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)

Opsoclonus is a rare disorder of the saccadic system, in which fixation is continuously interrupted by multivectorial, back-to-back saccades that at times can be seen only with an ophthalmoscope. To diagnose it reliably, eye movement recording is required. Opsoclonus may be a harbinger of an occult malignancy, though many cases are postinfectious, toxic-metabolic or idiopathic. The underlying malignancy is usually neural crest tumors in children and lung, breast, or gynecologic cancer in adults. Opsoclonus can be accompanied by myoclonus and ataxia. Concurrent appearance of oscillations affecting eyes and limbs suggests a common brainstem generator. Dysfunction of the glycinergic omnipause neurons in the nucleus raphe interpositus has been proposed. Autoantibodies against neural epitopes shared with a tumor are implicated in the pathogenesis of opsoclonus in paraneoplastic cases. Because of the association with malignancies, full oncological work-up is indicated in every case. Coexisting opsoclonus carries a relatively good prognosis for the cancer; however, the neurologic disability may remain even if the tumor has been arrested. New, potentially effective immunoadsorption therapy for opsoclonus is currently under investigation.
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PMID:Opsoclonus. 887 53

The development of a normal cell into a tumor cell appears to depend in part on mutations in genes that normally control cell cycle and cell death, thereby resulting in inappropriate cellular survival and tumorigenesis. ATM ("mutated in ataxia-telangiectasia") and p53 are two gene products that are believed to play a major role in maintaining the integrity of the genome such that alterations in these gene products may contribute to increased incidence of genomic changes such as deletions, translocations, and amplifications, which are common during oncogenesis. p53 is a critical participant in a signal transduction pathway that mediates either a G1 arrest or apoptosis in response to DNA damage. In addition, p53 is believed to be involved in the mitotic spindle checkpoint and in the regulation of centrosome function. Following certain cytotoxic stresses, normal ATM function is required for p53-mediated G1 arrest. ATM is also involved in other cellular processes such as S phase and G2-M phase arrest and in radiosensitivity. The understanding of the roles that both p53 and ATM play in cell cycle progression and cell death in response to DNA damage may provide new insights into the molecular mechanisms of cellular transformation and may help identify potential targets for improved cancer therapies.
Adv Cancer Res 1997
PMID:p53 and ATM: cell cycle, cell death, and cancer. 911 62

We report on a Mexican boy with microcephaly, short stature, and a high frequency of chromosome aberrations with rearrangements involving chromosomes 7 and 14, typical of ataxia telangiectasia (AT) patients. He had neither ataxia nor telangiectasia, and his immunological status and serum alpha feto protein (AFP) level were normal. Bleomycin hypersensitivity, which has been demon-strated in AT patients, was tested in the patient using AT and normal subjects for comparison. The frequency of spontaneously occurring chromosome aberrations in lymphocyte cultures was significantly higher in the patient and the AT patient than in the normal subject. Four cells from the patient showed structural rearrangements involving chromosomes 7 or 14, with breakpoints typical for AT. When exposed to 5.0 micrograms bleomycin, the lymphocytes from the AT patient showed the highest sensitivity to this agent; our patient had an intermediate sensitivity. In both patients several rearrangements involving chromosomes 7 and 14 were scored, while none were observed in the normal subject. A colony survival assay (CSA) [Huo et al., 1994: Cancer Res 54:2544-2547], using a lymphoblastoid cell line (LCL) derived from our patient, showed a survival fraction (SF) of 7%, which is in the same range as in AT patients. The clinical picture, together with the cytogenetic and radiosensitivity results, suggests that our patient fits the variable spectrum of Nijmegen breakage syndrome.
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PMID:Chromosome instability with bleomycin and X-ray hypersensitivity in a boy with Nijmegen breakage syndrome. 912 36

Cowden disease (CD) is an autosomal dominant cancer predisposition syndrome associated with an elevated risk for tumours of the breast, thyroid and skin. Lhermitte-Duclos disease (LDD) cosegregates with a subset of CD families and is associated with macrocephaly, ataxia and dysplastic cerebellar gangliocytomatosis. The common feature of these diseases is a predisposition to hamartomas, benign tumours containing differentiated but disorganized cells indigenous to the tissue of origin. Linkage analysis has determined that a single locus within chromosome 10q23 is likely to be responsible for both of these diseases. A candidate tumour suppressor gene (PTEN) within this region is mutated in sporadic brain, breast and prostate cancer. Another group has independently isolated the same gene, termed MMAC1, and also found somatic mutations throughout the gene in advanced sporadic cancers. Mutational analysis of PTEN in CD kindreds has identified germline mutations in four of five families. We found nonsense and missense mutations that are predicted to disrupt the protein tyrosine/dual-specificity phosphatase domain of this gene. Thus, PTEN appears to behave as a tumour suppressor gene in the germline. Our data also imply that PTEN may play a role in organizing the relationship of different cell types within an organ during development.
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PMID:Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. 914 Mar 96

Paraneoplastic cerebellar degeneration (PCD) presents with acute or subacute onset of ataxia, dysarthria, and intention tremor. In patients older than 50 years, acute or subacute cerebellar degeneration is paraneoplastic in origin in 50% of cases. Paraneoplastic cerebellar degeneration most often precedes a potentially curable remote malignancy. Less often, PCD occurs in a patient with a known malignancy or heralds the onset of a recurrence. The presence of specific antibodies in serum samples helps to guide identification of the occult underlying malignancy. Physicians should entertain the diagnosis of PCD when older patients present with signs of cerebellar degeneration without an obvious cause. A systematic evaluation, including the selection of appropriate imaging and laboratory studies, will often enable physicians to identify the responsible cancer. However, because PCD can precede a cancer by months to years, periodic reevaluation is needed when the cancer remains occult.
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PMID:Paraneoplastic cerebellar degeneration. Case report and literature review. 918 38

We report a 64-year-old woman who developed nausea, headache, and consciousness disturbance. She was well until four years before the onset of her neurologic illness when (April of 1990 at her 59 years of the age) she was found to have an early cancer in her anterior wall of the lower stomach. Subtotal gastrectomy was performed and the operative result was reported as curative. Four years after the surgery (December of 1994 at her 64 years of the age), she noted suboccipital headache and nausea which had become progressively worse and she was admitted to our service on May 24, 1995. On admission, she appeared chronically ill but general physical examination was unremarkable with normal vital signs. Neurologically she was alert and not demented, and the higher cerebral functions were intact. Cranial nerves were also unremarkable. She was able to walk in tandem and on heels. No motor weakness or ataxia was noted. Deep tendon reflexes were moderately increased, however, no Babinski sign was noted. Although she had headache, no meningeal signs were seen. Slight superficial and vibratory sensory loss was noted in both feet. Routine blood work was again unremarkable except for slight increase in CEA to 8.3 ng/dl (N < 5 ng/dl). The opening pressure of lumbar CSF was 180 mm H2O and the CSF contained 39 cells/microliter, 79 mg of protein, and 10 mg/dl of glucose. Approximately half of the cells were atypical malignant cells. Plain CT was unremarkable, however, tentorial border showed enhancement after contrast infusion. FGS showed no malignant tumors in the stomach. She was treated with intravenous glycerol and whole brain radiation, however, she continued to complain of severe headache, and her sensorium started to be disturbed one month after the admission. Follow-up cranial CT scan revealed enlargement of the lateral and the third ventricles. Her consciousness progressively deteriorated and she became comatose three months after the admission. Repeated cranial CT scan showed enlargement of the ventricles, but no mass lesions were seen within the brain. She developed respiratory arrest on September 25 of the same year. She was discussed in a neurological CPC and the chief discussant arrived at the conclusion that the patient had a gastric cancer with meningeal seeding developing meningeal carcinomatosis. The cause of deep coma was ascribed to damage of cerebral cortical areas secondary to metastatic carcinoma cells and fibrinous materials in the surface of the brain. Postmortem examination revealed thickening and clouding of leptomeninges of the cerebral convexity. On histologic observation, patchy areas of fibrous thickening were seen in the cerebral leptomeninges; in such areas, adenocarcinomatous cells were seen scattered. The basal meninges were free of carcinoma cells, however, leptomeninges of the cerebellum and brain stem tegmentum contained scattered carcinoma cells. The lateral and the third ventricles were enlarged, however, insides of the brain were free of pathologies; the ependymal layer were intact. In the stomach no carcinoma cells were remaining. Pneumonic changes were seen in the right upper and the left lower lobes which appeared to be the direct cause of her death. No evidence of tentorial herniation was noted. The cause of her deep coma was not clearly determined, however, combination of hydrocephalus and cortical malfunction due to leptomeningeal carcinoma cell infiltration and fibrinous material accumulation appeared to have played a role.
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PMID:[A 64-year-old woman with severe headache and progressive disturbance of consciousness]. 919 1

A 2-year-old cat was presented with generalised muscle tremors and progressive fore- and hindlimb ataxia, 5 months after the initiation of chemotherapy for thymic lymphoma. The lymphoma was treated with combination chemotherapy (cyclophosphamide, vincristine and prednisolone), which resulted in remission. The neurological signs progressed to paralysis and the cat subsequently died. On autopsy, multiple meningiomas were diagnosed, which is an unusual finding. It is possible that the lymphoma chemotherapy resulted in the development of the multiple meningiomas as secondary malignancies.
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PMID:Multiple malignant meningiomas in a young cat. 929 Oct 76

SDZ PSC 833 is a novel compound able to reverse the resistance to chemotherapy of cancer cells with the multidrug resistance (MDR) phenotype by inhibiting the 170 kd P-glyco-protein (P-gp). In vitro studies show that SDZ PSC 833 directly interacts with, but is not transported by P-gp, although the exact mechanism of action has not yet been defined. In cells with the MDR phenotype, intracellular concentration of various P-gp-transported anticancer drugs is restored to the same level as in sensitive cells by SDZ PSC 833 concentrations of 0.8 microM to 3.0 microM. In vivo SDZ PSC 833 was highly active in potentiating the anti-tumour activity of all tested anticancer drugs (ACs) in both sensitive and MDR tumours. Sensitivity of non-MDR tumours was increased by SDZ PSC 833 through pharmacokinetic interactions, that result in enhanced area-under-the-curve (AUC) of P-gp-transported ACs. However, an increased AC bioavailability is not sufficient to explain the therapeutic benefit of SDZ PSC 833 co-treatment in MDR tumour-bearing mice: in these animals, no survival increase could be achieved with the AC alone by simply increasing the cytotoxin dosage up to doses that were severely toxic for the non-tumour-bearing mice. In a series of phase I/II studies, the recommended doses of SDZ PSC 833 were established at: 10 mg/kg/day i.v. as a 24-hour continuous infusion after a 2 mg/kg loading dose as a 2-hour infusion; 20 mg/kg orally divided four times daily in solid tumours or 16 mg/kg orally divided four times daily in multiple myeloma. The dose limiting toxicity of SDZ PSC 833 is ataxia, which appears to be reversible and dose-related. Moreover, a predictable change in pharmacokinetic parameters of concomitantly administered P-gp-transported AC(s) which usually necessitate a 30-60% reduction from the standard dose of the AC in order to maintain the same time-exposure and dose-related toxicity of the cytotoxic drug alone. The results of experiments both in vitro and in vivo suggested that adequate blood levels (i.e. > or = 1.0 microM) of SDZ PSC 833 must be reached before and maintained during the administration of concomitant AC(s), in order to maximally reverse MDR. At the recommended doses, blood concentrations exceeding 1000 ng/mL (1.0 microM) can be achieved after both i.v. and oral administration. Indeed, SDZ PSC 833 concentrations that fully reverse MDR in vitro are achievable in vivo, plasma samples from patients treated with SDZ PSC 833 restored the sensitivity of MDR human sarcoma cells to paclitaxel, etoposide and doxorubicin. Clinical studies completed so far aimed first to determine the dose of both SDZ PSC 833 and the concomitant AC(s) to be used in ongoing pivotal trials. These studies accrued advanced stage cancer patients, however, tumour responses have been observed in both solid and hematological tumours. The in vitro finding that treatment with SDZ PSC 833 may suppress the activation of the MDR1 gene and prevent the emergence of resistant cancer cell clones with the MDR phenotype might support the use of this MDR modulator in earlier stages of disease.
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PMID:[SDZ PSC 833: a novel modulator of MDR]. 944 55

We report a 56-year-old female with chronic progressive sensory ataxic neuropathy presenting with alternating skew deviation on lateral gaze in the clinical course. She initially developed dysesthesias in the hands and feet asymmetrically, then gait disturbance developed over several months, and she was admitted to our hospital. Neurological examinations revealed profound deep sensory loss and mild superficial sensory disturbance with the absence of deep tendon reflexes, but muscular strength was completely preserved. EMG showed no evoked response of sensory nerve velocities and normal motor nerves. Sural nerve biopsy showed moderate demyelination with mild infiltration of inflammatory cells, and no vasculitis or onion bulb formation. CSF examination revealed elevation of cell counts and protein with marked intrathecal IgG synthesis and myelin basic protein, but finding of neurosyphillis. Serological examinations did not show any evidence of collagen disease, paraproteinemia, retrovirus infections or Lyme disease. Serum antiganglioside antibodies and anti-Hu antibody were negative. No evidence of malignancy was seen by radiological examinations and assays of tumor markers. In the weeks after admission, gait ataxia progressively worsened, and then she developed alternating skew deviation on lateral gaze, suggesting that the CNS was involved. No responsible lesion was detected on MRI. Corticosteroid administration improved not only the CSF findings, but also the neurologic symptoms, including the alternating skew deviation on lateral gaze. Although the disease entity was not identified, inflammatory demyelinating processes and immune-mediated mechanisms were considered to play important roles.
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PMID:[Inflammatory sensory ataxic neuropathy presenting with alternating skew deviation on lateral gaze: a case report]. 949 Sep 9

3,5-Dichloro-2,4-dimethoxy-6-(trichloromethyl)pyridine (penclomedine, NSC 338720, CRC 88-04) is an alpha-picoline derivative with anti-tumour activity in preclinical models. Penclomedine administration by 1-h intravenous infusion on 5 consecutive days was repeated 3 weekly in the absence of dose-limiting toxicity (DLT) or disease progression. Five dose levels were investigated (22.5-340 mg m(-2) day[-1]). Eight men and eight women were entered, median age 59 years (range 39-73 years), with good performance status (ECOG 0/1) in 11 patients. A total of 13 out of 16 patients had received previous chemotherapy. Common toxicity criteria grade (CTCg) II vomiting was recorded at all dose levels. Neurotoxicity (cerebellar ataxia and dizziness) was the DLT, CTCg III toxicity occurring in three out of three patients treated at 340 mg m(-2) day(-1). CTCg III dizziness was noted in one out of three patients at 250 mg m(-2) day(-1). Neurotoxicity developed during the 1-h infusion and persisted for a variable period (maximum 5 h) after infusion. Prophylactic antiemetic drugs appeared to reduce associated vomiting but did not prevent ataxia. No antiproliferative toxicities were noted and no anti-tumour responses were documented. Penclomedine pharmacokinetic studies confirmed preclinical evidence of extensive apparent distribution (93 l m[-2]) and rapid clearance (41 l h[-1] m[-2]). Purkinje cell loss has been identified in preclinical models after intraperitoneal administration (O'Reilly et al, 1996a) and further clinical development of penclomedine will focus on oral administration.
Br J Cancer 1998 Mar
PMID:Dose-limiting neurotoxicity in a phase I study of penclomedine (NSC 388720, CRC 88-04), a synthetic alpha-picoline derivative, administered intravenously. 951 62


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