Paroxysmal dystonic choreoathetosis: clinical features and investigation of pathophysiology in a large family.

Paroxysmal dystonic choreoathetosis (PDC) is an unusual hyperkinetic movement disorder characterized by attacks of chorea, dystonia, and ballism with onset in childhood. We report a large British family with dominantly inherited PDC linked to chromosome 2q and describe the clinical features in 20 affected family members. Attacks were precipitated by a variety of factors, including caffeine, alcohol, or emotion, and could be relieved by short periods of sleep in most subjects. The clinical features in the family are compared with those of 11 other PDC families in the literature and a core phenotype for PDC suggested. CSF monoamine metabolites measured at baseline and during an attack in one subject were found to increase during the attack. Magnetic resonance spectroscopy of brain and basal ganglia performed both during and between attacks was normal. Positron emission tomography using the D2 receptor ligand, 11C-raclopride, showed no abnormalities.

Primary torsion dystonia: the search for genes is not over.

A GAG deletion in the DYT1 gene accounts for most early, limb onset primary torsion dystonia (PTD). The genetic bases for the more common adult onset and focal PTD are less well delineated. Genetic loci for an "intermediate dystonia" phenotype and for torticollis, named DYT6 and DYT7 respectively, have recently been mapped in single families. To evaluate the contribution of these genetic loci to other families with familial "non-DYT1" dystonia five large families with dystonia were studied using genetic markers spanning the DYT6 and DYT7 regions. There was no evidence of linkage to either locus in any family. These findings illustrate the genetic heterogeneity of the dystonias and indicate the existence of one or more as yet unmapped genes for dystonia. Large collaborative efforts will be required to identify these, and additional genes, causing PTD.

The role of DYT1 in primary torsion dystonia in Europe.

Primary torsion dystonia (PTD) is a clinically and genetically heterogeneous movement disorder. DYT1 on chromosome 9q34 was the first PTD gene to be mapped. A 3-bp (GAG) deletion in this gene was reported to account for almost all early limb-onset generalized PTD. No relationship has been found with DYT1 in patients with prominent craniocervical involvement. To elucidate the DYT1-associated phenotype, we analysed the DYT1 mutation in 150 PTD patients, either sporadic or index cases from small PTD families. Twenty-two patients were positive for the GAG deletion in the DYT1 gene. Fifteen of them presented with the typical DYT1 phenotype (early, limb-onset generalized dystonia without spread to craniocervical muscles), four had limb-onset dystonia with spread to craniocervical muscles, two patients had arm-onset segmental dystonia and one had focal right-arm dystonia. One-hundred and twenty-eight patients were negative for the DYT1 mutation. Forty-six of them had segmental dystonia and 59 had focal dystonia. The other 23 patients presented with generalized dystonia, either with craniocervical involvement (13 patients) or without spread to the craniocervical region (typical DYT1 phenotype-10 patients). These data confirm the importance of the GAG deletion in European cases of PTD, and indicate phenotypic and genotypic heterogeneity.

GTP cyclohydrolase I mutations in patients with dystonia responsive to anticholinergic drugs.

OBJECTIVES: To investigate the hypothesis that GTP cyclohydrolase I (GCH1) mutations are responsible for the phenotype of highly anticholinergic responsive dystonia in patients with apparent primary torsion dystonia. METHODS: From 107 British patients with clinically diagnosed primary torsion dystonia, seven patients were identified with an excellent response to anticholinergic drugs. All six exons of the GCH1 gene were sequenced in these patients to identify mutations. RESULTS: Three novel GCH1 mutations were identified in two patients. One patient was a compound heterozygote with asymptomatic carrier parents. The clinical phenotype of patients with and without GCH1 mutations was similar. CONCLUSIONS: These findings show that a proportion of patients with apparent primary torsion dystonia and a good response to anticholinergic drugs have GCH1 mutations and therefore have a variant of dopa responsive dystonia. The difficulty in distinguishing clinically between patients with and without mutations underscores the importance of considering the diagnosis of a levodopa responsive dystonia in all such patients.

Hereditary geniospasm: linkage to chromosome 9q13-q21 and evidence for genetic heterogeneity.

Hereditary geniospasm is an unusual movement disorder causing episodes of involuntary tremor of the chin and the lower lip. Episodes typically start in early childhood and may be precipitated by stress, concentration, and emotion. Hereditary geniospasm is inherited as an autosomal dominant trait, and its cause is not known. We report the results of a genomewide genetic linkage study in a four-generation British family with hereditary geniospasm. Positive two-point LOD scores were obtained for 15 microsatellite markers on the peri-centromeric region of chromosome 9. A maximum two-point LOD score of 5.24 at theta = .00 was obtained for the marker D9S1837. Construction of haplotypes defined an interval of 2.1 cM between the flanking markers D9S1806 and D9S175, thus assigning one locus for hereditary geniospasm to the proximal long arm of chromosome 9q13-q21. Hereditary geniospasm in a second British family is not linked to this region, indicating genetic heterogeneity. These findings may have implications for other inherited focal movement disorders that as yet remain unmapped.

Paroxysmal dystonic choreoathetosis. Genetic linkage studies in a British family.

Paroxysmal dystonic choreoathetosis (PDC) is characterized by attacks of involuntary dystonic and choreoathetoid movements, typically several hours in duration with no sign of abnormality between attacks. Inheritance is autosomal dominant and the PDC locus has recently been assigned to the distal long arm of chromosome 2 in two families. We describe a six-generation British family with PDC and describe the results of fine genetic mapping and candidate gene linkage analysis. As part of a genome-wide search, linkage to chromosome 2q was confirmed in this family. Positive LOD scores were obtained for six markers on 2q. A LOD score of 5.08 at a recombination fraction of 0.0 was obtained for the marker D2S163. Construction of haplotypes allowed definition of a disease interval of 4 cM between the flanking markers D2S295 and D2S377. Polymorphic tandem repeats within the candidate genes CHRND (delta polypeptide of the nicotinic acetylcholine receptor) and SLC4A3 were examined yielding LOD scores of -7.68 and 6.08, respectively, at a recombination fraction of 0.0. This excludes CHRND as a candidate. Our data confirm the assignment of the locus for PDC to chromosome 2q and provide evidence for locus homogeneity in PDC. We have narrowed the disease interval to 4 cM and our findings provide support for the involvement of the gene for the chloride/bicarbonate exchanger as a candidate gene for PDC.

Case report: imaging of central nervous system sarcoidosis with gallium-67 single photon emission computed tomography.

Involvement of the nervous system is an uncommon and underdiagnosed complication of sarcoidosis. We used gallium single photon emission computed tomography (SPECT) to define areas of meningeal involvement in a patient with neurosarcoidosis. This technique may be of value in the assessment of patients with sarcoidosis and suspected central nervous system involvement.

Sarcoidosis presenting with chylothorax.

A patient in whom chylothorax was the presenting feature of sarcoidosis is reported. Mediastinal lymphadenopathy was shown by computed tomographic scanning. Obstruction of the thoracic duct by enlarged lymph nodes or fibrosis is the probable cause of chylothorax in this case. The association of chylothorax and sarcoidosis is extremely rare.

Hyperkalaemia in diabetes: prevalence and associations.

Hyperkalaemia is associated with diabetes, but there are no recent reports of its prevalence and associations. Serum potassium concentrations were measured in all 1764 patients attending a diabetic clinic over a 12-month period and found to be > 5.0 mmol/l in 270 (15%), and > 5.4 mmol/l in 67 (4%). There was no other evident cause of hyperkalaemia in 41 of these 67 patients. These data serve to highlight the risk of dangerous hyperkalaemia in diabetic patients, particularly with concurrent administration of angiotensin-converting-enzyme inhibitors and potassium-sparing diuretics.