Biomedical subjects
Publications and source records attributed to A Destée.
MR imaging findings have been reported in only a few cases of severe arterial hypertension. We report two cases of severe paroxysmal arterial hypertension associated with unusual brain stem hyperintensity. The lesions improved dramatically after stabilization of blood pressure, suggesting that edema could be the main cause of the MR imaging-observed hyperintensity.
Neurological impairment is a frequent cause of morbidity and mortality in patients with sarcoidosis. The aim of this study was to evaluate the clinical manifestations of the disease, the response to corticosteroids and alternative treatments. During a 5 year period, diagnosis of neurosarcoidosis was performed in 40 patients. We retrospectively analyzed clinical, laboratory data and response to treatments. Mean age was 41.3 years (range 17-72). Mean time of follow-up was 46 months. Neurologic signs were the first symptom in 50 p. 100 of cases and an isolated manifestation in 12.5 p. 100. Central nervous system impairment was seen in 60.7 p. 100, meningitis in 27 p. 100. Other clinical manifestations were cranial nerve palsies (27 p. 100), peripheral neuropathy (33 p. 100), myopathy (16 p. 100). Eighty percent of the patients were treated by corticosteroids. Because of a lack of efficacy 40 p. 100 of patient required alternative treatment (including methotrexate, cyclophosphamide, azathioprin, cyclosporin). Complete recovery was observed in only 27.5 p. 100 of cases confirming the severity of neurosarcoidosis. Forty percent of patients were clinically stable and 10 p. 100 worsened. No patient died. This study confirms that intensive initial treatment is often necessary to prevent irreversible lesions. Alternative treatment should be rapidly initiated in resistant forms.
In several neurodegenerative diseases, anticipation or increase in disease severity in succeeding generations within families correlates with expansions of an intragenic CAG/CTG repeat sequence above the normal range through the generations of a pedigree. Some kindreds of familial Parkinson's disease (PD) exhibit genetic anticipation. We used the repeat expansion detection (RED) method to detect repeat expansions directly in DNA samples from the index cases of 34 different PD families with anticipation. The mean age at onset of the younger probands was 48.8 +/- 10.8 years and the mean intergenerational difference was 19.2 +/- 10 years. The distribution of the RED products greater than 40 repeats was not significantly different between patients and controls with the Mann-Whitney U test (U = 510.5, p = 0.67). The samples were then screened for the two expanded-repeat loci, ERDA1 and CTG18.1. We found that in all cases the repeat expansion detected by the RED method may be accounted for by an expansion at these loci. Our results demonstrate that unstable CAG/CTG expansions corresponding to uncloned or cloned sequences (ERDA1, CTG18.1) are not involved in the etiology of rare familial case of PD with genetic anticipation. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:738-741, 1999
We present 11 families consistent with autosomal dominant inheritance of probable Parkinson's disease (PD). Although excluded as a cause of disease in these kindreds, mutations in the alpha-synuclein gene have been implicated in familial PD. The beta-synuclein gene is highly homologous, expressed in the nervous system and thus is a good candidate gene for PD. Multipoint linkage analysis was either equivocal or excluded 5q35 haplotype sharing among affected family members. Sequencing the translated exons of the beta-synuclein gene failed to identify any pathogenic mutation.
We found a new mutation in the GTP cyclohydrolase gene involved in dopa-responsive dystonia. We sequenced the GTP cyclohydrolase gene in a family with four siblings affected by this disorder and identified an A-T mutation in exon 2, leading to a non conservative amino acid substitution at codon 135 of the protein (Ile135Lys), which may change the conformation of the binding site of this enzyme. The clinical evolution was heterogeneous among carriers of the same mutation, underlining the involvement of other determinants modulating the occurrence of the disease such as genetic or environmental susceptibility factors.
A NEW CLASSIFICATION: The advent of molecular genetics has led to a total revision of earlier classifications of primary dystonias. LOCUS DYT-1 PRIMARY DYSTONIA: Locus DYT1, situated on chromosome 9, is responsible for the most common phenotypic expression of generalized primary dystonia, Ziehen-Oppenheim disease. This autosomal dominant disease has variable penetration. It has long been recognized that some individuals in families with typical disease only have segmentary, multifocal or even focal dystonia. It has been proven by molecular genetics that the disease can be expressed simply by familial writers cramp with particularly early, and often bilateral, onset. The mutation concerns the torsine A gene, whose function remains to be elucidated. Torsine A is found in the central nervous system, particularly in the dopaminergic neurons of the locus niger. GENERALIZED PRIMARY DYSTONIA UNRELATED TO DYT-1: These dystonias are phenotypically different: younger and more variable age at onset, focal localization early in the disease course generally involving the cervical or cephalic pole, less severe course. Certain forms are linked to chromosome 8 (locus DYT 6). PRIMARY FOCAL OR SEGMENTARY DYSTONIAS: These primary dystonias cause functional or postural disorders and were long considered as sporadic despite rare familial cases suggesting a genetic factor. When searched for systematically, familial cases are found in 20 to 30% of the cases. The dystonia is transmitted by dominant autosomal heredity with reduced penetration. Phenotypically, expression is heterogeneous with a constant frequency of unrecognized or neglected forms and of postural forms. One form is known to be linked to chromosome 18 (locus DYT 7). DOPA-RESPONSIVE DYSTONIA: This class represents 5 to 10% of childhood dystonias. The phenotypic expression is polymorphous but symptoms always improve with very small doses of L-dopa. Both sporadic, and more frequently familial, cases are described. Some forms are recessive, caused by mutation of the gene coding for tyrosine hydroxylase, others are autosomal dominant, often linked to mutation of the gene coding for GTP cyclohydrolase. RAPID ONSET DYSTONIA SYNDROME-PARKINSONISM: This dominant autosomal dystonia is quite exceptional, ... and intriguing.
The persyn (gamma-synuclein) gene is highly homologous to the alpha-synuclein gene and is highly expressed in the nervous system. It is therefore, an excellent candidate gene for Parkinson's disease. However, we have sequenced the gene in a large number of families with parkinsonism and failed to find pathogenic mutations.
Following the recent identification of multiple novel mutations and alleles of the cytochrome P450 CYP2D6 gene which cause decreased, increased, or absent enzyme activity, we re-examined the controversial hypothesis of a role of the CYP2D6 polymorphism in Parkinson's disease (PD) susceptibility. For this purpose, a strategy based on PCR-SSCP and RFLP analyses allowing the detection of all known CYP2D6 alleles was performed in DNA from 109 patients with sporadic PD. This strategy was also applied to DNA from 68 members of PD families including 18 affected and 50 unaffected members. Seventeen mutations occurring alone or in various combination on 14 alleles of CYP2D6 have been identified in patients with sporadic PD. Moreover, 12 mutations and nine alleles of the gene have been characterized in members of PD families. No significant difference was observed when the distribution of mutations and alleles of CYP2D6 was compared between the PD patients and 514 control subjects previously analyzed using the same strategy. There was also no difference in the distribution of phenotypes predicted from genotypes between both groups. In addition, when the distribution of CYP2D6 genotypes was compared, no difference between affected and unaffected members of PD families was observed. These data indicate that CYP2D6 polymorphism is not a susceptibility factor to PD.
To determine the benefit of motor programming analysis for distinguishing patients with parkinsonism, we compared the spatiotemporal pattern of event-related desynchronization (ERD) preceding a self-paced voluntary wrist flexion between two groups of 10 patients with progressive supranuclear palsy (PSP) and Parkinson's disease (PD) and 10 control subjects. ERD of the mu rhythm was computed from 11 source derivations covering the medial frontocentral, central, and parietocentral areas during two successive left and right experimental conditions (80 self-paced wrist flexions). ERD began in the control group 1750 ms before movement onset over the contralateral central area and then appeared bilaterally on movement execution. In both patient groups, spatiotemporal distribution differed from that in the control group. In the PSP group, ERD had a shorter latency over the contralateral primary sensorimotor area compared with the PD group (PSP: 375 ms before movement onset for both conditions; PD: right flexion 1125 ms before movement onset, left flexion 1000 ms). ERD was observed over the parietocentral area in both groups but also with a clear reduction of latency before movement onset in the PSP group. In both groups, a bilateral central pattern appeared 250 ms before movement execution. In conclusion, our study indicates that ERD analysis is a useful method for observing the changes in cortical activation and for measuring motor programming impairment in parkinsonism, which was more affected in PSP than in PD.
This study was aimed at determining the spatiotemporal distribution of event-related desynchronization (ERD) during self-paced voluntary movement in order to establish the interest of this method for the analysis of movement programming in Parkinson's disease. Desynchronization of mu rhythm was recorded 2 s before to 0.5 s after right then left self-paced voluntary wrist flexions from 11 leads covering the primary sensorimotor cortex (central), supplementary motor area (frontocentral) and parietal cortex (parietocentral). Recordings were obtained from ten control subjects, ten patients treated for Parkinson's disease (bilateral symptoms) and 20 patients presenting with right or left hemiparkinsonism before and after chronic administration of L-dopa. In the control group, ERD started over the contralateral primary sensorimotor cortex 1,750 ms before movement and was bilateral just before performance of the movement. In both treated and de novo Parkinson's disease groups, decrease in ERD latency (1,000 to 1,250 ms before movement) was only observed when movements were performed with the akinetic hand and corresponded to a decrease in motor cortical activity. This confirmed that programming of movement is affected in Parkinson's disease. Earlier ERD with central ipsilateral distribution were also observed, suggesting that other cortical areas might be activated to compensate for dysfunction of movement programming and to increase the level of cortical activity required for performance of the movement. The administration of L-dopa to de novo hemiparkinsonians patients resulted in increased ERD latency over contralateral and ipsilateral central areas. As in the treated Parkinson's disease group, frontocentral ERD could also be recorded. L-dopa would thus partially restore the affected motor programmation and modulate cortical activation in both supplementary motor area and primary motor cortex, the later receiving more afferences from basal ganglia.
In five generations of the French M-E kindred, 11 members are now known to be or have been affected by a form of spongiform encephalopathy previously recorded as Gerstmann-Sträussler-Scheinker disease. Mean age at onset was 28 years (range 21-34 years). In six instances, these patients were hospitalized in psychiatric institutions with various diagnoses, the most frequent being mania or mania-like symptoms. Dementia occurred progressively after a lengthy course. Histological studies showed atrophy of the cerebellar molecular layer, which contained kuru and multicentric plaques labelled with anti-prion protein antibodies. Spongiosis was not prominent and remained largely limited to the periphery of plaques; it was more marked in the thalamus, where plaques were scarce. A 192 base pair (bp) insert (eight extra repeats of 24 bp) in the octapeptide coding region of the prion protein gene (PRNP) within a codon-129 methionine allele was found in four symptomatic subjects. Early age at onset, the prominence of psychiatric symptoms and the long course of the disease are noticeable clinical features in this family with an inherited prion disease due to a new insertional mutation in PRNP.
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UNLABELLED: The aim of this study was to compare the regional cerebral blood flow measurements studied by SPECT in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) to determine the contribution of SPECT to the differential diagnosis of these two diseases. METHODS: SPECT analysis with 99mTc-hexamethyl propyleneamine oxime (HMPAO) was performed in 20 patients with probable DLB, 20 patients with probable AD and 20 patients with idiopathic Parkinson's disease (IPD). Ten pairs of regions of interest were analyzed. Tracer uptake was expressed as a corticocerebellar activity ratio. RESULTS: Compared with IPD, in the DLB group there was a global decrease of HMPAO uptake in cortical regions of interest except in the posterior frontal and occipital regions; in the AD group there was limited left temporal and parietal hypoperfusion. In the DLB group, frontal HMPAO uptake was significantly lower than in the AD group. Two predictive scores were established by a factorial discriminant analysis from six left cortical indices (medial frontal, lateral frontal, posterior frontal, temporoparietal, parietal and parietooccipital) and the Mini-Mental State Examination, which correctly classified 53 of 60 patients (88%) (DLB, 18 of 20; AD, 16 of 20; IPD, 19 of 20). CONCLUSION: These findings indicate the presence of diffuse cortical abnormalities in DLB and suggest that SPECT may be useful in discriminating in vivo DLB from AD, revealing mainly frontal hypoperfusion in the former group. We estimate that SPECT study increases the possibility of separating DLB and AD because both disorders share different patterns of cerebral blood flow abnormality.
A large number of patients with Parkinson's disease were reported to have abnormal visual-evoked potentials (VEPs) and spatiotemporal contrast sensitivity (STCS) suggesting dopaminergic deficiency in the visual pathway, probably the retina. Until now, VEPs and STCS have not been studied in multiple system atrophy (MSA). We investigated 12 patients with idiopathic Parkinson's disease (IPD) and 12 patients with MSA. The age medians were 64.5 years for IPD and 63.5 years for MSA. None of the patients showed any ocular disease that could interfere with the results. Checkboard VEPs and STCS measurements to horizontal sinusoidal gratings were evaluated. Statistical analysis was performed, including Student's t test and two- or three-way analysis of variance. A significant interocular difference in spatial contrast sensitivity was observed in IPD, which was not present in MSA. VEPs were not delayed in MSA, whereas latency of the major component and the second negative deflection were increased in IPD. VEPs and STCS measurements might provide useful help for distinguishing IPD from MSA.
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OBJECTIVES: To evaluate possible influences of CCG and delta2642 glutamic acid polymorphisms adjacent to the (CAG)n trinucleotide repeat in Huntington's disease gene IT15 on some clinical features (age and symptoms) at onset. METHODS: 84 patients and a control group of 68 unaffected relatives were studied. Patients all belonged to a group of affected persons tested for molecular confirmation of Huntington's disease. The length of the CAG repeat sequence in the IT15 gene and the adjacent CCG and delta2642 polymorphisms were determined by quantitative polymerase chain reaction. RESULTS: Two intragenic polymorphisms were studied: (CCG)n and delta2642 glutamic acid. Patients were classified firstly according to the size of the CCG rich segment adjacent to the CAG repeat into genotype groups CCG 7/7, 7/8, 7/9, 7/10, and 10/10 and then according to delta2642 polymorphism into genotype groups A/A (absence of the delta2642 deletion), A/B, and B/B (presence of the delta2642 deletion in respectively one and two alleles). The presence of delta2642 mutation was associated with a significant decrease in age at onset, although there was no significant increase in CAG size. A good correlation was found between the (CAG)n trinucleotide repeat size and the age at onset in patients with genotype AA (r2=0.72). Within patients of the A/B genotype group however, a significant correlation was found but with a drop of the r2 value to 0.44. No association was found between age at onset and the CCG polymorphism. Although an increased percentage of patients within the A/A genotype group had a neurological onset, we found no overall significant association between CCG or delta2642 polymorphisms and the nature of symptoms at onset. CONCLUSIONS: The delta2642 glutamic acid polymorphism did not affect CAG repeat size nor the nature of symptoms at onset but seems to influence the age at onset in patients with Huntington's disease.
OBJECTIVE: To establish the pathophysiological mechanisms of striatopallidal and thalamic dystonia. METHODS: Five patients from among 26 who presented (between March 1987 and July 1996) with focal dystonia, segmental dystonia, or hemidystonia caused by a single localised vascular lesion, were selected. Patients with lesions with indefinite boundaries, and diffuse, or multiple, or large brain lesions were excluded. Three dimensional T1 weighted MRI (1.5 tesla) was performed to determine the topography of the lesions. The atlas of Hassler allowed the stereotactic localisation of the lesions to be specified exactly. RESULTS: Three patients had dystonic spasms associated with striatopallidal lesions and one with a thalamic and striatopallidal lesion. One other patient presented with a myoclonic dystonia related to a thalamic lesion. The striatopallidal lesions were located in the sensorimotor area with a somatotopical distribution. The pure thalamic lesion involved the centromedian nucleus, the sensory nuclei, and the pulvinar whereas the thalamic and striatopallidal lesion was located in the pallidonigral thalamic territory, which receives pallidonigral inputs. CONCLUSION: The striatopallidal dystonia might be the consequence of the interruption of the cortico-striato-pallido-thalamo-cortical loop induced by lesions located within the sensorimotor part of the striatopallidal complex. By contrast, it is suggested that thalamic dystonia might be caused by lesions located in the centro-median or the ventral intermediate nuclei, outside the pallidonigral territory, but leading also to a dysfunction of the cortico-striato-pallido-thalamo-cortical loop.
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