Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We reported previously that the DNA polymerase gamma (POLG) W748S mutation, a common cause of mitochondrial recessive ataxia syndrome (MIRAS), has a common ancient founder for all the disease chromosomes in Finland, Norway, United Kingdom, and Belgium. Here, we present results showing that the same ancestral chromosome underlies MIRAS and Alpers syndrome in Australia and New Zealand. Furthermore, we show that a second common POLG mutation, A467T, also shows common European ancestry: patients from Australia, New Zealand, and the United States share a common haplotype with the previously reported European patients. These data of ancestral haplotypes indicate that the POLG locus is quite stable and that the recessive W748S and A467T mutations, and probably also G848S, have occurred once in history. They have effectively spread to populations of European descent with carrier frequencies up to 1% in several populations. Our data predict that these mutations are common causes of ataxia and Alpers disease in the Western world.
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PMID:Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders. 1742 23

Twinkle is a mitochondrial replicative helicase, the mutations of which have been associated with autosomal dominant progressive external ophthalmoplegia (adPEO), and recessively inherited infantile onset spinocerebellar ataxia (IOSCA). We report here a new phenotype in two siblings with compound heterozygous Twinkle mutations (A318T and Y508C), characterized by severe early onset encephalopathy and signs of liver involvement. The clinical manifestations included hypotonia, athetosis, sensory neuropathy, ataxia, hearing deficit, ophthalmoplegia, intractable epilepsy and elevation of serum transaminases. The liver showed mtDNA depletion, whereas the muscle mtDNA was only slightly affected. Alpers-Huttenlocher syndrome has previously been associated with mutations of polymerase gamma, a replicative polymerase of mtDNA. We show here that recessive mutations of the close functional partner of the polymerase, the Twinkle helicase, can also manifest as early encephalopathy with liver involvement, a phenotype reminiscent of Alpers syndrome, and are a new genetic cause underlying tissue-specific mtDNA depletion.
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PMID:Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion. 1792 Nov 79

Carcinomatous encephalitis is a rare entity, originally described by Madow and Alpers in 1951, which is characterized by tumoral spreading perivascular, without mass effect. Clinical manifestations such as hemiparesis, seizures, ataxia, speech difficulties, cerebrospinal fluid findings as well as computed tomography are nonspecific. This leads the physician to pursue more frequent diseases that could explain those manifestations--toxic, metabolic, and/or infectious encephalopathy. A magnetic resonance imaging (MRI) with gadolinium, the method of choice, presumes the diagnosis. Previous reports of this unusual form of metastatic disease have described patients with prior diagnosis of pulmonary adenocarcinoma. We present the case of carcinomatous encephalitis in a 76-year-old woman as the primary manifestation of occult pulmonary adenocarcinoma with its clinical, imaging, and anatomopathological findings.
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PMID:Carcinomatous encephalitis as clinical presentation of occult lung adenocarcinoma: case report. 1795 93

Parkinsonism has been described in patients with mutations in POLG1 gene. The W748S mutation is one of the most common mutations in this gene and it has been found to be a frequent cause of autosomal recessive ataxia in adults and the Alpers syndrome in children. We found the W748S mutation in a 65-year-old man with a late-onset syndrome consisting of ataxia, parkinsonism, ophthalmoplegia, peripheral neuropathy, and sensorineural hearing loss. Parkinsonism is one of the phenotypic features associated also with the W748S mutation.
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PMID:Parkinsonism associated with the homozygous W748S mutation in the POLG1 gene. 1832 54

We report a 5-year-old child carrying polymerase gamma (POLG1) mutations, but strikingly normal oxidative phosphorylation analysis in muscle, fibroblasts and liver. Mutations in POLG1 have so far been described in children with severe combined oxidative phosphorylation (OXPHOS) deficiencies and with the classical Alpers-Huttenlocher syndrome. The patient presented with a delayed psychomotor development and ataxia during the first two years of life. From the third year of life he developed epilepsy and regression in development, together with symptoms of visual impairment and sensorineuronal deafness. Cerebrospinal fluid showed elevated lactic acid and protein concentrations. An elder brother had died due to combined OXPHOS deficiencies. Despite the clinical similarity with the elder brother, except for liver involvement, the OXPHOS system analysis in a frozen muscle biopsy was normal. For this reason a fresh muscle biopsy was performed, which has the advantage of the possibility of measuring the substrate oxidation rates and ATP production, part of the mitochondrial energy-generating system (MEGS). During the same session, biopsies of liver and fibroblasts were taken. These three tissues showed normal measurements of the MEGS capacity. Based on the phenotype of Alpers-Huttenlocher syndrome in the elder brother, we decided to screen the POLG1 gene. Mutation analysis showed compound heterozygosity with two known mutations, A467T and G848S. The normal MEGS capacity in this patient expands the already existing complexity and heterogeneity of the childhood POLG1 patients and, on the basis of the high frequency of POLG1 mutations in childhood, warrants a liberal strategy with respect to mutation analysis.
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PMID:Normal biochemical analysis of the oxidative phosphorylation (OXPHOS) system in a child with POLG mutations: a cautionary note. 1850 May 70

Different mutations, or combinations of mutations, in POLG1, the gene encoding pol gammaA, the catalytic subunit of mitochondrial DNA polymerase, are associated with a spectrum of clinical presentations including autosomal dominant or recessive progressive external ophthalmoplegia (PEO), juvenile-onset ataxia and epilepsy, and Alpers-Huttenlocher syndrome. Parkinsonian features have been reported as a late complication of POLG1-associated dominant PEO. Good response to levodopa or dopamine agonists, reduced dopamine uptake in the corpus striatum and neuronal loss of the Substantia Nigra pars compacta have been documented in a few cases. Here we report two novel mutations in POLG1 in a compound heterozygous patient with autosomal recessive PEO, followed by pseudo-orthostatic tremor evolving into levodopa-responsive parkinsonism. These observations support the hypothesis that mtDNA dysfunction is engaged in the pathogenesis of idiopathic Parkinson's disease.
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PMID:Two novel POLG1 mutations in a patient with progressive external ophthalmoplegia, levodopa-responsive pseudo-orthostatic tremor and parkinsonism. 1850 41

Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial disease in children and adults. They are responsible for a heterogeneous group of at least 6 major phenotypes of neurodegenerative disease that include: 1) childhood Myocerebrohepatopathy Spectrum disorders (MCHS), 2) Alpers syndrome, 3) Ataxia Neuropathy Spectrum (ANS) disorders, 4) Myoclonus Epilepsy Myopathy Sensory Ataxia (MEMSA), 5) autosomal recessive Progressive External Ophthalmoplegia (arPEO), and 6) autosomal dominant Progressive External Ophthalmoplegia (adPEO). Due to the clinical heterogeneity, time-dependent evolution of symptoms, overlapping phenotypes, and inconsistencies in muscle pathology findings, definitive diagnosis relies on the molecular finding of deleterious mutations. We sequenced the exons and flanking intron region from approximately 350 patients displaying a phenotype consistent with POLG related mitochondrial disease and found informative mutations in 61 (17%). Two mutant alleles were identified in 31 unrelated index patients with autosomal recessive POLG-related disorders. Among them, 20 (67%) had Alpers syndrome, 4 (13%) had arPEO, and 3 (10%) had ANS. In addition, 30 patients carrying one altered POLG allele were found. A total of 25 novel alterations were identified, including 6 null mutations. We describe the predicted structural/functional and clinical importance of the previously unreported missense variants and discuss their likelihood of being pathogenic. In conclusion, sequence analysis allows the identification of mutations responsible for POLG-related disorders and, in most of the autosomal recessive cases where two mutant alleles are found in trans, finding deleterious mutations can provide an unequivocal diagnosis of the disease.
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PMID:Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. 1854 65

The organ most frequently affected in mitochondrial disorders, particularly respiratory chain diseases (RCDs), in addition to the skeletal muscle, is the central nervous system (CNS). CNS manifestations of RCDs comprise stroke-like episodes, epilepsy, migraine, ataxia, spasticity, movement disorders, psychiatric disorders, cognitive decline, or even dementia (mitochondrial dementia). So far mitochondrial dementia has been reported in MELAS, MERRF, LHON, CPEO, KSS, MNGIE, NARP, Leigh syndrome, and Alpers-Huttenlocher disease. Mitochondrial dementia not only results from mutations in the mitochondrial genome but also from mutations in nuclear genes, such as POLG, thymidine kinase 2, or DDP1. Often mitochondrial dementia starts with specific cognitive deficits, particularly in visual construction, attention, abstraction, or flexibility but without a general intellectual deterioration. Cognitive impairment in RCDs is diagnosed upon neuropsychological testing, imaging studies, such as MRI, PET, or MR-spectroscopy, CSF-investigations, or electroencephalography. Therapy of mitochondrial dementia relies on symptomatic measures. Only single patients profit from cholinesterase inhibitors or memantine, antioxidants, vitamins, coenzyme-Q, or other substitutes. Overall, mitochondrial dementia is an important differential of dementias and should be considered in patients with multi-system disease.
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PMID:Mitochondrial disorders, cognitive impairment and dementia. 1926 75

Autosomal dominant Progressive External Ophthalmoplegias are Mendelian disorders characterized by the accumulation of multiple deletions of mitochondrial DNA in critical tissues. Most of the Autosomal dominant Progressive External Ophthalmoplegias families carry heterozygous mutations in one of three genes: ANT1, encoding the muscle-heart specific mitochondrial adenine nucleotide translocator, Twinkle, encoding the mitochondrial DNA helicase, and POLG1, encoding the catalytic subunit of the mitochondrial DNA-specific polymerase. Mutations in both POLG1 alleles are also found in autosomal recessive Progressive External Ophthalmoplegias sibships with multiple affected members and in apparently sporadic cases. In addition, recessive POLG1 mutations are responsible for three additional diseases: Alpers-Huttenlocher hepatopathic poliodystrophy, Sensory-Ataxic Neuropathy Dysarthria and Ophthalmoplegia and juvenile SpinoCerebellar Ataxia-Epilepsy syndrome. Mitochondrial neuro-gastro-intestinal encephalomyopathy is an autosomal recessive disorder of juvenile onset, caused by mutations in the gene encoding Thymidine Phosphorylase. Thymidine Phosphorylase is involved in the control and maintenance of the pyrimidine nucleoside pool of the cell. Finally, mitochondrial DNA depletion syndrome is a heterogeneous group of disorders characterized by a reduction in mitochondrial DNA copy number. Clinically, they include a myopathic form, a more generalized encephalomyopathic form and a fatal infantile hepato-cerebral syndrome leading to rapidly progressive liver and brain failure. To date, eight genes have been associated with mitochondrial DNA depletion syndrome. Novel disease genes have recently been added to this list, including OPA1 and GFER, and new clinical variants add further complexity to this expanding area of mitochondrial medicine.
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PMID:Encephalomyopathies caused by abnormal nuclear-mitochondrial intergenomic cross-talk. 1977 89

More than 150 different point mutations in POLG, the gene encoding the human mitochondrial DNA polymerase gamma (pol gamma), cause a broad spectrum of childhood and adult onset diseases like Alpers syndrome, ataxia-neuropathy syndrome and progressive external ophthalmoplegia. These disease mutations can affect the pol gamma enzyme's properties in numerous ways, thus potentially influencing the severity of the disease. Hence, a detailed characterization of disease mutants will greatly assist researchers and clinicians to develop a clear understanding of the functional defects caused by these mutant enzymes. Experimental approaches for characterizing the wild-type (WT) and mutant pol gamma enzymes are extensively described in this manuscript. The methods start with construction and purification of the recombinant wild-type and mutant forms of pol gamma protein, followed by assays to determine its structural integrity and thermal stability. Next, the biochemical characterization of these enzymes is described in detail, which includes measuring the purified enzyme's catalytic activity, its steady-state kinetic parameters and DNA binding activity, and determining the physical and functional interaction of these pol gamma proteins with the p55 accessory subunit.
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PMID:Purification and functional characterization of human mitochondrial DNA polymerase gamma harboring disease mutations. 2017 7


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