Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although levodopa is the gold standard for treating motor symptoms of Parkinson's disease (PD), long-term therapy leads to levodopa-induced dyskinesia (LID). Dyskinesia refers to involuntary movements other than tremor and most commonly consists of chorea that occurs when levodopa-derived dopamine is peaking in the brain ("peak-dose dyskinesia"). However, dyskinesia can also consist of dystonia or myoclonus and occur during other parts of the levodopa dosing cycle. New validated rating scales and home diaries can better help the health care provider assess the timing and severity of dyskinesia. The exact etiology of LID is unknown, but there is evidence that abnormal pulsatile stimulation of dopamine receptors may be contributory. Treatment of LID includes adjustment of PD medications to maximize "on" time without troublesome dyskinesia. Amantadine is the only medication available with demonstrated ability to reduce the expression of established LID without reducing antiparkinsonian benefit. Other medications that are currently being studied to treat established LID include antiepileptics and serotonergic medications. Deep brain stimulation of the subthalamic nucleus is now the most commonly used surgical procedure for PD patients, and it is very effective in treating LID.
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PMID:Levodopa-induced dyskinesia in Parkinson's disease: epidemiology, etiology, and treatment. 1761 36

Patients with Parkinson's disease (PD) often complain of unsteadiness. This can occur as the result of various neurological dysfunctions, including changes in postural adjustments, loss of postural reflexes, axial akinesia and rigidity, freezing and/or postural hypotension. In some cases these symptoms remain unexplained, and rare cases of unsteadiness have been attributed to tremor on standing. To delineate this condition, we investigated 11 consecutive PD patients with unexplained unsteadiness because of tremor on standing, seen in our department over a 6-year period. All the patients had detailed clinical and electrophysiological investigations based on surface polygraphic electromyographic recordings. Four patients had fast orthostatic tremor (13-18 Hz), one had intermediate orthostatic tremor (8-9 Hz), and three had slow orthostatic tremor (4-6 Hz). The remaining 3 patients had orthostatic myoclonus, a condition that has not previously been reported in PD. Patients with fast tremor improved on clonazepam. Patients with slow tremor and myoclonus improved on levodopa and sometimes benefited further when clonazepam was added. These observations show the usefulness of neurophysiological investigations for diagnosing and treating unexplained unsteadiness in Parkinson's disease.
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PMID:Myoclonus or tremor in orthostatism: an under-recognized cause of unsteadiness in Parkinson's disease. 1767 13

Because of the occurrence of different types of mutations, comprehensive genetic testing for Parkinson's disease (PD), dopa-responsive dystonia (DRD), and myoclonus-dystonia (M-D) should include screening for small sequence changes and for large exonic rearrangements in disease-associated genes. In diagnostic and research settings, the latter is frequently omitted or performed by laborious and expensive quantitative real-time PCR (qPCR). Our study aimed to evaluate the utility of a novel method, multiplex ligation-dependent probe amplification (MLPA), in molecular diagnostics of movement disorders. We have analyzed, by MLPA, genomic DNA from 21 patients affected with PD, DRD, or M-D, in which the presence of exon rearrangement(s) (n = 20) or of a specific point mutation (detectable by MLPA, n = 1) had been established previously by qPCR or sequencing. In parallel, we have studied, in a blinded fashion, DNA from 49 patients with an unknown mutational status. Exon rearrangements were evident in 20 samples with previously established mutations; in the 21st sample the known specific point mutation was detected. We conclude that MLPA represents a reliable method for large-scale and cost-effective gene dosage screening of various movement disorders genes. This finding reaches far beyond a simple technical advancement and has two major implications: (1) By improving the availability of comprehensive genetic testing, it supports clinicians in the establishment of a genetically defined diagnosis; (2) By enabling gene dosage testing of several genes simultaneously, it significantly facilitates the mutational analysis of large patient and control populations and thereby constitutes the prerequisite for meaningful phenotype-genotype correlations.
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PMID:Rapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation-dependent probe amplification. 1767 14

Parkinsonism or dystonia are associated with myoclonus in several extrapyramidal diseases. Although the latter symptom is not always prominent, stimulus-sensitive, distal, or focal reflex myoclonus is frequently observed. This review will consider the clinical and electrophysiological features of myoclonus in Parkinson's disease, multiple system atrophy, Lewy body dementia, corticobasal degeneration, progressive supranuclear palsy, Huntington's disease, dentatorubral-pallidoluysian atrophy and myoclonus with dystonia. The evidence of a long-latency reflex response, the presence of giant somatosensory evoked potentials, and the demonstration of a back-averaged premyoclonus focal cortical EEG activity often lead to classify myoclonus as a cortical phenomenon. However, a subcortical origin cannot always be ruled out.
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PMID:[Extrapyramidal disorders: interest of myoclonus analysis]. 1803 54

Converging data suggest that abnormal synchronised oscillatory activity in the basal ganglia may contribute to bradykinesia in patients with Parkinson's disease. This synchrony preferentially occurs over 10-30 Hz, the so-called beta band. Correlative evidence has been supplemented by experiments in which direct stimulation of the basal ganglia in the beta band slows movement. Yet questions remain regarding the small scale of the latter effects and whether synchrony is an early or even obligatory feature of parkinsonism. Nevertheless, the principle that abnormally synchronised activity in the beta band can disrupt the function finds a precedent in the syndrome of cortical myoclonus. Here, pathologically synchronised discharges of pyramidal neurons are transmitted to the healthy spinal cord. The result is the synchronous discharge of motor units leading to rhythmic jerking.
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PMID:Abnormal oscillatory synchronisation in the motor system leads to impaired movement. 1822 64

Individuals with familial Parkinson's disease (PD) due to a monogenic defect can show considerable clinical and neuropathological variability. To identify factors underlying this variability, histopathological analysis was performed in two clinically different A53T alpha-synuclein heterozygotes from Family H, a multigenerational alpha-synuclein A53T kindred. To determine whether additional genetic factors could contribute to phenotypic variability, Family H and another multigenerational A53T kindred were analyzed for parkin polymorphisms. We identified a previously described variant in parkin exon 4 associated with increased PD risk (S167N). The two A53T heterozygotes had markedly different neuropathology and different parkin genotypes: A N167 homozygote had early onset rapidly progressive disease, early dementia, myoclonus and sleep disorder, while a S167 homozygote had late onset, slowly progressive disease and late dementia. Both had brainstem, cortical, and intraneuritic Lewy bodies (LB). The N167 individual had widespread cortical neurofibrillary degeneration, while the S167 individual had only medial temporal lobe neurofibrillary degeneration. The N167 individual had severe neuronal loss in CA2 associated with Lewy neurites (LN), while the S167 individual had severe neuronal loss in CA1 associated with TDP-43 immunoreactive neuronal inclusions. These findings implicate TDP-43 in the pathology of familial PD and suggest that parkin may act as a modifier of the A53T alpha-synuclein phenotype of familial PD. Furthermore, they suggest a mechanism by which a rare genetic variant that is associated with a minor increase of PD risk in the heterozygous state may, in the homozygous state, exacerbate a disease phenotype associated with a highly penetrant dominant allele.
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PMID:Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson's disease. Variability in familial Parkinson's disease. 1838 63

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited, neurodegenerative disease. It can manifest either with a cerebellar syndrome or as Parkinson's syndrome, while later stages involve mainly brainstem, spinal cord and thalamus. This particular atrophy pattern resembles sporadic multi-system-atrophy (MSA) and results in some clinical features indicative of SCA2, such as early saccade slowing, early hyporeflexia, severe tremor of postural or action type, and early myoclonus. For treatment, levodopa is temporarily useful for rigidity/bradykinesia and for tremor, magnesium for muscle cramps, but neuroprotective therapy will depend on the elucidation of pathogenesis. The disease cause lies in the polyglutamine domain of the protein ataxin-2, which can expand in families over successive generations resulting in earlier onset age and faster progression. Genetic testing in SCA2 and other polyglutamine disorders like the well-studied Huntington's disease is now readily available for family planning. Although these disorders differ clinically and in the affected neuron populations, it is not understood how the different polyglutamine proteins mediate such tissue specificity. The neuronal intranuclear inclusion bodies described in other polyglutamine disorders are not frequent in SCA2. For the quite ubiquitously expressed ataxin-2, a subcellular localization at the Golgi, the endoplasmic reticulum and the plasma membrane, in interaction with proteins of mRNA translation and of endocytosis have been observed. As a first victim of SCA2 degeneration, cerebellar Purkinje neurons may be preferentially susceptible to alterations of these subcellular pathways, and therefore our review aims to portray the particular profile of the SCA2 disease process and correlate it to the specific features of ataxin-2.
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PMID:Spinocerebellar ataxia 2 (SCA2). 1841 84

We determined plasma amantadine concentrations in patients with Parkinson's disease (PD) in daily clinical practice and investigated the relationship between plasma concentration and adverse reactions to clarify the safe therapeutic range. Seventy-eight consecutive PD patients on stable amantadine treatment were recruited. Plasma concentration of amantadine was measured 3h after the administration of morning amantadine dose. Serum creatinine was measured to estimate renal function. The mean daily dose of amantadine was 135.1+/-62.3mg/day, and the mean plasma amantadine concentration was 812.5+/-839.5 ng/ml (range, 91-4400 ng/ml). Plasma amantadine concentration increased according to increasing renal dysfunction. Three patients exhibited adverse reactions, such as myoclonus, hallucinations, and delirium, and all of them showed plasma amantadine concentration >3000 ng/ml. None of the three cases had previously shown such side effects. PD patients who have not developed any psychiatric symptoms as adverse reactions to the treatment may develop myoclonus, hallucination, or delirium when the plasma concentration of amantadine exceeds 3000 ng/ml. It is therefore recommended to use amantadine at the plasma concentration of less than 3000 ng/ml in the treatment of Parkinson's disease, especially in elderly patients.
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PMID:Plasma amantadine concentrations in patients with Parkinson's disease. 1882 13

Duplications and triplications of the alpha-synuclein (SNCA) gene have been reported in Parkinson's disease patients belonging to the Southern Swedish "Lister family". Further genealogical research has now shown that these individuals are descended from a large kindred characterized by Herman Lundborg in 1901-1913. In the expanded pedigree, a total of 25 individuals had Parkinson's disease with an autosomal dominant pattern of inheritance. Hereditary dementia, and, historically, dementia praecox have been described in other family members. Furthermore, an autosomal recessively inherited pediatric disease with nocturnal tonic-clonic fits, subsequent progressive myoclonus, startle reactions, tremor and muscle rigidity was described by Lundborg in the same pedigree. The entity was later designated Unverricht-Lundborg disease (ULD) or progressive myoclonus epilepsy type 1 (EPM1). However, Lundborg's clinical description of this disease, based on 17 patients within this kindred, differs from the modern definition of EPM1, which relies on patients with a mutation in the cystatin B (CSTB) gene. We hypothesize that the former pediatric disease, as well as the parkinsonism and dementia phenotypes, are associated with duplications, triplications and possibly higher-order multiplications of the alpha-synuclein (SNCA) gene. This hypothesis is supported by the distribution of afflicted family members within the pedigree and by recently obtained genealogical information.
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PMID:Alpha-synuclein multiplications with parkinsonism, dementia or progressive myoclonus? 1882 90

Corticobasal degeneration (CBD) is a neurodegenerative disorder characterized clinically by a combination of cortical and basal ganglia signs. Pathologically, it is classified as a tauopathy. The most distinctive clinical feature is its unilateral or markedly asymmetric presentation; among parkinsonian syndromes, with rare exceptions, only Parkinson's disease presents with such asymmetry. The most common presenting cortical features include apraxia (patients often complain of a "useless" limb), aphasia (usually nonfluent), parietal lobe sensory signs (agraphesthesia, extinction, astereognosis), frontal dementia, or myoclonus. Basal ganglia signs include rigidity, akinesia, limb dystonia, and postural instability. The diagnosis is often challenging for three reasons: 1) The full complement of findings are rarely seen at presentation; 2) If CBD is not suspected, subtle but relevant findings (eg, extinction, language impairment, myoclonus, or apraxia) may not be searched for or appreciated; 3) The clinical picture of CBD has substantial overlap with a variety of other parkinsonian and dementing illnesses. The differential diagnosis includes Parkinson's disease, progressive supranuclear palsy, frontotemporal dementia, primary progressive aphasia, and Alzheimer's disease. The clinical diagnosis is not confirmed pathologically in up to half of cases, so the term corticobasal syndrome is often preferred during life, reserving the term corticobasal degeneration for pathologically verified cases. Treatment of CBD is primarily supportive, and most patients die within 10 years of onset. Parkinsonian signs may improve to a modest degree with levodopa, clonazepam can suppress myoclonus, and botulinum toxin can relieve dystonia. Early speech therapy, physical therapy, and occupational therapy, as well as assist devices such as a rolling walker may improve functioning and reduce complications such as aspiration pneumonia and falls. With time, however, most patients lose their independence and mobility. Throughout the course of the illness (particularly when it is advanced), caring for the caregiver is as important as caring for the patient.
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PMID:Corticobasal degeneration. 1936 52


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