[Topography of secondary dystonia lesions]. / Topographie des lésions des dystonies secondaires.

Biological causes provoking dystonia can not be systematized, with the exception of the small group of levodopa-responsive dystonia. Therefore the pathophysiology of the dystonic syndrome can be approached by considering the site of the lesions. In 40 cases of uni or bilateral symptomatic dystonias, this site could be identified with CT Scan or MRI. Twenty-one were located in the striatum, six in the pallidum, seven in the thalamus, six in the midbrain. Each group is characterized by etiologic and clinical criteria, sometimes associated with abnormal movements. In the striatal group, the most important, dystonia was often associated by athetosis or choreoathetoid abnormal movements. In some cases, in children, lesions were vascular due to impairment of lenticulo-striatal arteries, often following cranial trauma. The pallidal lesions were usually provoked by metabolic or infectious agents. Most thalamic dystonias were of vascular origin, sometimes accompanied by myoclonia. Midbrain lesions were usually vascular with tremor. Athetosis occurred after striatal rarely after pallidal lesions. It is advisable not to assimilate dystonia and athetosis as both are simultaneously observed if the lesions are located in the striatum, rarely in the the pallidum but not in the midbrain.

Four novel mutations in the tyrosine hydroxylase gene in patients with infantile parkinsonism.

Mutation detection in the tyrosine hydroxylase gene (TH) was performed in patients from two families. DNA sequencing revealed the presence of four novel missense mutations (exon 9 and 14 in family A, exon 8 and 9 in family B); the mutations were confirmed with restriction enzyme analysis, and did not occur in control alleles. Three mutations are in the catalytic domain of the enzyme and one may disturb tetramerization. At the moment, all patients are in the fourth decade of life. For more than 30 years they have been able to live a normal life with low-dose L-DOPA medication.

[Action of piribedil in Parkinson disease. Multicenter study]. / Activité du piribédil dans la maladie de Parkinson. Etude multicentrique.

OBJECTIVES: Several controlled trials have shown that Trivastal (piribedil), a direct dopamine agonist, is active in the treatment of Parkinson's disease. The aim of the present clinical trial was to assess the efficacy of Trivastal 50 mg LP administered as monotherapy in patients naive to treatment with L-dopa. PATIENTS AND METHODS: This 3-month multicenter study was conducted in 113 patients (66 men and 47 women), aged 63.1 +/- 0.6 years, with a 2.1 +/- 0.2 year history of Parkinson's disease and a mean Hoehn and Yahr stage of 1.82. Tremor was the predominant clinical feature in 42 patients; the 71 others presented with the full parkinsonian syndrome. Trivastal 50 mg LP doses were increased stepwise, up to doses of 150-250 mg/day at the end of the 3-month study period. Patients were clinically assessed at 1, 2 and 3 months using the Webster scale and the HARD depression scale. RESULTS: In the 90 patients who completed the study, tremor fell from 1.7 to 1.0 (-41%, p < 0.001), bradykinesia from 1.5 to 0.8 (-47%, p < 0.001) and rigidity from 1.3 to 0.9 (-31%, p < 0.001). The 32 patients in whom tremor was the predominant feature improved their total score on the Webster scale from 5.8 to 4.7 (-19%, p < 0.05). The 58 patients with the full parkinsonian syndrome improved their total Webster score from 11.8 to 6.9 (-42%, p < 0.001). The depression score fell from 10.2 to 7.3 (p < 0.001), the most marked improvement being in mood and inhibition. CONCLUSION: Monotherapy with Trivastal 50 mg LP at a mean dose of 200 mg/day is effective on the major symptoms of Parkinson's disease.

[Recessive dopa-responsive form of dystonia due to a mutation of the tyrosine hydroxylase gene]. / Dystonie dopa-sensible forme récessive mutation du gène de la tyrosine-hydroxylase.

The cause of Dystonia Musculorum Deformans (DMD) is most frequently unknown, therefore the treatment can only be symptomatic and often disappointing. In 1971 we reported the first two cases of recessive dopa-responsive dystonia, simulating a severe form of idiopathic DMD, however remarkably well reacting to levodopa treatment. We found that the first above mentioned two cases are related to mutations in the tyrosine hydroxylase gene itself in the chromosome 11p. An other variety which is dominant, with marked diurnal fluctuation, is due to mutations of a cofactor of the tyrosine hydroxylase, located in chromosome 14q. Consequently a trial of dopa treatment should be given in all diseases evoking a DMD diagnosis. Further more it is possible to confirm the diagnosis by a genetic inquiry.

Clinical assessment of olfactory dysfunction in Parkinson's disease.

We used two simple tasks to test the capacities of patients with Parkinson's disease to discriminate and identify olfactory stimuli. The patients presented defective odor identification abilities whereas their capacity to discriminate between odors was apparently unaffected. This raises a question about the nature of olfactory dysfunction in Parkinson's disease. Further clinical data is required for analysis of this dysfunction. We therefore propose simple and rapid tests appropriate for clinical use with Parkinson's disease patients.

Juvenile-onset spinal muscular atrophy caused by compound heterozygosity for mutations in the HEXA gene.

Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease) and in GM2 gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Analysis of SMN excluded SMA. Biochemical studies on GM2 gangliosidosis showed deficiency in hexosaminidase A activity and increased GM2 ganglioside accumulation in the patient's fibroblasts. The HEXA gene was first analyzed for the Gly269-->Ser mutation characteristic for adult GM2 gangliosidosis. Since the patient was carrying the adult mutation heterozygously, all 14 exons and adjacent intron sequences were analyzed. A novel mutation in exon 1 resulting in an A-to-T change in the initiation codon (ATG to TTG) was identified. The adult patient is a compound heterozygote, with each allele containing a different mutation. Although mRNA was transcribed from the novel mutant allele, expression experiments showed no enzyme activity, suggesting that neither the TTG nor an alternative codon serve as an initiation codon in the HEXA gene.

[Juvenile GM2 gangliosidosis with progressive spinal muscular atrophy onset]. / Gangliosidose à GM2 juvénile débutant par une amyotrophie spinale progressive.

GM2 gangliosidosis are caused by a beta-hexosaminidase A enzyme deficiency. Mutations in the gene leaving residual enzyme activity give rise to juvenile and adult forms of the disease which have a great clinical heterogeneity. We report three cases which have been considered for some time as Kugelberg-Welander disease. beta-hexosaminidase A was determined with the sulfated synthetic substrate, 4-méthylumbelliferyl-N-acetylglucosamine 6-sulfate (4-MUGS), which allowed the diagnosis. Two of these cases from one family had normal values of hexosaminidase A in serum as found in the B1 variant. Compound mutations were detected. The B1 variants had a classical B1 mutation (G533-->A) and a new mutation located on exon 11. The patient of the second family had the classical mutation of adult GM2 gangliosidosis (Gly269-->Ser) and a new mutation on exon 1, at the initiation codon.

A new mutation in the HEXA gene associated with a spinal muscular atrophy phenotype.

We describe two adult siblings who had had mild GM2 gangliosidosis since childhood. They presented with spinal muscular atrophy and dysarthria, and one sibling also had mental disturbances. Laboratory studies established the diagnosis of the B1 variant of GM2 gangliosidosis, because the hexosaminidase (Hex) A deficiency was not present upon testing with the unsulfated synthetic substrate 4-methylumbelliferyl N-acetylglucosaminide. HEXA gene analysis proved that the patients are compound heterozygotes for the previously identified G533-->A mutation and for a new mutation, G1171-->A, at exon 11. This new mutation affects a conserved amino acid and results in a Val-->Met substitution at position 391 of the HEXA gene. Full sequence of the alpha-subunit cDNA of Hex A revealed no other mutation. Assays for Hex A activities in patients suspected of having GM2 gangliosidosis should be performed with the sulfated substrate 4-methylumbelliferyl N-acetylglucosamine 6-sulfate.

Abnormal movement related potentials in patients with lesions of basal ganglia and anterior thalamus.

Movement-related cortical potentials (MRCPs) were recorded from scalp electrodes during wrist flexion in 15 dystonic patients with bilateral (nine) or unilateral (six) circumscribed lesions in the striatum (eight), pallidum (six), or anterior thalamus (one). The results were compared with those of 10 age-matched healthy volunteers. The early (BP) and late (NS') MRCP components were assessed in terms of their gradients and distribution on the scalp in Cz, C3', and C4'. The gradients of both BP and NS' components were significantly flatter in the patients with bilateral lesions than in the control subjects. Also, the BP gradient was maximum at Cz, and the NS' component was contralaterally predominant in the control subjects but not in the patients. In patients with unilateral lesions, the gradients were flatter (p < 0.05) during movement of the dystonic wrist than during movement of the normal wrist. This difference was significant for BP and NS', regardless of the location of the electrodes. Also, the normal topographic predominance of BP at Cz and of contralateral NS' disappeared. The BP and NS' components of the MRCPs are thought to reflect preparatory activity in the supplementary motor area and the primary motor cortex before movement. Reduced BP and NS' gradients in patients with both bilateral and unilateral lesions of the basal ganglia, which project towards the supplementary motor area, are consistent with this hypothesis. The bilateral nature of these reductions suggests that both the ipsilateral and the contralateral motor cortex are involved in the genesis of the MRCPs and that the dystonia in these patients is associated with impaired motor preparation.

Botulinum antibodies in dystonic patients treated with type A botulinum toxin: frequency and significance.

We measured serum antibodies to botulinum toxin (ABT) in 96 patients with focal dystonia who had been treated with type A botulinum toxin. The frequency of detectable ABT was 3% (three patients). Patients with ABT had received more than 50 ng of botulinum toxin, and the shortest time between two injections was significantly less than in patients without ABT. The clinical evolution of the three patients was heterogeneous: one had decreased effectiveness with repeated injections, another had persistent improvement, and the third never responded to toxin injections.

Linkage analysis in British and French families with idiopathic torsion dystonia.

Idiopathic torsion dystonia is most commonly caused by an autosomal dominant gene or genes with reduced penetrance. An idiopathic torsion dystonia locus has been mapped to chromosome 9q34 in one large non-Jewish and several Jewish kindreds in the USA. Linkage analysis was performed in 27 (26 British, one French) small families with idiopathic torsion dystonia, three of which were Ashkenazi Jewish, using the highly polymorphic loci argininosuccinate synthetase (ASS) and Abelson oncogene (ABL) which map to 9q34. The cumulative lod score for the more informative ASS locus at a recombination fraction of 0.001 was -6.72. A large component of this score was derived from three non-Jewish families, indistinguishable clinically from the others, in which individual lod scores excluded a disease locus tightly linked to ASS. Analysis of all the data using HOMOG showed significant heterogeneity, but evidence for linkage of an idiopathic torsion dystonia gene to 9q34 in a subset of families. The allelic association observed between ASS/ABL and idiopathic torsion dystonia in Ashkenazi families in the USA was also present in British Jewish kindreds. These data suggest genetic heterogeneity in idiopathic torsion dystonia but indicate the existence of a locus for idiopathic torsion dystonia at 9q34 in both Jewish and non-Jewish kindreds in the UK.

[Positron-emission tomographic study of the dopaminergic system in a case of secondary unilateral tremor after mesencephalic hematoma]. / Etude du système dopaminergique en tomographie par émission de positons dans un cas de tremblement unilatéral secondaire à un hématome mésencéphalique.

A 30 year-old woman developed a postural and rest tremor of the left hand following a right peduncular post-traumatic hematoma. Two years later, positron emission tomography showed a marked decrease in [18F] fluorodopa uptake contrasting with a normal [76Br] bromolisuride uptake in the right striatum. This suggests that: 1) chronic unilateral dopaminergic striatal denervation may occur without persistent D2 dopaminergic receptor upregulation in humans; and 2) symptomatic mesencephalic tremor may be, at least in part, related to dopaminergic striatal denervation.

Chronic administration of L-dopa affects the movement-related cortical potentials of patients with Parkinson's disease.

The chronic effect of L-Dopa administration on the movement-related cortical potentials (MRCPs) was studied in two groups of patients with Parkinson's disease (PD): patients de novo (DN) and patients with on-off fluctuations. The BP and NS' premovement components of MRCPs associated with wrist flexion were assessed by their gradients and by their distribution on the midline (CZ) and the ipsilateral and contralateral hand sensorimotor areas. The treatment efficacy was controlled by a decrease in PD score (Columbia University Rating Scale). The BP component was absent in four out of nine patients DN. After 3 months of treatment, BP and NS' were recorded in six out of seven patients, and the NS' slope was significantly increased in all patients. In the off phase, MRCPs from patients with on-off fluctuations did not present a BP component. In the on phase, the NS' slope was increased and the BP was recorded in two out of nine patients. These patients exhibited an earlier PD stage (Hoehn and Yahr, stage 3). These two patterns of changes in the MRCPs induced by L-Dopa treatment suggest that the BP component was recorded in patients DN when a partial resolution of the nigrostriatal activity could occur. In patients with severe fluctuations, the dopaminergic striatal pathway was more severely affected and the increase of the NS' component demonstrated the activation of extrastriatal dopamine sites within the central nervous system (limbic and cortical structures, in particular).

Postural disturbances due to homonymous hemianopic visual ataxia.

Patients with visual defects often complain of disturbances of equilibrium. In order to measure the influence of visual stimulation on posture, a study was made comparing the posture of hemianopic patients with that of healthy volunteers before and after occlusion of half of the monocular visual field. Hemianopia increases lateral oscillations in patients in the standing position and the projection of the body's centre of gravity shifts towards the hemianopia: in the volunteers, the same shift is noted after masking half the visual field. A tonic effect of visual information is discussed.

[Dopa-sensitive dystonia]. / Dystonies dopa-sensibles.

Dopa-sensitive dystonia has been recognised for twenty years. It may occur in the first years of life. It first affects the lower limbs, then generalized becomes, as in torsion dystonia. Eight clinical cases are presented in five boys and three girls. The absence of the disorder in the parents, but its presence in siblings in three cases suggests that it might be recessively inherited. The symptoms are severe enough to cause major functional disability. In some cases, the intensity of the motor disorder varies during the days being, less pronounced in the morning or after a nap and more marked in the evening. Nonetheless, this feature is not constant and thus cannot be considered as an essential diagnostic criterion. Treatment with levodopa gives remarkable and durable results, but it must be continued indefinitely. Abnormal movements accompany an overdose but regress when the dosage is decreased. Unlike Parkinson's disease, it is not necessary to increase or fragment doses to avoid fluctuations in the efficacy of treatment during the day. On the contrary, after several years of the illness a decrease in daily dosage sometimes to a single dose is possible. Discontinuing treatment leads to reappearance of dystonia after two or three days. There are no established biological criteria to aid diagnosis. However, a decrease in urine levels of homovanillic acid was observed in two cases. Dopa-sensitive dystonia should be regarded as distinct from juvenile Parkinson's disease, firstly because of its symptomatology and secondly, and more importantly, because of its particular course, since fluctuations in therapeutic efficacy are never observed. It is the only known example of dopaminergic insufficiency that is chronically almost completely controlled by a modest exogenous supply of levodopa.

Activity and acceptability of piribedil in Parkinson's disease: a multicentre study.

Several controlled trials have shown that the dopamine agonist, Trivastal (piribedil), is active in the treatment of Parkinson's disease, particularly with regard to tremor. To determine its efficacy as monotherapy in patients previously untreated with levodopa, a 3-month multicentre study was conducted with Trivastal 50 mg LP in 113 patients with idiopathic Parkinson's disease. The study population consisted of 66 men and 47 women, aged 63.1, SD 0.6 (43-79) years with a 2.1, SD 0.2 (1-15) year history of Parkinson's disease. Mean disease stage was 1.82 (1-4) by the Hoehn and Yahr classification. Tremor was the predominant clinical feature in 42 patients; the remaining 71 patients displayed the full parkinsonian syndrom. Trivastal 50 mg LP was prescribed stepwise up to doses of 150-250 (207, SD 6.4) mg/day at the end of 3 months. No concomitant anti-parkinsonian medication was given. Patients were clinically assessed at 1, 2 and 3 months on the Webster scale, a specific tremor scale and the HARD depression scale. Mean results were as follows in the 90 patients completing the study. On the Webster scale, tremor fell from 1.7 to 1 (-41%, P less than 0.001), bradykinesia from 1.5 to 0.8 (-47%, P less than 0.001) and rigidity from 1.3 to 0.9 (-31%, P less than 0.001); on the specific scale, rest tremor decreased in daily duration and amplitude from 3.9 to 2.4 (-39%, P less than 0.001) and from 2.9 to 2.1 (-35%, P less than 0.001), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)