[Carbohydrate-deficient glycoprotein (CDG) syndrome (Jaeken syndrome)].
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Asialoglycoproteins↗
Biomedical subjects
K Ohno
Publications and source records attributed to K Ohno.
[Niemann-Pick disease (type C)].
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Age of Onset↗
[Releasing phenomenon of learned movements].
Involuntary movements that resembled the shooting of a basketball and piano playing were observed after brain damage in a 13-year-old female and a 74-year-old female, respectively. The movements were characterized as involuntarily triggered movements that occurred in the presence and absence of exteroceptive stimuli, movements had been practiced repeatedly just before the occurrence of the brain damage, and that could be stopped on command. According to the MRI findings, the lesions extended into the pre-supplementary motor area (pre-SMA). The characteristics of the patients movements were different from previously reported involuntary movements such as compulsive manipulation of tools, utilization behavior, and imitation behavior. Hikosaka et al (1996) reported the role of the pre-SMA in learning new sequential procedures. We speculate that damage to the pre-SMA may be associated with the etiology of these movements.
Adolescent↗
New autosomal-recessive syndrome of Leber congenital amaurosis, short stature, growth hormone insufficiency, mental retardation, hepatic dysfunction, and metabolic acidosis.
We report on a new autosomal-recessive syndrome in 4 Japanese children in 2 families. The key manifestations are Leber congenital amaurosis, short stature, growth hormone insufficiency, mental retardation, hepatic dysfunction, metabolic acidosis, and autosomal-recessive inheritance. There were no consanguineous marriages. Abnormal eye movements were noticed neonatally, and ophthalmological examinations showed no visual acuity, pigmentary retinal degeneration, and nonrecordable electroretinograms in all cases. Inadequate weight gain and short stature gradually became apparent after birth, and at present the height range is -4.6 - -7.2 SD (standard deviations). Developmental delay was noted at age 4 months, and the developmental quotient is 50-70 at present. Deterioration of development and convulsions were not recognized. Elevated serum aminotransferase levels and metabolic acidosis were also found at age 4 months. Proximal renal tubular acidosis was clarified by bicarbonate tolerance tests in 1 case, and may have caused metabolic acidosis. Growth hormone secretion was insufficient by insulin tolerance test in 3 cases. One year of growth hormone therapy in 2 cases did not affect growth velocity. Hepatic dysfunction and metabolic acidosis ameliorated later. No renal cysts were found. A cranial computed tomographic scan and magnetic resonance imaging showed normal findings. Amino acids, organic acids, and very long chain fatty acid levels in plasma were all normal in the 3 cases examined. Histopathological and mitochondrial DNA analyses showed no evidence of mitochondrial disorders.
Acidosis↗
Slow-channel myasthenic syndrome caused by enhanced activation, desensitization, and agonist binding affinity attributable to mutation in the M2 domain of the acetylcholine receptor alpha subunit.
We describe a novel genetic and kinetic defect in a slow-channel congenital myasthenic syndrome. The severely disabled propositus has advanced endplate myopathy, prolonged and biexponentially decaying endplate currents, and prolonged acetylcholine receptor (AChR) channel openings. Genetic analysis reveals the heterozygous mutation alphaV249F in the propositus and mosaicism for alphaV249F in the asymptomatic father. Unlike mutations described previously in the M2 transmembrane domain, alphaV249F is located N-terminal to the conserved leucines and is not predicted to face the channel lumen. Expression of the alphaV249F AChR in HEK fibroblasts demonstrates increased channel openings in the absence of ACh, prolonged openings in its presence, enhanced steady-state desensitization, and nanomolar rather than micromolar affinity of one of the two binding sites in the resting activatable state. Thus, neuromuscular transmission is compromised because cationic overloading leads to degenerating junctional folds and loss of AChR, because an increased fraction of AChR is desensitized in the resting state, and because physiological rates of stimulation elicit additional desensitization and depolarization block of transmission.
Acetylcholine↗
Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis.
Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)-derived cholesterol. By positional cloning methods, a gene (NPC1) with insertion, deletion, and missense mutations has been identified in NP-C patients. Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking. The 1278-amino acid NPC1 protein has sequence similarity to the morphogen receptor PATCHED and the putative sterol-sensing regions of SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase.
Amino Acid Sequence↗
Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene.
An integrated human-mouse positional candidate approach was used to identify the gene responsible for the phenotypes observed in a mouse model of Niemann-Pick type C (NP-C) disease. The predicted murine NPC1 protein has sequence homology to the putative transmembrane domains of the Hedgehog signaling molecule Patched, to the cholesterol-sensing regions of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and SREBP cleavage-activating protein (SCAP), and to the NPC1 orthologs identified in human, the nematode Caenorhabditis elegans, and the yeast Saccharomyces cerevisiae. The mouse model may provide an important resource for studying the role of NPC1 in cholesterol homeostasis and neurodegeneration and for assessing the efficacy of new drugs for NP-C disease.
Amino Acid Sequence↗
A partial deficiency of dehydrodolichol reduction is a cause of carbohydrate-deficient glycoprotein syndrome type I.
Carbohydrate-deficient glycoprotein (CDG) syndrome type I is a congenital disorder that involves the underglycosylation of N-glycosylated glycoproteins (Yamashita, K., Ideo, H., Ohkura, T., Fukushima, K., Yuasa, I., Ohno, K., and Takeshita, K. (1993) J. Biol. Chem. 268, 5783-5789). In an effort to further elucidate the biochemical basis of CDG syndrome type I in our patients, we investigated the defect in the multi-step pathway for biosynthesis of lipid-linked oligosaccharides (LLO) by the metabolic labeling method using [3H]glucosamine, [3H]mannose, and [3H]mevalonate. The LLO levels in synchronized cultures of fibroblasts from these patients were severalfold lower than those in control fibroblasts in the S phase, and the oligosaccharides released from LLO showed the same structural composition, Glc1 approximately 3.Man9.GlcNAc.GlcNAc, in the case of both the patients and controls. The amount of [3H]mannose incorporated into mannose 6-phosphate, mannose 1-phosphate, and GDP-mannose was greater in fibroblasts from these patients than in the control fibroblasts in the G1 period, although the ratios of these acidic mannose derivatives as indicated by the relative levels of radioactivity were the same for the two types of fibroblasts. Furthermore, upon metabolic labeling with [3H]mevalonate, the level of [3H]dehydrodolichol in fibroblasts from these patients increased in the S phase, and the levels of [3H]dolichol and [3H]dolichol-PP oligosaccharides concomitantly decreased, although the chain length distribution of the respective dolichols and dehydrodolichols was the same in the two types of fibroblasts. These results indicate that the conversion of dehydrodolichol to dolichol is partially defective in our patients and that the resulting loss of dolichol leads directly to underglycosylation.
Cells, Cultured↗
Granule cell disinhibition in dentate gyrus of genetically seizure susceptible El mice.
Paired-pulse inhibition was investigated electrophysiologically in the dentate gyrus using hippocampal slices from epileptic El mice. At short interpulse intervals (IPIs), the inhibition was 30% in the El, and 90% in the control ddY mice at the ages of 10 and 15 weeks. No difference in inhibition was observed at the age of 5 weeks. Bicuculline, a GABAA receptor antagonists, attenuated the inhibition during short IPIs n the ddY mice, while in the El mice, phenobarbital and flunitrazepam, which enhance GABAA receptor function, restored the inhibitory activity comparable to that of the ddY. The disinhibition progressed with growth, closely correlating with seizure development in El mice. These results suggest that decrease in the GABAergic inhibition occurs in the dentate gyrus of the El mice with growth. GABA concentration in the hippocampus was also quantified using HPLC. In El mice, GABA level was significantly lower than that in ddY mice at the ages of 5 and 15 weeks. Thus, the disinhibition observed in the El dentate gyrus at 15 weeks of age does not appear to be directly related to the content of GABA. GABAergic disinhibition suggests possible loss of unknown inhibition control factor(s) in the El dentate gyrus as growth progresses. The growth-dependent disinhibition in the granule cells may be prerequisite for epileptogenesis in El mice.
Aging↗
Retrovirus vectors displaying the IgG-binding domain of protein A.
We have designed and constructed retrovirus particles displaying the IgG-binding domain of protein A. We fused the gene for the synthetic antibody-binding portion of protein A with the envelope gene of ecotropic Moloney murine leukemia virus. The fusion gene was coexpressed in ecotropic retroviral packaging cells, and retrovirus particles with IgG-binding activities were recovered. In principle, the protein A-envelope chimeric retrovirus complexed with specific monoclonal antibody could be used for cell-targeted gene delivery.
Animals↗
A mixed mesodermal tumor of the cecum: report of a case.
We herein report the case of a 69-year old woman presenting with an abdominal mass, who was found to have a mixed mesodermal tumor (MMT) of the cecum. Imaging studies and endoscopic investigations were consistent with the diagnosis of a nonepithelial malignant tumor of the cecum. On laparotomy, a knuckle-sized firm mass involving the cecum was noticed. As a result, a right hemicolectomy was performed. Pathological examinations, including immunohistochemical staining, resulted in the diagnosis of mesodermal mixed tumor, homologous type. The patient was advised to undergo postoperative chemotherapy but she did not comply. She has been followed up as an outpatient and is still alive 1.5 years after the operation.
Aged↗
MELAS presenting as migraine complicated by stroke: case report.
A case of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) which presented as migraine complicated by stroke is reported. Strokes associated with migraine have often been reported, but the mechanism remains unclear and may include a variety of pathologies. MELAS also presents with migrainous headache, vomiting, and stroke-like symptoms. Magnetic resonance imaging demonstrates characteristic findings. MELAS should be considered in the differential diagnosis of infarct-like lesions with migrainous headaches in young adults, especially if the symptoms fluctuate and are accompanied by a homonymous hemianopia.
Adult↗
A C57BL/KsJ mouse model of Niemann-Pick disease (spm) belongs to the same complementation group as the major childhood type of Niemann-Pick disease type C.
A cell line (SPM-3T3) derived from a C57BL/KsJ mouse model of Niemann-Pick disease type C (NP-C) shows biochemical abnormalities similar to those in fibroblasts derived from NP-C. Somatic cell hybridization analysis of the SPM-3T3 cells and five fibroblast strains derived from NP-C patients (four childhood cases and one adult case) was carried out. The criterion for complementation was the restoration of a normal intracellular fluorescent pattern in multinucleated cells stained with filipin to demonstrate cholesterol accumulation. These cells can be assigned to two complementation groups. The SPM-3T3 cells did not complement cell strains derived from childhood-type NP-C, while they complemented a cell strain derived from an adult patient. Our results suggest that SPM-3T3 represents a genetically authentic model of a major complementation group of NP-C, and that NP-C consists of genetically heterogeneous groups.
3T3 Cells↗
Mediastinoscopic extirpation of mediastinal ectopic parathyroid gland.
We report a case of a 50-year-old man with hyperparathyroidism secondary to chronic renal failure who underwent extirpation of a mediastinal ectopic parathyroid gland by a transcervical approach under mediastinoscopy. This procedure provides an excellent approach to the mediastinal ectopic parathyroid gland, and is less invasive than median sternotomy or thoracotomy.
Choristoma↗
Behavioral correlates of transneuronal degeneration of substantia nigra reticulata neurons are reversed by ablation of the subthalamic nucleus.
In rats, acute injury of neurons in the caudate nucleus (CN) and globus pallidus (GP) by local injection of ibotenic acid (IA) or by transient forebrain ischemia has caused transneuronal cell death of neurons in the substantia nigra reticulata (SNr) weeks after the initial injury. Recently transient expression of an immediate early gene c-fos was induced specifically in neurons of the subthalamic nucleus (STN) and SNr at 36-48 h after the IA-lesions, prior to the delayed degeneration of SNr neurons. These cellular and molecular events may alter the level of inhibitory output from the basal ganglia and lead to movement disorders. To test (i) whether movement disorders occur in the early period after unilateral lesions of the CN and GP by IA-injection, and (ii) whether ablation of the STN reverses the early movement disorders, we used a modified version of Porsolt forced swim test in which the lesion-induced asymmetry of motor function becomes apparent as rotation when the animals are forced to swim. Following unilateral IA-lesions of the right CN and GP in rats, rapid contraversive rotation appeared transiently 36-48 h after the lesions, and, in turn, slow ipsiversive rotation appeared at 3-5 days postlesion. Prior ablation of the ipsilateral STN reversed these early movement disorders produced by the unilateral IA-lesions of the CN and GP and instead created persistent contraversive rotation 7-10 days after the lesions. Each phase of the dominant rotation behavior was dependent on asymmetrical limb motor activity; decreased left limb activity caused contraversive rotation, and increased left limb activity caused ipsiversive rotation. Reversal of these early movement disorders suggests that ablation of the STN prevents the transneuronal degeneration of the SNr.
Animals↗
Kainate excitotoxicity is mediated by AMPA- but not kainate-preferring receptors in embryonic rat hippocampal cultures.
We investigated kainate-induced excitotoxicity in embryonic rat hippocampal cells cultured in a chemically defined medium. Treatment with kainate for 24 h resulted in neuronal death, as assessed by the release of lactate dehydrogenase into the culture media. This neurotoxic effect was kainate dose- and culture age-dependent. EC50 of kainate was 127 +/- 11 microM. 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo (f)quinoxaline (NBQX) completely blocked the toxicity, while MK801, an N-methyl-D-aspartate (NMDA) receptor antagonist, also blocked it but not completely. Furthermore, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) attenuated the kainate injury, while the selective and noncompetitive AMPA-preferring receptor antagonist 1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2,3-benzo-diazepine (GYKI 52466) blocked it completely. Concanavalin A (ConA), which potentiates the response to kainate at kainate-preferring receptors, had little effect on kainate toxicity. Further, AMPA alone induced little toxicity, but produced remarkable toxicity when cyclothazide was used to block the desensitization of AMPA-preferring receptors. These results indicate that kainate excitotoxicity in hippocampal cultures is mediated by AMPA- but not kainate-preferring receptors, and that it involves NMDA-receptor-mediated toxicity. The non-desensitizing response at AMPA-preferring receptors may play an important role in kainate-induced excitotoxicity.
Animals↗
Tissue reaction around miniplates used for the fixation of vascularized iliac crest bone grafts.
MATERIAL/METHOD: In six miniature pigs revascularized autologous iliac crest bone grafts were fixed with two 2.0 mm titanium miniplates to a defined defect in the angle of the mandible. Tissue reaction around the implants was examined histologically and histomorphometrically at 2, 4, and 8 weeks after surgery. RESULTS: According to the evaluation of fluorescence microradiography, the cortical and medullary circulation and healing processes of bone in the vicinity of the implanted material were not disturbed after 2 weeks. At 4 weeks after surgery osseous healing occurred at the mandibula/graft interface. The histomorphometric results for the calculated percentage of direct bone/screw contact at 2 weeks were 24% with the grafted bone and 53% with the mandible. Intensive bone formation was observed in all parts of the graft by 4 weeks. The results of direct bone/screw. contact at 4 weeks were 56% and 64% and at 8 weeks 75% and 77% for the grafted and the mandibular bone, respectively. CONCLUSION: With 2.0 mm titanium miniplates used in the animal model, stable osteosynthesis and osseous healing was evident after 8 weeks of surgery. In addition, intensive remodeling of the transplanted bone without signs of creeping substitution was noted, and the bone/screw contact of the miniplate system increased with time.
Animals↗
Parenchymal damage in the territory of the anterior choroidal artery following supraophthalmic intracarotid administration of CDDP for treatment of malignant gliomas.
We treated ten patients with malignant glioma by intracarotid chemotherapy with cis-diamminedichloroplatinum (CDDP) and/or 3-(4-amino-2-methyl-5-pyrimidinyl)methyl-1-(2-chloroethyl)-3-nitrosourea (ACNU). Three of the patients who underwent supraophthalmic intracarotid infusion of CDDP developed a low-density area in the basal ganglia on CT scan or an enhancing lesion in the hypothalamic region on MRI, with or without neurologic symptoms. No patient had such complications with supraophthalmic infusions of ACNU, or with cervical intracarotid infusion of CDDP or selective infusion of CDDP via the anterior or middle cerebral arteries. Supraophthalmic intracarotid administration of CDDP may augment drug delivery to tumors and prevent visual complications, but is accompanied by considerable risk of parenchymal damage in the territory of the anterior choroidal artery. Possible mechanisms for such complications are discussed.
Adult↗