The spectrum of epilepsy caused by POLG mutations

Janssen, Wouter; Quaegebeur, Annelies; Goethem, Gert Van; Löfgren, Ann; Smets, Katrien; Vandenberghe, Rik; Paesschen, Wim Van

doi:10.1007/s13760-015-0499-8

Cited by 19 publications

(17 citation statements)

References 29 publications

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“…69 Our result is consistent with previous observations of a predisposition for occipital lobe involvement in POLGrelated epilepsy, especially among those with juvenile and adult onset, in terms of clinical, radiologic, and histopathologic findings; however, the precise explanation of such preferential involvement remains enigmatic. 12,70 The stroke-like lesions in POLG-related epilepsy appear to overlap in those observed in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) caused by the m.3243A>G mutation and other primary pathogenic mtDNA mutations. 29 However, thalamic (37%) and cerebellar lesions with restricted diffusion are more commonly observed in cases with POLG mutations compared to the m.3243A>G mutation.…”

Section: Discussionmentioning

confidence: 99%

Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Anagnostou

Taylor

et al. 2016

Epilepsia

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We performed a systematic review of the clinical, molecular, and biochemical features of polymerase gamma (POLG)-related epilepsy and current evidence on seizure management. Patients were identified from a combined electronic search of articles using Ovid Medline and Scopus databases, published from January 2000 to January 2015. Only patients with a confirmed genetic diagnosis of POLG mutations were considered. Seventy-two articles were included for analysis. We identified 128 pathogenic variants in 372 patients who had POLG-related epilepsy. Among these, 84% of the cases harbored at least one of these pathogenic variants: p.Ala467Thr, p.Trp748Ser, and p.Gly848Ser. A bimodal distribution of disease onset was present in early childhood (<5 years) and adolescence; female patients had a later presentation than male patients (median age 4.00 vs. 1.83 years, p-value = 0.041). Focal-onset seizure including convulsive, myoclonus, and occipital seizures was common at the outset and was refractory to pharmacotherapy. We confirmed that homozygous pathogenic variants located in the linker region of POLG were associated with later age of onset and longer survival compared to compound heterozygous variants. In addition, biochemical and molecular heterogeneities in different tissues were frequently observed. POLG-related epilepsy is clinically heterogeneous, and the prognosis is, in part, influenced by the location of the variants in the gene and the presence of hepatic involvement. Normal muscle and fibroblast studies do no exclude the diagnosis of POLG-related mitochondrial disease and direct sequencing of the POLG gene should be the gold standard when investigating suspected cases.

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Section: Discussionmentioning

confidence: 99%

Epilepsy due to mutations in the mitochondrial polymerase gamma (POLG) gene: A clinical and molecular genetic review

Anagnostou

Taylor

et al. 2016

Epilepsia

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“…Administration of VPA can also lead to worsening of an underlying mitochondrial disorder . It has been suggested that POLG1 gene testing should be performed for all patients with suspected mitochondrial disease before starting VPA therapy …”

Section: Discussionmentioning

confidence: 99%

“…37,38 It has been suggested that POLG1 gene testing should be performed for all patients with suspected mitochondrial disease before starting VPA therapy. 6,[12][13][14][15] Sensitivity to VPA toxicity associated with mitochondrial disease has raised the question of whether nonpathogenic POLG1 variants can genetically predispose otherwise healthy patients to adverse effects of VPA. In contrast with the present results, a prospective study by Stewart et al suggested that the common heterozygous POLG1 p.Q1236H variant was strongly associated with hepatotoxicity via VPA-induced nonapoptotic cell death.…”

Section: Discussionmentioning

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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“…Presentations range from childhood onset Alpers-Huttenlocher syndrome to adult-onset sensory ataxic neuropathy dysarthria and ophthalmoplegia (SANDO). [4][5][6][7][8][9] Epilepsy is a common presentation of POLG mutations. 6,7 In the majority of patients there is an occipital EEG focus, causing occipital seizures, which are characterised by flickering coloured lights, often persistent for long periods of time; in addition there may also be nystagmus, metamorphopsias and ictal visual loss.…”

Section: Discussionmentioning

confidence: 99%