Complete Deletion of a POLG1 Allele in a Patient with Alpers Syndrome

Naess, K; Barbaro, Michela; Bruhn, Helene; Wibom, Rolf; Nennesmo, Inger; Döbeln, Ulrika von; Larsson, Nils‐Göran; Németh, Antal; Lesko, Nicole

doi:10.1007/8904_2011_73

Cited by 6 publications

(5 citation statements)

References 24 publications

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“…The most common type of variant is missense (77%), followed by splicing variants (9%), nonsense (stop codon) variants (8%), deletions, and insertion and duplication (collectively 6%). In addition, a complete deletion of a POLG allele has been reported …”

Section: Resultsmentioning

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: Resultsmentioning

confidence: 99%

“…In addition, a complete deletion of a POLG allele has been reported. 11 Age at onset, age at death, and genotypes…”

Section: Pathogenic Variants Associated With Polg-related Epilepsymentioning

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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“…MtDNA sequence data were compared with the revised Cambridge reference sequence for human mtDNA (GenBank NC_012920.1) and for POLG to the reference sequence NM_002693.2. MLPA analysis, using kit P010 (MRC Holland, Amsterdam), for detection of deletions or duplications of each exon of the POLG gene was performed according to the manufacturer’s protocol as described earlier ( 43 ). RT-PCR was performed on isolated RNA, using GeneAmp RNA PCR kit (Applied Biosystems) and exons 2–23 of POLG cDNA were amplified by PCR in 10 overlapping fragments.…”

Section: Methodsmentioning

confidence: 99%

A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma

Siibak

Clemente

Bratić

et al. 2017

Human Molecular Genetics

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Mutations in the mitochondrial DNA polymerase, POLG, are associated with a variety of clinical presentations, ranging from early onset fatal brain disease in Alpers syndrome to chronic progressive external ophthalmoplegia. The majority of mutations are linked with disturbances of mitochondrial DNA (mtDNA) integrity and maintenance. On a molecular level, depending on their location within the enzyme, mutations either lead to mtDNA depletion or the accumulation of multiple mtDNA deletions, and in some cases these molecular changes can be correlated to the clinical presentation. We identified a patient with a dominant p.Y955H mutation in POLG, presenting with a severe, early-onset multi-systemic mitochondrial disease with bilateral sensorineural hearing loss, cataract, myopathy, and liver failure. Using a combination of disease models of Drosophila melanogaster and in vitro biochemistry analysis, we compare the molecular consequences of the p.Y955H mutation to the well-documented p.Y955C mutation. We demonstrate that both mutations affect mtDNA replication and display a dominant negative effect, with the p.Y955H allele resulting in a more severe polymerase dysfunction.

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“…POLG mutations are associated to premature mitochondrial dysfunction with increased oxidative stress and nuclear DNA damage, apoptosis activation, repression of regulators of mitochondrial biogenesis and cellular antioxidant response ( Compton et al, 2011 ; Naess et al, 2011 ; Rouzier et al, 2014 ; Safdar et al, 2016 ). Secondary to these primary dysfunctions and similarly to what observed in FRDA, multiple pathways with differential cell vulnerability are involved ( Synofzik et al, 2012 ).…”

Section: Oculomotor Phenotypic Characterization Of Arcasmentioning

confidence: 99%

Autosomal recessive cerebellar ataxias: a diagnostic classification approach according to ocular features

Lopergolo,

Rosini,

Pretegiani

et al. 2024

Front. Integr. Neurosci.

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Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of neurodegenerative disorders affecting primarily the cerebellum and/or its afferent tracts, often accompanied by damage of other neurological or extra-neurological systems. Due to the overlap of clinical presentation among ARCAs and the variety of hereditary, acquired, and reversible etiologies that can determine cerebellar dysfunction, the differential diagnosis is challenging, but also urgent considering the ongoing development of promising target therapies. The examination of afferent and efferent visual system may provide neurophysiological and structural information related to cerebellar dysfunction and neurodegeneration thus allowing a possible diagnostic classification approach according to ocular features. While optic coherence tomography (OCT) is applied for the parametrization of the optic nerve and macular area, the eye movements analysis relies on a wide range of eye-tracker devices and the application of machine-learning techniques. We discuss the results of clinical and eye-tracking oculomotor examination, the OCT findings and some advancing of computer science in ARCAs thus providing evidence sustaining the identification of robust eye parameters as possible markers of ARCAs.

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Complete Deletion of a POLG1 Allele in a Patient with Alpers Syndrome

Abstract: Mutations in the gene encoding the catalytic subunit of polymerase g (

Cited by 6 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

A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma

Autosomal recessive cerebellar ataxias: a diagnostic classification approach according to ocular features

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