Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report a family with autosomal dominant parkinsonism. The propositus developed parkinsonism at a relatively young age (45 years) and came to autopsy after a 6-year illness. She had typical features of Parkinson's disease except for an absence of rest tremor, although this was present in other family members. A diagnosis of Lewy body parkinsonism was confirmed by neuropathological examination. Additional pathological features included the presence of cortical Lewy bodies and anti-ubiquitin-positive neurites in the cornu Ammonis 2 and 3 (CA2-3) region of the hippocampus. This kindred is similar both clinically and pathologically to a few previously reported pedigrees, further strengthening recent evidence of a genetic etiology of some forms of Parkinson's disease.
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PMID:Autosomal dominant Lewy body parkinsonism in a four-generation family. 828 94

Several observations suggest that the cortical lesions of progressive supranuclear palsy (PSP) play a role in the clinical symptoms and signs of the disease, although direct evidence for this is lacking. We addressed the significance of these lesions in a series of 10 cases of definite PSP. Tau positive cortical lesions were constant, and the mean density of neurofibrillary tangles (NFTs) was highest in the precentral and angular gyri. Their cortical distribution was singular: they were mainly located in the deepest cortical layers, affecting small as well as large neurons. They were weakly and rarely labelled with anti-ubiquitin antibodies. The tau metabolism impairment appeared more diffuse than previously thought, since neuropil threads, tau positive astrocytic tangles and oligodendroglial inclusions were also seen in the cortex and the subcortical structures. A factorial analysis of NFT density in cortex and subcortex isolated two factors, cortical and subcortical, both linked to the pedunculopontine nucleus. This suggests a prominent role of this nucleus in the spread of the lesions. A pathological subgroup exhibited mild lesions in the pedunculopontine nucleus, which were always associated with mild cortical density of NFTs. In this subgroup, the clinical data were unusual: absence of oculomotor palsy and axial rigidity in one case, of dementia in another, and presence of tremor at rest in the third case. The presence of cortical NFTs could be related to the selective involvement of cortical pathways perhaps connected with the pedunculopontine nucleus.
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PMID:The significance of cortical pathology in progressive supranuclear palsy. Clinico-pathological data in 10 cases. 881 77

Genetic influences are thought by many to play an important role in the cause of Parkinson's disease. We studied two closely intermarried families (Family G) whose ancestors immigrated to the United States from Russia. We investigated this family clinically, genealogically, and pathologically. Our pedigree contained 102 members spanning six generations, with 10 affected individuals and 1 affected spouse. Detailed telephone interviews were conducted with affected individuals, with their spouses, and with their at-risk siblings. Medical records of deceased and living affected patients were collected. Physical examinations were performed on 7 at-risk and 5 affected persons. Typical levodopa-responsive parkinsonism with bradykinesia, rigidity, resting tremor, and impaired postural reflexes was seen in 4 members, dementia was present in 3, and 3 had both dementia and parkinsonism. An autopsy completed on 1 individual, our index case, demonstrated Lewy bodies in the brainstem and neocortex and ubiquitin-positive neuritic degeneration in the CA2-3 region of the hippocampus, consistent with the limbic (transitional) form of Lewy body disease. This family is distinct both clinically and pathologically from several previously reported parkinsonian kindreds.
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PMID:Familial parkinsonism, dementia, and Lewy body disease: study of family G. 938 76

This report concerns an autopsy case of amyotrophic lateral sclerosis (ALS) with unusual clinical and neuropathological findings. The patient was a Japanese man without hereditary burden who was 49 years old at the time of death. His clinical manifestation included dysarthria at age 48, followed by dysphagia, atrophy and fasciculation of the tongue, muscle weakness in the four extremities, tremor, rigidity, increased deep tendon reflexes in the upper and lower extremities, and incoordination of the four extremities. He died of respiratory failure 12 months after the disease onset. No respirator administration was performed throughout the clinical course. The neuropathological examination revealed not only degeneration of upper and lower motor neuron systems, including the presence of Bunina bodies and ubiquitin-immunoreactive neuronal inclusions in the lower motor neurons, but also prominent degeneration of the substantia nigra and dentate nucleus with slight neuronal loss in the locus ceruleus and pontine nucleus. To our knowledge, this is the first reported case of sporadic ALS without dementia and respirator support, showing degeneration of the substantia nigra and dentate nucleus. This report may contribute to the resolution of the question concerning the neuropathological heterogeneity of sporadic ALS with respiratory support.
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PMID:Sporadic amyotrophic lateral sclerosis with multiple system degeneration: a report of an autopsy case without respirator administration. 1054 75

Juvenile parkinsonism (onset age <20 yrs) is uncommon and few cases with neuropathologic confirmation have been reported. We present the case of a 17-year-old boy who presented with asymmetric arm tremor and bulbar symptoms. His paternal great aunt had parkinsonism with onset at age 22 years. Examination revealed parkinsonism in the absence of additional neurologic signs except for delayed pupillary responses to light. He responded well to levodopa but developed motor fluctuations and disabling dyskinesias after 3 years of treatment. Following attempted withdrawal of levodopa at age 24 years, he developed severe aspiration pneumonia complicated by cardiorepiratory arrests and he died 6 months later. At autopsy, the dominant histologic feature was wide-spread neuronal hyaline intranuclear inclusions. Neuronal depletion was observed in the substantia nigra, locus ceruleus, and, to a lesser extent, in the frontal cortex, and inclusions were particularly prominent in these areas. Inclusions were immunoreactive for ubiquitin and were typical of those seen in neuronal intranuclear inclusion disease (NIID), a rare, multisytem neurodegenerative disease. NIID should be considered in the differential diagnosis of juvenile parkinsonism. A link between NIID and hereditary neurodegenerative disorders characterized by expanded polyglutamine tracts is supported by the similar appearance of intranuclear inclusions in both conditions and by a family history in some cases of NIID.
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PMID:Neuronal intranuclear inclusion disease and juvenile parkinsonism. 1100 11

In mammalian cells, regulation of the expression of proteins involved in iron metabolism is achieved through interactions of iron-sensing proteins known as iron regulatory proteins (IRPs), with transcripts that contain RNA stem-loop structures referred to as iron responsive elements (IREs). Two distinct but highly homologous proteins, IRP1 and IRP2, bind IREs with high affinity when cells are depleted of iron, inhibiting translation of some transcripts, such as ferritin, or turnover of others, such as the transferrin receptor (TFRC). IRPs sense cytosolic iron levels and modify expression of proteins involved in iron uptake, export and sequestration according to the needs of individual cells. Here we generate mice with a targeted disruption of the gene encoding Irp2 (Ireb2). These mutant mice misregulate iron metabolism in the intestinal mucosa and the central nervous system. In adulthood, Ireb2(-/-) mice develop a movement disorder characterized by ataxia, bradykinesia and tremor. Significant accumulations of iron in white matter tracts and nuclei throughout the brain precede the onset of neurodegeneration and movement disorder symptoms by many months. Ferric iron accumulates in the cytosol of neurons and oligodendrocytes in distinctive regions of the brain. Abnormal accumulations of ferritin colocalize with iron accumulations in populations of neurons that degenerate, and iron-laden oligodendrocytes accumulate ubiquitin-positive inclusions. Thus, misregulation of iron metabolism leads to neurodegenerative disease in Ireb2(-/-) mice and may contribute to the pathogenesis of comparable human neurodegenerative diseases.
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PMID:Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. 1117 92

Parkinson's disease (PD) is morphologically characterized by progressive loss of neurons in the substantia nigra pars compacta (SNpc) and other subcortical nuclei associated with intracytoplasmic Lewy bodies and dystrophic (Lewy) neurites mainly in subcortical nuclei and hippocampus und, less frequently in cerebral cortex. SN cell loss is significantly related to striatal dopamine (DA) deficiency as well as to both the duration and clinical severity of disease, The two major clinical subtypes of PD show different morphologic lesion patterns: the akinetic-rigid form has more severe cell loss in the ventrolateral part of SN with negative correlation to DA loss in the posterior putamen, and motor symptoms related to overacitivty of the GABAergic "indirect" motor loop, which causes inhibition of the glutamatergic thalamocortical pathway and reduced cortical activation. The tremor-dominant type shows more severe cell loss in the medial SNpc and retrorubal field A 8, which project to the matrix of the dorsolateral striatum and ventromedial thalamus, thus causing hyperactivity of thalamomotor and cerebellar projections. These and experimental data suggesting different pathophysiological mechanisms for the major clinical subtypes of PD may have important therapeutic implications. Lewy bodies, the morphologic markers of PD, are composed of hyperphosphorylated neurofilament proteins, lipids, redox-active iron, ubiquitin, and alpha-synuclein, showing a continuous accumulation in the periphery and of ubiquitin in the central core. Alpha-synuclein, is usually unfolded in alpha-helical form. By gene mutation, environmental stress or other factors it can be transformed to beta-folding which is sensible to self-aggregation in filamentous fibrils and formation of insoluble intracellular inclusions that may lead to functional disturbances and, finally, to death of involved neurons. While experimental and tissue culture studies suggest that apoptosis, a genetically determined form of programmed cell death, represents the most common pathway in neurodegeneration, DNA fragmentation, overexpression of proapoptotic proteins and activated caspase-3, the effector enzyme of the terminal apopoptic cascade, have only extremely rarely been detected in SN of PD brains. This is in accordance with the rapid course of apoptotis and the extremely slow progression of the neurodegenerative process in PD. The biological role of Lewy bodies and other intracellular inclusions, the mechanisms of the intracellular aggregation of insoluble protein deposits, and their implication for cellular dysfunction resulting in neurodegeneration and cell demise are still unresolved. Further elucidation of the basic molecular mechanisms of cytoskeletal lesions will provide better insight into the pathogenesis of neurodegeneration in PD and related disorders.
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PMID:Recent developments in the pathology of Parkinson's disease. 1245 78

Recent studies have reported that alleles in the premutation range in the FMR1 gene in males result in increased FMR1 mRNA levels and at the same time mildly reduced FMR1 protein levels. Some elderly males with premutations exhibit an unique neurodegenerative syndrome characterized by progressive intention tremor and ataxia. We describe neurohistological, biochemical and molecular studies of the brains of mice with an expanded CGG repeat and report elevated Fmr1 mRNA levels and intranuclear inclusions with ubiquitin, Hsp40 and the 20S catalytic core complex of the proteasome as constituents. An increase was observed of both the number and the size of the inclusions during the course of life, which correlates with the progressive character of the cerebellar tremor/ataxia syndrome in humans. The observations in expanded-repeat mice support a direct role of the Fmr1 gene, by either CGG expansion per se or by mRNA level, in the formation of the inclusions and suggest a correlation between the presence of intranuclear inclusions in distinct regions of the brain and the clinical features in symptomatic premutation carriers. This mouse model will facilitate the possibilities to perform studies at the molecular level from onset of symptoms until the final stage of the disease.
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PMID:The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndrome. 1270 Jan 64

Fragile X syndrome is a neurodevelopmental disorder that is not known to have any progressive neurological sequelae in adulthood. However, a neurological condition involving intention tremor, ataxia, and cognitive decline has recently been identified among older male carriers of premutation alleles of the FMR1 gene. This condition is clinically distinct from fragile X syndrome and arises through a different molecular mechanism involving the same gene (FMR1). Characteristic findings on magnetic resonance imaging include cerebral and cerebellar volume loss and altered signal intensities of the middle cerebellar peduncles. A striking feature of this fragile X-associated tremor/ataxia syndrome is the presence of ubiquitin-positive neuronal and astroglial intranuclear inclusions. Unlike the CAG repeat expansion diseases, which lead to altered protein products, there is no known protein abnormality among FMR1 premutation carriers. Thus, inclusion formation may reflect a gain-of-function effect of the FMR1 mRNA or the CGG repeat itself. Finally, since this syndrome may represent one of the more common single-gene causes of tremor, ataxia, and dementia among older males, FMR1 DNA testing should be considered when evaluating adult patients with tremor/ataxia.
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PMID:A cerebellar tremor/ataxia syndrome among fragile X premutation carriers. 1452 82

Abnormal accumulation of ferritin was found to be associated with an autosomal dominant slowly progressing neurodegenerative disease clinically characterized by tremor, cerebellar ataxia, parkinsonism and pyramidal signs, behavioral disturbances, and cognitive decline. These symptoms may appear sequentially over a period of 4 decades. Pathologically, intranuclear and intracytoplasmic bodies were found in glia and subsets of neurons in the central nervous system as well as in extraneural tissue. Biochemical analyses of these bodies isolated from the striatum and cerebellar cortex revealed that ferritin light polypeptide (FTL) and ferritin heavy polypeptide (FTH1) were the main constituents. Molecular genetic studies revealed a 2-bp insertion mutation in exon 4 of the FTL gene. The resulting mutant polypeptide is predicted to have a carboxy terminus that is altered in amino-acid sequence and length. In tissue sections, the bodies were immunolabeled by anti-ferritin and anti-ubiquitin antibodies and were stained by Perls' method for ferric iron. Synthetic peptides homologous to the altered and wild-type carboxy termini were used to raise polyclonal antibodies. These novel antibodies as well as an antibody recognizing FTH1 immunolabeled the bodies. This study of this disorder has provided additional knowledge and insights in the growing area of ferritin-related neurodegeneration.
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PMID:Intracellular ferritin accumulation in neural and extraneural tissue characterizes a neurodegenerative disease associated with a mutation in the ferritin light polypeptide gene. 1509 26


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