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

Brinjikji, Waleed; Swanson, Jerry W.; Zabel, Carrie; Dyck, Peter J.; Tracy, Jennifer A.; Gavrilova, Ralitza H.

doi:10.1007/8904_2011_22

Cited by 8 publications

(9 citation statements)

References 24 publications

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“…Our result is consistent with previous observations of a predisposition for occipital lobe involvement in POLG ‐related 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 . 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 . 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: Discussionsupporting

confidence: 91%

“…Details on general anesthetic agents were provided in 16 cases; midazolam (n = 11) and pentobarbital (n = 7) were the most commonly used drugs. Possible efficacious treatments for seizure were identified in 18 cases: ketogenic diet/low glycemic diet (n = 3), phenobarbital (n = 3), combined midazolam and thiopentone with other AEDs (n = 2), magnesium infusion (n = 2), combined propofol and thiopentone (n = 1), ketamine infusion (n = 1), folinic acid (n = 1), and carnitine for hepatic encephalopathy (n = 1) (Table ). Palliative hemispherectomy was performed in a single patient .…”

Section: Resultsmentioning

confidence: 99%

“…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. These may reflect the drug-resistant and prolonged nature of the seizure activity associated with POLG variants as well as the inherent role of the epileptogenesis in these structures.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…Pathology in these patients is often described in posterior regions [12,24], though in our clinical experience, frontal lobe involvement is not uncommon. In fact, ischaemic‐like lesions in frontal lobes were documented in four patients in this study, including patient 1 (m.3243A>G), patient 2 (m.3243A>G), patient 9 ( POLG ) and patient 10 ( POLG ) which suggests greater brain involvement than perhaps originally perceived [25,26]. Indeed, high heteroplasmy levels of mutated mtDNA were detected in homogenate DNA extracted from all three brain regions.…”

Section: Discussionmentioning

confidence: 49%

Extensive respiratory chain defects in inhibitory interneurones in patients with mitochondrial disease

Lax

Grady

Laude

et al. 2015

Neuropathology Appl Neurobio

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Aims Mitochondrial disorders are among the most frequently inherited cause of neurological disease and arise due to mutations in mitochondrial or nuclear DNA . Currently, we do not understand the specific involvement of certain brain regions or selective neuronal vulnerability in mitochondrial disease. Recent studies suggest γ‐aminobutyric acid ( GABA )‐ergic interneurones are particularly susceptible to respiratory chain dysfunction. In this neuropathological study, we assess the impact of mitochondrial DNA defects on inhibitory interneurones in patients with mitochondrial disease. Methods Histochemical, immunohistochemical and immunofluorescent assays were performed on post‐mortem brain tissue from 10 patients and 10 age‐matched control individuals. We applied a quantitative immunofluorescent method to interrogate complex I and IV protein expression in mitochondria within GABA ergic interneurone populations in the frontal, temporal and occipital cortices. We also evaluated the density of inhibitory interneurones in serial sections to determine if cell loss was occurring. Results We observed significant, global reductions in complex I expression within GABA ergic interneurones in frontal, temporal and occipital cortices in the majority of patients. While complex IV expression is more variable, there is reduced expression in patients harbouring m.8344 A > G point mutations and POLG mutations. In addition to the severe respiratory chain deficiencies observed in remaining interneurones, quantification of GABA ergic cell density showed a dramatic reduction in cell density suggesting interneurone loss. Conclusions We propose that the combined loss of interneurones and severe respiratory deficiency in remaining interneurones contributes to impaired neuronal network oscillations and could underlie development of neurological deficits, such as cognitive impairment and epilepsy, in mitochondrial disease.

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“…149 The characteristics of mitochondrial strokes are different from those of thrombotic events, primarily in that they do not conform to vascular territories. [150][151][152][153][154][227][228][229][230] MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) typically presents in a previously normal child with a history of migrainous headaches and vomiting. [230][231][232] Children with MELAS often have short stature and a history of seizures.…”

Section: Systemic Causes: Inflammatory and Genetic/metabolicmentioning

confidence: 99%

Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Association/American Stroke Association

Ferriero¹,

Fullerton²,

Bernard³

et al. 2019

Stroke

494

515

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Purpose-Much has transpired since the last scientific statement on pediatric stroke was published 10 years ago. Although stroke has long been recognized as an adult health problem causing substantial morbidity and mortality, it is also an important cause of acquired brain injury in young patients, occurring most commonly in the neonate and throughout childhood. This scientific statement represents a synthesis of data and a consensus of the leading experts in childhood cardiovascular disease and stroke. Methods-Members of the writing group were appointed by the American Heart Association Stroke Council's Scientific Statement Oversight Committee and the American Heart Association's Manuscript Oversight Committee and were chosen to reflect the expertise of the subject matter. The writers used systematic literature reviews, references to published clinical and epidemiology studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize existing evidence and to indicate gaps in current knowledge. This scientific statement is based on expert consensus considerations for clinical practice. Results-Annualized pediatric stroke incidence rates, including both neonatal and later childhood stroke and both ischemic and hemorrhagic stroke, range from 3 to 25 per 100 000 children in developed countries. Newborns have the highest risk ratio: 1 in 4000 live births. Stroke is a clinical syndrome. Delays in diagnosis are common in both perinatal and childhood stroke but for different reasons. To develop new strategies for prevention and treatment, disease processes and risk factors that lead to pediatric stroke are discussed here to aid the clinician in rapid diagnosis and treatment. The many important differences that affect the pathophysiology and treatment of childhood stroke are discussed in each section. Conclusions-Here we provide updates on perinatal and childhood stroke with a focus on the subtypes, including arterial ischemic, venous thrombotic, and hemorrhagic stroke, and updates in regard to areas of childhood stroke that have not received close attention such as sickle cell disease. Each section is highlighted with considerations for clinical practice, attendant controversies, and knowledge gaps. This statement provides the practicing provider with much-needed updated information in this field. (Stroke. 2019;50:e00-e00.

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

Cited by 8 publications

References 24 publications

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

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

Extensive respiratory chain defects in inhibitory interneurones in patients with mitochondrial disease

Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Association/American Stroke Association

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