Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder similar to Huntington's disease, with clinical manifestations including chorea, incoordination, ataxia, and dementia. It is caused by an expansion of a CAG trinucleotide repeat encoding polyglutamine in the atrophin-1 gene. Both patients and DRPLA transgenic mice have nuclear accumulation of atrophin-1, especially an approximately 120-kDa fragment, which appears to represent a cleavage product. We now show that this is an N-terminal fragment that does not correspond to the previously described caspase-3 fragment, or any other known caspase cleavage product. The atrophin-1 sequence contains a putative nuclear localization signal in the N terminus of the protein and a putative nuclear export signal in the C terminus. We have tested the hypothesis that endogenous localization signals are functional in atrophin-1, and that nuclear localization and proteolytic cleavage contribute to atrophin-1 cell toxicity. In transient cell transfection experiments using a neuroblastoma cell line, full-length atrophin-1 with 26 (normal) or 65 (expanded) glutamines localized to both nucleus and cytoplasm, with no significant difference in toxicity between the normal and mutant proteins. A construct with 65 glutamine repeats encoding an N-terminal fragment (which removes an NES) of atrophin-1 similar in size to the truncation product in DRPLA patient tissue, showed increased nuclear labeling, and an increase in cellular toxicity, compared with a similar fragment with 26 glutamines. Full-length atrophin-1 with 65 polyglutamine repeats and mutations inactivating the NES also yielded increased nuclear localization and increased toxicity. These data suggest that truncation enhances cellular toxicity of the mutant protein, and that the NES is a relevant region deleted during truncation. Furthermore, mutating the NLS in the truncated protein shifted atrophin-1 more to the cytoplasm and eliminated the increased toxicity, consistent with the idea that nuclear localization enhances toxicity. In none of the experiments were inclusions visible in the nucleus or cytoplasm suggesting that inclusion formation is unrelated to cell death. These data indicate that truncation of atrophin-1 may alter its ability to shuttle between the nucleus and cytoplasm, leading to abnormal nuclear interactions and cell toxicity.
 ...
PMID:Nuclear localization of a non-caspase truncation product of atrophin-1, with an expanded polyglutamine repeat, increases cellular toxicity. 1246 7

Various paraneoplastic autoantibodies have been linked to discrete neurologic syndromes and tumors in adults, but little is known about their incidence in children. We report a cross-sectional study of known paraneoplastic antibodies in 59 children with opsoclonus-myoclonus-ataxia, 86% of whom were moderately or severely symptomatic, and 68% of whom had relapsed at the time of testing. This total number of patients includes 18 children with low-stage neuroblastoma (tested after tumor resection), six of whom had never been treated with immunosuppressants. All were seronegative for anti-Hu, anti-Ri, and anti-Yo, the three paraneoplastic antibodies most associated with opsoclonus-myoclonus or ataxia in adults. These data contrast with reports of anti-Hu-positive sera in children with high-stage tumors and suggest that anti-Hu, anti-Ri, and anti-Yo do not explain relapses in pediatric opsoclonus-myoclonus-ataxia. They underscore the need to search for unique autoantibodies, as well as cellular mechanisms of pediatric paraneoplastic disease.
 ...
PMID:Screening for autoantibodies in children with opsoclonus-myoclonus-ataxia. 1250 7

Doppel protein has been discovered in prnp knock-out mouse lines, with overproduction of this protein in the brain causing ataxia and neurodegeneration. We investigated whether Doppel expression (i) affected or was affected by the course of prion propagation in neuroblastoma cells, or (ii) modulated Creutzfeldt-Jakob disease pathogenesis. No change in Doppel production was detected in N2a cells, before or after infection. Transient murine Doppel gene expression had no effect on N2a viability or PrP(Sc) production. A sensitive immunometric assay revealed low levels of Doppel in human brain, reflecting weak transcription of the corresponding gene. No difference in brain Doppel levels was observed between Creutzfeldt-Jakob disease patients and controls, adding further evidence that Doppel is unlikely to be involved in prion disease pathogenesis.
 ...
PMID:Prion-like protein Doppel expression is not modified in scrapie-infected cells and in the brains of patients with Creutzfeldt-Jakob disease. 1258 39

Acute cerebellar ataxia and opsomyoclonus are presenting signs of occult neuroblastoma for a substantial proportion of paediatric patients. Cerebellar ataxia may be due to antibodies against the neuroblastoma cross-reacting with cerebellar tissue. This report is of a 26-month-old boy who presented with encephalitis-like features of ataxia, seizures, decreased consciousness, and involuntary movements. Magnetic resonance imaging of the brain and spine were normal 2 weeks after presentation. The child did not have the classical signs of opsoclonus or myoclonus at any stage of the disease but was found to have occult neuroblastoma. The late demyelinating changes seen on magnetic resonance imaging of the brain support an immunological basis for the paraneoplastic manifestations of occult neuroblastoma in this child. Occult neuroblastoma should be considered as one of the differential diagnoses for children presenting with persisting encephalitis-like features in the presence of normal neuroimaging findings.
 ...
PMID:Unusual neurological presentation of neuroblastoma. 1266 29

Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 is an autosomal dominant spinocerebellar degeneration characterized by a wide range of clinical manifestations. Unstable CAG trinucleotide repeat expansion in the MJD gene has been identified as the pathologic mutation of MJD. In this study, human SK-N-SH neuroblastoma cells stably transfected with full-length MJD with 78 CAG repeats were established. Compared with the parental cells, cells expressing mutant ataxin-3 displayed normal morphology for over 80 generations. Less than 1% of the transfected cells contained nuclear aggregates under basal conditions, indicating that this cellular model represented an early disease stage. While t-butyl hydroperoxide (TBH) was used to assess the oxidative tolerance of cells, the results demonstrated that the transfected cells were more susceptible to low concentrations of TBH than the parental cells. Most interestingly, from 2D gel electrophoresis analysis, we identified that the expression of heat shock protein 27 (HSP27), known as a suppressor of poly(Q)-mediated cell death, dramatically decreased in SK-N-SH cells stably transfected with full-length mutant MJD. The same reduction of HSP27 was further confirmed in lymphoblastoid cells from MJD patients. Our results demonstrated that both neuronal and non-neuronal cells with expanded full-length ataxin-3 revealed reduced protein expression of HSP27. We propose that the reduction of HSP27 in the early stage of the disease plays an important role during cell death process in MJD.
 ...
PMID:Down-regulation of heat shock protein 27 in neuronal cells and non-neuronal cells expressing mutant ataxin-3. 1283 59

The presence of rare paraneoplastic syndromes, the opsoclonus-myoclonus-ataxia syndrome (OMA), presumably caused by antineuronal antibody production, and diarrhea, caused by vasoactive intestinal peptide (VIP) secreted by neuroblastoma, may strongly signal the presence of neuroblastoma. The authors describe a child who presented with both syndromes concurrently; this has never been described previously in the same patient. However, diagnosis of neuroblastoma was delayed by a workup focused on the prolonged diarrhea rather than the ataxia. The diarrhea resolved after tumor resection, whereas OMA required further therapy. Increased awareness of VIP-secretory diarrhea, especially in an ataxic child, might contribute to an earlier diagnosis of neuroblastoma.
 ...
PMID:Ataxia and secretory diarrhea: two unusual paraneoplastic syndromes occurring concurrently in the same patient with ganglioneuroblastoma. 1534 80

The diagnosis of neuroblastoma is sometimes preceded by development of a paraneoplastic syndrome, most commonly opsoclonus-myoclonus-ataxia (OMA). The authors describe a patient who developed a hyperexcitable blink reflex, without symptoms of OMA, prior to his oncologic diagnosis. The authors believe this may represent a distinct paraneoplastic process caused by increased dopaminergic stimulation of the blink reflex and suggest that children manifesting an unexplained hyperexcitable blink reflex should be screened for occult neuroblastoma.
 ...
PMID:Hyperexcitable blink reflex preceding the diagnosis of neuroblastoma. 1545 39

Machado-Joseph disease (MJD) is an inherited neurodegenerative disorder caused by ataxin-3 with a polyglutamine expansion. It is proposed that a toxic cleavage fragment of mutant ataxin-3 alternatively spliced isoform mjd1a triggers neurodegeneration, although this fragment has not yet been detected in the brains of MJD patients or in animal models. We have now generated transgenic mice expressing human mutant (Q71) or normal (Q20) ataxin-3 mjd1a under the control of the mouse prion promoter. Q71 transgenic mice expressing mutant ataxin-3 mjd1a above a critical level developed a phenotype similar to MJD including progressive postural instability, gait and limb ataxia, weight loss, premature death, neuronal intranuclear inclusions, and decreased tyrosine hydroxylase-positive neurons in the substantia nigra (determined by unbiased stereology). Q20 transgenic mice had normal behavior and pathology. Brains from sick Q71 transgenic mice contained an abundant mutant ataxin-3 mjd1a putative-cleavage fragment (Fragment), which was scarce in normal Q71 transgenic mice. Reactivity of the Fragment with a panel of antibodies and comigration with truncations of mutant ataxin-3 revealed that it contained residues C terminal to amino acid 221 to include the polyglutamine expansion. A similar portion of mutant ataxin-3 mjd1a expressed in transfected neuroblastoma cells was toxic above a critical concentration. The Fragment was more abundant in two affected brain regions of MJD patients. Thus, we have developed a murine model for mutant ataxin-3 mjd1a toxicity and identified a putative-cleavage fragment of the disease protein in the brains of these transgenic mice and MJD patients that is cytotoxic above a critical concentration.
 ...
PMID:A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. 1553 99

A 2 year old boy presented with features of opsoclonus, myoclonus and ataxia. Routine investigations of blood, urine, x-ray chest, bone scan, EEG and MRI of brain, were normal. Urine for VMA was negative. A right suprarenal mass was detected at MRI of abdomen. The mass was resected completely and was found histologically to be of differentiating type of neuroblastoma. The child was treated initially with prednisolone for 6 weeks along with sodium valproate. He is still on sodium valproate for his neurological symptoms. His symptoms still persist though they have decreased in intensity.
 ...
PMID:A case of opsoclonus-myoclonus-ataxia with neuroblastoma. 1586 78

Opsoclonus-myoclonus-ataxia syndrome (OMA) in children is most commonly associated with occult neuroblastoma (NB). Although children with OMA and NB have decreased mortality, they suffer from increased neurologic morbidity. The pathogenesis of OMA in NB is not well understood, but current research and treatments support an immune-mediated process. The authors describe an unusual presentation of OMA occurring following 6 months of chemotherapy in a child with stage 4S NB who presented with partial Horner syndrome. Histopathologic examination of his primary cervical tumor showed NB maturation, which may have played a role in precipitating OMA syndrome. Further study of unusual cases of OMA in NB may provide better understanding of the syndrome and additional treatment options for these children.
 ...
PMID:Late presentation of opsoclonus-myoclonus-ataxia syndrome in a child with stage 4S neuroblastoma. 1595 91


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>