The wide POLG-related spectrum: An integrated view

Béreau, Matthieu; Anheim, Mathieu; Echaniz‐Laguna, Andoni; Magot, Armelle; Verny, Christophe; Goideau-Sevrain, M.; Barth, Magalie; Amati-Bonneau, P.; Allouche, Stéphane; Ayrignac, Xavier; Bedat‐Millet, A.‐L.; Guyant‐Maréchal, Lucie; Küntzer, Thierry; Ochsner, François; Petiot, P.; Vial, Cecilia; Omer, Salah; Solé, Guilhem; Taïeb, Guillaume; Carvalho, Nicolas; Tio, Grégory; Kremer, Stéphane; Acquaviva‐Bourdain, Cécile; Camaret, Bénédicte Mousson de; Tranchant, C.

doi:10.1016/j.jns.2016.06.062

Cited by 11 publications

(6 citation statements)

References 24 publications

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“…Recently, 19 patients harboring POLG mutations were studied [33]. Histochemical abnormalities were found in 17/19 cases: cox-negative fibers in 13 cases (68.4%) and ragged red fibers in 12 cases (63.2%) [33]. Interestingly, in the presented case, muscle histology showed no evidence for ragged-red fibres (RRF).…”

Section: Discussionmentioning

confidence: 75%

“…Gomori trichrome staining has been postulated as the most sensible and reliable method for detection of mitochondrial abnormalities [32]. Recently, 19 patients harboring POLG mutations were studied [33]. Histochemical abnormalities were found in 17/19 cases: cox-negative fibers in 13 cases (68.4%) and ragged red fibers in 12 cases (63.2%) [33].…”

Section: Discussionmentioning

confidence: 99%

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Camptocormia as a Novel Phenotype in a Heterozygous POLG2 Mutation

Urban

Scholle²,

Alt

et al. 2020

Diagnostics

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Mitochondrial dysfunction is known to play a key role in the pathophysiological pathway of neurodegenerative disorders. Nuclear-encoded proteins are involved in mtDNA replication, including DNA polymerase gamma, which is the only known replicative mtDNA polymerase, encoded by nuclear genes Polymerase gamma 1 (POLG) and Polymerase gamma 2 (POLG2). POLG mutations are well-known as a frequent cause of mitochondrial myopathies of nuclear origin. However, only rare descriptions of POLG2 mutations leading to mitochondriopathies exist. Here we describe a 68-year-old woman presenting with a 20-year history of camptocormia, mild proximal weakness, and moderate CK increase. Muscle histology showed COX-negative fibres. Genetic analysis by next generation sequencing revealed an already reported heterozygous c.1192-8_1207dup24 mutation in the POLG2 gene. This is the first report on a POLG2 mutation leading to camptocormia as the main clinical phenotype, extending the phenotypic spectrum of POLG2 associated diseases. This underlines the broad phenotypic spectrum found in mitochondrial diseases, especially in mitochondrial disorders of nuclear origin.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Camptocormia as a Novel Phenotype in a Heterozygous POLG2 Mutation

Urban

Scholle²,

Alt

et al. 2020

Diagnostics

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“…However, ataxia was typically present in recessive POLG cases. All POLG related syndromes are associated with extensive alterations of mitochondrial function (Béreau et al, ), as a direct consequence of its essential role in mitochondrial DNA replication machinery (Lestienne, ). The presence of the POLG variant even in the unaffected sister (III‐1) casts doubt about its pathogenic role.…”

Section: Discussionmentioning

confidence: 99%

Homozygous variant in OTX2 and possible genetic modifiers identified in a patient with combined pituitary hormone deficiency, ocular involvement, myopathy, ataxia, and mitochondrial impairment

Catania

Legati

Peverelli

et al. 2019

American J of Med Genetics Pt A

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Here we report on a singleton patient affected by a complicated congenital syndrome characterized by growth delay, retinal dystrophy, sensorineural deafness, myopathy, ataxia, combined pituitary hormone deficiency, associated with mitochondrial impairment. Targeted clinical exome sequencing led to the identification of a homozygous missense variant in OTX2. Since only dominant mutations within OTX2 have been associated with cases of syndromic microphthalmia, retinal dystrophy with or without pituitary dysfunctions, this represents the first report of an OTX2 recessive mutation. Part of the phenotype, including ataxia, myopathy and multiple mitochondrial respiratory chain defects, seemed not related to OTX2. Further analysis of next generation sequencing (NGS) data revealed additional candidate variants: a homozygous variant in LETM1, and heterozygous rare variants in AFG3L2 and POLG. All three genes encode mitochondrial proteins and the last two are known to be associated with ataxia, a neurological sign present also in the father of the proband. With our study, we aim to encourage the integration of NGS data with a detailed analysis of clinical description and family history in order to unravel composite genotypes sometimes associated with complicated phenotypes. K E Y W O R D S AFG3L2, complex congenital syndrome, LETM1, OTX2, POLG 1 | INTRODUCTION In the last decade, the development of new next generation sequencing (NGS) technologies such as whole genome/exome sequencing, has rapidly offered a growing opportunity to provide large-scale and high sensitivity genomic screening allowing the identification of new pathogenic variants associated with rare inherited diseases and overcoming most of the limitations of a candidate-gene based approach to diagnostics. Even though, complex congenital phenotypes in singleton cases, thus without a clear Mendelian inheritance pattern, still represent one of the main pitfalls of these techniques. A close interaction between clinicians and geneticists is fundamental in order to allow a proper evaluation of the NGS data, especially considering the growing number of reports about cases with intricate clinical presentation and composite genetic basis.In this report, we describe a singleton patient affected by a complicated congenital syndrome characterized by growth delay, retinal dystrophy, sensorineural deafness, myopathy, ataxia, combined pituitary hormone deficiency (CPHD), associated with mitochondrial impairment. Genetic and clinical data were deeply investigated in order to find genotype-phenotype correlations. | MATERIALS AND METHODSClinical, genetic, and histo/biochemical evaluations were performed upon acquisition of informed consent from all the subjects involved in this study, as required by the Ethical Committee of the Fondazione † Alessia Catania and Andrea Legati contributed equally to this study.

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“…19,20 Another POLG1 variant c.3708G>T (p.Q1236H) in exon 23, previously described as a neutral polymorphism, has been reported in one patient with AHS in homozygous state with the c.3286C>T (p.R1096C) mutation, 21 in two siblings with sensory axonal neuropathy in compound with p.Y837C, p.D122Y, and p.K601E, 22 in five patients with inclusion body myositis as a single heterozygous mutation with mtDNA deletions, 23 and in two patients with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) in cis with p.R627Q and in trans with p.W748S and p.E1143G. 24 The p.Q1236H variant has a frequency of 8.3% in the European population, 16 14.8%-15.9% in the Finnish population, 16,25 and about 1% in Africans and Asians. 16 Stewart et al 14 reported that petite frequency and mtDNA point mutability increased in their yeast strains with the p.Q1236H substitution, and the heterozygous variants p.Q1236H and p.E1143G were strongly associated with VPA-induced hepatotoxicity (VHT) in their patient cohort.…”

Section: Key Pointsmentioning

confidence: 99%

Variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma POLG1 are not associated with increased risk for valproate‐induced hepatotoxicity or pancreatic toxicity: A retrospective cohort study of patients with epilepsy

et al. 2018

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Summary Objective Previous studies have suggested that heterozygous variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma (POLG1) increase the risk for liver injury for patients on valproate (VPA) therapy. We assessed the prevalence of these common variants and seven other pathogenic mutations in POLG1 and determined the occurrence of VPA‐induced hepatotoxicity (VHT) or pancreatic toxicity in a cohort of patients with epilepsy. Methods Patients with epilepsy (N = 367) were retrospectively identified from medical record files and screened for mutations in POLG1. Patients who had received VPA monotherapy and carried either of the two variants, p.Q1236H or p.E1143G, without other pathogenic mutations in POLG1 (n = 33, variant group) and patients without these variants (n = 28, nonvariant group) were included in the study. Clinical data on epilepsy, characteristics of VPA treatment, risk factors for VHT, laboratory data on liver and pancreas functions, and adverse effects were collected. Results A total of 122 patients had either the POLG1 p.Q1236H (n = 99) or p.E1143G (n = 24) variant in the heterozygous or homozygous state. Transient liver dysfunction was identified in three (n = 33, 9.1%) variant group patients and in one (n = 28, 3.6%) nonvariant group patient (P = 0.62). Mild to moderate elevations in liver enzymes were encountered in both groups. Furthermore, two patients on VPA polytherapy developed acute pancreatitis, and two pediatric patients with heterozygous p.Q1236H variants and mutations in IQSEC2 and GLDC, respectively, had elevated levels of VPA metabolites in urine, elevated plasma glycine, and/or increased acylglycine excretion. Significance POLG1 p.Q1236H and p.E1143G variants could not be identified as statistically significant risk factors for VHT or pancreatic toxicity. We suggest that VPA treatment could be suitable for patients who harbor these common variants in the absence of other pathogenic mutations in POLG1.

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The wide POLG-related spectrum: An integrated view

Cited by 11 publications

References 24 publications

Camptocormia as a Novel Phenotype in a Heterozygous POLG2 Mutation

Camptocormia as a Novel Phenotype in a Heterozygous POLG2 Mutation

Homozygous variant in OTX2 and possible genetic modifiers identified in a patient with combined pituitary hormone deficiency, ocular involvement, myopathy, ataxia, and mitochondrial impairment

Variants p.Q1236H and p.E1143G in mitochondrial DNA polymerase gamma POLG1 are not associated with increased risk for valproate‐induced hepatotoxicity or pancreatic toxicity: A retrospective cohort study of patients with epilepsy

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