Novel POLG1 mutations in a patient with adult-onset progressive external ophthalmoplegia and encephalopathy.
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PROVIDER: S-EPMC3028303 | BioStudies |
REPOSITORIES: biostudies
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Project description:BACKGROUND: The c.2447G>A (p.R722H) mutation in the gene POLG1 of the catalytic subunit of human mitochondrial polymerase gamma has been previously found in a few occasions but its pathogenicity has remained uncertain. We set out to ascertain its contribution to neuromuscular disease. METHODS: Probands from two families with probable mitochondrial disease were examined clinically, muscle and buccal epithelial DNA were analyzed for mtDNA deletions, and the POLG1, POLG2, ANT1 and Twinkle genes were sequenced. RESULTS: An adult proband presented with progressive external ophthalmoplegia, sensorineural hearing impairment, diabetes mellitus, dysphagia, a limb myopathy and dementia. Brain MRI showed central and cortical atrophy, and 18F-deoxyglucose PET revealed reduced glucose uptake. Histochemical analysis of muscle disclosed ragged red fibers and cytochrome c oxidase-negative fibers. Electron microscopy showed subsarcolemmal aggregates of morphologically normal mitochondria. Multiple mtDNA deletions were found in the muscle, and sequencing of the POLG1 gene revealed a homozygous c.2447G>A (p.R722H) mutation. His two siblings were also homozygous with respect to the p.R722H mutation and presented with dementia and sensorineural hearing impairment. In another family the p.R722H mutation was found as compound heterozygosity with the common p.W748S mutation in two siblings with mental retardation, ptosis, epilepsy and psychiatric symptoms. The estimated carrier frequency of the p.R722H mutation was 1:135 in the Finnish population. No mutations in POLG2, ANT1 and Twinkle genes were found. Analysis of the POLG1 sequence by homology modeling supported the notion that the p.R722H mutation is pathogenic. CONCLUSIONS: The recessive c.2447G>A (p.R722H) mutation in the linker region of the POLG1 gene is pathogenic for multiple mtDNA deletions in muscle and is associated with a late-onset neurological phenotype as a homozygous state. The onset of the disease can be earlier in compound heterozygotes.
| S-EPMC2873323 | BioStudies
Project description:<h4>Background</h4>Mutations in the POLG1 gene have variable phenotypic presentations and a high degree of clinical suspicion is necessary for their recognition. Parkinsonism and ataxia are the most common movement disorders associated with POLG1 mutations but no phenotype-genotype correlation has been established.<h4>Case presentation</h4>We identified a male patient with progressive external ophthalmoplegia who also developed a progressive bradykinesia, rigidity and camptocormia in the third decade. Parkinsonism was partially responsive to dopaminegic replacement. His father and brother had reportedly similar clinical problems. Genetic analysis identified a novel mutation p.K512M in the POLG1 gene.<h4>Conclusion</h4>This report further expands the spectrum of POLG1-associated neurologic problems with the report of a novel mutation in the linker region of the gene, which are rarely associated with parkinsonism.
| S-EPMC3728152 | BioStudies
Project description:The human mitochondrial genome is replicated by DNA polymerase ?, which is encoded by polymerase ? gene (POLG1) on chromosome 15q25. Patients with POLG1 mutations usually present as Alpers' syndrome or progressive external ophthalmoplegia. Our patient was a 48-year old woman with sensory ataxic neuropathy, dysarthria, ophthalmoplegia, and dysphagia. Sequence analysis revealed that she has two heterozygous missense mutations in the POLG1, a c.1774C>T substitution in exon 10, which results in a p.L591F amino acid change; and a c.3286C>T substitution in exon 21, which results in a p.R1096C amino acid change. The 1774C>T substitution is a novel mutation. Previously described adult patients with one mutation in exon 10 and the other in exon 21 of POLG1 had presented with progressive external ophthalmoplegia. We now describe a patient with mutations in the same exons but suffering from the more complex clinical syndrome of sensory ataxic neuropathy, dysarthria, ophthalmoplegia.
| S-EPMC3832984 | BioStudies
Project description:POLG1 mutations have been associated with MELAS-like phenotypes. However given several clinical differences it is unknown whether POLG1 mutations are possible causes of MELAS or give raise to a distinct clinical and genetic entity, named POLG1-associated encephalopathy.We describe a 74 years old man carrying POLG1 mutations presenting with strokes, myopathy and ragged red fibers with some atypical aspects for MELAS such as late onset, lack of cerebral calcification and presence of frontal and occipital MRI lesions better consistent with the POLG associated-encephalopathy spectrum.The lack of available data hampers a definite diagnosis in our patient as well as makes it difficult to compare MELAS, which is a clearly defined clinical syndrome, with POLG1-associated encephalopathy, which is so far a purely molecularly defined syndrome with a quite heterogeneous clinical picture. However, the present report contributes to expand the phenotypic spectrum of POLG1 mutations underlining the importance of searching POLG1 mutations in patients with mitochondrial signs and MELAS like phenotypes but negative for common mtDNA mutations.
| S-EPMC3570393 | BioStudies
Project description:Chronic progressive external ophthalmoplegia is one of mitochondrial disorders, characterized by ptosis, limitation of eye movement, variably severe bulbar muscle weakness and proximal limb weakness. Chronic progressive external ophthalmoplegia complicated with acquired disease is extremely rare. We report a 44 years old male patient with more than 20 years of chronic progressive bilateral ptosis and limitation of eye movements manifested dysarthria, dysphagia and neck muscle weakness for 3 years. The first muscle biopsy showed red-ragged fibers and cytochrome c oxidase negative fibers as well as inflammatory cells infiltration. Electron microscopy revealed paracrystalline inclusions. Mitochondrial genetic analysis demonstrated a large-scale mtDNA deletion of m.8470_13446del4977. The patient was treated with prednisone. In a three-year follow-up study, the second biopsy was performed. Before the treatment, except bilateral ptosis and external ophthalmopelgia, this patient presented bulbar muscle weakness and neck muscle weakness. After treated with prednisone, the symptoms of dysphagia, dysarthria and neck muscle weakness were significantly improved, and the second biopsy showed only mitochondrial myopathy pathology but the inflammations disappeared. Here, we report a patient with chronic progressive external ophthalmoplegia complicated with inflammatory myopathy and after treated with prednisone as myositis, he had a significant therapeutic effect.
| S-EPMC4314000 | BioStudies
Project description:Germline mutations in mitochondrial DNA polymerase gamma (POLG1) induce mitochondrial DNA (mtDNA) mutations, depletion, and decrease oxidative phosphorylation. Earlier, we identified somatic mutations in POLG1 and the contribution of these mutations in human cancer. However, a role for germline variations in POLG1 in human cancers is unknown. In this study, we examined a role for disease associated germline variants of POLG1, POLG1 gene expression, copy number variation and regulation in human cancers. We analyzed the mutations, expression and copy number variation in POLG1 in several cancer databases and validated the analyses in primary breast tumors and breast cancer cell lines. We discovered 5-aza-2'-deoxycytidine led epigenetic regulation of POLG1, mtDNA-encoded genes and increased mitochondrial respiration. We conducted comprehensive race based bioinformatics analyses of POLG1 gene in more than 33,000 European-Americans and 5,000 African-Americans. We identified a mitochondrial disease causing missense variation in polymerase domain of POLG1 protein at amino acid 1143 (E1143G) to be 25 times more prevalent in European-Americans (allele frequency 0.03777) when compared to African-American (allele frequency 0.00151) population. We identified T251I and P587L missense variations in exonuclease and linker region of POLG1 also to be more prevalent in European-Americans. Expression of these variants increased glucose consumption, decreased ATP production and increased matrigel invasion. Interestingly, conditional expression of these variants revealed that matrigel invasion properties conferred by these germline variants were reversible suggesting a role of epigenetic regulators. Indeed, we identified a set of miRNA whose expression was reversible after variant expression was turned off. Together, our studies demonstrate altered genetic and epigenetic regulation of POLG1 in human cancers and suggest a role for POLG1 germline variants in promoting tumorigenic properties.
| S-EPMC4607296 | BioStudies
Project description:Autosomal dominant progressive external ophthalmoplegia due to PEO1 mutations is considered relatively benign, but no data about long-term progression of this disease have been reported. The aim of this study was to provide a 16-year clinical follow-up of autosomal dominant progressive external ophthalmoplegia due to the p.R357P gene mutation in PEO1.Twenty-two members of an Irish-American family were examined in 1996, when PEO1 sequencing revealed a c.1071G>C/p.R357P mutation in 9 of them. We reexamined the family in 2012 using a standardized clinical protocol. Autosomal dominant progressive external ophthalmoplegia due to the p.R357P PEO1 mutation is a late-onset ocular myopathy beginning with ptosis and progressing slowly. Ophthalmoparesis, if present, is mild and evident only by neurological examination.Our results are important for prognosis and genetic counseling.
| S-EPMC3973017 | BioStudies
Project description:The extraocular fibrosis syndromes are congenital ocular-motility disorders that arise from dysfunction of the oculomotor, trochlear, and abducens nerves and/or the muscles that they innervate. Each is marked by a specific form of restrictive paralytic ophthalmoplegia with or without ptosis. Individuals with the classic form of congenital fibrosis of the extraocular muscles (CFEOM1) are born with bilateral ptosis and a restrictive infraductive external ophthalmoplegia. We previously demonstrated that CFEOM1 is caused by an autosomal dominant locus on chromosome 12 and results from a developmental absence of the superior division of the oculomotor nerve. We now have mapped a variant of CFEOM, exotropic strabismus fixus ("CFEOM2"). Affected individuals are born with bilateral ptosis and restrictive ophthalmoplegia with the globes "frozen" in extreme abduction. This autosomal recessive disorder is present in members of three consanguineous Saudi Arabian families. Genetic analysis of 70 individuals (20 affected individuals) reveals linkage to markers on chromosome 11q13, with a combined LOD score of 12.3 at the single nonrecombinant marker, D11S1314. The 2.5-cM CFEOM2 critical region is flanked by D11S4196/D11S4162 and D11S4184/1369. Two of the three families share a common disease-associated haplotype, suggesting a founder effect for CFEOM2. We hypothesize that CFEOM2 results from an analogous developmental defect to CFEOM1, one that affects both the superior and inferior divisions of the oculomotor nerve and their corresponding alpha motoneurons and extraocular muscles.
1998-01-01 | S-EPMC1377321 | BioStudies
Project description:Variations in the POLG1 gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma, have recently been associated with Parkinson's disease (PD), especially in patients diagnosed with progressive external ophthalmoplegia (PEO). However, the majority of the studies reporting this association mainly focused on the genetic identification of the variation in POLG1 in PD patient primary cells, and determination of mitochondrial DNA copy number, providing little information about the cellular alterations existing in patient brain cells, in particular dopaminergic neurons. Therefore, through the use of induced pluripotent stem cells (iPSCs), we assessed cellular alterations in novel p.Q811R POLG1 (POLG1Q811R) variant midbrain dopaminergic neuron-containing spheroids (MDNS) from a female patient who developed early-onset PD, and compared them to cultures derived from a healthy control of the same gender. Both POLG1 variant and control MDNS contained functional midbrain regionalized TH/FOXA2-positive dopaminergic neurons, capable of releasing dopamine. Western blot analysis identified the presence of high molecular weight oligomeric alpha-synuclein in POLG1Q811R MDNS compared to control cultures. In order to assess POLG1Q811R-related cellular alterations within the MDNS, we applied mass-spectrometry based quantitative proteomic analysis. In total, 6749 proteins were identified, with 61 significantly differentially expressed between POLG1Q811R and control samples. Pro- and anti-inflammatory signaling and pathways involved in energy metabolism were altered. Notably, increased glycolysis in POLG1Q811R MDNS was suggested by the increase in PFKM and LDHA levels and confirmed using functional analysis of glycolytic rate and oxygen consumption levels. Our results validate the use of iPSCs to assess cellular alterations in relation to PD pathogenesis, in a unique PD patient carrying a novel p.Q811R variation in POLG1, and identify several altered pathways that may be relevant to PD pathogenesis.
| S-EPMC6916051 | BioStudies
Project description:BACKGROUND:The clinical spectrum associated with POLG1 gene mutations ranges from non-syndromic epilepsy or mild isolated neurological signs to neurodegenerative disorders. Our aim was to review diagnostic findings, therapeutic approaches and outcomes of reported cases of epilepsy related to POLG1 mutation. METHODS:The articles for review were identified through a systematic research on PubMed and EMBASE databases from January 2003 to April 2020, searching for the terms "Epilepsy AND POLG OR polymerase gamma," OR "POLG1". RESULTS:Forty-eight articles were selected for review, which included 195 patients. Two main peaks of age at epilepsy onset were found: at ages 1 and 13 years. The most frequent seizure type was myoclonic. The occurrence of Status Epilepticus was reported in 46.4% of cases. Epileptiform and slow abnormalities were most frequently seen over occipital regions. Brain Magnetic Resonance Imaging (MRI) revealed increased T2 signal intensities in thalamic regions. Genetic analysis revealed a prevalence of A467T, W748S and G848S (74.2% of patients) mutations. Survival at 5 years was estimated at very low levels (30.2% of patients). CONCLUSION:In this review, we included cases with both pediatric and adult epilepsy onset. The analysis of data regarding prognosis showed that survival is related to age at onset of epilepsy.
| S-EPMC7690674 | BioStudies