Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0013362 (dysarthria)
 3,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The authors describe siblings with progressive external ophthalmoplegia (PEO) due to a novel heterozygous A to G transition at nucleotide 955 of C10Orf2 (Twinkle). The mutation was not identified in parents' blood, hair follicles, buccal mucosa, or urinary epithelium, indicating germ line mosaicism. One sibling presented with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO), a phenotype previously associated with the POLG1 gene, highlighting the clinical overlap in autosomal PEO.
 ...
PMID:Sensory ataxic neuropathy due to a novel C10Orf2 mutation with probable germline mosaicism. 1566 46

DNA polymerase gamma is responsible for replication and repair of the mitochondrial genome. Human DNA polymerase gamma is composed of a 140-kDa catalytic subunit and a 55-kDa accessory subunit. Mutations in the gene for the catalytic subunit (POLG) have been shown to be a frequent cause of mitochondrial disorders. To date over 40 disease mutations and 9 nonsynonymous polymorphisms in POLG have been found to be associated with autosomal recessive and dominant progressive external ophthalmoplegia (PEO), Alpers syndrome, sensory ataxia, neuropathy, dysarthria and ophthalmoparesis (SANDO), Parkinsonism, and male infertility. In this paper we review the literature of POLG mutations and discuss their impact on mitochondrial diseases. We also describe a public access web database to annotate POLG mutations for the research community.
 ...
PMID:Consequences of mutations in human DNA polymerase gamma. 1591 23

Depletion and multiple deletions of mitochondrial DNA (mtDNA) have been associated with a number of autosomal disorders classified as defects of nuclear-mitochondrial intergenomic signaling. The mendelian forms of progressive external ophthalmoplegia (PEO) are clinically and genetically heterogeneous disorders characterized by the accumulation of multiple deletions of mtDNA in postmitotic patient's tissues. Most of the autosomal dominant PEO (adPEO) families carry heterozygous mutations in either one of three genes: ANT1, Twinkle, and POLG1. Mutations in POLG1 can also cause autosomal recessive PEO (arPEO) and apparently sporadic cases. In addition, recessive POLG1 mutations are responsible for sensory-atactic neuropathy, dysarthria and ophthalmoplegia (SANDO), juvenile spino-cerebellar ataxia-epilepsy syndrome (SCAE) and Alpers-Huttenlocher hepatopathic poliodystrophy. Mutations in thymidine phosphorylase gene (TP) are linked to mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive disorder in which PEO is associated with gastrointestinal dysmotility and leukodystrophy. Finally, mitochondrial DNA depletion syndromes (MDS), defined by tissue-reduction in mtDNA copy number, have been linked to mutations in two genes involved in deoxyribonucleotide (dNTP) metabolism: thymidine kinase 2 (TK2) and deoxyguanosine kinase (DGUOK).
 ...
PMID:Disorders of nuclear-mitochondrial intergenomic signaling. 1592 63

Sensory ataxia with neuropathy, dysarthria and ophthalmoparesis represent the clinical triad of SANDO, a specific mitochondrial phenotype first reported in 1997 in association with multiple mitochondrial DNA deletions and mutations in POLG1 or more rarely in the C10orf2 (twinkle-helicase) gene. We report a 44-year-old man with SANDO who harboured two novel mutations (P648R/R807C) in the POLG1 gene.
 ...
PMID:SANDO: two novel mutations in POLG1 gene. 1691 51

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.
 ...
PMID:Encephalomyopathies caused by abnormal nuclear-mitochondrial intergenomic cross-talk. 1977 89

Involvement of peripheral nerves is frequent in mitochondrial disorders but with variable severity. Mitochondrial diseases causing peripheral neuropathies (PN) may be due to mutations of mitochondrial DNA (mtDNA), as is the case in MERRF and MELAS syndromes, or to mutations of nuclear genes. Secondary abnormalities of mtDNA (such as multiple deletions of muscle mtDNA) may result from mitochondrial disorders due to mutations in nuclear genes involved in mtDNA maintenance. This is the case in several syndromes caused by impaired mtDNA maintenance, such as Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO) due to recessive mutations in the POLG gene, which encodes the catalytic subunit of mtDNA polymerase (DNA polymerase gamma), or Mitochondrial Neuro-Gastro-Intestinal Encephalomyopathy (MNGIE), due to recessive mutations in the TYMP gene, which encodes thymidine phosphorylase. Genetically-determined PN due to mutations of mitofusin 2, a GTPase involved in the fusion of external mitochondrial membranes, were identified during the last few years. Characteristic ultrastructural lesions (abnormalities of axonal mitochondria) are observed on longitudinal sections of nerve biopsies in patients with PN due to mitofusin 2 mutations.
 ...
PMID:[Peripheral neuropathies due to mitochondrial disorders]. 1994 42

Mitochondria is an intracellular double membrane-bound structure and it can provide energy for intracellular metabolism. The metabolism includes Krebs cycle, beta-oxidation and lipid synthesis. The density of mitochondria is different in various tissues dependent upon the demands of oxidative phosphorylation. Mitochondrial diseases can occur by defects either in mitochondrial DNA or nuclear DNA. Human mitochondrial DNA (mtDNA) encoding for 22 tRNAs, 2 rRNAs and 13 mRNAs that are translated in the mitochondria. Mitochondrial genetic diseases are most resulted from defects in the mtDNA which may be point mutations, deletions, or mitochondrial DNA depletion. These patterns of inheritance in mitochondrial diseases include sporadic, maternally inherited, or of Mendelian inheritance. Mitochondrial DNA depletion is caused by defects in the nuclear genes that are responsible for maintenance of integrity of mtDNA or deoxyribonucelotide pools and mtDNA biogenesis. The mtDNA depletion syndrome (MDS) includes the following categories: progressive external ophthalmoplegia (PEO), predominant myopathy, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), sensory-ataxic neuropathy, dysarthria, and ophthalmoplegia (SANDO) and hepato-encephalopathy. The most common tissues or organs involved in MDS and related disorders include the brain, liver and muscles. These involved genes are divided into two groups including 1) DNA polymerase gamma (POLG, POLG2) and Twinkle genes whose products function directly at the mtDNA replication fork, and 2) adenine nucleotide translocator 1, thymidine phosphorylase, thymidine kinase 2, deoxyguanosine kinase, ADP-forming succinyl-CoA synthetase ligase, MPV17 whose products supply the mitochondria with deoxyribonucleotide triphosphate pools needed for mtDNA replication, and possible mutation in the RRM2B gene. The development has provided new information about the importance of the biosynthetic pathway of the nucleotides for mtDNA replication. Further investigation on the understatanding between the nuclear and mitochondrial genomes is expected.
 ...
PMID:[Mitochondrial disease and mitochondrial DNA depletion syndromes]. 2032 99

This 54year old woman presented with symptoms of sensory ataxic neuropathy, with cerebellar features. She developed further weakness, visual disturbances with diplopia, dysarthria and dysphasia. After her death at 66years, she was found to have compound heterozygous mutations of POLG1 gene in muscle, and Southern blot showed low levels of multiple deletions of mitochondrial DNA. Neuropathological examination showed profound dorsal column and dorsal spinocerebellar tract degeneration, degeneration of dorsal root ganglia and Clarke's nucleus in spinal cord and severe predominantly sensory peripheral neuropathy. The brain showed severe neuronal loss and gliosis in substantia nigra, medial posterior thalamus and head of caudate. Excess numbers of COX-negative fibres and "ragged-red" fibres were found in five skeletal muscles sampled.
 ...
PMID:A case of myelopathy, myopathy, peripheral neuropathy and subcortical grey matter degeneration associated with recessive compound heterozygous POLG1 mutations. 2235 63

Case histories of two unrelated patients suffering from sensory ataxic neuropathy, dysarthria/dysphagia and external ophthalmoplegia (SANDO) are reported. Both patients showed compound heterozygosity for POLG1 gene mutations, and presented with symptom of the clinical characteristics of SANDO. A patient with a p.A467T and p.W748S, well-known mutations showed a progressive course with early onset and multisystem involvement, including symptoms characteristics for mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). The second patient showed a less well-known p.T251I and p.G848S mutations with late onset and dysphagia/dysarthria dominated, moderate symptoms. This later is the second published case history, when these POLG1 gene mutations are the possible background of late onset SANDO, dominantly presenting with bulbar symptoms.
 ...
PMID:Sensory ataxic neuropathy with dysarthria/dysphagia and ophthalmoplegia (SANDO). Two case reports. 2261 2

A woman in her early 60s presented to our Movement Disorders Centre with a 5-year history of progressive peripheral neuropathy, gait instability with falls, blurred vision, cognitive impairment and tremors. The patient was found to have profound sensory ataxia, chronic ophthalmoplegia, dementia with significant deficits in registration and construction and bilateral resting tremor of the hands. Investigations revealed an unremarkable MRI of the brain, negative cerebrospinal fluid studies, and unremarkable chemistries. Nerve conduction studies found a severe sensorimotor axonal polyneuropathy. Genetic testing revealed a compound heterozygous mutation in the POLG1 gene consistent with the diagnosis of Sensory Ataxia Neuropathy Dysarthria and Ophthalmoplegia (SANDO) syndrome.
...
PMID:Diagnostic challenges in movement disorders: Sensory Ataxia Neuropathy Dysarthria and Ophthalmoplegia (SANDO) syndrome. 2399 76


1 2 Next >>