RESUMO
Mitochondrial disorders are a group of heterogeneous diseases associated with abnormalities of the oxidative phosphorylation (OXPHOS), the most important source of energy for the cell. The number of mitochondrial syndromes and of identified causative genes is constantly increasing. Taken as a whole they are among the most frequent genetic diseases in humans at any age. The respiratory chain is the only metabolic pathway under double genome control and molecular genetics of these disorders is complicated by the existence of strict interactions between mitochondrial DNA and nuclear DNA. In childhood and infancy, clinical presentation differs from mitochondrial disorders with adult onset. The phenotypes are much more severe, often involving brain, frequently presenting as multisystemic disorders and seldom as isolated myopathy. Mutations in nDNA are more frequent than in adulthood. The major phenotypes presenting in infancy are here correlated with genetic defects and biochemical data with the aim to facilitate diagnosis work-up.
RESUMO
The identification of the molecular basis of numerous hereditary neurological disorders allowed the feasibility of predictive genetic tests for at-risk family members. In agreement with international guidelines, we tested a protocol for a predictive test to optimize cooperation among specialists, well-being of participants, and organization of clinical activities. The psychiatrist/psychologist did not meet the at-risk subjects, but cooperated with the team, integrating psychological support for participants and clinicians. We enrolled 60 subjects at risk for Huntington disease, and 32 at risk for spinocerebellar ataxias. Seventy-two subjects (78%) continued the visit program; 55 (60%) received the genetic result, and 38 subjects (41%) completed the program. Participation and outcome were similar in both groups. Mean psychological scores were all below significant levels; however, the need for psychological support was recognized for 5 mutation carriers and a non-carrier. Our data provide a methodological example of a simple and safe procedure for a predictive test, and indicate that the clinical conference represents a good setting to handle psychosocial impact associated with disclosure of genetic results in hereditary late-onset disorders.
Assuntos
Aconselhamento/métodos , Aconselhamento Genético/psicologia , Testes Genéticos , Doença de Huntington/genética , Fosfoproteínas Fosfatases/genética , Ataxias Espinocerebelares/genética , Adulto , Distribuição de Qui-Quadrado , Avaliação da Deficiência , Feminino , Humanos , Doença de Huntington/diagnóstico , Doença de Huntington/psicologia , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fosfoproteínas Fosfatases/classificação , Valor Preditivo dos Testes , Escalas de Graduação Psiquiátrica , Risco , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/psicologia , Inquéritos e Questionários , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: The neostriatum is known to be affected in HD. In this work, our aim was to determine whether microstructural and volumetric alterations occur in the neostriatum of presymptomatic HD gene carriers and in patients with early-stage HD. MATERIALS AND METHODS: We studied a group of 15 presymptomatic gene carriers who were far from the estimated symptom onset (16% probability of developing the disease within 5 years), a group of 9 patients with early symptomatic HD, and 2 groups of age-matched controls. Volumetric MR imaging and DWIs were acquired, and statistical analyses were performed on the volumes of the caudate nucleus and putamen and on the corresponding MD measurements. RESULTS: Neostriatal volumes were significantly smaller in both presymptomatic HD gene carriers and symptomatic patients with respect to controls. However, whereas the diffusivity in the caudate nucleus was increased in the symptomatic patients, it was decreased in the presymptomatic gene carriers. CONCLUSIONS: Altered diffusivity and reduced volume of the caudate nucleus in presymptomatic HD gene carriers indicate that the neostriatum is affected well before the onset of symptoms. The observed initial decrease and subsequent increase of MD might be related to the combined effect of increased oligodendroglial population, putatively a developmental abnormality, and incipient neurodegeneration.
Assuntos
Núcleo Caudado/patologia , Imagem de Difusão por Ressonância Magnética/métodos , Triagem de Portadores Genéticos , Doença de Huntington/diagnóstico , Doença de Huntington/genética , Processamento de Imagem Assistida por Computador/métodos , Adulto , Diagnóstico Precoce , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Putamen/patologia , Valores de ReferênciaRESUMO
BACKGROUND: Bilateral high frequency subthalamic stimulation has been reported to be effective in the treatment of Parkinson's disease and levodopa-induced dyskinesias. To analyze the results of this surgical procedure we critically reviewed 17 parkinsonian patients with advanced disease complicated by motor fluctuations and dyskinesias. METHODS: Between January 1998 and June 1999 these 17 consecutive patients (age 48-68 years; illness duration 8-27 years) underwent bilateral stereotactically guided implantation of electrodes into the subthalamic nucleus in the Department of Neurosurgery of the Istituto Nazionale Neurologico "C. Besta." Parameters used for continuous high-frequency stimulation were: frequency 160 Hz, pulse width 90 microsec, mean amplitude 2.05 +/- 0.45 V. Parts II and III of the UPDRS were used to assess motor performance before and after operation by the neurologic team. The follow-up ranged between 6 and 18 months. RESULTS: At latest examination, mean UPDRS II and III scores had improved by 30% (on stimulation, off therapy) with mean 50% reduction in daily off time. Peak dyskinesias and early morning dystonias also improved in relation to therapy reduction. Side effects were persistent postoperative supranuclear oculomotor palsy and postural instability in one case, worsened off-medication hypophonia in three, and temporary nocturnal confusion episodes in three. Postoperative MRI revealed a clinically silent intracerebral haematoma in one case. One electrode required repositioning. CONCLUSIONS: Continuous high frequency STN stimulation is an effective treatment for advanced PD. A functionally useful and safe electrode placement can be performed without microrecording.
Assuntos
Terapia por Estimulação Elétrica , Doença de Parkinson/terapia , Núcleo Subtalâmico/fisiopatologia , Idoso , Terapia por Estimulação Elétrica/efeitos adversos , Terapia por Estimulação Elétrica/instrumentação , Eletrodos , Humanos , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/efeitos adversos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/cirurgia , Índice de Gravidade de Doença , Técnicas Estereotáxicas/efeitos adversosRESUMO
After implantation with subthalamic stimulators, nine patients with advanced Parkinson's disease were studied on the task of tracing out, as accurately as possible, the four corners of a square with the dominant hand. The task was performed in four treatment conditions: on stimulation-off medication, off stimulation-off medication, off stimulation-on medication, and on stimulation-on medication. Movement times and peak velocities improved significantly only in the on stimulation-on medication condition compared to off stimulation-off medication. The improvement in clinical parameters with stimulation only (relative to off stimulation off medication) was of borderline significance, while consistent and significant clinical improvement was only obtained with addition of medication (on medication-on stimulation). This study provides quantitative evidence of the effect of subthalamic stimulation on kinematic measures in Parkinson's disease (PD) and suggests that combined treatment (medication and stimulation) is superior to either treatment alone.
Assuntos
Dominância Cerebral/fisiologia , Terapia por Estimulação Elétrica , Doença de Parkinson/fisiopatologia , Desempenho Psicomotor/fisiologia , Núcleo Subtalâmico/fisiopatologia , Idoso , Terapia Combinada , Eletrodos Implantados , Feminino , Humanos , Levodopa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Exame Neurológico/efeitos dos fármacos , Doença de Parkinson/terapia , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Técnicas Estereotáxicas , Resultado do TratamentoRESUMO
Although deep brain stimulation (DBS) is a clinically effective therapy for patients with advanced Parkinson's disease (PD), its physiological effects on the brain and possible actions on non-motor functional systems remain largely unknown. This study evaluated the effects of DBS of the subthalamic nucleus (STN) on neurophysiological variables and on cardiovascular physiology. Nine patients affected by PD undergoing chronic DBS of the STN have been studied. We performed electroencephalography (EEG), somatosensory (SEPs) and visual evoked potentials (VEPs), exteroceptive masseteric silent period and sympathetic skin response (SSR) studies with DBS ON and OFF. To assess the effects of stimulation on the cardiovascular system the tilt test and plasma renin activity were studied. When we turned the DBS OFF, both SEP N20 and the VEP P100 component increased significantly in amplitude whereas the SSR decreased in amplitude and increased in latency. Although plasma renin activity tended to increase with DBS OFF, its modification induced by postural changes and blood pressure values did not significantly differ with DBS ON and OFF. We conclude that DBS of the STN in PD, besides inducing a clinical improvement, induces several non-motor effects.
Assuntos
Terapia por Estimulação Elétrica/efeitos adversos , Doença de Parkinson/fisiopatologia , Doença de Parkinson/terapia , Núcleo Subtalâmico/fisiopatologia , Vias Aferentes/fisiopatologia , Idoso , Pressão Sanguínea/fisiologia , Tronco Encefálico/fisiopatologia , Córtex Cerebral/fisiopatologia , Eletrodos Implantados , Eletroencefalografia , Potenciais Evocados/fisiologia , Humanos , Interneurônios/fisiologia , Músculo Masseter/fisiopatologia , Pessoa de Meia-Idade , Condução Nervosa/fisiologia , Doença de Parkinson/patologia , Tempo de Reação/fisiologia , Núcleo Subtalâmico/patologia , Sistema Nervoso Simpático/fisiopatologiaRESUMO
OBJECTIVES: Impairment of executive function is frequent in Parkinson's disease (PD), striatonigral degeneration-type multisystem atrophy (SND), and progressive supranuclear palsy (PSP); sometimes frank dementia is also present. However, the progression of cognitive decline has not been adequately studied. The objectives were to delineate the progression of cognitive impairment in these parkinsonisms and to elucidate interdisease differences. METHODS: Twenty three patients with SND and 21 with PSP, referred consecutively, and 18 patients with PD matched for severity of parkinsonism were compared on a comprehensive battery of cognitive tests and motor invalidity scales. A mean of 21 months later (range 18-24 months) the patients were called for retesting. RESULTS: Only 12 patients with PD (66.6%), 14 with SND (60.8%), and 11 with PSP (52.4%) were retested; those who dropped out refused, had died, or were too disabled. The patients with PSP performed worse than patients with PD or SND in the short tale, verbal fluency, visual search, and Benton tests at first evaluation. Overall cognitive performance was similar in the PD and SND groups except that the SND group did significantly worse on the verbal fluency test. Between group comparison of changes in scores from first to second evaluation showed that patients with PSP deteriorated significantly in the Nelson test compared with patients with PD or SND, and that patients with PSP or SND declined significantly on the visual search test compared with patients with PD. There was no difference between the groups for motor decline. Two patients with PSP were demented (DSM IV criteria) at first evaluation and six at second evaluation; no patients with PD or SND were demented at either evaluation. CONCLUSIONS: The greater decline of patients with PSP in attention, set shifting, and categorisation abilities is probably related to the conspicuous frontal deafferentation associated with direct premotor and prefrontal involvement, and to dysfunction of the midbrain ascending activating system, known to occur in PSP.
Assuntos
Doença de Parkinson/fisiopatologia , Substância Negra/patologia , Paralisia Supranuclear Progressiva/etiologia , Córtex Visual/patologia , Idoso , Atrofia , Estudos de Casos e Controles , Transtornos Cognitivos/classificação , Transtornos Cognitivos/etiologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/psicologia , Índice de Gravidade de Doença , Paralisia Supranuclear Progressiva/patologiaRESUMO
The purpose of this study was to quantitatively compare the motor response to L-dopa in Parkinson's disease (PD) and striatonigral-type multisystem atrophy (MSA) patients. Ten consecutive MSA patients were compared with nine PD patients selected to have similar overall motor compromise, age, and mental state. The performance of simple repetitive axial movements plus bilateral proximal and distal limb movements; overall motor response assessed by the Unified Parkinson Disease Rating Scale (UPDRS); as well as scores from the UPDRS items evaluating speech/facial expression, postural stability, and posture/gait were assessed 90 min and 12 h (baseline) after L-dopa administration. The total UPDRS score, all subcategory scores, and all body movements improved significantly in the PD group. Proximal and distal limb akinesias and speech/facial expression improved in some MSA patients. Lack of response of axial akinesia to L-dopa in MSA correlates with a presumed greater loss of postsynaptic dopaminergic receptors in the dorsolateral putamen, while improvement in distal and proximal limb muscle akinesias in MSA patients may be related to relative preservation of the ventral putamen.
Assuntos
Atrofia/tratamento farmacológico , Levodopa/farmacologia , Atividade Motora/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Idoso , Atrofia/fisiopatologia , Feminino , Marcha/efeitos dos fármacos , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologiaRESUMO
Cabergoline is a long-acting D2 dopamine (DA) agonist. We conducted an open study to investigate the effectiveness and tolerability of cabergoline, administered once a day orally, in 50 consecutive patients with Parkinson's disease complicated by motor fluctuations and dyskinesias. In 15 patients cabergoline replaced another direct DA agonist. Evaluation after 6 months of treatment (also including patients who dropped out during this period), showed an improvement in off or on hours, or both, in excess of 50% in 27 patients, comprising 20 of the 35 patients (57%) previously untreated with DA agonists and seven of the 15 patients (47%) already on DA agonists when the study began. Of the 22 patients who received the treatment for 1 year, the improvement was maintained up to final evaluation in the patients not on DA agonists at admission (n = 16), whereas a slight deterioration in clinical condition was observed in the patients already on DA agonists at admission (n = 6). Only six patients showed a detectable increase in dyskinesias. The most common side effects were gastric upset (n = 12), orthostatic hypotension (n = 3), and ankle edema (n = 3), all mild; also observed were two cases of pleural effusion/pulmonary fibrosis. Twenty patients (40%) failed to complete the treatment; of these, five (10% of total) dropped out because of adverse effects. It is concluded that once-daily administrations of cabergoline are useful for treating patients with Parkinson's disease with motor fluctuations and may advantageously substitute other DA agonists. The side effects of the drug are generally mild, although two cases involving pleuropulmonary complications did emerge.
Assuntos
Agonistas de Dopamina/efeitos adversos , Agonistas de Dopamina/uso terapêutico , Discinesia Induzida por Medicamentos/etiologia , Ergolinas/efeitos adversos , Ergolinas/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Idoso , Cabergolina , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Ergolinas/farmacologia , Humanos , Pessoa de Meia-Idade , Receptores de Dopamina D2/efeitos dos fármacosRESUMO
A poor response to L-DOPA in addition to parkinsonian, cerebellar, and autonomic signs is commonly regarded as indicative of clinical multiple system atrophy (MSA). We compared the motor response to a single oral administration of 250 mg L-DOPA/25 mg carbidopa in eight MSA patients and eight Parkinson's disease (PD) patients with the "on-off" phenomenon, evaluating L-DOPA peripheral pharmacokinetics. Motor response was consistently good in all PD patients, but only four MSA patients had a (moderate) response. Pharmacokinetic parameters did not differ between the groups. The varying extent of putaminal damage could be responsible for the differing motor response to L-DOPA in MSA patients.
Assuntos
Levodopa/uso terapêutico , Atrofias Olivopontocerebelares/tratamento farmacológico , Adulto , Idoso , Carbidopa/uso terapêutico , Feminino , Humanos , Levodopa/farmacocinética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Movimento/efeitos dos fármacos , Transtornos dos Movimentos/tratamento farmacológico , Transtornos dos Movimentos/fisiopatologia , Rigidez Muscular/tratamento farmacológico , Rigidez Muscular/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Tremor/tratamento farmacológico , Tremor/fisiopatologiaRESUMO
The study was conducted on 120 patients (76 men and 44 women) affected by idiopathic Parkinson's disease (IPD) responsive to L-dopa and observed for many years. Sixty had clinical onset between the ages of 20-40, representing 10.2% of our PD population; in the others the symptoms began after the 40th birthday. The two groups were matched for sex and length of illness. In all patients a diagnosis of IPD depended on history and clinical and neuroradiological findings. Clinical, pharmacological, evolutive, and epidemiological data were collected on all patients. Thirty-six patients from each group performed motor dexterity tests (reaction time to expected and unexpected stimuli) and cognitive tests (Wechsler Adult Intelligence Scale. Benton, Short tale, and Zazzo's speed and accuracy test). To assess the prevalence of dementia and the severity of psychiatric side effects of L-dopa administration, the 60 patients with early-onset PD were compared with 134 consecutive unselected PD patients. Five percent of early-onset PD patients had a family history of the disorder. Our study showed that early-onset PD does not differ fundamentally from the late-onset form except that the former is characterized by a more rapid establishment of the full-blown parkinsonian clinical picture and deterioration of the therapeutic efficacy of L-dopa, with an earlier appearance of side effects. The results of our neuropsychological investigations suggest that early-onset PD may be a "pure" form of extrapyramidal compromise with exclusively motor manifestations.
Assuntos
Doença de Parkinson/diagnóstico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Demência/diagnóstico , Demência/genética , Feminino , Humanos , Levodopa/administração & dosagem , Levodopa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Doença de Parkinson/genética , Psicoses Induzidas por Substâncias/diagnóstico , Fatores de RiscoRESUMO
Terguride, a partial DA-agonist with both dopaminergic and antidopaminergic properties, was tested in 11 PD patients in the "decompensated" phase of the disease, characterized by the presence of dyskinesias and motor fluctuations. Combined treatment of these patients with 1 mg/day of terguride and stabilized doses of levodopa reduced the severity and frequency of dyskinesias and motor fluctuations along with a slight but significant improvement of parkinsonian clinical picture. The "modulatory" effect of terguride on DA receptors, in this experimental conditions, is discussed.