Mutation Query
| | | | Allele 1: | T914P | | Allele 2: | R1096C | Allelic information known | | Refine query |
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| | | Residue T914 | | Cluster assignment: | | | Cluster description: | Polymerase active site and environs | | Subcluster: | 1E (residues 914-966) | | Subcluster description: | This subcluster comprises most of the fingers subdomain of the pol domain, including the O-helix and the Pol B motif (Loh and Loeb, 2005). | | POLG domain: | Polymerase 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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| T914P | | | | Number of patients: (with T914P) | 27 | | Found together with: | PNF=Putatively Non-Functional enzyme |  | Show Patient Data |
| Patient data are sorted by mutation combination frequency. | Reference: | Ashley et al, 2008; | | Description: | reported as Alpers, onset at 7 months, presenting encephalopathy with epilepsy, hepatopathy, and movement disorder (ataxia). 39% mtDNA copy number in muscle. | | Mutations: | A467T, T914P | | Age group: | infantile | | Age of Onset: 0.58, Age of Patient: n/a, Age of Death: n/a |
| Reference: | Blok et al, 2009; | | Description: | Epilepsy, myoclonus, and developmental delay. | | Mutations: | A467T, T914P | | 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 1.5 years with encephalopathy and hepatopathy and cortical blindness. Diagnosed as Alpers. | | Mutations: | A467T, T914P | | Age group: | infantile | | Age of Onset: 1.5, Age of Patient: 2, Age of Death: n/a |
Back to top | Reference: | Horvath et al, 2006; | | Description: | Onset at 4 years with encephalopathy, myoclonus, and SLE. | | Mutations: | A467T, T914P | | Age group: | childhood | | Age of Onset: 4, Age of Patient: 8, Age of Death: n/a |
| Reference: | Taanman et al, 2009; | | Description: | Onset at 9 months with alpers, death at 12 months. 8% mtDNA copy number in liver, 8% mtDNA copy number in muscle. | | Mutations: | A467T, T914P | | Age group: | infantile | | Age of Onset: 0.8, Age of Patient: n/a, Age of Death: 1 |
| Reference: | Tang et al, 2011; | | Description: | Developmental delay, headaches/migraines, seizures, hemiparesis, intractable seizure, high CSF lactate, high CSF protein, hearing loss, abnormal EEG, increased signal basal ganglia, abnormal MRI. 88% mtDNA copy number in blood. | | Mutations: | A467T, T914P | | Age group: | childhood | | Age of Onset: n/a, Age of Patient: 5, Age of Death: n/a |
| Reference: | Tang et al, 2011; | | Description: | Developmental delay, hypotonia, dementia/encephalopathy, seizures, intractable seizure, lactic acidosis, high CSF lactate, abnormal MRI, no liver problem at 3.5 years. 24% mtDNA copy number in blood. | | Mutations: | A467T, T914P | | Age group: | childhood | | Age of Onset: n/a, Age of Patient: 3, Age of Death: n/a |
| Reference: | Tang et al, 2011; | | Description: | Developmental delay, hypotonia, seizures, myoclonic seizures, hemiparesis, intractable seizure, elevated transaminases, FTT, lactic acidosis, high CSF lactate, elevated pyruvate, high CSF protein, dementia/encephalopathy. 112% mtDNA copy number in muscle, 63% mtDNA copy number in blood. | | Mutations: | A467T, T914P | | Age group: | infantile | | Age of Onset: n/a, Age of Patient: 0.9, Age of Death: n/a |
Back to top | Reference: | Tang et al, 2011; | | Description: | Developmental delay, seizures, myoclonic seizures, intractable seizure, respiratory deficiency/failure, abnormal EEG, abnormal MRI. 60% mtDNA copy number in blood. | | Mutations: | A467T, T914P | | Age group: | infantile | | Age of Onset: n/a, Age of Patient: 0.8, Age of Death: n/a |
| Reference: | Tang et al, 2011; | | Description: | Seizures, hepatic failure, duplicated cyst of ileum, FTT, diarrhea. 13% mtDNA copy number in liver. | | Mutations: | A467T, T914P | | Age group: | infantile | | Age of Onset: n/a, Age of Patient: 4, Age of Death: n/a |
| Reference: | Wong et al, 2008; | | Description: | Developmental delay, dementia, seizures, Alpers | | Mutations: | A467T, T914P | | Age group: | infantile | | Age of Onset: 2, Age of Patient: n/a, Age of Death: n/a |
| Reference: | Wong et al, 2008; | | Description: | Onset 2 years with dementia, seizures, and liver failure. Alpers | | Mutations: | A467T, T914P | | Age group: | infantile | | Age of Onset: 2, Age of Patient: n/a, Age of Death: n/a |
Back to top | Reference: | Dhamija et al, 2011; | | Description: | myoclonic status epilepticus, myoclonic seizures at 8 months, developmental regression, febrile upper respiratory tract infection, nearly continuous myoclonic jerks, normocephalic, nondysmorphic, diffuse hypotonia, died secondary to complications of hepatic failure. | | Mutations: | A467T, T914P | | Age group: | infantile | | Age of Onset: 0.8, Age of Patient: n/a, Age of Death: 1 |
| Reference: | Ashley et al, 2008; | | Description: | mtDNA depletion in muscle, Epilepsy, hepatopathy, movement disorder | | Mutations: | T914P, W748S | | Age group: | infantile | | Age of Onset: 1.1, Age of Patient: n/a, Age of Death: n/a |
| Reference: | Ashley et al, 2008; | | Description: | reported as Alpers, onset at 4 years, presenting encephalopathy with epilepsy, hepatopathy, and movement disorder (ataxia). 15% mtDNA copy number in liver. | | Mutations: | T914P, W748S | | Age group: | childhood | | Age of Onset: 4, Age of Patient: n/a, Age of Death: n/a |
| Reference: | Isohanni et al, 2011; | | Description: | developmental delay, vomiting, partial status epilepticus, epilepsia partialis continua, myoclonus, ataxia, alive at age 3. | | Mutations: | T914P, W748S | | SNPs: | E1143G | | Age group: | infantile | | Age of Onset: 2.5, Age of Patient: 3, Age of Death: n/a |
| Reference: | Tang et al, 2011; | | Description: | Age 0.8, developmental delay, hypotonia, myoclinic seizures, spasticity, dystonia, exercise intolerance, GI reflux, abnormal EEG, elevated transaminases, increased signal basal ganglia, abnormal MRI, lactic acidosis, high CSF lactate. | | Mutations: | T914P, W748S | | 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. 98% mtDNA copy number in blood. | | Mutations: | T914P, W748S | | Age group: | childhood | | Age of Onset: n/a, Age of Patient: 5, Age of Death: n/a |
| Reference: | Hinnell et al, 2012; | | Description: | Presented with generalized epilepsy and mild long-standing learning difficulties requiring special education, developed liver failure after taking valproate, migraines, right-sided epilepsia partialis continua, myoclonic arm jerks, a pancerebellar syndrome, and progressive cognitive impairment. mild external ophthalmoplegia, saccadic pursuit, writhing tongue movements, dysarthria, bilateral dysdiadochokinesis and dysmetria, mild sensory axonal peripheral neuropathy, ptosis | | Mutations: | T914P, W748S | | Age group: | juvenile | | Age of Onset: 15, Age of Patient: n/a, Age of Death: n/a |
| Reference: | Rouzier et al, 2013; | | Description: | Refractory generalized epilepsy with status epilepticus, hepatic cholestasis and cytolysis, proximal tubulopathy, hyperintensity of thalamus. mtDNA depletion. | | Mutations: | T914P, W748S | | Age group: | childhood | | Age of Onset: 6, Age of Patient: n/a, Age of Death: n/a |
| Reference: | Roos et al, 2013; | | Description: | bilateral ptosis. At the age of 37 years, he was found to have PEO. A year later, he had onset of muscle pain and examinations showed muscular atrophy and mitochondrial myopathy. Progressive mental fatigue was present from age 45 years. At the age of 55 years, he had dysarthria and dysphagia and severe muscle pain at activity that in combination with muscle weakness reduced his walking ability. progressive respiratory muscle weakness. | | Mutations: | T914P | | SNPs: | PNF | | Age group: | adult | | Age of Onset: 20, Age of Patient: 63, Age of Death: n/a |
| Reference: | Roos et al, 2013; | | Description: | onset of ptosis at the age of 50 years. moderate to severe weakness in proximal muscles of the upper and lower extremities and also reduced strength in tongue, facial, neck flexor and respiratory muscles. His verbal memory and psychomotor speed were profoundly reduced and he showed loss of initiative. Type II diabetes. | | Mutations: | T914P | | SNPs: | PNF | | Age group: | adult | | Age of Onset: 50, Age of Patient: 65, Age of Death: 71 |
Back to top | Reference: | Ashley et al, 2008; | | Description: | reported as Alpers, onset at birth, presenting encephalopathy with epilepsy, hepatopathy, and movement disorder (ataxia). 5% mtDNA copy number in liver, 54% mtDNA copy number in muscle. | | Mutations: | R627W, T914P | | Age group: | infantile | | Age of Onset: 0.01, Age of Patient: n/a, 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 |
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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 1 and 3: Age of onset information is extracted from a total of 18 patients and/ or patient families. | Age of onset | | |
18- 9- | 9
| 2
| 2
| 5
| | | infantile | childhd | juvenile | adult | | | 50% | 11% | 11% | 28% | |
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 cluster1-cluster3 mutations | |
| Symptoms in patients with combination
cluster1:cluster3 | | Movement disorder (ataxia) | 44.4% | | Encephalopathy | 33.3% | | Developmental delay | 33.3% | | Epilepsy | 27.8% | | PEO | 27.8% | | Failure to thrive | 22.2% | | Hypotonic | 22.2% | | Peripheral neuropathy | 16.7% | | Ptosis | 16.7% | | Dysarthria | 16.7% | | Lactic acidosis | 11.1% | | Ragged red fibers | 11.1% | | Muscle weakness | 11.1% | | Liver failure | 11.1% | | Headache/ migraine | 11.1% | | Dementia | 11.1% | | Retardation | 11.1% | | GI dysmotility | 11.1% | | Myoclonic seizures | 5.6% | | Sensory ataxia | 5.6% | | Polyneuropathy | 5.6% | | Demyelinating neuropathy | 5.6% | | Axonal sensorimotor polyneuropathy | 5.6% | | Abnormal muscle ultrastructure | 5.6% | | Exercise intolerance | 5.6% | | Cox-negative | 5.6% | | Diplopia | 5.6% | | Liver dysfunction | 5.6% | | Growth retardation | 5.6% | | Vomiting | 5.6% | | GI reflux | 5.6% | | Cyclic vomiting | 5.6% | | Delayed gastric emptying | 5.6% | | Tremor | 5.6% | | Hearing loss | 5.6% |
| | Data gathered from clinical descriptions for 18 patients |
| Symptoms by group | | Developmental Delay | 50.0% | | Ataxia | 44.4% | | CPEO | 38.9% | | Seizures | 33.3% | | Neuropathy | 27.8% | | Alpers syndrome | 22.2% | | CNS symptoms | 22.2% | | Hypotonia | 22.2% | | GI symptoms | 16.7% | | Hepatopathy | 16.7% | | Myopathy | 16.7% | | Migraines | 11.1% | | Other | 5.6% |
| | [Show grouping information] |
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