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)

There has been gradual increase of interest in olfactory dysfunction since it was realised that anosmia was a common feature of idiopathic Parkinson's disease (IPD) and Alzheimer-type dementia. It is an intriguing observation that a premonitory sign of a disorder hitherto regarded as one of movement or cognition may be that of disturbed sense of smell. In this review of aging, IPD, parkinsonian syndromes, tremor, Alzheimer's disease (AD), motor neuron disease (MND), Huntington's chorea (HC) and inherited ataxia, the following observations are made: (1) olfactory senescence starts at about the age of 36 years in both sexes and accelerates with advancing years, involving pleasant odours preferentially; (2) olfactory dysfunction is near-universal, early and often severe in IPD and AD developing before any movement or cognitive disorder; (3) normal smell identification in IPD is rare and should prompt review of diagnosis unless the patient is female with tremor-dominant disease; (4) anosmia in suspected progressive supranuclear palsy and corticobasal degeneration is atypical and should likewise provoke diagnostic review; (5) subjects with hyposmia and one ApoE4 allele have an approximate 5-fold increased risk of later AD; (6) impaired sense of smell may be seen in some patients at 50% risk of parkinsonism, and possibly in patients with unexplained hyposmia; (7) smell testing in HC and MND where abnormality may be found is not likely to be of clinical value, and (8) biopsy of olfactory nasal neurons reveals non-specific changes in IPD and AD and at present will not aid diagnosis.
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PMID:Olfaction in neurodegenerative disorder. 1673 38

Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion mutation located in the 3' untranslated portion of the dystrophica myotonin protein kinase gene. The identification and characterization of RNA-binding proteins that interact with expanded CUG repeats and the discovery that a similar transcribed but untranslated CCTG expansion in an intron causes myotonic dystrophy type 2 (DM2) have uncovered a new type of mechanism in which microsatellite expansion mutations cause disease through an RNA gain-of-function mechanism. This review discusses RNA pathogenesis in DM1 and DM2 and evidence that similar mechanisms may play a role in a growing number of dominant noncoding expansion disorders, including fragile X tremor ataxia syndrome (FXTAS), spinocerebellar ataxia type 8 (SCA8), SCA10, SCA12, and Huntington's disease-like 2 (HDL2).
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PMID:RNA-mediated neuromuscular disorders. 1677 86

A substantial portion of the human genome has been found to consist of simple sequence repeats, including microsatellites and minisatellites. Microsatellites, tandem repeats of 1-6 nucleotides, form the template for dynamic mutations, which involve heritable changes in the lengths of repeat sequences. In recent years, a large number of human disorders have been found to be caused by dynamic mutations, the most common of which are trinucleotide repeat expansion diseases. Dynamic mutations are common to numerous nervous system disorders, including Huntington's disease, various spinocerebellar ataxias, fragile X syndrome, fragile X tremor/ataxia syndrome, Friedreich ataxia and other neurodegenerative disorders. The involvement of dynamic mutations in brain disorders will be reviewed, with a focus on the large group caused by CAG/glutamine repeat expansions. We will also outline a proposed role of tandem repeat polymorphisms (TRPs), with unique 'digital' genetic distributions, in modulating brain development and normal function, so as to generate additional mutational diversity upon which natural selection may act.
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PMID:Dynamic mutations as digital genetic modulators of brain development, function and dysfunction. 1750 92

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

The general model that dominant diseases are caused by mutations that result in a gain or change in function of the corresponding protein was challenged by the discovery that the myotonic dystrophy type 1 mutation is a CTG expansion located in the 3' untranslated portion of a kinase gene. The subsequent discovery that a similar transcribed but untranslated CCTG expansion in an intron causes the same multisystemic features in myotonic dystrophy type 2 (DM2), along with other developments in the DM1 field, demonstrate a mechanism in which these expansion mutations cause disease through a gain of function mechanism triggered by the accumulation of transcripts containing CUG or CCUG repeat expansions. A similar RNA gain of function mechanism has also been implicated in fragile X tremor ataxia syndrome (FXTAS) and may play a role in pathogenesis of other non-coding repeat expansion diseases, including spinocerebellar ataxia type 8 (SCA8), SCA10, SCA12 and Huntington disease-like 2.
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PMID:Dominant non-coding repeat expansions in human disease. 1872 54

Some movement disorders can be treated successfully by surgical procedures such as chronic deep brain stimulation of the subthalamic nucleus, the thalamus or the globus pallidus, as well as lesioning techniques of thalamotomy and pallidotomy, radiosurgical treatment with the Gamma Knife in the thalamus or globus pallidus, and cerebral graft in Parkinson's and Huntington's diseases. The major indications of these surgical techniques are Parkinson's disease, essential tremor, dystonia, Huntington's disease and tremor in multiple sclerosis.
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PMID:[Surgical treatment of movement disorders]. 1894 72

There is evidence that cannabinoid-based medicines that are selective for different targets in the cannabinoid signalling system (e.g. receptors, inactivation mechanism, enzymes) might be beneficial in basal ganglia disorders, namely Parkinson's disease (PD) and Huntington's disease (HD). These benefits not only include the alleviation of specific motor symptoms [e.g. choreic movements with cannabinoid receptor type 1 (CB(1))/transient receptor potential vanilloid type 1 agonists in HD; bradykinesia with CB(1) antagonists and tremor with CB(1) agonists in PD], but also the delay of disease progression due to the neuroprotective properties demonstrated for cannabinoids (e.g. CB(1) agonists reduce excitotoxicity; CB(2) agonists limit the toxicity of reactive microglia; and antioxidant cannabinoids attenuate oxidative damage). In addition, extensive biochemical, anatomical, physiological and pharmacological studies have demonstrated that: (i) the different elements of the cannabinoid system are abundant in basal ganglia structures and they are affected by these disorders; (ii) the cannabinoid system plays a prominent role in basal ganglia function by modulating the neurotransmitters that operate in the basal ganglia circuits, both in healthy and pathological conditions; and (iii) the activation and/or inhibition of the cannabinoid system is associated with important motor responses that are maintained and even enhanced in conditions of malfunctioning and/or degeneration. In this article we will review the available data regarding the relationship between the cannabinoid system and basal ganglia activity, both in healthy and pathological conditions and will also try to identify future lines of research expected to increase current knowledge about the potential therapeutic benefits of targeting this system in PD, HD and other basal ganglia disorders.
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PMID:The endocannabinoid system as a target for the treatment of motor dysfunction. 1922 Feb 90

Abnormal involuntary movements are major features of a large group of neurologic disorders, some of which are neurodegenerative and pose a significant diagnostic and treatment challenge to treating physicians. This article presents a concise review of clinical features, pathogenesis, epidemiology, and management of seven of the most common movement disorders encountered in a primary care clinic routinely. The disorders discussed are Parkinson disease, essential tremor, restless legs syndrome, Huntington disease, drug-induced movement disorder, Wilson disease, and Tourette syndrome.
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PMID:Movement disorders. 1927 14

Endogenous protein quality control machinery has long been suspected of influencing the onset and progression of neurodegenerative diseases characterized by accumulation of misfolded proteins. Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expansion of a polyglutamine (polyQ) tract in the protein huntingtin (htt), which leads to its aggregation and accumulation in inclusion bodies. Here, we demonstrate in a mouse model of HD that deletion of the molecular chaperones Hsp70.1 and Hsp70.3 significantly exacerbated numerous physical, behavioral and neuropathological outcome measures, including survival, body weight, tremor, limb clasping and open field activities. Deletion of Hsp70.1 and Hsp70.3 significantly increased the size of inclusion bodies formed by mutant htt exon 1, but surprisingly did not affect the levels of fibrillar aggregates. Moreover, the lack of Hsp70s significantly decreased levels of the calcium regulated protein c-Fos, a marker for neuronal activity. In contrast, deletion of Hsp70s did not accelerate disease in a mouse model of infectious prion-mediated neurodegeneration, ruling out the possibility that the Hsp70.1/70.3 mice are nonspecifically sensitized to all protein misfolding disorders. Thus, endogenous Hsp70s are a critical component of the cellular defense against the toxic effects of misfolded htt protein in neurons, but buffer toxicity by mechanisms independent of the deposition of fibrillar aggregates.
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PMID:Loss of Hsp70 exacerbates pathogenesis but not levels of fibrillar aggregates in a mouse model of Huntington's disease. 1960 47

Neuronal intranuclear inclusions (NIIs) are a histopathological hallmark of several neurodegenerative disorders. However, the role played by NIIs in neurodegenerative pathogenesis remains enigmatic. Defining their molecular composition represents an important step in understanding the pathophysiology of these disorders. Recently, a nuclear protein, "fused-in-sarcoma" (FUS) was identified as the pathological protein in two forms of frontotemporal lobar degeneration (FTLD-IF, formerly known as neuronal intermediate filament inclusion disease, and FTLD-UPS, formerly known as atypical FTLD-U), both of which are characterized by the presence of NII. The objective of the present study was to determine the range of neurodegenerative disorders characterized by FUS-positive NIIs. Immunostaining for FUS revealed intense reactivity of NIIs in FTLD-IF and FTLD-UPS as well as in Huntington's disease, spinocerebellar ataxias 1 and 3, and neuronal intranuclear inclusion body disease. In contrast, there was no FUS staining of NIIs in inherited forms of FTLD-TDP caused by GRN and VCP mutations, fragile-X-associated tremor ataxia syndrome, or oculopharyngeal muscular dystrophy. In a cell culture model of Huntington's disease, NIIs were intensely FUS-positive. NII-bearing cells displayed loss of the normal diffuse nuclear pattern of FUS staining. This suggests that sequestration of nuclear FUS by NIIs may interfere with its normal nuclear localization.
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PMID:FUS-immunoreactive intranuclear inclusions in neurodegenerative disease. 1983 37


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