The unfolding clinical spectrum of POLG mutations

Department of Clinical Genetics, Maastricht University Medical Centre, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
Journal of Medical Genetics (Impact Factor: 6.34). 08/2009; 46(11):776-85. DOI: 10.1136/jmg.2009.067686
Source: PubMed


Mutations in the DNA polymerase-gamma (POLG) gene are a major cause of clinically heterogeneous mitochondrial diseases, associated with mtDNA depletion and multiple deletions.
To determine the spectrum of POLG mutations in our Dutch patient cohort, to evaluate the pathogenicity of novel mutations, and to establish genotype-phenotype correlations.
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 POLG 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.
The clinical features of the patient are the most important features to select putative POLG 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.

Download full-text


Available from: Hubert J Smeets
  • Source
    • "We would suggest, however, that these figures may represent an under estimation as only more recent publications have discerned between peripheral and central components of ataxia, that is, ataxia due either to cerebellar dysfunction or pathology of the dorsal root ganglion. Premature ovarian failure (POF) was also observed in a small number of female patients [15] [39] [40]. Other symptoms included dysphagia, dysarthria and diabetes mellitus. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Progressive external ophthalmoplegia (PEO) is an eye movement disorder characterised by paresis of the extra ocular muscles and muscle restricted multiple mitochondrial DNA (mtDNA) deletions. Classification of patients is particularly difficult due to overlapping phenotypes and a poor genotype-phenotype relationship. Despite the identification of several nuclear encoded genes causing PEO, over half of patients with clinically confirmed PEO do not have a genetic diagnosis. Objective: To systematically review genotypic and phenotypic correlates of published cases of adult-onset PEO. Methods: Patients were identified from interrogation of articles from Scopus, Medline via PubMed, and Genetic Abstracts databases using electronic searches (1st January 1970 to 8th November 2013). Reference lists and UniProt entries were also manually checked for additional articles. Results: Twelve nuclear encoded genes were identified (TYMP, SLC25A4, POLG, C10ORF2, OPA1, POLG2, RRM2B, TK2, DGUOK, MPV17, MGME1, and DNA2) systematically from 583 patients. At the time of writing, mutations in SPG7 and AFG3L2 genes were reported to be associated with ophthalmoparesis and multiple mtDNA deletions in fourteen additional adult-onset PEO patients, bringing the total number of known genes to fourteen. Conclusions: Diagnostic yield is still critically dependent on the meticulous clinical and biochemical characterisation of patients. Understanding the intimate relationship between genotype and phenotype remains a fundamental challenge. The results of this systematic review provide guidance to both patients and clinician about future prognosis, and will serve, in future, to assess methods of disease prevention and evaluation of targeted therapeutic strategies.
    Full-text · Article · Sep 2014
  • Source
    • "Furthermore, we show that age of onset can be used to predict the symptoms that a patient will manifest and provide a timeline of the disease progression that may be expected. Individuals carrying mutations in POLG can manifest a disease at any age, depending on the mutation combination as well as the severity of the Pol γ functional defects [5] [26] [50]. Presumably, the most severe Pol γ mutations would be embryonic lethal in compound heterozygous form with any other, even slightly deleterious mutation, and we speculate that they may also have the potential to be dominant. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We establish the genotype-phenotype correlations for the complete spectrum of POLG syndromes, by refining our previously described protocol for mapping pathogenic mutations in the human POLG gene to functional clusters in the catalytic core of the mitochondrial replicase, Pol γ (1). We assigned 136 mutations to five clusters and identify segments of primary sequence that can be used to delimit the boundaries of each cluster. We report that compound heterozygotes with two mutations from different clusters manifested more severe, earlier onset POLG syndromes, whereas two mutations from the same cluster are less common and generally are associated with less severe, later onset POLG syndromes. We also show that specific cluster combinations are more severe than others, and have a higher likelihood to manifest at an earlier age. Our clustering method provides a powerful tool to predict the pathogenic potential and predicted disease phenotype of novel variants and mutations in POLG, the most common nuclear gene underlying mitochondrial disorders. We propose that such a prediction tool would be useful for routine diagnostics for mitochondrial disorders. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference. Guest Editors: Manuela Pereira and Miguel Teixeira.
    Full-text · Article · Jul 2014 · Biochimica et Biophysica Acta
  • Source
    • "Other symptoms of PEOþ include sensory ataxia, neuropathy , dysarthria, myopathy, and restless leg syndrome (Fadic et al. 1997; Van Goethem et al. 2001; Milone et al. 2008; Aitken et al. 2009; Blok et al. 2009). Cosegregating with PEO families are features of Parkinsonism (Luoma et al. 2004), premature ovarian failure, sensory ataxia (Pagnamenta et al. 2006), and cataracts (Luoma et al. 2004; Blok et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The inability to replicate mitochondrial genomes (mtDNA) by the mitochondrial DNA polymerase (pol γ) leads to a subset of mitochondrial diseases. Many mutations in POLG, the gene that encodes pol γ, have been associated with mitochondrial diseases such as myocerebrohepatopathy spectrum (MCHS) disorders, Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), and progressive external ophthalmoplegia (PEO). This chapter explores five important topics in POLG-related disease: (1) clinical symptoms that identify and distinguish POLG-related diseases, (2) molecular characterization of defects in polymerase activity by POLG disease variants, (3) the importance of holoenzyme formation in disease presentation, (4) the role of pol γ exonuclease activity and mutagenesis in disease and aging, and (5) novel approaches to therapy and avoidance of toxicity based on primary research in pol γ replication.
    Full-text · Article · Apr 2013 · Cold Spring Harbor perspectives in biology
Show more