1 and D2 receptor antagonists reduced the severity of dystonia, the present findings clearly support the hypothesis that striatal dopaminergic overactivity plays a crucial role for the manifestation of dystonic attacks in the hamster model of paroxysmal dystonia.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2000

Two phenotypes and anticipation observed in Japanese cases with early onset torsion dystonia (DYT1) - pathophysiological consideration.

Early onset torsion dystonia (DYT1) is a dominantly inherited dystonia caused by a deletion of three bases, GAG, coding glutamic acid, in chromosome 9q34. The protein coded by this gene was named as torsin A. DYT1 is common among the Ashkenazi Jewish population, but has been thought to be rare among Japanese. Among the idiopathic torsion dystonias being followed in this clinic, we found five families with DYT1 by gene analysis. This is the first report of genetically proven Japanese DYT1.The clinical features of five proband cases were divided into two types. One type is postural dystonia with marked trunkal torsion, and the other is action dystonia associated with violent dyskinetic movements. The affected family members in the upper generations presented with focal or segmental dystonia; it was postural dystonia of the legs in the former, and writer's cramp or tremor of the arms in the latter families. There was an asymptomatic carrier in the upper generation. Anticipation in the age of onset and severity of the disease was observed in all families. Medical treatment, including anticholinergics and levodopa, did not show apparent effects, while stereotactic thalamotomy to the nucleus ventralis lateralis (VL) or ventralis intermedius (Vim), with or without posterior ventral pallidotomy, were effective with action dystonia, but not postural dystonia. This study suggests the existence of at least two phenotypes in DYT1, in which different pathways of the basal ganglia are involved.

Adolescent↗
PubMed1999

The Symptom Checklist-90 Revised questionnaire: no psychological profiles in complex regional pain syndrome-dystonia.

Complex regional pain syndrome (CRPS) is a syndrome usually localized in the extremities, mostly occurring after a preceding trauma or operation. Dystonia is present in a minority of CRPS patients, but, when present, leads to severe disability. Various pathological factors have been postulated to present in CRPS-dystonia, such as involvement of the sympathetic system, reorganization of the central nervous system, and psychological distress. In the present study, we investigated the involvement of psychological distress in CRPS-dystonia with the aid of the Symptom Checklist-90 Revised (SCL-90R) questionnaire. The SCL-90R is a multidimensional self-report inventory covering various dimensions of psychological distress. In a population of 1006 CRPS patients, we analyzed the SCL-90R scores of 27 patients with CRPS-dystonia (23 female and 4 male) and compared the scores to sample scores of a control female (n = 577) and a control rehabilitation population (n = 56). Insomnia scored significantly higher in the female CRPS-dystonia population, as compared to the control female population (P < 0.001), and in the total CRPS-dystonia population, as compared to the rehabilitation population (P < 0.01). Remarkable was the significantly higher score of somatization in the rehabilitation population, as compared to the CRPS-dystonia population (P = 0.006). For the other dimensions of psychological distress of the SCL-90R, the scores of the CRPS-dystonia and control populations were similar. With regard to the SCL-90R scores, we conclude that specific psychological profiles are not present in CRPS-dystonia.

Adolescent↗