Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 44-year-old man suffered from repeated impairment of consciousness associated with flapping tremor, myoclonus and generalized convulsions, and died in coma 6 months after admission. He had had a psychosomatically underdeveloped childhood, with a propensity for legumes without a family history of the same or a record of consanguinity. On admission, he had disturbed consciousness and emaciation without other physical abnormalities. The EEG revealed diffuse slow waves with occasional appearance of triphasic waves. A high level of serum citrulline (534.7 nmol/ml) was recognized and the assay of urea cycle enzymes in the liver demonstrated decreased argininosuccinate synthetase (ASS) activity (0.062 U/g liver, 7.4% of that in normal liver), although no kinetic abnormality was found. Accordingly he was diagnosed as having type II citrullinemia. In addition, this case could be classified as cluster type of localization of the ASS in the liver by immunohistochemical study. There were characteristic findings concerning his clinical picture and laboratory data, such as a significant correlation between the grade of disturbed consciousness and arterial blood gas pH (r = 0.61, p less than 0.01). However, the blood ammonia level did not always correlate with the severity of disturbed consciousness. Oral treatment with sodium citrate and sodium benzoate was very effective, though transiently, for disturbed consciousness in this case. Pathological findings of the autopsied liver were fatty change and fibrosis. Neuropathologically, characteristic findings were brain edema with cerebellar tonsilar herniation, laminar necrosis with spongy formation in cerebral cortex, and Alzheimer type II glia. The relationship between citrullinemia and other hepatic encephalopathy was also discussed.
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PMID:[An autopsied case of type II citrullinemia--transient effectiveness with either citrate or benzoate to the consciousness disturbance]. 269 30

The adhesion molecule on glia (AMOG) has been reported to function as cell adhesion molecule and also to constitute the beta 2-subunit of the murine Na,K-ATPase. In order to elucidate these functions in vivo, Magyar et al. have generated mice carrying a targeted deletion of the AMOG gene. These mice exhibit behaviourally normal development till postnatal day P16. At this time, they develop muscular weakness, incoordination, and tremor. Death invariably occurs 24-36 hours after onset of the symptoms. Histological and ultrastructural examination of brain sections show enlarged ventricles, brain edema, and swelling of astrocyte end feet. However, no disturbances of the architecture or cell migration in the brain can be detected. In order to identify long-term consequences of AMOG deficiency which might not yet be detectable at the time of death, we have established a CNS grafting model. The embryonal brain anlage (E10.5-E13.5) was grafted into the caudoputamen of wild type mice. The graft recipients are sacrificed up to 7 months after the procedure. Both wild type and AMOG deficient grafts develop and form solid neural tissue with neurons, myelinated axons, glial cells, and ventricular structures, as shown by histological and immunocytochemical analysis. However, no differences in grafts derived from wild type, heterozygous, and AMOG-deficient donors can be detected. Proliferation has been examined by BrdU immunocytochemistry. The blood-brain barrier as examined by repeated magnetic resonance imaging after injection of Gadolinium-DTPA has been shown to be largely reconstituted five weeks after grafting.
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PMID:[Morphology and development of neural transplants of AMOG-deficient mice]. 753 17

The objective of this study was to demonstrate the effects of prolonged exposure to 6-ANA at low dose-levels in dogs. A male and a female Beagle dog received daily oral repetitive doses of 1 mg/kg or less for 20 weeks. Both dogs showed lacrimation, conjunctivitis, reduced motility and anemia since the second week of treatment. The female dog was more affected than the male and at the end of treatment period it had tremor, hanging lower jaw, stepping gait of the hind limbs, hunched posture, and general debilitation. Post-mortem examination of the female dog revealed prominent brain edema with pressure atrophy of the dorsal cranial bones. Microscopic examination of the nervous system revealed spongiform neuropathy in both animals mainly affecting the telencephalic cortex and hippocampal fascia dentata, the substantia gelatinosa in the spinal cord and the dorsal root and autonomic ganglia. The changes were produced by vacuolation of astrocytes in the central nervous system and perineuronal satellite cells in the ganglia. Examination of the other organs revealed thymic atrophy and high hematopoietic activity of the bone marrow in both dogs. The male had severe interstitial edema and vacuolar degeneration of the testicular seminiferous tubules and the female had marked chronic pyelonephritis. This chemically induced spongiform neuropathy in dogs obviously represents a subchronic form of the "energy deprivation syndrome" induced by impaired glucose utilization. Vacuolar degeneration of the testicular seminiferous epithelium may have the same pathogenesis.
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PMID:Spongiform neuropathy induced in dogs by prolonged, low-level administration of 6-aminonicotinamide (6-ANA). 978 99

The human immunodeficiency virus type 1 (HIV-1) Tat protein is a key pathogenic factor in a variety of acquired immune deficiency syndrome (AIDS)-associated disorders. A number of studies have documented the neurotoxic property of Tat protein, and Tat has therefore been proposed to contribute to AIDS-associated neurological diseases. Nevertheless, the bulk of these studies are performed in in vitro neuronal cultures without taking into account the intricate cell-cell interaction in the brain, or by injection of recombinant Tat protein into the brain, which may cause secondary stress or damage to the brain. To gain a better understanding of the roles of Tat protein in HIV-1 neuropathogenesis, we attempted to establish a transgenic mouse model in which Tat expression was regulated by both the astrocyte-specific glial fibrillary acidic protein promoter and a doxycycline (Dox)-inducible promoter. In the present study, we characterized the phenotypic and neuropathogenic features of these mice. Both in vitro and in vivo assays confirmed that Tat expression occurred exclusively in astrocytes and was Dox-dependent. Tat expression in the brain caused failure to thrive, hunched gesture, tremor, ataxia, and slow cognitive and motor movement, seizures, and premature death. Neuropathologies of these mice were characterized by breakdown of cerebellum and cortex, brain edema, astrocytosis, degeneration of neuronal dendrites, neuronal apoptosis, and increased infiltration of activated monocytes and T lymphocytes. These results together demonstrate that Tat expression in the absence of HIV-1 infection is sufficient to cause neuropathologies similar to most of those noted in the brain of AIDS patients, and provide the first evidence in the context of a whole organism to support a critical role of Tat protein in HIV-1 neuropathogenesis. More importantly, our data suggest that the Dox inducible, brain-targeted Tat transgenic mice offer an in vivo model for delineating the molecular mechanisms of Tat neurotoxicity and for developing therapeutic strategies for treating HIV-associated neurological disorders.
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PMID:Neuropathologies in transgenic mice expressing human immunodeficiency virus type 1 Tat protein under the regulation of the astrocyte-specific glial fibrillary acidic protein promoter and doxycycline. 1270 54

Canavan disease is an early onset leukodystrophy associated with psychomotor retardation, seizures, and premature death. This disorder is caused by mutations in the gene encoding the enzyme aspartoacylase (ASPA). Normally, ASPA is enriched in oligodendrocytes and ASPA deficiency results in elevated levels of its substrate molecule, N-acetylaspartate (NAA), brain edema, and dysmyelination. Using adeno-associated virus, we permanently expressed ASPA in CNS neurons of the tremor rat, a genetic model of Canavan disease, and examined the efficacy of the treatment by monitoring NAA metabolism, myelination, motor behavior, and seizures. Assessment of ASPA protein and enzyme activity in whole brain hemispheres showed restoration to normal levels as long as 6 months after treatment. This finding correlated with a reduction of NAA levels, along with a rescue of the seizure phenotype. However, gross brain pathology, such as dilated ventricles and spongiform vacuolization, was unchanged. Moreover, hypomyelination and motor deficits were not resolved by ASPA gene transfer. Our data suggest that NAA-mediated neuronal hyperexcitation but not oligodendrocyte dysfunction can be compensated for by neuronal ASPA expression.
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PMID:Restoration of aspartoacylase activity in CNS neurons does not ameliorate motor deficits and demyelination in a model of Canavan disease. 1585 Oct 13

Citrullinemia is an inborn error of the urea cycle caused by deficient argininosuccinate synthetase, which leads to accumulation of L-citrulline and ammonia in tissues and body fluids. The main symptoms include convulsions, tremor, seizures, coma, and brain edema. The pathophysiology of the neurological signs of citrullinemia remains unclear. In this context, we investigated the in vitro effects of L-citrulline and ammonia in cerebral cortex from 30-day-old rats on oxidative stress parameters, namely thiobarbituric acid-reactive substances (TBA-RS), chemiluminescence, mitochondrial membrane protein thiol content, intracellular content of hydrogen peroxide, total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR) as well as on the activities of the antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase). L-Citrulline significantly diminished TRAP (26%) and TAR (37%), while ammonia decreased TAR (30%). Ammonia increased SOD activity (65%) and L-citrulline did not affect the activities of any antioxidant enzymes. We also observed that L-citrulline and ammonia did not alter lipid peroxidation parameters, levels of hydrogen peroxide, and mitochondrial membrane protein thiol content. Taken together, these results may indicate that L-citrulline and ammonia decreased the antioxidant capacity of the brain, which may reflect a possible involvement of oxidative stress in the neuropathology of citrullinemia.
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PMID:Citrulline and ammonia accumulating in citrullinemia reduces antioxidant capacity of rat brain in vitro. 1677 71

Ammonia is a ubiquitous waste product of protein metabolism that can accumulate in numerous metabolic disorders, causing neurological dysfunction ranging from cognitive impairment to tremor, ataxia, seizures, coma and death. The brain is especially vulnerable to ammonia as it readily crosses the blood-brain barrier in its gaseous form, NH3, and rapidly saturates its principal removal pathway located in astrocytes. Thus, we wanted to determine how astrocytes contribute to the initial deterioration of neurological functions characteristic of hyperammonemia in vivo. Using a combination of two-photon imaging and electrophysiology in awake head-restrained mice, we show that ammonia rapidly compromises astrocyte potassium buffering, increasing extracellular potassium concentration and overactivating the Na(+)-K(+)-2Cl(-) cotransporter isoform 1 (NKCC1) in neurons. The consequent depolarization of the neuronal GABA reversal potential (EGABA) selectively impairs cortical inhibitory networks. Genetic deletion of NKCC1 or inhibition of it with the clinically used diuretic bumetanide potently suppresses ammonia-induced neurological dysfunction. We did not observe astrocyte swelling or brain edema in the acute phase, calling into question current concepts regarding the neurotoxic effects of ammonia. Instead, our findings identify failure of potassium buffering in astrocytes as a crucial mechanism in ammonia neurotoxicity and demonstrate the therapeutic potential of blocking this pathway by inhibiting NKCC1.
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PMID:Ammonia triggers neuronal disinhibition and seizures by impairing astrocyte potassium buffering. 2497 82

We describe the case of a 3-year-old boy diagnosed with the fulminant form of acute disseminated encephalomyelitis (ADEM). He developed general fatigue, fever, drowsiness and difficulty in walking. He had extensive multiple high-intensity lesions in the white matter of the cerebrum and cerebellum, which are typical findings of ADEM. He became comatose and developed decerebrate rigidity with severe brain edema despite high-dose methylprednisolone therapy, and then was subjected to mild hypothermia therapy, and given i.v. immunoglobulin. The patient recovered remarkably with the sequela of only mild action tremor. The patient was considered to have acute hemorrhagic leukoencephalitis (AHLE), an extremely severe form of ADEM, in terms of the rapidly deteriorating clinical course and neuroimaging features. It was speculated that AHLE and ADEM might be a continuous disease spectrum. It is considered that the severe brain edema associated with ADEM or AHLE is a suitable indication for mild hypothermia therapy.
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PMID:Fulminant form of acute disseminated encephalomyelitis in a child treated with mild hypothermia. 2433 Mar