Etiology of Parkinson's disease. The role of environment and heredity.
Explore the source record for details and available documents.
Adult↗
Biomedical subjects
G Campanella
Publications and source records attributed to G Campanella.
The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia.
Friedreich ataxia (FA) is associated with the expansion of a GAA trinucleotide repeat in the first intron of the X25 gene. We found both alleles expanded in 67 FA patients from 48 Italian families. Five patients from three families were compound heterozygotes with expansion on one allele and an isoleucine-->phenylalanine change at position 154 on the other one. We found neither expansions nor point mutations in three patients. The length of FA alleles ranged from 201 to 1,186 repeat units, with no overlap with the normal range, and showed a negatively skewed distribution with a peak between 800 and 1,000 repeats. The FA repeat showed meiotic instability with a median variation of 150 repeats. The lengths of both larger and smaller alleles in each patient inversely correlated with age at onset of the disorder. Smaller alleles showed the best correlation, accounting for approximately 50% of the variation of age at onset. Mean allele length was significantly higher in patients with diabetes and in those with cardiomyopathy.
Adolescent↗
Early-onset ataxia with cardiomyopathy and retained tendon reflexes maps to the Friedreich's ataxia locus on chromosome 9q.
Absence of lower limb tendon reflexes has been considered an essential diagnostic criterion for Friedreich's ataxia (FA). However, preservation of knee and ankle jerks has been reported in a few patients. Linkage analysis to FA locus (FRDA) on chromosome 9q13-21.1 was performed in 11 patients from 6 families with FA phenotype, including cardiomyopathy, but retained reflexes (FARR). A maximal lod score of 3.38 at recombination fraction theta equal to 0.00 was obtained demonstrating that FARR maps to the FRDA locus. These results suggest that FARR is a variant phenotype of FA.
Adolescent↗
Magnetic resonance imaging in "typical" and "late onset" Friedreich's disease and early onset cerebellar ataxia with retained tendon reflexes.
MRI makes it possible to study the in vivo brain and spinal cord morphology of patients with hereditary ataxia. We performed T1- and T2-weighted studies in eleven patients with Friedreich's disease (FD), five with "late onset" FD and ten with early onset cerebellar ataxia with retained tendon reflexes (EOCA). Cervical cord atrophy was constant in FD and "late onset" FD and often associated with atrophy of the cerebellum and of the brainstem; T2-weighted studies showed posterior column degeneration in the cervical cord. The most frequent finding in EOCA was cerebellar atrophy, pure or associated with cervical cord or brainstem atrophy; the cerebellar atrophy was marked in a few cases and was related to disease duration.
Adolescent↗
Has spinocerebellar ataxia type 2 a distinct phenotype? Genetic and clinical study of an Italian family.
The gene for spinocerebellar ataxia type 2 (SCA2) is mapped to chromosome 12q23-24.1. Using D12S79 and D12S105, we performed linkage analysis in nine individuals including six affected members of a four-generation family in which we excluded SCA1 by direct mutation analysis. We obtained a lod score = 2.37 at theta = 0.00 for the compound haplotype. The clinical picture appeared homogeneous, showing the absence of corticospinal signs and the presence of peripheral neuropathy. The present study suggests that this SCA2 family is clinically different from most SCA1 families.
Adult↗
A genetic study of Parkinson's disease.
We performed a case-control study on 100 patients with Parkinson's disease, their spouses and the same number of sex- and age-matched neurological controls to clarify if family history of Parkinson's disease or essential tremor may increase the risk for the disease. We included in the study 68 male and 32 female parkinsonian patients with a mean age +/- SD of 62.0 +/- 9.9 years and a mean disease duration of 7.5 +/- 5.7. The odds ratio for familial Parkinson's disease was 13.4 (95% confidence limits = 6.5-27.7) and for familial essential tremor 3.1 (95% confidence limits = 1.5-6.3). We also reviewed the genetic features of 122 parkinsonian patients with at least one affected relative. The presence of secondary cases among both first-degree (n = 83) and less close relatives (n = 72) suggests that sharing environmental factors does not explain the familial aggregation of the disease. Secondary cases were significantly more frequent in the paternal than in the maternal line (70 vs. 39). The presence of secondary cases among both siblings (46) and parents (37) and the unilateral distribution of ancestral secondary cases suggest an autosomal dominant inheritance with incomplete penetrance.
Adult↗
Dopamine mediated responses in 6-hydroxydopamine lesioned rats involve changes of the signal transduction.
A single dose of the D1 agonist SKF 38393 (3 mg/kg) produces contralateral turning in unilaterally 6-hydroxydopamine lesioned rats only after a previous exposure of the animals to a dopamine agonist. This priming phenomenon is here investigated by studying the phosphorylation of DARPP-32, a dopamine- and cyclic AMP-regulated phosphoprotein functionally linked to D1 receptors in striatum. Dephospho-form of DARPP-32 in striatal tissue was measured by a back-phosphorylation assay. While the levels of DARPP-32 protein, as measured by quantitative immunoblotting, remained unchanged, a significant decrease of dephospho-DARPP-32 was observed in the denervated striatum of primed rats, indicating an increased phosphorylation in vivo of DARPP-32 in response to the D1 agonist. This study shows that an alteration of the dopamine-dependent signal transduction is related to the behavioral response to dopamine agents, suggesting a possible mechanism involved in the effects of these drugs in parkinsonian patients.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Ambulatory monitoring of left ventricular function in patients with Parkinson's disease and postural hypotension.
Left ventricular (LV) function was continuously monitored using a radionuclide detector (VEST) after intravenous injection of 25 mCi technetium-99m labelled red blood cells in nine patients with Parkinson's disease and postural hypotension (group 1) and ten patients with Parkinson's disease but without postural hypotension (group 2). LV function and blood pressure were monitored in the supine position for 15 min (period A), upon changing posture from the supine to the upright position for 10 min (period B), and upon returning to the supine position for 10 min (period C). In group 1, the passage from period A to period B induced a significant decrease in end-diastolic volume, end-systolic volume and ejection fraction (all P < 0.01). In group 2, ejection fraction increased (P < 0.05) upon changing posture from the supine to the upright position. Ejection fraction (F = 33, P < 0.01), end-diastolic volume (F = 9, P < 0.05) and end-systolic volume (F = 10, P < 0.05) were significantly different between the two groups. In group 1, stroke volume, cardiac output and vascular peripheral resistance decreased from period A to period B (all P < 0.001). In group 2, no changes in stroke volume, cardiac output and vascular peripheral resistance were observed from period A to period B. All parameters were similar in the two groups during the periods A and C. Upon changing posture from the supine to the upright position, patients with Parkinson's disease and postural hypotension showed marked changes in parameters of LV function induced by vascular abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)
Electrocardiography, Ambulatory↗
Behavioural sensitization in 6-hydroxydopamine lesioned rats involves the dopamine signal transduction: changes in DARPP-32 phosphorylation.
"Priming" is a phenomenon of behavioural sensitization observed in unilaterally 6-hydroxydopamine lesioned rats following exposure to a dopamine agonist. After priming, a single dose of the D1 agonist SKF 38393 (3 mg/kg) produces contralateral turning, while the same dose is inactive in drug-naive, lesioned animals. The molecular mechanisms of "priming" were investigated here by studying the phosphorylation of dopamine and adenosine 3'-5' monophosphate regulated phosphoprotein (DARPP-32), a dopamine- and cyclic AMP-regulated phosphoprotein functionally linked to D1 receptors in striatum. Dephospho-form of DARPP-32 were measured by a back-phosphorylation assay. All assays were performed in striata from both lesioned and unlesioned sides. A significant decrease of dephospho-DARPP-32 (27%) was observed in the denervated striatum of primed rats, indicating an increased phosphorylation in vivo of DARPP-32 in response to the D1 agonist. The levels of DARPP-32 protein, as measured by quantitative immunoblotting, remained unchanged in all experimental groups. This study shows that priming is expressed as an increased transduction of the D1 receptor message.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Polymorphism analysis of the huntingtin gene in Italian families affected with Huntington disease.
Two sources of variation in the huntingtin gene, the length of the CCG-rich segment downstream to the (CAG)n stretch undergoing expansion in Huntington disease (HD) and the deletion of 3 bp at codon positions 2642-2645 (delta 2642), were analysed on the normal and HD chromosomes of 80 Italian families affected with HD. No instances of meiotic instability of the CCG-rich segment were detected. A strong linkage disequilibrium was found between the HD mutation and alleles at both polymorphic regions: CCG-rich length alleles different from 176 bp are underrepresented while delta 2642 is overrepresented on HD chromosomes. The presence of such alleles on HD chromosomes does not affect age at onset of the disease. Normal chromosomes displayed a non-random association, shorter (CAG)n segments being preferentially followed by longer CCG-rich segments. Finally, the finding, among normal subjects, of carriers of variants on both chromosomes denotes that variation at either of the two polymorphisms does not impair the function of the huntingtin gene product.
Adult↗
Linkage disequilibrium between FD1-D9S202 haplotypes and the Friedreich's ataxia locus in a central-southern Italian population.
We used two recently described genetic markers in the region of the Friedreich's ataxia locus to study 33 affected pedigrees from central-southern regions of Italy. These markers are predicted, by physical mapping, to be localised more closely to the Friedreich's ataxia locus than other previously described markers. No recombination was found between these markers and the disease locus. Strong linkage disequilibrium is present between the compound haplotype and the disease locus. Since this population was also previously studied by using three other more distal genetic markers, a total of five markers has been used to identify the extended haplotype. Homozygosity in consanguineous pedigrees was also studied. Extended haplotype analysis and homozygosity studies suggest the presence of few common disease causing mutations in our population.
Base Sequence↗
Late onset Friedreich's disease: clinical features and mapping of mutation to the FRDA locus.
Twenty two patients from 17 families with Friedreich's disease phenotype but with onset ranging from the ages of 21 to 36 are described. Comparison with "typical" Friedreich's disease with onset before 20 years of age showed only a lower occurrence of skeletal deformities. The peripheral and central neurophysiological findings, sural nerve biopsy, and the neuroradiological picture did not allow the differentiation between "late onset" and "typical" Friedreich's disease. Duration of disease from onset to becoming confined to a wheelchair was five years longer in late onset patients. Sixteen patients and 25 healthy members from eight families were typed with the chromosome 9 markers MLS1, MS, and GS4 tightly linked to the FRDA locus. All families showed positive lod scores with a combined value of 5.17 at a recombination fraction of theta = 0.00. It is concluded that "late onset" Friedreich's disease is milder than the "typical" form and that it maps to the same locus on chromosome 9.
Adaptor Proteins, Signal Transducing↗
A clinical sign of Parkinson's disease: the absence of lateral foot drop.
Explore the source record for details and available documents.
Aged↗
Hand deformities in extrapyramidal disorders.
Hand deformities cause severe discomfort and functional limitations to patients with Parkinson disease (PD) and related disorders. In clinical practice the problem is often overlooked or misdiagnosed. This paper reports on four cases whose characteristics are discussed.
Aged↗
Expression of c-fos protein in the experimental epilepsy induced by pilocarpine.
The expression of the c-fos proto-oncogene, as estimated by immunohistochemistry of the FOS nuclear protein, was studied in both focal and generalized seizures induced in rats by systemic administration of pilocarpine. Focal seizures, as indicated by the occurrence of stereotyped oral movements, chewing and sniffing, were evoked by either a subconvulsant dose of pilocarpine (200 mg/kg) or the association of a convulsant dose of pilocarpine (400 mg/kg) with SCH 23390, a selective D-1 dopamine receptor antagonist. This seizure pattern resulted in FOS accumulation in certain limbic areas, namely, the piriform cortex, amygdala, and olfactory tubercle. On the other hand, in rats developing generalized seizures, accumulation of FOS was also found in hippocampus, cingulate cortex, frontal cortex, striatum, accumbens, as well as in certain thalamic nuclei. Generalized seizures, including motor limbic seizures and status epilepticus, were induced by either a convulsant dose of pilocarpine (400 mg/kg) or a low dose of pilocarpine (15-200 mg/kg) combined with either lithium or the D-1 selective agonist SKF 38393. These findings indicate a close correlation between the sequence of behavioural alterations induced by pilocarpine and the proto-oncogene activation. The results provide the basis for mapping the areas of origin and the pathways of generalization of seizure activity. As shown by the effects of dopamine receptor agonists and antagonists, the process of generalization appears to be controlled by the dopamine system.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Evidence of a genetic marker associated with early onset in Friedreich's ataxia.
We evaluated the association between age at onset of Friedreich's ataxia and alleles of two restriction fragment length polymorphisms (RFLP) at D9S15 and D9S5 in the 9q13-9q21.1 region. We studied 65 Italian patients from 49 families. Age at onset was not normally distributed in our patients, suggesting allelic heterogeneity. Patients homozygous for allele 1 of MspI RFLP detected by probe MCT112 at D9S15 (M1) had an earlier onset (mean 9.3, SD 3.4 years) than patients homozygous for allele 2 (M2; mean 12.1, SD 4.3). Heterozygotes had an onset age similar to that of the M2 homozygotes. These findings suggest that the M1 allele might be a marker of one allelic early-onset Friedreich's ataxia mutation.
Adolescent↗
Heterogeneous findings in four cases of cerebellar ataxia associated with hypogonadism (Holmes' type ataxia).
We report four sporadic cases of cerebellar ataxia associated with hypogonadism. All patients were female. The neurological symptoms appeared in the first three decades. Apart from ataxia, the most frequent features were nystagmus, dysarthria, mental impairment, brisk tendon reflexes, skeletal deformities, peripheral neuropathy, and tremor. Neuroimaging studies showed constant cerebellar atrophy, in some instances associated with involvement of either grey or white cerebral matter. Neurophysiological studies demonstrated an axonal neuropathy. Endocrine evaluation showed heterogeneity of the hypogonadism, which was hypogonadotrophic in one patient and hypergonadotrophic in the other three. One patient had partial deficiency of muscle cytochrome c oxidase. The syndrome appears to be a heterogeneous multisystem disorder and in some cases a mitochondrial metabolism deficiency could be suspected.
Adolescent↗
A double-blind cross-over trial of amantadine hydrochloride in Friedreich's ataxia.
We performed a double-blind cross-over study with amantadine hydrochloride in 12 patients with Friedreich's disease and 2 with autosomal dominant cerebellar ataxia. Patients were randomly assigned to a placebo-amantadine or amantadine-placebo sequence. The interval between the treatments was two weeks. Patients were graded according to a functional ataxia scoring scale and videotaped in basal conditions and 90 min after a single oral dose of 100 mg amantadine or placebo. Three evaluators independently scored the videotapes. Statistical analysis showed no significant effect of amantadine in Friedreich's disease.
Adolescent↗