Additive effects of POLG1 and ANT1 mutations in a complex encephalomyopathy

Galassi, Giuliana; Lamantea, Eleonora; Invernizzi, Federica; Tavani, Federica; Pisano, Isabella; Ferrero, Ileana; Palmieri, Luigi; Zeviani, Massimo

doi:10.1016/j.nmd.2008.03.013

Cited by 32 publications

(26 citation statements)

References 19 publications

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“…Digenic inheritance or synergistic heterozygosity30 due to a single heterozygous POLG mutation in combination with a mutation in another gene may theoretically contribute to the clinical phenotype. Additive deleterious effects due to POLG and ANT1 mutations were proposed as an explanation for a complex encephalomyopathy 31. Digenic mutations in POLG and SCN1A were identified in a patient with severe myoclonic epilepsy of infancy 32.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA polymerase mutations: an ever expanding molecular and clinical spectrum

Tang

Wang

Lee

et al. 2011

Journal of Medical Genetics

144

142

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Mutations in the POLG gene have emerged as one of the most common causes of inherited mitochondrial diseases in children and adults. This study sequenced the exons and flanking intronic regions of the POLG gene from 2697 unrelated patients with clinical presentations suggestive of POLG deficiency. Informative mutations have been identified in 136 unrelated individuals (5%), including 92 patients with two recessive pathogenic alleles and three patients harbouring a dominant mutation. Twenty-four novel recessive mutations and a novel possible dominant mutation, p.Y951N, were identified. All missense mutations occurred at evolutionarily conserved amino acids within functionally important regions identified by molecular modelling analyses. Oligonucleotide array comparative genomic hybridisation analyses performed on DNA samples from 81 patients with one mutant POLG allele identified a large intragenic deletion in only one patient, suggesting that large deletions in POLG are rare. The 92 patients with two mutant alleles exhibited a broad spectrum of disease. Almost all patients in all age groups had some degree of neuropathy. Seizures, hepatopathy, and lactic acidaemia were predominant in younger patients. By comparison, patients who developed symptoms in adulthood had a higher percentage of myopathy, sensory ataxia, and chronic progressive external ophthalmoplegia (CPEO)/ptosis. In conclusion, POLG mutations account for a broad clinical spectrum of mitochondrial disorders. Sequence analysis of the POLG gene should be considered as a part of routine screening for mitochondrial disorders, even in the absence of apparent mitochondrial DNA abnormalities.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA polymerase mutations: an ever expanding molecular and clinical spectrum

Tang

Wang

Lee

et al. 2011

Journal of Medical Genetics

144

142

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“…MEMSA. MEMSA is clinically characterized by myopathy, epilepsy, and ataxia [93]. Ataxia is usually followed by focal epilepsy, which generalizes with progression of the disease.…”

Section: Mendelian Peomentioning

confidence: 99%

“…MEMSA is most frequently due to POLG1 mutations, which secondarily cause multiple mtDNA deletions. Only in single cases mutations in the PEO1 or SLC25A4 genes have been described as causal [93]. No detailed description of the PNP is available from the literature.…”

Section: Mendelian Peomentioning

confidence: 99%

Inherited mitochondrial neuropathies

Finsterer

2011

Journal of the Neurological Sciences

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“…In previous years, other patients with POLG1 gene mutation and parkinsonism have been reported (Galassi et al 2008;Betts-Henderson et al 2009). Two sisters with early-onset parkinsonism (dystonic toe curling, action tremor, masked face, bradykinesia, stooped posture, and rigidity), together with clinical and electrophysiological signs of sensorimotor axonal peripheral neuropathy, were reported to have ragged-red and cytochrome c oxidasenegative fibers in muscle biopsy (Davidzon et al 2006).…”

Section: Polg1-associated Parkinsonismmentioning

confidence: 95%

POLG1-Related and other “Mitochondrial Parkinsonisms”: an Overview

et al. 2011

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Mitochondrial dysfunction has been implicated in the pathogenesis of sporadic, idiopathic Parkinson disease. In some cases, mitochondrial DNA primary genetic abnormalities, or more commonly, secondary rearrangements due to polymerase gamma (POLG1) gene mutation, can directly cause parkinsonism. The case of a Parkinson disease patient with some signs or symptoms suggestive of mitochondrial disease (i.e., ptosis, myopathy, neuropathy) is a relatively common event in the neurological practice. Mitochondrial parkinsonisms do not have distinctive features allowing an immediate diagnosis, and a negative family history does not rule out a possible diagnosis of mitochondrial disorder. In this article, we do not revise the mitochondrial hypothesis of sporadic, idiopathic Parkinson disease, extensively discussed elsewhere, but we review POLG1-related parkinsonism and other well-defined forms of "mitochondrial parkinsonisms", with mtDNA mutations or rearrangements. Lastly, we try to introduce a possible diagnostic approach for patients with parkinsonism and suspected mitochondrial disorder.

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Additive effects of POLG1 and ANT1 mutations in a complex encephalomyopathy

Cited by 32 publications

References 19 publications

Mitochondrial DNA polymerase mutations: an ever expanding molecular and clinical spectrum

Mitochondrial DNA polymerase mutations: an ever expanding molecular and clinical spectrum

Inherited mitochondrial neuropathies

POLG1-Related and other “Mitochondrial Parkinsonisms”: an Overview

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