Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029089 (ophthalmoplegia)
 3,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spinocerebellar ataxia 7 (SCA7) is caused by the expansion of an unstable CAG repeat in the first exon of the SCA7 gene. We have analyzed the SCA7 mutation in 19 families and one isolated case of various geographical origins, presenting with autosomal dominant cerebellar ataxia with progressive macular dystrophy. The SCA7 CAG repeat was expanded in 77 patients and in 11 at-risk individuals, with alleles containing from 37 to 130 repeats, demonstrating that SCA7 is genetically homogeneous. Repeats on normal alleles contained from 7 to 35 CAGs. There was a strong negative correlation (r = -0.84) between the age at onset and the size of the CAG repeat expansion in SCA7 patients. Larger expansions were associated with earlier onset, a more severe and rapid clinical course, and a higher frequency of decreased vision, ophthalmoplegia, extensor plantar response and scoliosis. The frequency of other clinical signs such as dysphagia and sphincter disturbances increased with disease duration. The mutation was highly unstable during transmission, with a mean increase of 10 +/- 16 CAG repeats, which was significantly greater in paternal (15 +/- 20) than in maternal (5 +/- 5) transmissions. This correlated well with the marked anticipation (19 +/- 13 years) observed in the families. Gonadal mosaicism, observed in the sperm of a patient, was particularly important, with expanded alleles ranging from 42 to >155 CAG repeats. The degree of instability during transmission, resulting mostly in expansions, is greater than in the seven other neurodegenerative disorders caused by polyglutamine expansions.
Hum Mol Genet 1998 Feb
PMID:Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7). 942 22

Mitochondrial DNA (mtDNA) deletions are present in both human oocytes and embryos. It has been found that these tissues contain a mtDNA mutation which is present in high amounts in patients with Kearns-Sayre syndrome (KSS) and progressive external ophthalmoplegia. In the present study, the frequency of this KSS deletion was investigated in human oocytes and embryos. Using a nested primer polymerase chain chian reaction (PCR) strategy, the frequency of the KSS deletion in 74 human oocytes and 137 embryos was found to be 32.8 and 8.0% respectively. Using a 'long PCR-short PCR' nested primer strategy, the frequency of the KSS deletion in 181 human oocytes and 104 embryos was found to be 47.0 and 20.2% respectively. There was no statistical correlation between the age of the patients at the time of oocyte retrieval and the presence of the deleted molecules. There was a statistical difference between the presence of the deleted molecules in oocytes versus embryos using either technique (P < 0.0001). The relevance of these findings to the accumulation of low levels of deleted mtDNA in both oocytes and embryos is discussed in this study.
Mol Hum Reprod 1998 Sep
PMID:Mitochondrial DNA deletion in human oocytes and embryos. 978 50

A patient with 2-oxoadipic aciduria and 2-aminoadipic aciduria presented at 2 years of age with manifestations typical of organic acidemia, episodes of ketosis and acidosis, progressive to coma. This resolved and the key metabolites disappeared from the urine and blood. At 9 years of age she developed typical Kearns-Sayre syndrome with complete heart block, retinopathy, and ophthalmoplegia. Southern blot revealed a deletion in the mitochondrial genome.
Mol Genet Metab 2000 Jan
PMID:Kearns-Sayre syndrome presenting as 2-oxoadipic aciduria. 1065 59

A polymerase chain reaction (PCR) based procedure was modified to determine the deletion of mitochondrial DNA (mtDNA). The protocol consists of coamplification both of deleted and wild-type segments of mtDNA using a long PCR technique; evaluation of the deleted portion within the amplified DNA segments by restriction enzyme digestion followed by densitometrical analysis; and direct subcloning into a plasmid vector for DNA sequencing. The procedure revealed a 5.3 kb deletion of mtDNA in the biopsied muscle tissue obtained from a patient clinically diagnosed with progressive external ophthalmoplegia. The 5' and 3' sequences at both sides of the breakpoint comprise a 17 bp palindrome and 5 bp tandem repeats, suggesting that the deletion might occur through slipped mispairing and other novel mechanisms. This improved procedure has the potential to detect deletions occurring in the entire length of mtDNA, and mighty be useful for clinical screening of progressive external ophthalmoplegia.
Mol Pathol 2000 Dec
PMID:A unique junctional palindromic sequence in mitochondrial DNA from a patient with progressive external ophthalmoplegia. 1119 53

We present the current knowledge on the genetic and phenotypic aspects of mitochondrial DNA depletion syndromes. The human mitochondrial DNA encodes 13 of the 82 structural proteins of the mitochondrial electron transport chain. The replication and maintenance of the mtDNA require a large number of nuclear encoded enzymes and balanced nucleotide pools. Mitochondrial nucleotide synthesis is of major importance because of the constant need for nucleotides for mtDNA maintenance even in quiescent cells. As de novo enzymes are not present in the mitochondria, synthesis is accomplished via the salvage pathway. Defective mtDNA synthesis and maintenance manifest by multiple deletions or by depletion of the mitochondrial genome. Patients with multiple deletions typically present with progressive external ophthalmoplegia, ptosis and, exercise intolerance after the first decade of life. mtDNA depletion is usually an infantile disease characterized by severe muscle weakness, hepatic failure, or renal tubulopathy with fatal outcome. Linkage analysis in families with multiple mtDNA deletions reveal mutations in proteins that participate in mtDNA replication, the mitochondrial DNA polymerase gene, and the Twinkle gene, a putative mitochondrial helicase and in factors which play a role in mitochondrial nucleotide metabolism, the adenine nucleotide translocator, and the thymidine phosphorylase gene. We have recently identified mutations in an additional two essential proteins in the nucleotide salvage pathway, the mitochondrial deoxyribonucleoside kinases. The phenotype was distinctive for each gene, with hepatic failure and encephalopathy associated with mutations in the deoxyguanosine kinase gene and isolated devastating myopathy as the sole manifestation of thymidine kinase 2 deficiency. The tissue selectivity of these disorders and especially the exclusive muscle involvement in thymidine kinase 2 mutations is puzzling. The normal sequence of the remaining mtDNA copies in spite of a serious mitochondrial nucleotide imbalance is also unexpected. We propose several tissue-specific protective mechanisms and a time window, likely encompassing fetal life and even early infancy, during which nuclear nucleotide synthesis provides mitochondrial needs in all organs. We also speculate on future genes to be discovered in other phenotypes of mtDNA depletion.
J Mol Med (Berl) 2002 Jul
PMID:Depletion of the other genome-mitochondrial DNA depletion syndromes in humans. 1211 Sep 44

Adenine nucleotide translocase (Ant) is primarily involved in ATP/ADP exchange across the mitochondrial inner membrane. Recently, the A114P missense mutation in the human Ant1 protein was found to be associated with autosomal dominant progressive external ophthalmoplegia (adPEO). Ant1(A114P) was proposed to cause an imbalance of the mitochondrial deoxynucleotide pool that subsequently affects the accuracy of mtDNA replication, thereby leading to accumulation of mutant mtDNA. In the present study, it has been shown that the A128P mutation of the Saccharomyces cerevisiae Aac2 protein, equivalent to A114P in human Ant1p, does not always affect respiratory growth. However, expression of aac2(A128P) results in depolarization, structural swelling and disintegration of mitochondria, and ultimately an arrest of cell growth in a dominant-negative manner. The aac2(A128P) mutation likely induces an unregulated channel allowing free passage of solutes across the inner membrane. These data raise the possibility that the formation of an unregulated channel, rather than a defect in ATP/ADP exchange, is a direct pathogenic factor in human adPEO. The accumulation of mtDNA mutations might be a consequence of mitochondrial dysfunction.
Hum Mol Genet 2002 Aug 01
PMID:Induction of an unregulated channel by mutations in adenine nucleotide translocase suggests an explanation for human ophthalmoplegia. 1214 Jan 86

Behcet's disease is a multisystem vasculitis. Its neurologic complications include different syndromes. The purpose of this investigation was to study the prevalence of neurologic manifestations among patients with Behcet's disease and to determine the frequency of different symptoms, signs, and syndromes in neuro-Behcet's disease. Ninety-six consecutive patients who were referred to the Behcet's Disease Clinic in Shiraz (southern Iran) were interviewed and thoroughly examined. Psychiatric evaluation, CSF analysis, electroencephalography, electrodiagnostic studies, and neuroradiologic imaging (preferably MRI) were performed in appropriate cases. Six patients (6.3%) had definite neuro-Behcet's disease. They were 4 males and 2 females (mean age 37.5 years). In 2 patients Behcet's disease had not been diagnosed before. The most frequent symptoms of neuro-Behcet's disease were headache (83.3%), paresthesia (83.3%), unsteadiness (66.7%), diplopia (66.7%), and weakness (50%). The most frequent signs were gait abnormalities (66.7%), sensory abnormalities (66.7%), ophthalmoplegia (50%), cerebellar ataxia (50%), and hemiplegia (50%). The most common syndrome was brain-stem+ type (50%). Subacute onset and relapsing-remitting course were the most common temporal patterns. Neurological manifestation is a relatively less frequent complication of Behcet's disease but it produces severe disabilities. It must be considered in differential diagnosis of multiple sclerosis.
Exp Mol Pathol 2003 Feb
PMID:Neuro-Behcet's disease: a masquerader of multiple sclerosis. A prospective study of neurologic manifestations of Behcet's disease in 96 Iranian patients. 1264 28

The ryanodine receptor (RYR1) is an essential component of the calcium homeostasis of the skeletal muscle in mammals. Inactivation of the RYR1 gene in mice is lethal at birth. In humans only missense and in-frame mutations in the RYR1 gene have been associated so far with various muscle disorders including malignant hyperthermia, central core disease and the moderate form of multi-minicore disease (MmD). We identified a cryptic splicing mutation in the RYR1 gene that resulted in a 90% decrease of the normal RYR1 transcript in skeletal muscle. The 14646+2.99 kb A-->G mutation was associated with the classical form of MmD with ophthalmoplegia, whose genetic basis was previously unknown. The mutation present at a homozygous level was responsible for a massive depletion of the RYR1 protein in skeletal muscle. The mutation was not expressed in lymphoblastoid cells, pointing toward a tissue specific splicing mechanism. This first report of an out-of-frame mutation that affects the amount of RYR1 raised the question of the amount of RYR1 needed for skeletal muscle function in humans.
Hum Mol Genet 2003 May 15
PMID:A homozygous splicing mutation causing a depletion of skeletal muscle RYR1 is associated with multi-minicore disease congenital myopathy with ophthalmoplegia. 1271 81

Although antiviral nucleoside analog therapy successfully delays progression of HIV infection to AIDS, these drugs cause unwelcome side-effects by inducing mitochondrial toxicity. We and others have demonstrated that the mitochondrial polymerase, DNA polymerase gamma (pol gamma), participates in mitochondrial toxicity by incorporating these chain-terminating antiviral nucleotide analogs into DNA. Here, we explore the role of three highly conserved amino acid residues in the active site of human pol gamma that modulate selection of nucleotide analogs as substrates for incorporation. Sequence alignments, crystal structures and mutagenesis studies of family A DNA polymerases led us to change Tyr951 and Tyr955 in polymerase motif B to Phe and Ala, and Glu895 in polymerase motif A was changed to Ala. The mutant polymerases were tested for their ability to incorporate natural nucleotides and the five antiviral nucleoside analogs currently approved for antiviral therapy: AZT, ddC, D4T, 3TC and carbovir. Steady-state kinetic analysis of the pol gamma derivatives with the normal and antiviral nucleotides demonstrated that Tyr951 is largely responsible for the ability of pol gamma to incorporate dideoxynucleotides and D4T-MP. Mutation of Tyr951 to Phe renders the enzyme resistant to dideoxynucleotides and D4T-TP without compromising the activity of the polymerase. Alteration of Glu895 and Tyr955 to Ala had the largest effect on overall polymerase activity with normal nucleotides, producing dramatic increases in K(m(dNTP)) and large decreases in k(cat). Mutation of Tyr955 in pol gamma causes the degenerative disease progressive external ophthalmoplegia in humans, and we show that this residue partially accounts for the ability of pol gamma to incorporate D4T-MP and carbovir. Alteration of Glu895 to Ala slightly increased discrimination against dideoxynucleotides and D4T-TP. The mechanisms by which pol gamma selects certain nucleotide analogs are discussed.
J Mol Biol 2003 May 23
PMID:Structural determinants in human DNA polymerase gamma account for mitochondrial toxicity from nucleoside analogs. 1274 17

Alterations in the expression of free radical scavenging enzymes and production of reactive oxygen species (ROS) in tissue cells may contribute to the pathogenesis of mitochondrial diseases such as chronic progressive external ophthalmoplegia (CPEO) syndrome. Since the mitochondria with impaired respiratory function in affected tissues generate more ROS via electron leakage, we examined the expression levels of free radical scavenging enzymes in primary culture of muscle fibroblasts of eight patients with CPEO syndrome. The results showed that the enzyme activity and protein levels of Mn-SOD of the fibroblasts from CPEO patients were significantly increased but those of Cu,Zn-SOD, catalase and glutathione peroxidase (GPx) were not increased compared with controls. A similar pattern was observed in the mRNA levels of Mn-SOD and GPx in muscle fibroblasts of all CPEO patients. The activity ratios of Mn-SOD/catalase and Mn-SOD/GPx in muscle fibroblasts of the CPEO patients were increased 1.7-3.4 and 1.8- to 5.3-fold, respectively, compared to those of the controls. Moreover, by using flow cytometry we found that the production of O2(*-) and H2O2 in the fibroblasts was about 2 times higher than those of controls. The 8-OHdG/dG ratios in total DNA of muscle biopsies from three CPEO patients were much higher than those of age-matched controls as determined by high performance liquid chromatography (HPLC). In the light of these findings, we suggest that the increase in expression of Mn-SOD, ROS production and oxidative damage in affected tissues may play an important role in the pathogenesis and progression of the CPEO syndrome.
Mol Genet Metab 2003 Nov
PMID:Increased expression of manganese-superoxide dismutase in fibroblasts of patients with CPEO syndrome. 1468 Sep 79


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