<i>POLG1</i>Mutations Associated With Progressive Encephalopathy in Childhood

Kollberg, Gittan; Moslemi, Ali‐Reza; Darín, Niklas; Nennesmo, Inger; Bjarnadóttir, Ingibjörg; Uvebrant, Paul; Holme, Elisabeth; Melberg, Atle; Tulinius, M.; Oldfors, Anders

doi:10.1097/01.jnen.0000229987.17548.6e

Cited by 89 publications

(81 citation statements)

References 36 publications

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“…The origin of the G848S chromosomes remains an open issue due to the lack of European G848S disease chromosomes in this study. However, a European origin is most likely, since the G848S mutation has also been reported in one Italian, 18 one Belgian, 19 one Swedish, 20 and one German patient. 5 A conservative estimation of the age of the mutations suggests that the common ancestor for the A467T haplotype lived more than 15 -30 generations ago (ie before 1700 -1400 A.D.), and for the shorter W748S haplotype, more than 40 -60 generations ago (ie before 1200 -800 A.D.), based on the length of the shared haplotype regions.…”

Section: Discussionmentioning

confidence: 99%

Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders

et al. 2007

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We reported previously that the DNA polymerase c (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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Section: Discussionmentioning

confidence: 99%

Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders

et al. 2007

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“…Including the above two cases, we found 22 reported cases of POLG1 mutations associated with stroke and stroke-like symptoms in the literature (Table 1) (Blok et al 2009;Deschauer et al 2007;Horvath et al 2006;Kollberg et al 2006;Wong et al 2008). Five of these 22 patients were clinically characterized to have AtaxiaNeuropathy Spectrum phenotype, 13 had a phenotype consistent with Alpers, and four patients were unclassified.…”

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confidence: 99%

Stroke and Stroke-Like Symptoms in Patients with Mutations in the POLG1 Gene

et al. 2011

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Introduction/Methods Mutations in POLG1, the gene encoding mitochondrial polymerase gamma (Polg), have been associated with a number of well-characterized phenotypes. In this study, we report two cases of patients with biallelic POLG1 mutations and stroke. We also performed a review of the literature and report on all clinical studies of patients with POLG1 mutations in which stroke was described in the phenotype. For each patient, genotype and phenotype are reported.Results Including our two patients, a total of 22 patients have been reported with POLG1 mutations and stroke. The average age of onset of stroke in these patients was 9 years with a range of 1-23 years. In cases where localization was reported, the occipital lobes were the primary location of the infarct. Mutations in the linker-linker or linker-polymerase domains were the most frequent genotype observed. Seizures (16/22) and hepatic dysfunction/failure (8/22) were the most commonly reported symptoms in the stroke cohort.Conclusion This article raises an underrecognized point that patients with POLG1 mutations may suffer a cerebrovascular accident at a young age. The most common location of the infarction is in the occipital lobe. The presentation may be similar to MELAS and can be misdiagnosed as a migrainous stroke.

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“…The p.Arg232His mutation has previously been described in trans with three other mutations in patients with Leigh, Alpers or Charcot-Marie-Tooth disease. [18][19][20] Patient 18a exhibited late-onset CPEO with a sensory neuronopathy and a Parkinsonian syndrome. Her sister, patient 18b, had a similar phenotype without Parkinsonian syndrome.…”

Section: Resultsmentioning

confidence: 99%

Quantitative multiplex PCR of short fluorescent fragments for the detection of large intragenic POLG rearrangements in a large French cohort

et al. 2013

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Polymerase gamma (POLG) is the gene most commonly involved in mitochondrial disorders with mitochondrial DNA instability and causes a wide range of diseases with recessive or dominant transmission. More than 170 mutations have been reported. Most of them are missense mutations, although nonsense mutations, splice-site mutations, small deletions and insertions have also been identified. However, to date, only one large-scale rearrangement has been described in a child with Alpers syndrome. Below, we report a large cohort of 160 patients with clinical, molecular and/or biochemical presentation suggestive of POLG deficiency. Using sequencing, we identified POLG variants in 22 patients (18 kindreds) including five novel pathogenic mutations. Two patients with novel mutations had unusual clinical presentation: the first exhibited an isolated ataxic neuropathy and the second was a child who presented with endocrine signs. We completed the sequencing step by quantitative multiplex PCR of short fluorescent fragments (QMPSF) analysis in 37 patients with either only one POLG heterozygous variant or a family history suggesting a dominant transmission. We identified a large intragenic deletion encompassing part of intron 21 and exon 22 of POLG in a child with refractory epilepsia partialis continua. In conclusion, we describe the first large French cohort of patients with POLG mutations, expanding the wide clinical and molecular spectrum observed in POLG disease. We confirm that large deletions in the POLG gene are rare events and we highlight the importance of QMPSF in patients with a single heterozygous POLG mutation, particularly in severe infantile phenotypes.

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POLG1Mutations Associated With Progressive Encephalopathy in Childhood

Cited by 89 publications

References 36 publications

Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders

Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders

Stroke and Stroke-Like Symptoms in Patients with Mutations in the POLG1 Gene

Quantitative multiplex PCR of short fluorescent fragments for the detection of large intragenic POLG rearrangements in a large French cohort

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