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

Angelman syndrome (AS) is a human genetic disorder characterized by mental retardation, seizures, inappropriate laughter, abnormal galt, tremor and ataxia. There is strong genetic evidence that the disorder is associated with a maternally expressed, imprinted gene mapping to chromosome 15q11-13. Affected patients demonstrate varied molecular abnormalities, including large maternal deletions, uniparental paternal disomy (UPD). Imprinting mutations and loss of function mutations of E6-associated-protein (E6-AP) ubiquitin-protein ligase (UBE3A). All of these abnormalities are associated with loss of maternal expression of UBE3A. Although mutations in UBE3A cause AS, indicating that maternal-specific expression of UBE3A is essential for a normal phenotype, evidence for maternal-specific expression of UBE3A has been lacking. Using mice with partial paternal UPD encompassing Ube3a to differentiate maternal and paternal expression, we found by in situ hybridization that expression of Ube3a in Purkinje cells, hippocampal neurons and mitral cells of the olfactory bulb in UPD mice was markedly reduced compared to non-UPD littermates. In contrast, expression of Ube3a in other regions of the brain was only moderately or not at all reduced in UPD mice. The major phenotypic features of AS correlate with the loss of maternal-specific expression of Ube3a in hippocampus and cerebellum as revealed in the mouse model.
 ...
PMID:Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. 928 1

We report a review on progress in the etiology and pathogenesis of Parkinson's disease (PD). We also report the long-term prognosis of PD patients seen in our clinic. Modern research on the pathogenesis started after the discovery of MPTP. We found inhibition of mitochondrial complex I by MPTP and MPP+. Mitochondrial respiratory failure induces oxidative damage to high molecular weight substances. Both mitochondrial failure and oxidative stress are important triggers of apoptosis. We found TUNEL positive nigral neurons in PD patients suggesting involvement of apoptosis in the pathogenesis. Interaction of genetic risk factors and environmental neurotoxins has been implicated in the etiology of PD. While we were investigating MnSOD gene polymorphism in PD patients, we found a young onset autosomal recessive PD family that was linked to the MnSOD locus. Subsequent linkage analysis on 13 families of young onset autosomal recessive families disclosed the linkage of this disease to the telomeric region of the long arm of chromosome 6 (6q25.2-27). Then we were lucky enough to find a patient who had a deletion of one of the microsatellite markers (D6S305) that we were using in the linkage analysis. We thought this marker might be located within the disease gene and this was the case. We screened the Keio BAC library with this marker, and eventually we cloned a novel gene encompassing 1.4 Mb; we named it parkin. The coding region consisted of 1,395 base pairs. The parkin protein had an unique sequence in that there was a 30% homology in the amino terminal region and two RING-finger motives on the carboxy terminal side. This unique structure suggested that the parkin protein was related to the ubiquitin-proteasome system. Parkin protein turned out to be an ubiquitin-protein ligase. Numbers of parkin-interacting proteins were reported in the literature and accumulation of parkin-substrates is likely to be the cause for the nigral neuronal death in this familial PD. Regarding the prognosis of PD, we analyzed the patients who visited our clinic from January 1, 1989 to December 31, 2002. The total of patients recruited was 1,772. The average age of onset was 57.2 years. Mean levodopa dose at the final examination was 479 mg/day. The most common initial symptom was tremor which was seen in 51% of the patients. Total percentage of patients who had tremor during the course of the disease was 75%. Long-term prognosis was evaluated on a subgroup of the patients who visited our clinic within 5 years from the onset and Hoehn and Yahr stage III or less when first seen. Analysis was done by the Kaplan-Meier survival curve. Percentages of patients who reached Hoehn and Yahr III 5, 10, and 15 years after the onset were 24%, 46%, and 65%, respectively. Percentages of patients who developed wearing off fluctuations were 5, 10, and 15 years after the start of levodopa were 18%, 46%, and 55%, respectively. Overall mortality on the total investigated patients was 7.9%. When compared to the age at death of Japanese population, mortality of men PD patients became very close to that of the general population in the year 2003. However, that in women PD patients showed significantly shorter survival compared to Japanese female population. Average ages of onset and the death were essentially similar between men and women PD patients. Survival curves to reach stage III and wearing off showed slightly but significantly faster time courses for women compared to those of men. This was an unexpected observation and its mechanism was discussed. It is our conclusion that overall prognosis of PD patients is improving and both patients and treating physicians should take an optimistic attitude to the disease.
 ...
PMID:[Progress in the basic and clinical aspects of Parkinson's disease]. 1565 Dec 81