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)

Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) are related to pathogenic mutations of the Tau gene. One of these, located at codon 279, results in an asparagine to lysine substitution. It was detected in three unrelated families from different origins. This mutation affects splicing, allowing exon 10 to be incorporated more frequently in the Tau transcripts, causing an abnormal preponderance of three-over four-repeat isoforms in soluble tau and the presence of the four-repeat isoforms in the insoluble tau. To better understand this newly described pathology, we analysed data from the three previously reported families. The American family, described as "pallido-ponto-nigral degeneration" is a large family which has been extensively studied (13 neuropathological studies). The Japanese family was initially presented as "pallidonigroluysian degeneration with iron deposition" and recently found to be related to N279 K mutation. We reported clinical, pathological and genetic data from the French family. Clinical particularities are ocular movements alterations with vertical supranuclear palsy, extrapyramidal signs (rigidity, dyskinesia, with atypical resting and postural tremor) and progressive dementia. Partial or no L-DOPA responsiveness is noted. These features led to discuss progressive supranuclear palsy, in some cases. There is no amyotrophy, nor any sensibility to neuroleptics, both signs being observed in other FTDP-17 syndromes. Neuropathology and immunohistochemistry confirm the presence of Tau immunolabeled inclusions, affecting mainly neurons in brain stem nuclei and glial cells in supratentorial white matter. Neuronal loss, which is moderate in frontal and temporal cortex, is severe in substantia nigra and globus pallidum. It is variable in other subcortical structures. In these structures, it is associated with iron deposition. This latter may participate in the degenerative process of cells and led to death in some specific neurons. The selectivity of neuronal death in hereditary diseases, when compared to data concerning sporadic neurodegenerative diseases which share similar clinical signs and neuropathological lesions, reinforces the hypothesis of an increased vulnerability of some neuronal populations which express specific sets of tau isoforms. Neurons particularly involved in these diseases express exclusively exon 10 + tau isoforms.
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PMID:[Neurodegenerative disease associated with a mutation of codon 279 (N279K) in exon 10 of Tau protein]. 1098 64

Frontotemporal dementia (FTD) displays significant neuropathological and genetic heterogeneity among and within affected families. An early diagnosis is often difficult because cognitive symptoms are manifest only at a late stage of the disease. We have been studying a large pedigree segregating frontotemporal dementia (FTD) to which belong 34 identified affected persons, 11 of whom were personally examined. The kindred has been genealogically reconstructed; all FTD patients have been linked to the same ancestors who lived in the early 18(th) century (11 generations before the present one). Autosomal dominant transmission was evident. Clinical features were uniform within the kindred and met the Lund-Manchester criteria. Personality changes with absence of insight, lack of empathy and of social awareness manifested up to 5 years before medical advice was sought. Loss of fluency was the earliest neuropsychological sign, in the absence of memory, orientation and praxis deficits, which evolved late, together with hyperorality. Akinesia was observed early, rigidity appeared late, tremor was absent. Two patients showed myoclonus late in their evolution. No ALS signs were observed in this kindred. Mutations of the MAPt gene, coding for the Tau protein, were not detected in affected family members. Linkage studies excluded chromosomes 3 and 9 and gave indeterminate results that were model dependent for chromosome 17.
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PMID:A large Calabrian kindred segregating frontotemporal dementia. 1214 Jun 77

Frontotemporal dementia (FTD) is characterized by cognitive and behavioral changes and, in a significant subset of patients, Parkinsonism. Histopathologically, FTD frequently presents with tau-containing lesions, which in familial cases result from mutations in the MAPT gene encoding tau. Here we present a novel transgenic mouse strain (K3) that expresses human tau carrying the FTD mutation K369I. K3 mice develop a progressive histopathology that is reminiscent of that in human FTD with the K369I mutation. In addition, K3 mice show early-onset memory impairment and amyotrophy in the absence of overt neurodegeneration. Different from our previously generated tau transgenic strains, the K3 mice express the transgene in the substantia nigra (SN) and show an early-onset motor phenotype that reproduces Parkinsonism with tremor, bradykinesia, abnormal gait, and postural instability. Interestingly, motor performance of young, but not old, K3 mice improves upon L-dopa treatment, which bears similarities to Parkinsonism in FTD. The early-onset symptoms in the K3 mice are mechanistically related to selectively impaired anterograde axonal transport of distinct cargos, which precedes the loss of dopaminergic SN neurons that occurs in aged mice. The impaired axonal transport in SN neurons affects, among others, vesicles containing the dopamine-synthesizing enzyme tyrosine hydroxylase. Distinct modes of transport are also impaired in sciatic nerves, which may explain amyotrophy. Together, the K3 mice are a unique model of FTD-associated Parkinsonism, with pathomechanistic implications for the human pathologic process.
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PMID:Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia. 1883 65

Frontotemporal dementia is a clinically and pathologically heterogeneous group of neurodegenerative disorders, with progressive impairment of behavior and language. They can be closely related to amyotrophic lateral sclerosis, clinically and through shared genetics and similar pathology. Approximately 40% of people with frontotemporal dementia report a family history of dementia, motor neuron disease or parkinsonism, and half of these familial cases are attributed to mutations in three genes (C9orf72, MAPT and PGRN). Akinetic-rigidity is a common feature in several types of frontotemporal dementia, particularly the behavioral variant and the non-fluent agrammatic variant of primary progressive aphasia, and the familial dementias. The majority of patients develop a degree of parkinsonism during the course of the illness, and signs may be present at the time of initial diagnosis. However, the parkinsonism of frontotemporal dementia is very different from that observed in idiopathic Parkinson's disease: it may be symmetric, axial, and poorly responsive to levodopa. Tremor is uncommon, and may be postural, action or occasionally rest tremor. The emergence of parkinsonism is often part of an evolving phenotype, in which frontotemporal dementia comes to resemble corticobasal syndrome or progressive supranuclear palsy. This chapter describes the prevalence and phenomenology of parkinsonism in each of the major syndromes, and according to the common genetic forms of frontotemporal dementia. We discuss the changing nosology and terminology surrounding the diagnoses, and the significance of parkinsonism as a core feature of frontotemporal dementia, relevant to clinical management and the design of future clinical trials.
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PMID:Parkinsonism in frontotemporal dementias. 3177 15