<i>POLG</i>
            mutations in Alpers syndrome

Nguyen, Khue Vu; Østergaard, Elsebet; Ravn, Søren; Balslev, Thomas; Danielsen, E. Michael; Vardag, A; McKiernan, PJ; Gray, George F.; Naviaux, Robert K.

doi:10.1212/01.wnl.0000182814.55361.70

Cited by 141 publications

(116 citation statements)

References 7 publications

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“…The clinical phenotypes of POLG-related disorders include autosomal recessive and dominant adult-onset PEO [70][71][72][73], myoclonic epilepsy, myopathy, sensory ataxia (MEMSA) syndrome [74,75], ataxia-neuropathy spectrum including mitochondrial recessive ataxia syndrome (MIRAS), and sensory ataxia, neuropathy, dysarthria, ophthalmoplegia (SANDO) syndrome [76][77][78][79], and hepatocerebral MDS (Alpers-Huttenlocher syndrome) [80][81][82][83][84][85][86][87][88][89][90]. More recently, POLG mutations were identified in individuals with clinical features of MNGIE, but no leukoencephalopathy [91].…”

Section: Polg-related Hepatocerebral Mdsmentioning

confidence: 99%

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Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

2013

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Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2,

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Section: Polg-related Hepatocerebral Mdsmentioning

confidence: 99%

“…mtDNA content is reduced in liver. Disease progression is variable, with life expectancy from onset of symptoms ranging from 3 months to 12 years [80][81][82][83][84][85][86][87][88][89][90].…”

Section: Polg-related Hepatocerebral Mdsmentioning

confidence: 99%

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

2013

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“…In addition to European countries, the W748S mutation has been reported in Australia 6 and in one patient with undefined nationality. 7 In all patients, the mutation has been found in cis with E1143G, a common polymorphism with B3% frequency in the normal population (dbSNP). However, a modifying role for E1143G in POLG diseases remains possible.…”

Section: Introductionmentioning

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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“…5 However, the p.Trp748Ser mutation is the most common mutation in our cohort (5/20 alleles, 25% of all mutant alleles) contrary to previous articles, which reported the p.Ala467Thr to be the most common POLG mutation in patients with autosomal recessive inheritance. 5,23,24 The p.Ala467Thr mutation was the second most common mutation in our cohort (4/20 alleles, 20% of all mutant alleles).…”

Section: Discussionmentioning

confidence: 78%

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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POLG mutations in Alpers syndrome

Cited by 141 publications

References 7 publications

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

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

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

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