Genetic linkage analysis in primary torsion dystonia

We studied five families, each containing two siblings affected with torsion dystonia and having phenotypically normal parents, for linkage of dystonia to 18 marker systems, including HLA. Analysis assumed an autosomal recessive mode of inheritance. Linkage was not found. Two markers, HLA and MN, were excluded from tight linkage, and evidence against tight linkage to ABO, Rh, GC, and GLO was obtained.     

X-linked centronuclear myopathy: mapping the gene to Xq28.

The X-linked recessive centronuclear/myotubular myopathy (XLR-CNM/MTM1), a severe neonatal disorder characterized by generalized hypotonia, muscle weakness and primary asphyxia, has recently been mapped to Xq28. This report presents linkage analysis data of eight families with X-linked centronuclear myopathy. Four probes from the region Xq26-27 and five Xq28 probes were used to get more precise gene localization and marker order. St14 (DXS52), fully informative in all families, shows significant linkage to the CNM gene (z = 3.60; theta = 0.05), followed by DX13 (DXS15) (z = 2.03; theta = 0.06) and F8 (z = 1.86; theta = 0.00). Combination of the physical map derived by Kenwrick and Gitschier (1989) and our linkage data lead to the most probable order R/GCP-G6PD-(XLR-CNM-F8)-p767-St14-cpX67-++ +DX13 placing the CNM gene close to F8. The results of this study confirm strong linkage of the CNM gene to the region Xq28 and will permit carrier testing and prenatal diagnosis in CNM families. We conclude that the precise localization of this devastating disorder may be of great importance for genetic counselling in families at risk. The lack of information about gene frequency and mutation rate as well as the severity and burden of the disease point to the inevitable need for accurate clinical diagnosis.     

Polysomnography of torsion dystonia

Nocturnal EEG, electro-oculograms, and electromyograms were studied in nine patients with dystonia musculorum deformans and in nine healthy controls. Electrodes were placed over frontal, central, and occipital regions in accordance with the international 10-20 system of electrode placement. A standard bipolar montage was used for the recordings, and records were scored independently in accordance with the manual of Rechtschaffen and Kales. All patients were found to sleep poorly. Patients in advanced stages of dystonia all displayed an EEG pattern characterized by pronounced, high-amplitude (greater than 150 microV) spindles that were continuous for all stage 2 and portions of stage 3 sleep. Other sleep parameters were also disturbed. Sleep spindles become less frequent and diminish in amplitude with advancing age. The spindle activity of patients with advanced dystonia presents a stark contrast to this pattern and may underscore their clinical significance.     

Temporal discrimination thresholds in adult-onset primary torsion dystonia: an analysis by task type and by dystonia phenotype

Adult-onset primary torsion dystonia (AOPTD) is an autosomal dominant disorder with markedly reduced penetrance. Sensory abnormalities are present in AOPTD and also in unaffected relatives, possibly indicating non-manifesting gene carriage (acting as an endophenotype). The temporal discrimination threshold (TDT) is the shortest time interval at which two stimuli are detected to be asynchronous. We aimed to compare the sensitivity and specificity of three different TDT tasks (visual, tactile and mixed/visual-tactile). We also aimed to examine the sensitivity of TDTs in different AOPTD phenotypes. To examine tasks, we tested TDT in 41 patients and 51 controls using visual (2 lights), tactile (non-painful electrical stimulation) and mixed (1 light, 1 electrical) stimuli. To investigate phenotypes, we examined 71 AOPTD patients (37 cervical dystonia, 14 writer's cramp, 9 blepharospasm, 11 spasmodic dysphonia) and 8 musician's dystonia patients. The upper limit of normal was defined as control mean +2.5 SD. In dystonia patients, the visual task detected abnormalities in 35/41 (85%), the tactile task in 35/41 (85%) and the mixed task in 26/41 (63%); the mixed task was less sensitive than the other two (p = 0.04). Specificity was 100% for the visual and tactile tasks. Abnormal TDTs were found in 36 of 37 (97.3%) cervical dystonia, 12 of 14 (85.7%) writer's cramp, 8 of 9 (88.8%) blepharospasm, 10 of 11 (90.1%) spasmodic dysphonia patients and 5 of 8 (62.5%) musicians. The visual and tactile tasks were found to be more sensitive than the mixed task. Temporal discrimination threshold results were comparable across common adult-onset primary torsion dystonia phenotypes, with lower sensitivity in the musicians.     

Linkage analyses between dominant X-linked Charcot-Marie-Tooth disease, and 15 Xq11–Xq21 microsatellites in a new large family: Three new markers are closely linked to the gene

X-linked dominant inheritance was suspected in a large family with Charcot-Marie-Tooth disease since no male to male transmission was observed, and since the sensory and motor neuropathy was more severe in males than in females. To test linkage to the dominant X-linked Charcot-Marie-Tooth disease (DCMTX) locus in Xq13, genotypes of 19 affected and 19 unaffected individuals from this family were determined for 4 microsatellite markers. Close linkage to mfd66 (DXS453) was found by bipoint analysis (Zmax = 4.8 at θ = 0.00). Multipoint analysis mapped the gene between the androgen receptor and DXYS1. In addition, linkage analysis performed with 11 microsatellite markers, derived from a high density map spanning 16 cM on Xq11–Xq21 revealed 3 new tightly linked loci: afm287zgl (DXS1216), afm261zh5 and afm207zg5 (DXS995). Multipoint analysis localized the DCMTX gene to a 7.5 cM interval between afm123xd4 (DXS988) and afm116xg1 (DXS986). Combined analysis with these new microsatellites provides a powerful tool for carrier detection because of their high informativity and the small genetic distance (< 10 cM) between the markers flanking the gene.     

The gene for X-linked myotubular myopathy is located in an 8 Mb region at the border of Xq27.3 and Xq28

X-linked recessive myotubular myopathy (XLMTM) is a rare and severe neonatal neuromuscular disease characterized by muscle weakness, hypotonia, and respiratory problems. Here we report an extensive linkage analysis in two families with XLMTM. Using 18 markers in the Xq27-Xqter region we found a maximum two-point lod score of Z = 4.00 at Θ = 0.00 for the marker II-10 (DXS466). Three recombinations were detected between markers and the disease locus. At the distal side of Xq27.3 a recombination was present in between RNI (DXS369) and VK23b (DXS297), another in between VK23b (DXS297) and II-10 (DXS466), and at the proximal side of Xq28 a recombination in between U6.2 (DXS304) and Cpx67 (DXS134). Combining the results of both families we conclude that XLMTM is located in the 8 Mb (11 cM) region between VK23b (DXS297) and Cpx67 (DXS134).     

Familial dystonia: a case of idiopathic torsion dystonia]

A 43 year old man suffered from the involuntary movements since 10-th year of age. Those movements, initially mild, have progressed in the course of the disease. In the neurological examination the dystonic involuntary movements of the neck, trunk and limbs, more expressed on the right side, were observed. The laboratory findings were normal, except the level of dopamine beta-hydroxylase, which was increased. Similar results were observed also in the closest relatives of our patient. After the treatment with high doses of L-Dopa we achieved a considerable decrease of the symptoms.     

Turnover of catecholamines in torsion dystonia

It is believed that an imbalance of neurotransmitters plays an important role in the pathogenesis of dystonic hyperkinesis. However, the results of different studies on the exchange of catecholamines during dystonia are contradictory. We found a tendency to an increase in the noradrenaline (NA) level and a trend to a decrease in the level of homovanillic acid (HVA) in the blood of patients with dystonia. This finding indicates that the exchange of catecholamines is disturbed during dystonia. However, the changes observed were significant only for some of the statistical methods used; therefore, this problem needs further investigation.     

Expression of the early-onset torsion dystonia gene (DYT1) in human brain

Early-onset torsion dystonia, an autosomal dominant disease associated with the DYT1 locus on 9q34, is the most frequent genetic form of dystonia. Recent work has revealed that the causative mutation in most cases is deletion of a glutamate residue from the carboxy terminal of torsinA, a 332 amino acid protein encoded by the DYT1 gene. To gain insight into how deletion of a single amino acid can produce such a profound movement disorder, we have mapped the expression of the DYT1 gene in normal human postmortem brain. DYT1 mRNA is highly enriched in the dopamine neurons of the substantia nigra pars compacta. Intense expression was also found in the cerebellum and hippocampal subfields. The prominent expression of the DYT1 gene within the substantia nigra pars compacta, which provides dopaminergic innervation to the basal ganglia, implicates a disturbance of dopaminergic function in the pathophysiology of early-onset torsion dystonia.     

Serum trihexyphenidyl levels in the treatment of torsion dystonia

Using a radioreceptor technique, we assayed serum trihexyphenidyl levels in patients with dystonia being treated chronically with high dosage. We found a significant correlation between total daily dose and the daily lowest (trough) serum levels. There was no relationship between serum levels and therapeutic response or toxicity. Toxicity was more closely related to patient age than to serum level. Although levels may be useful to monitor patient compliance, they cannot be used to judge adequacy of therapy.     

X-linked nonprogressive congenital cerebellar hypoplasia: Clinical description and mapping to chromosome Xq

We examined a large family in which an X-linked recessive congenital ataxia manifested in 7 males from three generations. The affected boys first exhibited a marked delay of early developmental motor milestones. A neurological syndrome became evident by 5 to 7 years of age and included cerebellar ataxia, dysarthria, and external ophthalmoplegia; there were no symptoms of mental retardation, spastic paraparesis, or sensory loss. Neuroimaging studies revealed hypoplasia of cerebellar hemispheres and vermis. The disease showed no progression beyond early childhood. The unique heredity and clinical features clearly distinguish this new entity from a variety of previously described familial ataxias. Pairwise linkage analysis and haplotype reconstruction allowed us to map the gene responsible for this disorder to a 38-cM interval on chromosome Xp11.21-q24 flanked by the loci DXS991 and DXS1001. Upon multipoint linkage analysis, the disease gene was determined to be located most likely in the proximal part of chromosome Xq, with the maximal lod score of 4.66 at the locus DXS1059 (Xq23). This is the first example of the genetic mapping of a pure congenital cerebellar hypoplasia syndrome.     

5-hydroxytryptamine in platelets of torsion dystonia patients

In an effort to explore possible changes in 5-hydroxytryptamine (5-HT) metabolism in idiopathic torsion dystonia (ITD), platelets from patients were studied. Platelet 5-HT concentrations did not differ from those in matched controls. 5-HT uptake by the platelets was also studied, and the results demonstrated significantly higher Km values, but Vmax values were normal among patients. Inhibition by imipramine of 5-HT uptake by platelets taken from ITD patients was also normal. The therapeutic implications of the low affinity of 5-HT to its platelet receptors are discussed.     

Genetic and clinical features of primary torsion dystonia

Primary torsion dystonia (PTD) is defined as a syndrome in which dystonia is the only clinical sign (except for tremor), and there is no evidence of neuronal degeneration or an acquired cause by history or routine laboratory assessment. Seven different loci have been recognized for PTD but only two of the genes have been identified. In this review we will describe the phenotypes associated with these loci and discuss the responsible gene. This article is part of a Special Issue entitled "Advances in dystonia".     

A case-control study of idiopathic torsion dystonia.

A study of 71 patients with idiopathic torsion dystonia (ITD) and 71 matched controls was performed to investigate the range of possible clinical expression of ITD and the role of environmental factors in the development of the disease. A family history of tremor and stuttering were the only factors significantly associated with ITD. No associated environmental factor was identified.     

Idiopathic torsion dystonia linked to chromosome 8 in two mennonite families

The DYT1 locus on chromosome 9q34 is responsible for most childhood limb-onset idiopathic torsion dystonia (ITD). Linkage to DYT1 has been excluded in families with adult-onset, and predominantly cranial–cervical, ITD. We mapped a locus (DYT6) associated with prominent cranial–cervical ITD in two large Mennonite families to chromosome 8. An identical haplotype spanning 40?cM segregates with ITD in these families, suggesting a shared mutation from the recent past.