Mutation Query
| | | | Allele 1: | L591F | | Allele 2: | R1096C | Allelic information known | | Refine query |
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| | | Residue L591 | | Cluster assignment: | | | Cluster description: | Upstream DNA binding channel | | Subcluster: | 2C (residues 561-617) | | Subcluster description: | Subcluster 2C contains motif 1, which in Pol I was shown to fold into a loop that binds DNA in the channel (Loh and Loeb, 2005). Motif 1, together with subcluster 2D, form the major face of the putative DNA binding channel. | | POLG domain: | Spacer domain |
| Residue R1096 | | Cluster assignment: | | | Cluster description: | Partitioning loop | | Subcluster: | 3D (residues 1047-1096) | | Subcluster description: | The partitioning loop, which is a novel structural module conserved in PolG (residues 1050-1095) that is located between the fingers and palm subdomains of the pol domain, and is not present in any other known DNA polymerase (Euro et al, 2011). | | POLG domain: | Polymerase domain |
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Mutation Information
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| L591F | | | | Number of patients: (with L591F) | 1 | | Non-allelic with: | R1096C (100%) |  | Show Patient Data |
| Patient data are sorted by mutation combination frequency. | Reference: | Kurt et al, 2012; | | Description: | sensory ataxic neuropathy, dysarthria, ophthalmoplegia, and dysphagia. At the age of 41, progressive diplopia and ptosis were added to the symptoms. Five years later, she gradually had dysarthria and restless leg syndrome. ragged red fibers. | | Mutations: | L591F, R1096C | | Age group: | adult | | Age of Onset: 38, Age of Patient: 48, Age of Death: n/a |
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| R1096C | | | | Number of patients: (with R1096C) | 15 | | Found as the only mutation: | 7% of entries (1 patient) | | Found together with: | | | Show Patient Data |
| Patient data are sorted by mutation combination frequency. | Reference: | Ashley et al, 2008; | | Description: | Epilepsy, Cellular depletion, Hepatopathy | | Mutations: | R1096C, R1096C | | Age group: | infantile | | Age of Onset: 0.42, Age of Patient: n/a, Age of Death: n/a |
| Reference: | Horvath et al, 2006; | | Description: | Onset at 2 years with encephalopathy, hepatopathy, and myoclonus achalasia. Diagnosed as Alpers. | | Mutations: | R1096C, R1096C | | SNPs: | Q1236H, Q1236H | | Age group: | infantile | | Age of Onset: 2, Age of Patient: n/a, Age of Death: n/a |
| Reference: | Tang et al, 2011; | | Description: | Developmental delay, seizure, lactic acidosis, elevated transaminases. 50% mtDNA copy number in blood. | | Mutations: | R1096C, R1096C | | Age group: | infantile | | Age of Onset: n/a, Age of Patient: 2, Age of Death: n/a |
| Reference: | Tang et al, 2011; | | Description: | Seizures, dementia/encephalopathy. 56% mtDNA copy number in blood. | | Mutations: | R1096C, R1096C | | Age group: | infantile | | Age of Onset: n/a, Age of Patient: 0.8, Age of Death: n/a |
Back to top | Reference: | Tang et al, 2011; | | Description: | Seizures, liver failure. | | Mutations: | R1096C, R1096C | | Age group: | infantile | | Age of Onset: n/a, Age of Patient: 1, Age of Death: n/a |
| Reference: | Wong et al, 2008; | | Description: | developmental delay, dementia, seizures, Alpers, Family history of Alpers syndrome. | | Mutations: | R1096C, R1096C | | SNPs: | Q1236H, Q1236H | | Age group: | infantile | | Age of Onset: 1, Age of Patient: n/a, Age of Death: n/a |
| Reference: | Bijarnia-Mahay et al, 2014; | | Description: | altered sensorium, seizures (requiring ventilation and critical-care management), hypotonia and mild hepatomegaly. Child deteriorated rapidly because of liver failure and died within two weeks of admission. Mainly hepatic failure and central nervous system (CNS) involvement (encephalopathy, seizures), high plasma lactate levels – and family history, a clinical diagnosis of mitochondrial disorder of the mtDNA depletion (Alpers – Huttenlocher syndrome or Pyruvate carboxylase deficiency) was made. mtDNA depletion syndrome. | | Mutations: | R1096C, R1096C | | Age group: | infantile | | Age of Onset: 0.3, Age of Patient: 0.6, Age of Death: 0.6 |
| Reference: | Stewart et al, 2011; | | Description: | Alpers. Multifocal therapy-refractory epilepsy. hippocampal sclerosis. COX-negative fibers, reduced mtDNA copy number. mtDNA deletions. | | Mutations: | R1096C, R1096C | | Age group: | infantile | | Age of Onset: n/a, Age of Patient: 1, Age of Death: n/a |
| Reference: | Horvath et al, 2006; | | Description: | Onset at 53 years with PEO, neuropathy. | | Mutations: | P648R, R1096C | | Age group: | adult | | Age of Onset: 53, Age of Patient: n/a, Age of Death: n/a |
Back to top | Reference: | Tang et al, 2011; | | Description: | Developmental delay, hypotonia, dementia/encephalopathy, exercise intolerance, muscle weakness, easy fatigability, ptosis, GI reflux, delayed gastric emptying, cyclic vomiting, hepatic failure, elevated transaminases, lactic acidosis, short statue, FTT. 53% mtDNA copy number in blood. | | Mutations: | G848S, R1096C | | Age group: | infantile | | Age of Onset: n/a, Age of Patient: 2, Age of Death: n/a |
| Reference: | Ashley et al, 2008; | | Description: | reported as Alpers, onset at <1 year, presenting encephalopathy with epilepsy, hepatopathy, and movement disorder (ataxia). 7% mtDNA copy number in liver, 23% mtDNA copy number in muscle | | Mutations: | R1096C, T914P | | Age group: | infantile | | Age of Onset: 1, Age of Patient: n/a, Age of Death: n/a |
| Reference: | Lax et al, 2012a; | | Description: | CPEO, Ptosis, Peripheral neuropathy, COX-deficient fibers, ragged red fibers, presence of mitochondrial dna deletions in muscle, Sensory and motor neuronopathy, Distal and proximal neurogenic change | | Mutations: | A467T, R1096C | | Age group: | juvenile | | Age of Onset: 17, Age of Patient: 42, Age of Death: n/a |
| Reference: | Lax et al, 2012a; | | Description: | CPEO, Ptosis, Peripheral neuropathy, COX-deficient fibers, ragged red fibers, presence of mitochondrial dna deletions in muscle, epilepsy, Severe sensory and moderate motor neuronopathy, Distal neurogenic change, proximal myopathy | | Mutations: | R1096C, W748S | | Age group: | adult | | Age of Onset: 25, Age of Patient: 49, Age of Death: n/a |
| Reference: | Kurt et al, 2012; | | Description: | sensory ataxic neuropathy, dysarthria, ophthalmoplegia, and dysphagia. At the age of 41, progressive diplopia and ptosis were added to the symptoms. Five years later, she gradually had dysarthria and restless leg syndrome. ragged red fibers. | | Mutations: | L591F, R1096C | | Age group: | adult | | Age of Onset: 38, Age of Patient: 48, Age of Death: n/a |
Back to top | Reference: | Agostino et al, 2003; | | Description: | PEO, bilateral ptosis, severe limitation of ocular motility, and a mosaic distribution of ragged-red and cytochrome c oxidase negative fibers in the muscle biopsy. All patients had multiple deletions of muscle mtDNA. | | Mutations: | R1096C | | Age group: | adult | | Age of Onset: 23, Age of Patient: n/a, Age of Death: n/a |
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The following information is based on existing patient data and pathogenic cluster assignment.
Pathogenicity information for a patient with mutations in Clusters 2 and 3: Age of onset information is extracted from a total of 33 patients and/ or patient families. | Age of onset | | |
33- 17- | 14
| 2
| 3
| 14
| | | infantile | childhd | juvenile | adult | | | 42% | 6% | 9% | 42% | |
All mutations mapping within the pathogenic clusters are at high risk for pathogenicity. In general, a patient must have a pathogenic mutation in both of his/ her POLG genes to develop a POLG-related syndrome. | Symptoms described in patients with cluster2-cluster3 mutations | |
| Symptoms in patients with combination
cluster2:cluster3 | | PEO | 45.5% | | Epilepsy | 27.3% | | Ptosis | 24.2% | | Encephalopathy | 24.2% | | Dysphagia | 21.2% | | Developmental delay | 18.2% | | Myopathy | 15.2% | | Movement disorder (ataxia) | 12.1% | | Ragged red fibers | 12.1% | | Liver failure | 12.1% | | Liver dysfunction | 12.1% | | Lactic acidosis | 9.1% | | Muscle weakness | 9.1% | | Stroke | 9.1% | | Hypotonic | 9.1% | | Dysarthria | 9.1% | | Areflexia | 9.1% | | Status epilepticus | 6.1% | | Myoclonic seizures | 6.1% | | Sensory ataxia | 6.1% | | Ophthalmoplegia | 6.1% | | Failure to thrive | 6.1% | | Psychomotor delay | 6.1% | | GI dysmotility | 6.1% | | +21 other symptoms in under 5.0% of the patients |
| | Data gathered from clinical descriptions for 33 patients |
| Symptoms by group | | CPEO | 57.6% | | CNS symptoms | 36.4% | | Developmental Delay | 36.4% | | Myopathy | 36.4% | | Seizures | 33.3% | | Hepatopathy | 24.2% | | Ataxia | 18.2% | | Other | 18.2% | | Alpers syndrome | 12.1% | | GI symptoms | 12.1% | | Hypotonia | 9.1% | | Neuropathy | 9.1% |
| | [Show grouping information] |
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