POLG1-related levodopa-responsive parkinsonism (original) (raw)
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BMC Medical Genetics, 2013
Background: Disorders of oxidative phosphorylation affects 1/5000 individuals and present heterogeneous involvement of tissues highly dependent upon ATP production. Case presentation: Here we present the case of a 48-year-old woman carrying a homozygous mutation (p.A899T) in mitochondrial polymerase gamma (POLG) and manifesting with a complex neurological phenotype including Dopamine-agonist responsive Parkinsonism. Conclusion: This case report is further evidence that mitochondrial dysfunction might play a role in Parkinson's Disease pathogenesis and helps in identification of apparent mutation-specific clinical characteristics. Mutations in POLG should be looked for in cases of Parkinsonism, especially when multisystem neurological involvement is found.
SANDO: Two novel mutations in POLG1 gene
Neuromuscular Disorders, 2006
Parkinsonian features have been described in patients with POLG1 mutations. Notwithstanding, the clinical expression has been revealed heterogeneous and the response to dopaminergic treatment has been document in few cases. We aim to describe the longitudinal clinical features and the treatment response of three unrelated patients with neurodegenerative parkinsonism, preceded by PEO and SANDO syndromes, who harbor POLG1 mutations, including two novel mutations. It was documented a sustained response to levodopa, at 3 and 8 years of follow-up of parkinsonian syndrome, and reduced striatal dopamine uptake. We review the genotypic and phenotypic spectrum of POLG1-related parkinsonism. Our observations stimulate the debate around the role of mitochondrial DNA defects in the pathogenesis of neurodegenerative parkinsonism.
Levodopa response in Parkinsonism with multiple mitochondrial DNA deletions
Movement Disorders, 2007
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 ␥ (POLG), adenine nucleotide translocase (ANT-1) or C10orf2 (Twinkle). She presented with prominent Parkinsonism characterized by prolonged benefit from levo-This article contains supplementary video clips, available online at
Neuromuscular Disorders, 2008
Different mutations, or combinations of mutations, in POLG1, the gene encoding pol cA, the catalytic subunit of mitochondrial DNA polymerase, are associated with a spectrum of clinical presentations including autosomal dominant or recessive progressive external ophthalmoplegia (PEO), juvenile-onset ataxia and epilepsy, and Alpers-Huttenlocher syndrome. Parkinsonian features have been reported as a late complication of POLG1-associated dominant PEO. Good response to levodopa or dopamine agonists, reduced dopamine uptake in the corpus striatum and neuronal loss of the Substantia Nigra pars compacta have been documented in a few cases. Here we report two novel mutations in POLG1 in a compound heterozygous patient with autosomal recessive PEO, followed by pseudoorthostatic tremor evolving into levodopa-responsive parkinsonism. These observations support the hypothesis that mtDNA dysfunction is engaged in the pathogenesis of idiopathic Parkinson's disease.
Do somatic mitochondrial DNA mutations contribute to Parkinson's disease?
Parkinson's disease, 2011
A great deal of evidence supports a role for mitochondrial dysfunction in the pathogenesis of Parkinson's disease (PD), although the origin of the mitochondrial dysfunction in PD remains unclear. Expression of mitochondrial DNA (mtDNA) from PD patients in "cybrid" cell lines recapitulates the mitochondrial defect, implicating a role for mtDNA mutations, but the specific mutations responsible for the mitochondrial dysfunction in PD have been difficult to identify. Somatic mtDNA point mutations and deletions accumulate with age and reach high levels in substantia nigra (SN) neurons. Mutations in mitochondrial DNA polymerase γ (POLG) that lead to the accumulation of mtDNA mutations are associated with a premature aging phenotype in "mutator" mice, although overt parkinsonism has not been reported in these mice, and with parkinsonism in humans. Together these data support, but do not yet prove, the hypothesis that the accumulation of somatic mtDNA mutations in SN neurons contribute to the pathogenesis of PD.
Mitochondrial DNA polymerase gamma variants in idiopathic sporadic Parkinson disease
Neurology, 2007
Objective: Dysfunction of mitochondrial DNA polymerase gamma (POLG) has been recently recognized as an important cause of inherited neurodegenerative diseases. We have reported dominant and recessive inheritance of parkinsonism, mitochondrial myopathy, and premature amenorrhea in five ethnically distinct families with POLG1 mutations. This prompted us to carry out a detailed analysis of the coding region and intron-exon boundaries of POLG1 in Finnish patients with idiopathic sporadic Parkinson disease (PD) and in nonparkinsonian controls. Methods: The coding region of POLG1 was analyzed in 140 Finnish patients with PD and their 127 spouses as age-and ethnically matched controls. Further, we analyzed the intragenic CAGrepeat region of POLG1 in 126 additional patients with nonparkinsonian neurologic disorders and in 516 Finnish population controls. Results: We found clustering of rare variants of the POLG1 CAG-repeat, encoding a polyglutamine tract, in Finnish patients with idiopathic PD as compared to their spouses (p ϭ 0.003; OR 3.01, 95% CI 1.35 to 6.71), population controls (p ϭ 0.001; OR 2.45, 95% CI 1.45 to 4.14), and patients with nonparkinsonian neurologic disorders (p ϭ 0.05, OR 1.98, 95% CI 0.97 to 4.05). We found several amino acid substitutions, none of them associating with PD. These included a previously parkinsonism-associated POLG variant Y831C, found in one patient with PD, but also in five controls, suggesting that it is a neutral amino acid polymorphism. Conclusions: Our results suggest that POLG polyglutamine tract variants should be considered as a predisposing genetic factor in idiopathic sporadic Parkinson disease.
Parkinson's disease and mitochondrial gene variations: A review
Parkinson's disease (PD) is a common disorder of the central nervous system in the elderly. The pathogenesis of PD is a complex process, with genetics as an important contributing factor. This factor may stem from mitochon-drial gene variations and mutations as well as from nuclear gene variations and mutations. More recently, a particular role of mitochondrial dysfunction has been suggested, arising from mitochondrial DNA variations or acquired mutations in PD pathogenesis. The present review summarizes and weighs the evidence in support of mitochondrial DNA (mtDNA) variations as important contributors to the development and course of PD.
Mitochondrial oxidative phosphorylation defects in Parkinson's disease
Annals of Neurology, 1992
Parkinson's disease has been associated with defects in oxidative phosphorylation (Oxphos). We analyzed mitochondria isolated from muscle biopsies of 6 patients with Parkinson's disease for deficiencies in Oxphos enzymes and for mutations in the mitochondrial DNA. Oxphos enzyme assays were compared to the 5 to 95% confidence intervals from 16 control subjects. Four patients had complex I defects, whereas 1 patient had a complex IV defect. A genetic basis for Parkinson's disease was suggested by the presence of affected relatives of 2 patients with Parkinson's disease. Known pathological mitochondrial DNA mutations (insertion-deletions or point mutations) were not found. We conclude that Parkinson's disease is a systemic disorder of Oxphos, probably of a complex genetic etiology. Premature cell death in the nigrostriatal dopamine pathway could be due to energetic impairment and accentuated free radical generation caused by an Oxphos defect.
Mitochondrial alterations in Parkinson’s disease: new clues
Journal of Neurochemistry, 2008
Mitochondrial dysfunction has long been associated with Parkinson's disease (PD). In particular, complex I impairment and subsequent oxidative stress have been widely demonstrated in experimental models of PD and in post-mortem PD samples. A recent wave of new studies is providing novel clues to the potential involvement of mitochondria in PD. In particular, (i) mitochondria-dependent programmed cell death pathways have been shown to be critical to PD-related dopaminergic neurodegeneration, (ii) many disease-causing proteins associated with familial forms of PD have been demonstrated to interact either directly or indirectly with mitochondria, (iii) aging-related mitochondrial changes, such as alterations in mitochondrial DNA, are increasingly being associated with PD, and (iv) anomalies in mitochondrial dynamics and intra-neuronal distribution are emerging as critical participants in the pathogenesis of PD. These new findings are revitalizing the field and reinforcing the potential role of mitochondria in the pathogenesis of PD. Whether a primary or secondary event, or part of a multifactorial pathogenic process, mitochondrial dysfunction remains at the forefront of PD research and holds the promise as a potential molecular target for the development of new therapeutic strategies for this devastating, currently incurable, disease.