Novel POLG Splice Site Mutation and Optic Atrophy

Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
Archives of neurology (Impact Factor: 7.42). 06/2011; 68(6):806-11. DOI: 10.1001/archneurol.2011.124
Source: PubMed


To investigate the molecular etiology of 2 unrelated patients with a multisystem mitochondrial disorder accompanied by optic atrophy in one of them.
Clinical examination and neurophysiological, radiological, morphological, and molecular analyses.
Tertiary care neuromuscular clinic and molecular genetics laboratory.
A 65-year-old man (patient 1) with dyschromatopsia and vision loss since childhood developed progressive external ophthalmoplegia, ptosis, and myopathy in the seventh decade of life and was found to have optic atrophy. A 63-year-old man (patient 2) with a similar phenotype, without visual symptoms, experienced also hearing loss and parkinsonism.
Description of the clinical and molecular findings.
A muscle biopsy specimen showed ragged-red, ragged-blue, and cytochrome c oxidase-negative fibers in both patients. Because optic atrophy in patient 1 suggested an autosomal dominant OPA1-related disorder, the OPA1 gene was first sequenced, the results of which did not detect any mutations. Southern blot and polymerase chain reaction analyses of muscle mitochondrial DNA revealed multiple deletions. Sequencing of POLG detected a novel variant, c.3104 + 3A>T, in both patients. Patient 1 was compound heterozygous for a known p.F749S mutation; patient 2 had p.G848S as the second mutation. Analysis of POLG complementary DNA showed that c.3104 + 3A>T results in skipping of exon 18.
Early-onset dyschromatopsia and optic atrophy can occur not only in OPA1-related but also in POLG-related disorders with significant impact on genetic counseling.

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    • "Optic neuropathy, as part of a more complex spectrum of clinical symptoms, is common in hereditary neurodegenerative disorders with evidence of mitochondrial dysfunction [for a review see Ref. (2)] such as OPA1 “plus” syndrome (3), mitochondrial encephalomyopathy lactic acidosis and stroke-like syndrome (MELAS) (4), LHON/dystonia/MELAS/Leigh overlapping syndrome (5, 6), myoclonic epilepsy with ragged red fibers (MERRF) (7), POLG1-related syndrome (8), Friedreich ataxia (9), Charcot–Marie Tooth type 2A (10), Mohr–Tranebjerg syndrome (11), SPG7 syndrome (12), Wolfram syndrome (13), spinocerebellar ataxias (14), and DNMT1-related disorders (15). "
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    ABSTRACT: Hereditary optic neuropathies are diseases affecting the optic nerve. The most common are mitochondrial hereditary optic neuropathies, i.e., the maternally inherited Leber's hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA). They both share a mitochondrial pathogenesis that leads to the selective loss of retinal ganglion cells and axons, in particular of the papillo-macular bundle. Typically, LHON is characterized by an acute/subacute loss of central vision associated with impairment of color vision and swelling of retinal nerve fibers followed by optic atrophy. DOA, instead, is characterized by a childhood-onset and slowly progressive loss of central vision, worsening over the years, leading to optic atrophy. The diagnostic workup includes neuro-ophthalmologic evaluation and genetic testing of the three most common mitochondrial DNA mutations affecting complex I (11778/ND4, 3460/ND1, and 14484/ND6) for LHON and sequencing of the nuclear gene OPA1 for DOA. Therapeutic strategies are still limited including agents that bypass the complex I defect and exert an antioxidant effect (idebenone). Further strategies are aimed at stimulating compensatory mitochondrial biogenesis. Gene therapy is also a promising avenue that still needs to be validated.
    Full-text · Article · Jul 2014 · Frontiers in Neurology
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    • "The most important observation in these patients was that they all had a mitochondrial myopathy with accumulation of multiple mtDNA deletions, thus implicating the OPA1 gene function in mtDNA maintenance. Interestingly, a single report recently presented a similar phenotype associated with compound heterozygote mutations in the polymerase gamma (POLG1) gene, demonstrating a genetic heterogeneity of optic atrophy associated with mitochondrial myopathy and mtDNA multiple deletions (Milone et al., 2011). Over recent years, other phenotypes have been described within the frame of the OPA1-related DOA " plus " syndrome with mtDNA multiple deletions, including MS-like features, Behr-like spastic paraparesis and cases with absent or subclinical ocular involvement, thus defining an increasingly large spectrum of " OPAopathies " (Yu-Wai-Man et al., 2010; Milone et al., 2009; Marelli et al., 2011; Pretegiani et al., 2011; Schaaf et al., 2011). "
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    ABSTRACT: Retinal ganglion cells (RGCs) project their long axons, composing the optic nerve, to the brain, transmitting the visual information gathered by the retina, ultimately leading to formed vision in the visual cortex. The RGC cellular system, representing the anterior part of the visual pathway, is vulnerable to mitochondrial dysfunction and optic atrophy is a very frequent feature of mitochondrial and neurodegenerative diseases. The start of the molecular era of mitochondrial medicine, the year 1988, was marked by the identification of a maternally inherited form of optic atrophy, Leber's hereditary optic neuropathy, as the first disease due to mitochondrial DNA point mutations. The field of mitochondrial medicine has expanded enormously over the last two decades and many neurodegenerative diseases are now known to have a primary mitochondrial etiology or mitochondrial dysfunction plays a relevant role in their pathogenic mechanism. Recent technical advancements in neuro-ophthalmology, such as optical coherence tomography, prompted a still ongoing systematic re-investigation of retinal and optic nerve involvement in neurodegenerative disorders. In addition to inherited optic neuropathies, such as Leber's hereditary optic neuropathy and dominant optic atrophy, and in addition to the syndromic mitochondrial encephalomyopathies or mitochondrial neurodegenerative disorders such as some spinocerebellar ataxias or familial spastic paraparesis and other disorders, we draw attention to the involvement of the optic nerve in classic age-related neurodegenerative disorders such as Parkinson and Alzheimer disease. We here provide an overview of optic nerve pathology in these different clinical settings, and we review the possible mechanisms involved in the pathogenesis of optic atrophy. This may be a model of general value for the field of neurodegeneration. This article is part of a Special Issue entitled 'Mitochondrial function'.
    Full-text · Article · Aug 2012 · Molecular and Cellular Neuroscience
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    ABSTRACT: The aim of the study was to determine the prevalence of MNGIE-like phenotype in patients with recessive POLG1 mutations. Mutations in the POLG1 gene, which encodes for the catalytic subunit of the mitochondrial DNA polymerase gamma essential for mitochondrial DNA replication, cause a wide spectrum of mitochondrial disorders. Common phenotypes associated with POLG1 mutations include Alpers syndrome, ataxia-neuropathy syndrome, and progressive external ophthalmoplegia (PEO). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by severe gastrointestinal dysmotility, cachexia, PEO and/or ptosis, peripheral neuropathy, and leukoencephalopathy. MNGIE is caused by TYMP mutations. Rare cases of MNGIE-like phenotype have been linked to RRM2B mutations. Recently, POLG1 mutations were identified in a family with clinical features of MNGIE but no leukoencephalopathy. The coding regions and exon-intron boundaries of POLG1 were sequence analyzed in patients suspected of POLG1 related disorders. Clinical features of 92 unrelated patients with two pathogenic POLG1 alleles were carefully reviewed. Three patients, accounting for 3.3% of all patients with two pathogenic POLG1 mutations, were found to have clinical features consistent with MNGIE but no leukoencephalopathy. Patient 1 carries p.W748S and p.R953C; patient 2 is homozygous for p.W748S, and patient 3 is homozygous for p.A467T. In addition, patient 2 has a similarly affected sibling with the same POLG1 genotype. POLG1 mutations may cause MNGIE-like syndrome, but the lack of leukoencephalopathy and the normal plasma thymidine favor POLG1 mutations as responsible molecular defect.
    Full-text · Article · Oct 2011 · Journal of Neurology
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