Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gulf War syndrome (GWS) is a perplexing multi-symptom condition comprising a constellation of signs and symptoms consistently described in the literature. These include muscle fatigue and tiredness, malaise, myalgia, impaired cognition, ataxia, diarrhoea, bladder dysfunction, sweating disturbances, headaches, fever, arthralgia, skin rashes, and gastrointestinal and sleep disturbances. Excessive chemical sensitivity and odour intolerance is reported. Epidemiological analysis suggests association with pyridostigmine bromide (PB) use as nerve gas prophylaxis, insect repellent, certain vaccination regimes, a variety of possible chemical exposures and physical and psychological stress. Pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) are potent vasoactive (vasodilatory) neuropeptides (VNs) having pleiotropic functions as immunomodulators, neuroregulators and hormones. VNs also have neurotrophic and anti-apoptotic roles. VNs act on G protein-coupled receptors (GPCRs) to activate adenylate cyclase, an important step in cyclic AMP metabolism. Autoimmune dysfunction of these VNs or their receptors is postulated to give rise to fatigue-related conditions such as chronic fatigue syndrome (CFS). Complex mechanisms involving heat shock proteins (hsps) and cytosine-guanine dinucleotide (CpG) DNA fragments may also be associated with autoimmunity to VNs or their GPCRs in contributing to fatigue-related conditions. Dysfunction of certain VNs may be the missing link in explaining the nebulous nexus between PB and GWS. This paper explores a possible link between exposures to PB and other chemical, physical and psychological stressors in producing a fatigue-related illness possibly related to autoimmune dysfunction of certain VNs. Treatment options involving restoration of VN function are considered in the context of analogues with other neurotransmitter fatigue-related conditions such as myasthenia gravis (MG). While evidence associating these conditions is thin, vasoactive neuropeptide neurotransmitters of the VIP/PACAP family have acetylcholine co-transmission functions via specific GPCRs. Autoimmune reactions to these receptors may have parallels with muscarinic (e.g., Sjogren's syndrome) and nicotinic (e.g., MG) acetylcholine neurotransmission. Hence theoretically, treatment options such as thymectomy, corticosteroids, plasma exchange, anti-idiotype antibodies and receptor genomic expression reactivation/suppression may be considered. Paradoxically pyridostigmine may prove to have a role in therapy although VN treatment/replacement may be associated with tachyphylaxis.
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PMID:Do vasoactive neuropeptide autoimmune disorders explain pyridostigmine's association with Gulf War syndrome? 1600 38

Organophosphate-induced delayed polyneuropathy (OPIDP) is a rare toxicity resulting from exposure to certain organophosphorus (OP) esters. It is characterised by distal degeneration of some axons of both the peripheral and central nervous systems occurring 1-4 weeks after single or short-term exposures. Cramping muscle pain in the lower limbs, distal numbness and paraesthesiae occur, followed by progressive weakness, depression of deep tendon reflexes in the lower limbs and, in severe cases, in the upper limbs. Signs include high-stepping gait associated with bilateral foot drop and, in severe cases, quadriplegia with foot and wrist drop as well as pyramidal signs. In time, there might be significant recovery of the peripheral nerve function but, depending on the degree of pyramidal involvement, spastic ataxia may be a permanent outcome of severe OPIDP. Human and experimental data indicate that recovery is usually complete in the young. At onset, the electrophysiological changes include reduced amplitude of the compound muscle potential, increased distal latencies and normal or slightly reduced nerve conduction velocities. The progression of the disease, usually over a few days, may lead to non-excitability of the nerve with electromyographical signs of denervation. Nerve biopsies have been performed in a few cases and showed axonal degeneration with secondary demyelination. Neuropathy target esterase (NTE) is thought to be the target of OPIDP initiation. The ratio of inhibitory powers for acetylcholinesterase and NTE represents the crucial guideline for the aetiological attribution of OP-induced peripheral neuropathy. In fact, pre-marketing toxicity testing in animals selects OP insecticides with cholinergic toxicity potential much higher than that to result in OPIDP. Therefore, OPIDP may develop only after very large exposures to insecticides, causing severe cholinergic toxicity. However, this was not the case with certain triaryl phosphates that were not used as insecticides but as hydraulic fluids, lubricants and plasticisers and do not result in cholinergic toxicity. Several thousand cases of OPIDP as a result of exposure to tri-ortho-cresyl phosphate have been reported, whereas the number of cases of OPIDP as a result of OP insecticide poisoning is much lower. In this article, we mainly discuss OP pesticide poisoning, particularly when caused by chlorpyrifos, dichlorvos, isofenphos, methamidophos, mipafox, trichlorfon, trichlornat, phosphamidon/mevinphos and by certain carbamates. We also discuss case reports where neuropathies were not convincingly attributed to fenthion, malathion, omethoate/dimethoate, parathion and merphos. Finally, several observational studies on long-term, low-level exposures to OPs that sometimes reported mild, inconsistent and unexplained changes of unclear significance in peripheral nerves are briefly discussed.
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PMID:Organophosphate-induced delayed polyneuropathy. 1604 3

Mutations in the gene coding for the catalytic subunit of the mitochondrial DNA (mtDNA) polymerase gamma (POLG1) have recently been described in patients with diverse clinical presentations, revealing a complex relationship between genotype and phenotype in patients and their families. POLG1 was sequenced in patients from different European diagnostic and research centres to define the phenotypic spectrum and advance understanding of the recurrence risks. Mutations were identified in 38 cases, with the majority being sporadic compound heterozygotes. Eighty-nine DNA sequence changes were identified, including 2 predicted to alter a splice site, 1 predicted to cause a premature stop codon and 13 predicted to cause novel amino acid substitutions. The majority of children had a mutation in the linker region, often 1399G-->A (A467T), and a mutation affecting the polymerase domain. Others had mutations throughout the gene, and 11 had 3 or more substitutions. The clinical presentation ranged from the neonatal period to late adult life, with an overlapping phenotypic spectrum from severe encephalopathy and liver failure to late-onset external ophthalmoplegia, ataxia, myopathy and isolated muscle pain or epilepsy. There was a strong gender bias in children, with evidence of an environmental interaction with sodium valproate. POLG1 mutations cause an overlapping clinical spectrum of disease with both dominant and recessive modes of inheritance. 1399G-->A (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling.
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PMID:Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. 1680 39

Fragile X-associated tremor/ataxia syndrome (FXTAS) is generally considered to be uncommon in older female carriers of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene; however, neither prevalence, nor the nature of the clinical phenotype, has been well characterized in female carriers. In this study, we evaluated 146 female carriers (mean, 42.3 years; range, 20-75 years) with and without core features of FXTAS (tremor; gait ataxia), and 69 age-matched controls (mean, 45.8 years; range, 21-78 years). Compared with controls, carriers with definite or probable FXTAS had greater medical co-morbidity, with increased prevalence of thyroid disease (P = 0.0096), hypertension (P = 0.0020), seizures (P = 0.0077), peripheral neuropathy (P = 0.0040), and fibromyalgia (P = 0.0097), in addition to the typical symptoms of FXTAS-tremor (P < 0.0001) and ataxia (P < 0.0001). The non-FXTAS premutation group had more complaints of chronic muscle pain (P = 0.0097), persistent paraesthesias in extremities (P < 0.0001), and history of tremor (P < 0.0123) than controls. The spectrum of clinical involvement in female carriers with FXTAS is quite broad, encompassing a number of medical co-morbidities as well as the core movement disorder. The remarkable degree of thyroid dysfunction (17% in the non-FXTAS group and 50% in the FXTAS group) warrants consideration of thyroid function studies in all female premutation carriers, particularly those with core features of FXTAS.
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PMID:Expanded clinical phenotype of women with the FMR1 premutation. 1834 75

Within the past few years, there has been a significant change in identifying and characterizing the FMR1 premutation associated phenotypes. The premutation has been associated with elevated FMR1 mRNA levels and slight to moderate reductions in FMRP levels. Furthermore, it has been established that approximately 20% of female premutation carriers present primary ovarian insufficiency (POI) and that fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in one-third of all male premutation carriers older than 50 years. Besides POI and FXTAS, new disorders have recently been described among individuals (especially females) with the FMR1 premutation. Those pathologies include thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. However there are few reports related to FXTAS penetrance among female premutation carriers or regarding these disorders recently associated to the FMR1 premutation. Therefore, we have evaluated 398 fragile X syndrome (FXS) families in an attempt to provide an estimation of the premutation associated phenotypes penetrance. Our results show that signs of FXTAS are detected in 16.5% of female premutation carriers and in 45.5% of premutated males older than 50 years. Furthermore, among females with the FMR1 premutation, penetrance of POI, thyroid disease and chronic muscle pain is 18.6, 15.9 and 24.4%, respectively. The knowledge of this data might be useful for accurate genetic counselling as well as for a better characterization of the clinical phenotypes of FMR1 premutation carriers.
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PMID:Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. 1936 23

Gabapentin (GBP) is a drug which is frequently used in diabetic neuropathy. Common adverse effects of GBP include drowsiness, dizziness, ataxia, somnolence, and fatigue. Rhabdomyolysis is an extremely rare side effect of GBP. In this report we describe a case of GBP-induced rhabdomyolysis in a 63-year-old diabetic woman. She presented with severe muscle pain in her extremities, fatigue, decreased urine output and urine discoloration within 3 weeks after starting treatment with GBP (900 mg/day) for diabetic neuropathy. Laboratory tests revealed extreme elevations of muscle enzymes, increased creatinine and potassium levels. She required hemodialysis as a result of anuria. Investigation confirmed the diagnosis of rhabdomyolysis, and discontinuation of GBP resulted in resolution of clinical and biochemical features of rhabdomyolysis.
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PMID:Gabapentin-induced rhabdomyolysis in a patient with diabetic neuropathy. 1952 4

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG repeat expansion in the premutation range (55-200) in the fragile X mental retardation 1 gene. Onset is typically in the early seventh decade, and men are principally affected. The major signs are cerebellar gait ataxia, intention tremor, frontal executive dysfunction, and global brain atrophy. Other frequent findings are parkinsonism (mild), peripheral neuropathy, psychiatric symptoms (depression, anxiety, and agitation), and autonomic dysfunction. The clinical presentation is heterogeneous, with individuals presenting with varied dominating signs, such as tremor, dementia, or neuropathy. Magnetic resonance imaging shows atrophy and patchy white matter lesions in the cerebral hemispheres and middle cerebellar peduncles. The latter has been designated the middle cerebellar peduncle sign, which occurs in about 60% of affected men, and is relatively specific for FXTAS. Affected females generally have less severe disease, less cognitive decline, and some symptoms different from that of men, for example, muscle pain. Management of FXTAS is complex and includes assessment of the patient's neurological and medical deficits, treatment of symptoms, and provision of relevant referrals, especially genetic counseling. Treatment is empirical, based on anecdotal experience and on knowledge of what works for symptoms of other disorders that also exist in FXTAS. Presently, the disorder is underrecognized because the first published report was only in 2001 and because the presentation is variable and mainly consists of a combination of signs common in the elderly. However, accurate diagnosis is critical for the patient and for the family because they need education regarding their genetic and health risks.
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PMID:Fragile X-associated tremor/ataxia syndrome: clinical phenotype, diagnosis, and treatment. 1957 29

COL-3 is a chemically modified tetracycline that targets multiple aspects of matrix metalloproteinase regulation. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of COL-3 in adults with recurrent high-grade glioma, to describe the effects of enzyme-inducing antiseizure drugs (EIADs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Adults with recurrent high-grade glioma were stratified by EIAD use. COL-3 was given orally daily without interruption until disease progression or treatment-related dose-limiting toxicity (DLT). Three patients in each EIAD group were evaluated at each dose level beginning with 25 mg/m(2)/day and escalated by 25 mg/m(2)/day. Toxicity, response, and pharmacokinetics were assessed. Thirty-three patients were evaluated. The MTD was 75 mg/m(2)/day in the -EIAD patients while one was not determined in +EIAD patients. The common toxicities observed were anemia, ataxia, diarrhea, hypokalemia, CNS hemorrhage, and myalgia. One partial response was observed. -EIAD patients tended to have a higher steady-state trough concentration that was apparent only at the 100 mg/m(2)/day dose level (P = 0.01). This study suggests that: (a) EIAD use does affect the pharmacokinetics of COL-3 at higher doses; and (b) there was not enough suggestion of single-agent activity to warrant further study in recurrent high-grade gliomas.
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PMID:Phase I and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas. 2154 95

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an under-recognized disorder that is a significant cause of late-adult-onset ataxia. The etiology is expansion of a trinucleotide repeat to the premutation range (55-200 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene. Expansion to >200 CGGs causes fragile X syndrome, the most common heritable cause of cognitive impairment and autism. Core features of FXTAS include progressive action tremor and gait ataxia; with frequent, more variable features of cognitive decline, especially executive dysfunction, parkinsonism, neuropathy, and autonomic dysfunction. MR imaging shows generalized atrophy and frequently abnormal signal in the middle cerebellar peduncles. Autopsy reveals intranuclear inclusions in neurons and astrocytes and dystrophic white matter. FXTAS is likely due to an RNA toxic gain-of-function of the expanded-repeat mRNA. The disorder typically affects male premutation carriers over age 50, and, less often, females. Females also are at increased risk for primary ovarian insufficiency, chronic muscle pain, and thyroid disease. Treatment targets specific symptoms, but progression of disability is relentless. Although the contribution of FXTAS to the morbidity and mortality of the aging population requires further study, the disorder is likely the most common single-gene form of tremor and ataxia in the older adult population.
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PMID:Fragile X-associated tremor/ataxia syndrome. 2182 1

Gulf War syndrome (GWS) is a multi-symptom condition comprising a variety of signs and symptoms described in the literature, which not been fully resolved. The various symptoms of the condition include muscle fatigue and tiredness, malaise, myalgia, impaired cognition, ataxia, diarrhoea, bladder dysfunction, sweating disturbances, headaches, fever, arthralgia, skin rashes, and gastrointestinal and sleep disturbances. In addition, excessive chemical sensitivity and odour intolerance is reported. The aetiology of the condition is unclear, but many reviews and epidemiological analyses suggest association with pyridostigmine bromide (PB), certain vaccination regimes, a variety of possible chemical exposures, including smoke from oil-well fires or depleted uranium from shells, as well as physical and psychological stress. Recently, Shoenfeld et al. suggested that four conditions--siliconosis, macrophagic myofaciitis (MMF), GWS and post-vaccination phenomena--that share clinical and pathogenic resemblances, may be incorporated into common syndrome called 'Autoimmune (Autoinflammatory) Syndrome induced by Adjuvants' (ASIA). Symptoms and signs of the four conditions described by Shoenfeld et al. show that at least eight out of ten main symptoms are in correlation in all four conditions. Namely, myalgia, arthralgias, chronic fatigue, neurological cognitive impairment, gastrointestinal symptoms, respiratory symptoms, skin manifestations and appearance of autoantibodies. Regardless of the aetiology of GWS, be it exposure to environmental factors or chemical drugs, vaccinations or the adjuvants in them, GWS fits well with the definition of ASIA and is included as part of 'Shoenfeld's syndrome'.
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PMID:Gulf War syndrome as a part of the autoimmune (autoinflammatory) syndrome induced by adjuvant (ASIA). 2223 52


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