Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0241981 (loss of balance)
 452 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Butanal oxime is used as a volatile antiskinning agent in paints, inks, and similar products. Butanal oxime was chosen for toxicology testing as a representative of the aldoxime class. Male and female F344/N rats and B6C3F1 mice received butanal oxime (99 percent pure) in drinking water for 15 days or by gavage in 0.5 percent methylcellulose for 14 weeks. Animals were evaluated for clinical pathology, reproductive system effects, and histopathology. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. In the 15-day studies, groups of five male and five female rats and mice received 0, 312, 625, 1,250, 2,500, or 5,000 ppm butanal oxime in drinking water, resulting in average daily doses of approximately 40, 70, or 100 mg butanal oxime/kg body weight to male and female rats; 45, 90, 130, 200, or 300 mg/kg to male mice; and 45, 85, 100, 130, or 170 mg/kg to female mice. Due to body weight loss and lack of water consumption, all male and female rats receiving 2,500 or 5,000 ppm were removed from the study on day 9; average daily doses were not calculated for these groups. All other rats and mice survived until the end of the studies. Mean body weights of 1,250 ppm male and female rats and 2,500 and 5,000 ppm male and female mice were significantly less than those of the controls. Male mice receiving 5,000 ppm and females receiving 2,500 or 5,000 ppm lost weight during the study. Water consumption by rats and mice receiving 1,250 ppm or greater was less than that by the controls. Thinness in 2,500 and 5,000 ppm rats and mice was the only clinical finding of toxicity. Spleen weights were significantly decreased in 2,500 and 5,000 ppm female mice. No chemical-related lesions were observed grossly; histologic examinations were not performed. In the 14-week studies, groups of 10 male and 10 female rats and mice received butanal oxime by gavage at doses of 0, 25, 50, 100, 200, or 600 mg/kg, 5 days per week for 14 weeks. All 600 mg/kg rats died or were killed moribund during the first week of the study; in the 600 mg/kg mouse groups, seven males and nine females died, were killed moribund, or were killed accidentally before the end of the study. Mean body weights of 100 and 200 mg/kg male rats, 600 mg/kg male mice, and female mice administered 50 mg/kg or greater were less than those of the controls. Clinical findings of toxicity in 600 mg/kg rats included loss of coordination, wobbly gait, shaking, blinking, constant grooming and scratching of the face, head weaving, burying of the face in bedding, lethargy, and prostration; in 600 mg/kg mice, clinical findings included ataxia, loss of balance after rearing, squinting, and burying of the face in the bedding. Hematology results of the 14-week gavage studies indicate that butanal oxime induces a methemoglobinemia and a responsive anemia in rats and mice. Spleen weights of 100 and 200 mg/kg male rats, female rats administered 50 mg/kg or greater, and 200 and 600 mg/kg male mice were increased, as were the liver weights of 200 mg/kg female rats and mice. In animals that died early due to butanal oxime administration, hepatocellular necrosis was the primary pathologic finding. Degeneration of the nasal olfactory epithelium was observed in dosed rats and mice that died early as well as in animals that survived to the end of the studies. Additional chemical-related nasal findings were respiratory epithelial changes in male rats and suppurative exudate in male and female mice. Increased incidences and/or severities of splenic hematopoietic cell proliferation and pigmentation (hemosiderin) as well as bone marrow hyperplasia were also observed in dosed groups, particularly in the 200 and 600 mg/kg groups, and were indicative of erythrocyte damage. Butanal oxime (3 to 10,000 ug/plate) was mutagenic in S. typhimurium strain TA1535 in the presence of 5 percent or 10 percent rat liver S9; an equivocal response was seen in TA100 with 30 percent rat S9, and no mutagenic activity was seen in TA98, with or without rat or hamster liver S9. Butanal oxime induced chromosomal aberrations in cultured Chinese hamster ovary cells, with and without S9. Significant increases in the frequencies of micronucleated normochromatic erythrocytes were observed in vivo in peripheral blood of male and female mice administered 25 to 600 mg/kg butanal oxime for 14 weeks by gavage. Synonyms: Butanaloxime; butylaldoxime; butyraldehyde oxime; n-butyraldehyde oxime; butyraldoxime; n-butyraldoxime Trade names: Exkin 1, Exkin No. 1 Anti-Skinning Agent, Skino #1, Troykyd Anti-Skin BTO
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PMID:NTP technical report on the toxicity studies of Butanal oxime (CAS No. 110-69-0) administered in drinking water and by gavage to F344/N rats and B6C3F1 mice. 1501 36

Many human inherited neurodegenerative disorders are characterized by loss of balance due to cerebellar Purkinje cell (PC) degeneration. Although the disease-causing mutations have been identified for a number of these disorders, the normal functions of the proteins involved remain, in many cases, unknown. To gain insight into the function of proteins involved in PC degeneration, we developed an interaction network for 54 proteins involved in 23 inherited ataxias and expanded the network by incorporating literature-curated and evolutionarily conserved interactions. We identified 770 mostly novel protein-protein interactions using a stringent yeast two-hybrid screen; of 75 pairs tested, 83% of the interactions were verified in mammalian cells. Many ataxia-causing proteins share interacting partners, a subset of which have been found to modify neurodegeneration in animal models. This interactome thus provides a tool for understanding pathogenic mechanisms common for this class of neurodegenerative disorders and for identifying candidate genes for inherited ataxias.
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PMID:A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. 1671 57

The mitochondrial m-AAA protease has a crucial role in axonal development and maintenance. Human mitochondria possess two m-AAA protease isoenzymes: a hetero-oligomeric complex, composed of paraplegin and AFG3L2 (Afg3 like 2), and a homo-oligomeric AFG3L2 complex. Loss of function of paraplegin (encoded by the SPG7 gene) causes hereditary spastic paraplegia, a disease characterized by retrograde degeneration of cortical motor axons. Spg7(-/-) mice show a late-onset degeneration of long spinal and peripheral axons with accumulation of abnormal mitochondria. In contrast, Afg3l2(Emv66/Emv66) mutant mice, lacking the AFG3L2 protein, are affected by a severe neuromuscular phenotype, due to defects in motor axon development. The role of the homo-oligomeric m-AAA protease and the extent of cooperation and redundancy between the two isoenzymes in adult neurons are still unclear. Here we report an early-onset severe neurological phenotype in Spg7(-/-) Afg3l2(Emv66/+) mice, characterized by loss of balance, tremor and ataxia. Spg7(-/-) Afg3l2(Emv66/+) mice display acceleration and worsening of the axonopathy observed in paraplegin-deficient mice. In addition, they show prominent cerebellar degeneration with loss of Purkinje cells and parallel fibers, and reactive astrogliosis. Mitochondria from affected tissues are prone to lose mt-DNA and have unstable respiratory complexes. At late stages, neurons contain structural abnormal mitochondria defective in COX-SDH reaction. Our data demonstrate genetic interaction between the m-AAA isoenzymes and suggest that different neuronal populations have variable thresholds of susceptibility to reduced levels of the m-AAA protease. Moreover, they implicate impaired mitochondrial proteolysis as a novel pathway in cerebellar degeneration.
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PMID:Genetic interaction between the m-AAA protease isoenzymes reveals novel roles in cerebellar degeneration. 1928 3

An adult cat was presented with the history of 3 months' weight loss and more recent loss of balance and ataxia. An abdominal mass was palpable; results of neurologic examination suggested a brainstem disorder. The owners elected euthanasia. Postmortem findings included suppurative jejunal lymphadenitis and bilateral demyelination in the ventral pons with sparing of axons and neuronal soma. The location and character of the lesion mimicked those of human central pontine myelinolysis, an iatrogenic condition that may follow rapid correction of hyponatremia or develop spontaneously in patients with malnutrition or energy deprivation. In this cat, the poor nutritional state may have contributed to the development of this novel pontine lesion.
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PMID:Primary bilateral pontine demyelination in a cat with similarity to central pontine myelinolysis. 2063 14

The hereditary cerebellar ataxias are a diverse group of neurodegenerative disorders primarily characterised by loss of balance and coordination due to dysfunction of the cerebellum and its associated pathways. Although many genetic mutations causing inherited cerebellar ataxia have been identified, a significant percentage of patients remain whose cause is unknown. The transient receptor potential (TRP) family member TRPC3 is a non-selective cation channel linked to key signalling pathways that are affected in cerebellar ataxia. Furthermore, genetic mouse models of TRPC3 dysfunction display cerebellar ataxia, making the TRPC3 gene an excellent candidate for screening ataxic patients with unknown genetic aetiology. Here, we report a genetic screen for TRPC3 mutations in a cohort of 98 patients with genetically undefined late-onset cerebellar ataxia and further ten patients with undefined episodic ataxia. We identified a number of variants but no causative mutations in TRPC3. Our findings suggest that mutations in TRPC3 do not significantly contribute to the cause of late-onset and episodic human cerebellar ataxias.
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PMID:Candidate screening of the TRPC3 gene in cerebellar ataxia. 2132 8

Spinocerebellar ataxia (SCA) in the Parson Russell Terrier (PRT) dog breed is a disease of progressive incoordination of gait and loss of balance. Clinical signs usually become notable between 6 and 12 months of age with affected dogs presenting with symmetric spinocerebellar ataxia particularly evident in the pelvic limbs. The degree of truncal ataxia, pelvic limb hypermetria and impaired balance is progressive, particularly during the initial months of disease. A certain degree of stabilisation as well as intermittent worsening may occur. At the later stages of the disease ambulation often becomes difficult, with owners often electing to euthanise affected dogs on welfare grounds. Using a GWAS approach and target-enriched massively-parallel sequencing, a strongly associated non-synonymous SNP in the CAPN1 gene, encoding the calcium dependent cysteine protease calpain1 (mu-calpain), was identified. The SNP is a missense mutation causing a cysteine to tyrosine substitution at residue 115 of the CAPN1 protein. Cysteine 115 is a highly conserved residue and forms a key part of a catalytic triad of amino acids that are crucial to the enzymatic activity of cysteine proteases. The CAPN1 gene shows high levels of expression in the brain and nervous system and roles for the protein in both neuronal necrosis and maintenance have been suggested. Given the functional implications and high level of conservation observed across species, the CAPN1 variant represents a provocative candidate for the cause of SCA in the PRT and a novel potential cause of ataxia in humans.
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PMID:Missense mutation in CAPN1 is associated with spinocerebellar ataxia in the Parson Russell Terrier dog breed. 2374 57

At age 35, a man with a genetic diagnosis of Charcot-Marie-Tooth disease type 1A (CMT1A) but no family history of neuropathy and no clinical symptoms developed rapidly progressive loss of balance, distal limb numbness, loss of manual dexterity, and hand tremor. Five years later, he walked with support and had mild pes cavus, marked sensory ataxia, severe leg and hand weakness, absent deep tendon reflexes (DTRs), severe sensory loss, and hand tremor. He had dramatically reduced motor nerve conduction velocity (MNCV), strikingly prolonged motor distal latencies, absent sensory action potentials and lower limb compound muscle action potentials. CMT1A duplication was reconfirmed but the dramatic change in his clinical course suggested a superimposed acquired neuropathy. An IgM-kappa monoclonal gammopathy of uncertain significance (MGUS) with high titer anti-myelin associated glycoprotein (anti-MAG) activity was found. Nerve biopsy showed severe loss of myelinated fibers with onion bulbs, no evidence of uncompacted myelin, and few IgM deposits. Rituximab was given and he improved. It is very likely that this is a chance association of two rare and slowly progressive neuropathies; rapidly worsening course may have been due to a "double hit". Interestingly, there are reports of possible superimposition of dysimmune neuropathies on hereditary ones, and the influence of the immune system on inherited neuropathies is matter for debate.
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PMID:Coexistence of Charcot-Marie-Tooth disease type 1A and anti-MAG neuropathy. 2378 67

It is well known that the cerebellum is important for movement control and plays a critical role in balance and locomotion. As such, one of the most characteristic and sensitive signs of cerebellar damage is gait ataxia. However, characterizing ataxic gait is no easy task, because gait patterns are highly variable. This variability seems to result from the interaction of different factors, namely, (1) the primary motor deficits in balance control and multi-joint coordination and oculomotor dysfunction, (2) the safety strategies used, and (3) inaccurate adjustments in patients with loss of balance. In this report, we review different approaches to analyzing ataxic gait and studies to identify and quantify the different factors contributing to this movement disorder. We also discuss the influence of the cerebellum in adaptive locomotor control, the interaction between cognitive load and gait in dual-task paradigms, and the recent advances in rehabilitation of gait and posture for patients with cerebellar degeneration. In the second part, we discuss open questions concerning cerebellar mechanisms in multi-joint coordination during different walking conditions. Furthermore, we point out potential future directions in motor rehabilitation, with the objective of identifying predictors of rehabilitation outcome and the development of individualized training programs that potentially involve rehabilitation technology.
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PMID:Gait ataxia--specific cerebellar influences and their rehabilitation. 2413 45

Recently there is increased regulatory interest in the assessment of physical dependence and withdrawal as part of the safety assessment for novel therapeutic entities. Choosing appropriate and sensitive parameters to detect withdrawal syndromes, and relevant positive control comparator drugs that can be administered in the same manner as the test agent, are critical study design elements. Pilot studies to determine the effects of oral ketamine in cynomolgus monkeys during, and following cessation of treatment, were explored. Detailed behavioral observations (both remote and interactive), food consumption, and body weight and temperature, were assessed during the dose-ranging, repeat dose (5 or 14 days), and withdrawal phases (3 or 5 days). Doses explored during dose-ranging included 20, 40, 100, or 200 mg/kg ketamine; subsequent withdrawal assessments were conducted following repeat dosing of 150 mg/kg. In the 14-day dosing study, exposure to ketamine and norketamine was assessed following 8 days of dosing. Administration of 150 mg/kg ketamine produced decreased activity, loss of balance, ataxia, hunched posture, nystagmus, lateral recumbence, and changes in alertness levels during dosing phases. When ketamine was withdrawn, increased reactivity, increased activity, and stereotypic behaviors were demonstrated that were absent during baseline or the dosing phase of the studies.
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PMID:Withdrawal assessment following subchronic oral ketamine administration in Cynomolgus macaques. 2464 80

Cerebellar dysfunction causes ataxia characterized by loss of balance and coordination. Until now, the molecular and neuronal mechanisms of several types of inherited cerebellar ataxia have not been completely clarified. Here, we report that leucine-rich G protein-coupled receptor 4 (Lgr4/Gpr48) is highly expressed in Purkinje cells (PCs) in the cerebellum. Deficiency of Lgr4 leads to an ataxia-like phenotype in mice. Histologically, no obvious morphological changes were observed in the cerebellum of Lgr4 mutant mice. However, the number of PCs was slightly but significantly reduced in Lgr4(-/-) mice. In addition, in vitro electrophysiological analysis showed an impaired long term depression (LTD) at parallel fiber-PC (PF-PC) synapses in Lgr4(-/-) mice. Consistently, immunostaining experiments showed that the level of phosphorylated cAMP-responsive element-binding protein (Creb) was significantly decreased in Lgr4(-/-) PCs. Furthermore, treatment with forskolin, an adenylyl cyclase agonist, rescued phospho-Creb in PCs and reversed the impairment in PF-PC LTD in Lgr4(-/-) cerebellar slices, indicating that Lgr4 is an upstream regulator of Creb signaling, which is underlying PF-PC LTD. Together, our findings demonstrate for first time an important role for Lgr4 in motor coordination and cerebellar synaptic plasticity and provide a potential therapeutic target for certain types of inherited cerebellar ataxia.
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PMID:Lgr4 protein deficiency induces ataxia-like phenotype in mice and impairs long term depression at cerebellar parallel fiber-Purkinje cell synapses. 2506 12


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