The unfolding clinical spectrum of POLG mutations

Blok, Marinus J.; Bosch, Bianca Jc van den; Jongen, Eveline; Hendrickx, Alexandra T.M.; Die-Smulders, Christine E. de; Hoogendijk, Jessica E.; Brusse, Esther; Visser, Marjolein; Poll-Thé, Bwee Tien; Bierau, Jörgen; Coo, I.F.M. de; Smeets, Hilde

doi:10.1136/jmg.2009.067686

Cited by 81 publications

(70 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…POLG1 mutations are associated with a broad range of clinical phenotypes including Alpers-Huttenlocher syndrome, PEO, and Ataxia-Neuropathy Spectrum Disorders; however, reports of cases involving stroke are rare (Blok et al 2009;Milone and Massie 2010;Rahman and Hanna …”

Section: Polg1 Mutations and Strokementioning

confidence: 99%

“…In 1999, Naviaux was the first to report POLG1 dysfunction and mtDNA depletion in a patient with Alpers syndrome (Naviaux et al 1999). Since its discovery less than a decade ago, more than 150 mutations in POLG1 have been associated with a spectrum of phenotypes including Progressive External Ophthalmoplegia (PEO), Alpers-Huttenlocher Syndrome (psychomotor retardation, intractable epilepsy, liver failure), and Ataxia Neuropathy Spectrum Disorders, among others (Blok et al 2009;Milone and Massie 2010;Rahman and Hanna 2009;Van Goethem et al 2001;Wong et al 2008).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2011

View full text Add to dashboard Cite

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.

show abstract

Section: Polg1 Mutations and Strokementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Both were found to be heterozygous for the p.Asp1184Asn mutation previously found in trans with p.Asn468Asp in a patient with PEO and tetraparesis and in a severe childhood multisystem disorder. 21,22 As in the previous family, all affected individuals shared the same POLG polymorphisms (6 in family 17 and 10 in family 18) and recessive transmission seemed likely. However, both parents died before the age at which the first clinical symptoms developed in patients 18a and b.…”

Section: Resultsmentioning

confidence: 57%

“…These results are consistent with previous reports. 5,22 Using QMPSF, we identified a second mutation in only one additional patient. Our results confirm the previously described mutation frequencies, the four most common mutations p.Ala467Thr, p.Trp748Ser, p.Gly848Ser and p.Thr914Pro accounting for 60% of disease alleles in cases with confirmed autosomal recessive phenotypes due to POLG mutations.…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…pR943C was previously reported in autosomal dominant PEO patients [16]. Most mutations in autosomal dominant PEO are in the polymerase domain [1], and therefore may be related to the onset of PEO in this case.…”

Section: Discussionmentioning

confidence: 77%

Genetic analysis of two Japanese families with progressive external ophthalmoplegia and parkinsonism

et al. 2011

View full text Add to dashboard Cite

Mutations in the progressive external ophthalmoplegia 1 (PEO1), adenine nucleotide translocator 1 (ANT1) and DNA polymerase gamma (POLG) genes were reported in patients with progressive external ophthalmoplegia and parkinsonism. However, the genotype-phenotype correlation and pathophysiology of these syndromes are still unknown. In order to define the molecular basis of progressive external ophthalmoplegia and parkinsonism, we screened for mutations in PEO1, ANT1, POLG genes and the whole mitochondrial genome in two families. In results, we identified a compound heterozygous POLG substitutions, c.830A>T (p.H277L) and c.2827C>T(p.R943C) in one of the families. These two mutations in the coding region of POLG alter conserved amino acids in the exonuclease and polymerase domains, respectively, of the POLG protein. Neither of these substitutions was found in the 100 chromosomes of ethnically matched control subjects. In the other family, no mutations were detected in any of the three genes and the whole mitochondrial genome in the blood sample, although mitochondrial DNA deletions were observed in the muscle biopsy sample.Progressive external ophthalmoplegia and parkinsonism are genetically heterogenous disorders, and part of this syndrome may be caused by mutations in other, unknown genes.

show abstract

The unfolding clinical spectrum of POLG mutations

Abstract: The unfolding clinical spectrum of POLG mutations Blok, M.J.; Bosch, B.J.; Jongen, E.; Hendrickx, A.; de Die-Smulders, C.E.; Hoogendijk, J.E.; Brusse, E.; de Visser, M.; Poll-The, B-T.; Bierau, J.; de Coo, I.F.; Smeets, H.J.

Cited by 81 publications

References 40 publications

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

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

Genetic analysis of two Japanese families with progressive external ophthalmoplegia and parkinsonism

Contact Info

Product

Resources

About