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| Author(s): |
Marcondes Cavalcante Franca Junior
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2008-11-19 |
| Examining board members: |
Íscia Teresinha Lopes Cendes;
Wilson Marques Junior;
Helio Afonso Ghizoni Teive;
Benito Pereira Damasceno;
Beatriz Helena Miranda Pfeilsticker
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| Advisor: | Anamarli Nucci; Íscia Teresinha Lopes Cendes |
| Abstract | |
Machado-Joseph disease or spinocerebellar ataxia 3 (SCA3/MJD) is the most frequent autosomal dominant ataxia in Brazil and caused by an unstable trinucleotide (CAG) repeat expansion in the 10th exon of the MJD1 gene on chromosome 14q. It is a chronic and debilitating neurologic disorder characterized by cerebellar ataxia, pyramidal dysfunction, dystonia, gaze abnormalities and peripheral neuropathy. Different types of neurons both in the central and peripheral nervous system are usually damaged in the disease. Although there are previous reports of peripheral involvement in patients with SCA3/MJD, there are still many unanswered questions. Therefore, we have designed this study aiming to evaluate the damage to the peripheral nervous system in SCA3/MJD, with especial emphasis on its clinical relevance, causative factors and natural history. We first looked at manifestations typically found in peripheral neuropathies, such as pain, muscle cramps, fasciculations, and disautonomia, but frequently overlooked in SCA3/MJD. In a cohort of 70 individuals with SCA3/MJD, we found chronic pain in 47% of patients, most of them with musculoskeletal characteristics. Peripheral dysfunction was also a contributing factor since at least two patients reported neuropathic pain in association with a predominantly sensory polyneuropathy. We then assessed muscle cramps and fasciculations and found that these were also common complaints, present in 82% and 50% of patients, respectively. Cramps were often a major complaint, disturbing sleep or work hours. We reported positive results with carbamazepine in the treatment of cramps in patients with SCA3/MJD. Peripheral neuropathy was clearly related to fasciculations, but not to muscle cramps. However, both manifestations were associated to abnormal excitability of motor neurons, as expressed by F-wave and H-reflex responses. Dysautonomia was another typical feature of patients with SCA3/MJD, and symptoms related to genitourinary and sudomotor systems were particularly frequent. Sympathetic skin response proved to be useful in the screening of patients with severe dysautonomia. We found higher proportions of patients with either "parkinsonian"or "neuropathic" phenotypes among those with severe autonomic impairment. In addition, we used nerve conductions studies and electromyography to determine the pattern of damage to the peripheral nervous system and its course over the time. We showed that overall 54% of patients with SCA3/MJD had peripheral neuropathy. Some of those had exclusive sensory impairment, others sensory-motor, and a few restricted motor involvement. The neurophysiological studies showed that the peripheral neuropathy in SCA3/MJD resembles a double neuronopathy, involving alpha motor neurons and dorsal root ganglia. Prospective data indicate that the peripheral involvement is mostly age-dependent, but progression is faster in individuals with larger (CAG) expansions. By contrast, progression of ataxia was mostly driven by age at onset, rather than length of expanded (CAG) repeat. These findings suggest that the determinants of damage to peripheral and cerebellar neurons may be different. The length of the expanded (CAG) allele explained roughly 70% of the variability in age at onset of the disease. As reported previously, it also contributes to progression of peripheral neuropathy, but this effect is small (40%). Therefore, other factors could exist, possibly genetic factors, which could influence the phenotypic variability in SCA3/MJD. We tested two potential genetic factors as candidates, the normal allele and the gene for the co-chaperone CHIP. We used regression models with age at onset as the dependent variable in the statistical analysis. We failed to show any modulating effect due to the protein CHIP. Nevertheless, the normal allele had a small, but significant contribution to variability in age at onset (about 2%). It remains to be determined whether this effect extends to other aspects of the phenotype, such as the peripheral damage. (AU) | |