Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033377 (prolapse)
 11,717 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the effects of the local administration into the periaqueductal gray matter of thiorphan, a selective inhibitor of endopeptidase 24.11 "enkephalinase", kelatorphan, (R)-3-(N-hydroxy-carboxamido-2-benzylpropanoyl)- L-alanine, and RB 38 A, (R)-3-(N-hydroxy-carboxamido-2-benzylpropanoyl)-L-phenylalanine, two almost complete inhibitors of enkephalin metabolism, on the naloxone-precipitated morphine withdrawal syndrome in rats. Local administration of these inhibitors decreased the severity of the withdrawal syndrome. Jumping, chewing, diarrhea, piloerection, salivation and hypothermia were decreased by all drugs. Lacrimation and weight loss were reduced by kelatorphan and RB 38 A whereas teeth chattering, tremor, eye twitch and rhinorrhea were decreased only by RB 38 A. The rise in plasma corticosterone levels was only slightly reduced by the three inhibitors. Wet dog shakes and ptosis remained unchanged. These results indicate that during the morphine withdrawal syndrome in rats there is a tonic or/and naloxone evoked release of opioid peptides, presumably enkephalins, into the periaqueductal gray matter and that inhibition of their degradation strongly decreases the severity of the withdrawal syndrome.
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PMID:Attenuation of the morphine withdrawal syndrome by inhibition of catabolism of endogenous enkephalins in the periaqueductal gray matter. 162 Feb 46

DL-beta-N-methylamino-alanine (DL-BMAA; 1-10 mumol i.c.v.) in mice induced a syndrome of: ataxia, ptosis, scratching, jumping, myoclonic jerks, clonic muscle spasms and tonic seizure, which was unaffected by pretreatment with D(-)-4-(3-phosphonoprop-2-enyl)-piperazine-2-carboxylate (D(-)-CPPene; i.p.), or by co-administration of gamma-D-glutamylamino-methylsulphonate (gamma-D-GAMS with DL-BMAA; i.c.v.). Pretreatment with 1-(aminophenyl)-4-methyl-7,8-methylendioxy-5H-2,3-benzodiazepine (GYKI 52466; i.v.) decreased the incidence of clonic seizures for DL-BMAA, kainic acid and RS-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (RS-AMPA; i.c.v.). These results suggest an involvement of the AMPA/quisqualate subtype of excitatory amino acid receptors in acute BMAA toxicity.
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PMID:Receptor site specificity for the acute effects of beta-N-methylamino-alanine in mice. 198 Feb 47

A new patient with Leigh's syndrome (subacute necrotizing encephalomyelopathy due to pyruvate dehydrogenase complex deficiency) is presented. A Turkish boy of consanguinously married healthy parents developed progressive muscle weakness since infancy. At the age of 3 years he was unable to sit, stand or walk. Clinical examination showed general muscle weakness, hypotonia, muscle hypotrophy, bilateral ptosis, partial bilateral external ophthalmoplegia, nystagmus, intention tremor and hypoactive tendon reflexes. The EEG showed diffuse slowing, the cerebral CT scan disclosed mild hydrocephalus e vacuo. Motor nerve conduction velocity was slightly decreased, the EMG revealed signs of neuropathy. In the biopsied muscle only a mild hypotrophy of type 2 fibres was found, no abnormal mitochondria could be detected. The sural nerve was slightly abnormal: loss of large myelinated axons, loss of unmyelinated nerves. CSF protein was elevated to 80 mg/dl, protein electrophoresis revealed the pattern of markedly impaired blood-CSF barrier. Serum lactate and pyruvate were permanently elevated. In the urine the excretion of alanine was raised. The clinical state deteriorated during intercurrent infections; somnolence, vomiting and Cheyne-Stoke's respiration occurred. At the age of 3 1/2 years the child died of pneumonia. In the liver tissue a decreased activity of the pyruvate dehydrogenase complex was found. Neuropathological examination of the brain demonstrated wide-spread changes of Leigh's spongiform encephalopathy. Several enzyme deficiencies have hitherto been associated with Leigh's syndrome: This patients confirms earlier findings that a subgroup of Leigh's syndrome is caused by pyruvate dehydrogenase complex deficiency.
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PMID:[Leigh's subacute necrotizing encephalomyelopathy due to decreased activity of the pyruvate dehydrogenase complex]. 312 26

Disorders characterized by both neurologic (ataxia, ophthalmoplegia, ptosis, neuromyopathy) and cardiologic (heart block, cardiomyopathy) abnormalities have been previously called the "ophthalmoplegia plus" syndromes. Most are not due to a specific enzyme defect or metabolic abnormality and thus may be similar phenotypic expressions of diverse causes. We studied seven patients with progressive external ophthalmoplegia and variable ataxia, with mitral valve prolapse and mitral regurgitation that progressed in severity as did the neuromuscular manifestations. Abnormal skeletal muscle biopsies showed "ragged-red" fibers or congenital fiber type disproportion; serum alanine levels were elevated; in-vivo and in-vitro tests of pyruvate metabolism gave abnormal results; C4 complement was decreased; and the patients' fibroblasts bound immunoglobulin when incubated with autologous serum. These data suggest a distinct neuromuscular disorder with metabolic and immunologic features associated with mitral valve prolapse and progressive mitral regurgitation.
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PMID:Mitral valve prolapse and ophthalmoplegia: a progressive, cardioneurologic syndrome. 634 61

Norepinephrine and epinephrine are critical determinants of minute-to-minute regulation of blood pressure. Here we review the characterization of two syndromes associated with a genetic abnormality in the noradrenergic pathway. In 1986, we reported a congenital syndrome of undetectable tissue and circulating levels of norepinephrine and epinephrine, elevated levels of dopamine, and absence of dopamine-beta-hydroxylase (DBH). These patients appeared with ptosis and severe orthostatic hypotension and lacked sympathetic noradrenergic function. In two persons with DBH deficiency, we identified seven novel polymorphisms. Both patients are compound heterozygotes for a variant that affects expression of DBH protein via impairment of splicing. Patient 1 also has a missense mutation in DBH exon 2, and patient 2 carries missense mutations in exons 1 and 6. Orthostatic intolerance is a common syndrome affecting young women, presenting with orthostatic tachycardia and symptoms of cerebral hypoperfusion on standing. We tested the hypothesis that abnormal norepinephrine transporter (NET) function might contribute to its etiology. In our proband, we found an elevated plasma norepinephrine with standing that was disproportionate to the increase in levels of dihydroxphenylglycol, as well as impaired norepinephrine clearance and tyramine resistance. Studies of NET gene structure revealed a coding mutation converting a conserved alanine residue in transmembrane domain 9 to proline. Analysis of the protein produced by the mutant cDNA demonstrated greater than 98% reduction in activity relative to normal. The finding of genetic mutations responsible for DBH deficiency and orthostatic intolerance leads us to believe that genetic causes of other autonomic disorders will be found, enabling us to design more effective therapeutic interventions.
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PMID:Genetic basis of clinical catecholamine disorders. 1243 71

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized clinically by progressive ptosis, dysphagia and limb weakness, and by unique intranuclear inclusions in the skeletal muscle fibers. The disease is caused by the expansion of a 10-alanine stretch to 12-17 alanine residues in the poly(A)-binding protein, nuclear 1 (PABPN1; PABP2). While PABPN1 is a major component of the inclusions in OPMD, the exact cause of the disease is unknown. To elucidate the molecular mechanism and to construct a useful model for therapeutic trials, we have generated transgenic mice expressing the hPABPN1. Transgenic mice lines expressing a normal hPABPN1 with 10-alanine stretch did not reveal myopathic changes, whereas lines expressing high levels of expanded hPABPN1 with a 13-alanine stretch showed an apparent myopathy phenotype, especially in old age. Pathological studies in the latter mice disclosed intranuclear inclusions consisting of aggregated mutant hPABPN1 product. Furthermore, some TUNEL positive nuclei were shown around degenerating fibers and a cluster of it in the lesion in necrotic muscle fibers. Interestingly, the degree of myopathic changes was more prominent in the eyelid and pharyngeal muscles. Further, muscle weakness in the limbs was apparent as shown by the fatigability test. Nuclear inclusions seemed to develop gradually with aging, at least after 1 week of age, in model mouse muscles. We established the first transgenic mouse model of OPMD by expressing mutated PABPN1, and our model mice appear to have more dramatic alternations in myofiber viability.
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PMID:Myopathy phenotype in transgenic mice expressing mutated PABPN1 as a model of oculopharyngeal muscular dystrophy. 1464 3

Premature ovarian failure in a subgroup of women with blepharophimosis-ptosis-epicanthus inversus type 1 syndrome has been associated with nonsense mutations in the gene encoding a Forkhead transcription factor, Forkhead L2 (FOXL2). However, the exact function of FOXL2 in the ovary is unclear. We investigated the expression of FOXL2 in the mouse ovary during follicular development and maturation by RT-PCR and in situ hybridization. The FOXL2 mRNA is expressed in ovaries throughout development and adulthood and is localized to the undifferentiated granulosa cells in small and medium follicles as well as cumulus cells of preovulatory follicles. FOXL2 belongs to a group of transcription factors capable of interacting with specific DNA sequences in diverse gene promoters. With the presence of multiple putative forkhead DNA consensus sites, the promoter of the human steroidogenic acute regulatory (StAR) gene was used to test for regulation by FOXL2. Cotransfection studies revealed that wild-type FOXL2 represses the activity of the StAR promoter, and the first 95 bp upstream of the transcriptional start site of the StAR gene is sufficient for FOXL2 repression. EMSAs confirmed that FOXL2 interacts directly with this region. Analyses using FOXL2 mutants also demonstrated the importance of the entire alanine/proline-rich carboxyl terminus of FOXL2 for transcriptional repression. Furthermore, these mutations produce a protein with a dominant-negative effect that disables the transcriptional repressor activity of wild-type FOXL2. Dominant-negative mutations of FOXL2 could increase expression of StAR and other follicle differentiation genes in small and medium follicles to accelerate follicle development, resulting in increased initial recruitment of dormant follicles and thus the premature ovarian failure phenotype.
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PMID:Forkhead l2 is expressed in the ovary and represses the promoter activity of the steroidogenic acute regulatory gene. 1505 56

Premature ovarian failure (POF) is a heterogeneous disorder whose aetiology is still unknown. Recently, the autosomal FOXL2 gene, highly expressed in the adult ovary, has been correlated with the disorder. FOXL2 mutations, causing a truncation of the FOXL2 protein in the forkhead domain or in the poly-Ala tract lead to blepharophimosis-ptosis-epicanthus-inversus syndrome associated with POF (BPES I). Interestingly, in two out of 70 idiopathic POF patients, a 30 bp deletion (898-927del) and a missense mutation (1009T-->A) were identified. To further evaluate the correlation between POF and FOXL2 mutations, 120 phenotypically normal women affected by POF were analysed by direct sequencing of the FOXL2 coding region. The analysis did not reveal any mutation in the 240 analysed chromosomes, indicating that mutations in the FOXL2 coding region are rarely associated with non-syndromic POF.
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PMID:Mutations in the coding region of the FOXL2 gene are not a major cause of idiopathic premature ovarian failure. 1518 Nov 79

Blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), an autosomal dominant syndrome in which eyelid malformation is associated with (type I BPES) or without premature ovarian failure (type II BPES). Mutations of a putative winged helix/forkhead transcription factor FOXL2 account for both types of BPES. We report on a 16-year-old adolescent girl with blepharophimosis and ptosis. Subsequently she developed oligomenorrhea, secondary amenorrhea for 6 months, and an extremely large cyst of one ovary. The cyst contained 8 l of cyst fluid and histopathology displayed a large corpus luteum cyst. Following laparotomy, gonadotropin levels were elevated (LH 17.2 U/l, FSH 29.4 U/l) and estradiol levels decreased (67 pmol/l). Because of clinical aspects of BPES and abnormal ovarian function we suspected a mutation of her FOXL2 gene and found a new in-frame mutation (904_939dup36) on one allele, leading to a 12 alanine expansion within the polyalanine domain. We conclude that the FOXL2 mutation 904_939dup36 may account not only for blepharophimosis and ptosis but also for ovarian dysfunction and growth of the large corpus luteum cyst. In contrast to known FOXL2 mutations with polyalanine expansions and association with BPES type II, clinical aspects of our girl may indicate some degree of ovarian dysfunction that might finally lead to BPES type I with premature ovarian failure.
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PMID:A new heterozygous mutation of the FOXL2 gene is associated with a large ovarian cyst and ovarian dysfunction in an adolescent girl with blepharophimosis/ptosis/epicanthus inversus syndrome. 1613 96

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset polyalanine disorder characterized clinically by progressive ptosis, dysphagia, and limb weakness and pathological hallmarked by unique intranuclear inclusions in the muscles. It is caused by heterozygous expansion of a 10-alanine stretch to 12-17 alanine residues in the N-terminus of the poly(A)-binding protein, nuclear 1 (PABPN1). Although PABPN1 is a major component of the inclusions in OPMD, the associated pathogenic mechanism is undetermined. No animal models of OPMD have been discovered in nature; therefore, we generated transgenic mice expressing human PABPN1 (hPABPN1) using a chicken beta-actin (CAG) promoter. While transgenic mice lines expressing normal hPABPN1 did not show myopathic changes, lines expressing high levels of expanded hPABPN1 with a 13-alanine stretch showed myopathy phenotype with aging. The latter mice disclosed intranuclear inclusions consisting of aggregated mutant hPABPN1 and scattered rimmed vacuoles restricted in the muscles. In particular, the nuclear inclusions closely resembled those of OPMD muscles on electron microscopy, and myopathic changes were more prominent in the eyelid and pharyngeal muscles. The results demonstrated that we had established the first transgenic OPMD model mouse. Recently, two other transgenic mice expressing mutated hPABPN1 with a 17-alanine stretch have been generated; however, the transgenic mouse using its natural promoter did not show myopathy phenotype, and the other using the human skeletal actin (HSA1) promoter disclosed quite different intranuclear inclusions from those of human OPMD muscles. Our transgenic OPMD model mouse appears to have more dramatic alterations in myofiber viability, but is useful for elucidating of molecular mechanisms and establishing therapeutic trials.
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PMID:Animal model of oculopharyngeal muscular dystrophy. 1655 Sep 22


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