Dominant Chronic Progressive External Ophthalmoplegia Research Articles

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

ObjectiveMounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.MethodsPatients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements.ResultsAffected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase‐negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy.InterpretationThe association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism. Ann Neurol 2015;78:21–38

Heterozygous Polg mutation causes motor dysfunction due to mtDNA deletions.

ObjectiveMutations in nuclear-encoded mitochondrial DNA (mtDNA) polymerase (POLG) are known to cause autosomal dominant chronic progressive external ophthalmoplegia (adCPEO) with accumulation of multiple mtDNA deletions in muscles. However, no animal model with a heterozygous Polg mutation representing mtDNA impairment and symptoms of CPEO has been established. To understand the pathogenic mechanism of CPEO, it is important to determine the age dependency and tissue specificity of mtDNA impairment resulting from a heterozygous mutation in the Polg gene in an animal model.MethodsWe assessed behavioral phenotypes, tissue-specific accumulation of mtDNA deletions, and its age dependency in heterozygous PolgD257A knock-in mice carrying a proofreading-deficient mutation in the Polg.ResultsHeterozygous PolgD257A knock-in mice exhibited motor dysfunction in a rotarod test. Polg+/D257A mice had significant accumulation of multiple mtDNA deletions, but did not show significant accumulation of point mutations or mtDNA depletion in the brain. While mtDNA deletions increased in an age-dependent manner regardless of the tissue even in Polg+/+ mice, the age-dependent accumulation of mtDNA deletions was enhanced in muscles and in the brain of Polg+/D257A mice.InterpretationHeterozygous PolgD257A knock-in mice showed tissue-specific, age-dependent accumulation of multiple mtDNA deletions in muscles and the brain which was likely to result in neuromuscular symptoms. Polg+/D257A mice may be used as an animal model of adCPEO associated with impaired mtDNA maintenance.

Dysfunctional mitochondrial maintenance: what breaks the circle of life?

Despite being recognized as the first Mendelian-inherited mitochondrial disorders (Zeviani et al ., 1990), it has taken over a quarter of a century to realize that disorders of mitochondrial DNA maintenance form a large proportion of the patients seen in adult neurogenetics clinics. Most conditions were initially identified in families presenting with the ‘classical’ mitochondrial phenotype of late-onset chronic progressive external ophthalmoplegia and bilateral ptosis. However, several papers published in Brain in the last 2 years have shown that the field may have been barking up the wrong (phenotypic) tree. The clinical manifestations associated with disorders of mitochondrial DNA maintenance are proving to be much more heterogeneous than was initially understood; and, interestingly, one of the more recently implicated nuclear genetic defects, OPA1 , is a major player in the stability of the mitochondrial network. This principle comes to the fore yet again in this issue of Brain , strongly suggesting that the burden of human disease associated with the accumulation of somatic mitochondrial DNA abnormalities and disturbed mitochondrial dynamics will expand further, whilst providing valuable mechanistic insight of much broader pathophysiological relevance. First defined at the molecular level in 2001 (Van Goethem et al ., 2001), large pedigrees with autosomal dominant chronic progressive external ophthalmoplegia due to mutations in POLG are well established and now feature routinely in neurology and ophthalmology textbooks. POLG codes for the only DNA polymerase present within mitochondria, polymerase γ, and mutations in this nuclear gene lead to point mutations and the accumulation of mitochondrial DNA deletions throughout life (Chan and Copeland, 2009). A combination of clonal expansion and recurrent mutation drive the level of these mutations upwards within individual cells (see Box 1 for a detailed explanation). When the percentage level exceeds a critical threshold, the cells express a biochemical defect that can affect …

The unfolding clinical spectrum of POLG mutations

Background:Mutations in the DNA polymerase-γ (POLG) gene are a major cause of clinically heterogeneous mitochondrial diseases, associated with mtDNA depletion and multiple deletions.Objective:To determine the spectrum of POLG mutations in...

A novel variation in the Twinkle linker region causing late-onset dementia

Variations in the mitochondrial helicase Twinkle (PEO1) gene are usually associated with autosomal dominant chronic progressive external ophthalmoplegia (PEO). We describe five patients from two unrelated Alsatian families with the new R374W variation in the Twinkle linker region who progressively developed an autosomal dominant multisystem disorder with PEO, hearing loss, myopathy, dysphagia, dysphonia, sensory neuropathy, and late-onset dementia resembling Alzheimer's disease. These observations demonstrate that Twinkle variations in the linker domain alter cerebral function and further implicate disrupted mitochondrial DNA integrity in the pathogenesis of dementia.

Molecular analysis in a family presenting with a mild form of late-onset autosomal dominant chronic progressive external ophthalmoplegia

Nuclear genes affecting mitochondrial genome stability were screened in an Italian family presenting with autosomal dominant progressive external ophthalmoplegia (adPEO) associated with multiple mitochondrial DNA (mtDNA) deletions. We report on a heterozygous c.907C>T (p.R303W) mutation found in the N-terminal domain of the human mitochondrial DNA helicase, Twinkle protein, in six members of a family, in which two individuals manifested late-onset PEO and morphological and molecular signs of mitochondrial dysfunction along with two carriers who are presently free of disease manifestation. We also investigated if the p.R303W mutation in PEO1 gene affected the relative copy number of mitochondrial DNA genomes.

Levodopa response in Parkinsonism with multiple mitochondrial DNA deletions

We report a patient with an autosomal dominant chronic progressive external ophthalmoplegia phenotype associated with multiple mtDNA deletions in muscle from a family in which linkage analysis excluded mutations in DNA polymerase gamma (POLG), adenine nucleotide translocase (ANT-1) or C10orf2 (Twinkle). She presented with prominent Parkinsonism characterized by prolonged benefit from levodopa (L-dopa) and the later development of L-dopa induced dyskinesias and motor fluctuations. Thus L-dopa responsiveness, L-dopa induced dyskinesias and motor fluctuations may also occur in atypical Parkinsonism of mitochondrial disease, just as they may in multiple system atrophy.

Mutations in SUCLA2: a tandem ride back to the Krebs cycle

Mitochondria are small membrane-bound intracellular organelles that are the principal source of adenosine triphosphate (ATP), the high-energy phosphate molecule required by all human cells. ATP is produced by the mitochondrial respiratory chain which is linked to oxidative phosphorylation. Thirteen essential respiratory chain polypeptides are synthesized from small circles of DNA present within each mitochondrion (the mitochondrial genome, mtDNA). Qualitative defects of mtDNA are a major cause of human disease: both point mutations and deletions of mtDNA cause a biochemical defect which often affects skeletal muscle and the nervous system, presenting with neurological features (Zeviani and Di Donato, 2004). MtDNA is inherited exclusively down the maternal line, and pathogenic mtDNA mutations are either maternally inherited or sporadic, affecting at least 1 in 5000 (Schaefer et al ., 2004). More recently, autosomal recessive mitochondrial disorders have gained increasing prominence (Table 1). Mutations have been described in nuclear genes coding for respiratory chain proteins or assembly factors, and nuclear-encoded intra-mitochondrial translation factors have recently entered the lime-light (Coenen et al ., 2004; Valente et al ., 2007). However, a new class of genetic disease has emerged as an important cause of human pathology, ranking along-side the primary mtDNA mutations in terms of their frequency. These diseases are also due to nuclear gene mutations, and all affect proteins that maintain a healthy mitochondrial genome. View this table: Table 1 Nuclear genes causing mitochondrial disease Genetic linkage in families with autosomal dominant chronic progressive external ophthalmoplegia (ad-PEO) led the way to pathogenic mutations in three nuclear genes: POLG which codes for the intra-mitochondrial DNA polymerase (pol γ), PEO1 which codes for the mtDNA helicase Twinkle, and SLC25A4 which codes for the adenine nucleotide translocase ANT1 (Kaukonen et al ., 1996; Spelbrink et al ., 2001; Van Goethem et al ., 2001). Subsequent candidate gene sequencing identified …

Neuro-ophthalmology of mitochondrial diseases

Purpose of review To review recent data on mitochondrial diseases with emphasis on their neuro-ophthalmic manifestations. Recent findings Numerous studies have associated mitochondrial diseases with neuro-ophthalmic manifestations. Although there has been an explosion of studies on the genetics of mitochondrial diseases over the past few years, pathogenesis is only partly understood and therapy remains very limited. Over the past year, new mutations in Leber's hereditary optic neuropathy have been reported, and at least three genes associated with autosomal dominant chronic progressive external ophthalmoplegia have been described. These findings allow a better definition of the specific genetic mutations and gene products as well as pathophysiology of Leber's hereditary optic neuropathy and chronic progressive external ophthalmoplegia. The current development of animal models allows a better understanding of the pathophysiology of human mitochondrial diseases. Summary The afferent and efferent visual pathways within the central nervous system are frequently involved in mitochondrial diseases. Neuro-ophthalmic signs figure prominently and may be the presenting or even sole manifestation of these disorders. The four most common neuro-ophthalmic abnormalities seen in mitochondrial disorders are bilateral optic neuropathy, ophthalmoplegia with ptosis, pigmentary retinopathy, and retrochiasmal visual loss.

Neuro-ophthalmology of mitochondrial diseases.

To review recent data on mitochondrial diseases with emphasis on their neuro-ophthalmic manifestations. Numerous studies have associated mitochondrial diseases with neuro-ophthalmic manifestations. Although there has been an explosion of studies on the genetics of mitochondrial diseases over the past few years, pathogenesis is only partly understood and therapy remains very limited. Over the past year, new mutations in Leber's hereditary optic neuropathy have been reported, and at least three genes associated with autosomal dominant chronic progressive external ophthalmoplegia have been described. These findings allow a better definition of the specific genetic mutations and gene products as well as pathophysiology of Leber's hereditary optic neuropathy and chronic progressive external ophthalmoplegia. The current development of animal models allows a better understanding of the pathophysiology of human mitochondrial diseases. The afferent and efferent visual pathways within the central nervous system are frequently involved in mitochondrial diseases. Neuro-ophthalmic signs figure prominently and may be the presenting or even sole manifestation of these disorders. The four most common neuro-ophthalmic abnormalities seen in mitochondrial disorders are bilateral optic neuropathy, ophthalmoplegia with ptosis, pigmentary retinopathy, and retrochiasmal visual loss.

Disorders of renal tubular phosphate transport.

<h3>Background:</h3> Mutations in the DNA polymerase-γ (<i>POLG</i>) gene are a major cause of clinically heterogeneous mitochondrial diseases, associated with mtDNA depletion and multiple deletions. <h3>Objective:</h3> To determine the spectrum of <i>POLG</i> mutations in our Dutch patient cohort, to evaluate the pathogenicity of novel mutations, and to establish genotype–phenotype correlations. <h3>Results:</h3> The authors identified 64 predominantly recessive mutations in 37 patients from a total of 232 patients, consisting of 23 different mutations. The substitution p.A467T was most frequently observed (n = 23), but was as frequent in childhood cases as in adult cases. Five new pathogenic recessive mutations, p.Lys925ArgfsX42, p.R275X, p.G426S, p.A804T and p.R869Q were identified. The known dominant chronic progressive external ophthalmoplegia (CPEO) mutation p.R943H was for the first time associated with premature ovarian failure as well. In 19 patients the authors identified only a single recessive mutation, or a sequence variant with unclear clinical significance. The data substantiate earlier observations that in <i>POLG</i> patients a fatal status epilepticus and liver failure can be triggered by sodium valproate. It is therefore important to exclude POLG mutations before administering this treatment. <h3>Conclusion:</h3> The clinical features of the patient are the most important features to select putative <i>POLG</i> mutation carriers and not the presence of mtDNA deletions or OXPHOS (oxidative phosphorylation) activity. The authors conclude that POLG mutations are an important cause of heterogeneous mitochondrial pathology and that more accurate genotype–phenotype correlations allow a more rapid genetic diagnosis and improved prognosis for mutation carriers.

Searching for genes affecting the structural integrity of the mitochondrial genome

Mendelian traits associated with qualitative or quantitative abnormalities of mtDNA are presumably caused by mutations in nucleus-encoded genes that deleteriously interact with the mitochondrial genome. Qualitative abnormalities of mtDNA are typically represented by pleioplasmic multiple mtDNA deletions, that are detected in stable tissues, including skeletal muscle, of patients affected by Autosomal Dominant Chronic Progressive External Ophthalmoplegia. Quantitative abnormalities are represented by tissue-specific depletion of mtDNA, associated with different clinical presentations in infancy or childhood. Linkage analysis and search for candidate genes are two complementary strategies aimed at identifying the genes responsible for these disorders.