Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations

Milone, Margherita; Brunetti‐Pierri, Nicola; Tang, Lin; Kumar, Neeraj; Mezei, Michelle M.; Josephs, Keith A.; Powell, Suzanne Zein-Eldin; Simpson, Ericka; Wong, Lee Jun

doi:10.1016/j.nmd.2008.05.009

Cited by 70 publications

(62 citation statements)

References 27 publications

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“…mtDNA multiple deletions are associated with aging and oxidative damage, or more importantly, secondary to primary mutations in nuclear genes responsible for mtDNA biosynthesis and integrity maintenance, such as POLG, TWINKLE, and OPA1. 16,39,40 Fifteen DNA samples from muscle showing mtDNA multiple deletions on MPS-based analysis were subjected to sequence analysis of a panel of nuclear genes responsible for the maintenance of mtDNA integrity. POLG mutations were identified in three patients and RRM2B and OPA1 mutations in one patient each (unpublished data).…”

Section: Detection and Mapping Of Mtdna Deletionsmentioning

confidence: 99%

Comprehensive next-generation sequence analyses of the entire mitochondrial genome reveal new insights into the molecular diagnosis of mitochondrial DNA disorders

Cui

Chen

et al. 2013

Genetics in Medicine

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110

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1-3Pathogenic mtDNA mutations, ranging from point mutations to large deletions, are often present in mixed proportions with wildtype mtDNA molecules within the same cell, a biological phenomenon termed heteroplasmy. The degree of mtDNA mutant heteroplasmy can vary significantly across different tissues of the same individual, and the percentage of a mutation is an important contributor to the clinical phenotype.4,5 Determination of the heteroplasmic status of any mtDNA mutation is clinically important to providing a family with informative genetic counseling regarding recurrence risk. Therefore, accurate measurement of heteroplasmy is an essential component of the molecular diagnostic scheme for mtDNA-related disorders.The diagnosis of an individual with suspected mtDNA-related disorders begins with a thorough clinical evaluation and assessment of family history.6 If a disorder with matrilineal inheritance can be established, common mtDNA point mutations and large deletions are typically analyzed using PCR-based targeted assays and Southern blotting methodology. If the screening for common point mutations and large deletions is negative, then the entire mitochondrial genome is usually analyzed by a conventional PCR-based Sanger sequencing approach with multiple pairs of primers. When a mutation is identified, analysis of the degree of heteroplasmy is carried out using various methods, including the commonly used allele refractory mutation system-based quantitative PCR (ARMS qPCR) for quantitative measurement.7 Large deletions are usually confirmed by PCR using primers encompassing the deletion break points followed by sequence analysis to map the break points, or, alternatively, by oligonucleotide array comparative genome hybridization.8 These sequential approaches are time consuming and costly. In an effort to improve efficiency and sensitivity of mtDNA mutation detection, we recently developed a comprehensive one-step long range/massively parallel sequencing (LR-PCR/MPS)-based approach that uses a single pair of PCR primers to amplify the entire mitochondrial genome. This method allows the simultaneous detection of point mutations with quantified heteroplasmy as well as large mtDNA deletions with accurately mapped break points. Purpose: The application of massively parallel sequencing technology to the analysis of the mitochondrial genome has demonstrated great improvement in the molecular diagnosis of mitochondrial DNA-related disorders. The objective of this study was to investigate the performance characteristics and to gain new insights into the analysis of the mitochondrial genome. Methods:The entire mitochondrial genome was analyzed as a single amplicon using a long-range PCR-based enrichment approach coupled with massively parallel sequencing. The interference of the nuclear mitochondrial DNA homologs was distinguished from the actual mitochondrial DNA sequences by comparison with the results obtained from conventional PCR-based Sanger sequencing using multiple pairs of primers. Results:Our results demo...

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Section: Detection and Mapping Of Mtdna Deletionsmentioning

confidence: 99%

Comprehensive next-generation sequence analyses of the entire mitochondrial genome reveal new insights into the molecular diagnosis of mitochondrial DNA disorders

Cui

Chen

et al. 2013

Genetics in Medicine

Self Cite

110

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“…However, analysis of multiple tissues is often beneficial since mtDNA molecules carrying large deletions are preferentially eliminated from blood. Furthermore, mtDNA multiple deletions may be secondary to primary mutations in the nuclear genes responsible for maintenance of mtDNA integrity [69][70][71][72][73].…”

Section: Additional Studies To Aid In Variant Classification and Intementioning

confidence: 99%

Challenges of Bringing Next Generation Sequencing Technologies to Clinical Molecular Diagnostic Laboratories

Wong

2013

Neurotherapeutics

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Molecular diagnosis of complex dual genome mitochondrial disorders is a challenge. It requires the identification of deleterious mutations in one of the~1,500 nuclear genes and the mitochondrial genome. If the molecular defect is in the mitochondrial genome, quantification of degree of mutation load (heteroplasmy) in affected tissues is important. Due to the extreme clinical and genetic heterogeneity, conventional sequence analysis of the candidate genes one-byone is impractical, if not impossible. The newly developed massively parallel next generation sequencing (NGS) technique, that allows simultaneous sequence analysis of multiple target genes, when appropriately validated with deep coverage and proper quality controls, can be used as an effective comprehensive diagnostic approach in CLIA certified clinical laboratories.

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“…Polymerase gamma (POLG) is a nuclear encoded gene, whose product is responsible for maintaining the integrity of mitochondrial DNA 18 . Mutations in POLG are associated with a variety of clinical phenotypes, which includes Alpers disease, parkinsonism, and external progressive ophthalmoplegia 18 .…”

Section: Ataxia With Mutation In Polymerase Gammamentioning

confidence: 99%

“…Mutations in POLG are associated with a variety of clinical phenotypes, which includes Alpers disease, parkinsonism, and external progressive ophthalmoplegia 18 . Two similar forms of autosomal recessive ataxias are associated with mutations in POLG: Mithocondrial Recessive Ataxic Syndrome (MIRAS) and Sensory Ataxia, Neuropathy, Dysarthria, and Ophthalmoplegia (SANDO) 18,19 .…”

Section: Ataxia With Mutation In Polymerase Gammamentioning

confidence: 99%

“…Loss of vibratory and position perception is commonly seen 19,20 . Epilepsy is a frequent manifestation in MIRAS, but not in SANDO, with both partial and generalized seizures, sometimes becoming refractory to antiepileptic drugs and evolving to status epilepticus [18][19][20] . Brain MRI discloses cerebellar atrophy and T2 weighed hypersignal on thalamus, and dentate and inferior olivary nuclei 19,20 .…”

Section: Ataxia With Mutation In Polymerase Gammamentioning

confidence: 99%

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Autosomal recessive ataxias: 20 types, and counting

Embiruçu

Martyn

Schlesinger

et al. 2009

Arq. Neuro-Psiquiatr.

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-More than 140 years after the first description of Friedreich ataxia, autosomal recessive ataxias have become one of the more complex fields in Neurogenetics. Currently this group of diseases contains more than 20 clinical entities and an even larger number of associated genes. Some disorders are very rare, restricted to isolated populations, and others are found worldwide. An expressive number of recessive ataxias are treatable, and responsibility for an accurate diagnosis is high. The purpose of this review is to update the practitioner on clinical and pathophysiological aspects of these disorders and to present an algorithm to guide the diagnosis.KEY WORDS: autosomal recessive ataxias, cerebellar ataxia, cerebellum, Friedreich ataxia.Ataxias autossômicas recessivas: 20 tipos e muito mais resumo -Mais de 140 anos após a primeira descrição da ataxia de Friedreich, as ataxias autossômicas recessivas se transformaram em um dos mais complexos campos da Neurogenética. Atualmente, este grupo de doenças é composto por mais de 20 entidades clínicas e possui um número ainda maior de genes associados. Algumas doenças são muito raras, tendo sido observadas apenas em populações isoladas, enquanto que outras são encontradas no mundo todo. Um número expressivo de ataxias é tratável, e a responsabilidade em se fazer um diagnóstico correto é alta. A finalidade desta revisão é a de atualizar o neurologista a respeito dos principais aspectos clínicos e fisiopatológicos destas doenças e de apresentar um algoritmo para auxiliar a sua investigação e o seu diagnóstico.

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Sensory ataxic neuropathy with ophthalmoparesis caused by POLG mutations

Cited by 70 publications

References 27 publications

Comprehensive next-generation sequence analyses of the entire mitochondrial genome reveal new insights into the molecular diagnosis of mitochondrial DNA disorders

Comprehensive next-generation sequence analyses of the entire mitochondrial genome reveal new insights into the molecular diagnosis of mitochondrial DNA disorders

Challenges of Bringing Next Generation Sequencing Technologies to Clinical Molecular Diagnostic Laboratories

Autosomal recessive ataxias: 20 types, and counting

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