MELAS associated with mutations in the POLG1 gene

Department of Neurology, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany.
Neurology (Impact Factor: 8.29). 06/2007; 68(20):1741-2. DOI: 10.1212/01.wnl.0000261929.92478.3e
Source: PubMed
Download full-text


Available from: Torsten Kraya, Oct 16, 2014
  • Source
    • "Moreover, throughout the years a wide spectrum of clinical findings including parkinsonism , neuropathy, optic neuritis, psychiatric disorders has been described in POLG1 mutations carriers [12] [14] [15] [16] [17] [18] [19]. Deschauer et al. 2007 described a patient presenting with occipital seizures and residual homonymous hemianopsia , headache and ataxia and carrying two heterozygous POLG1 mutations [7]. The presence of occipital symptoms and lesions, interpreted as stroke-like episodes , together with elevated CSF lactate and ragged red fibers, posed the suspicion of MELAS, raising the question whether POLG1 mutations could be associated with a MELAS like phenotype [7] [20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background POLG1 mutations have been associated with MELAS-like phenotypes. However given several clinical differences it is unknown whether POLG1 mutations are possible causes of MELAS or give raise to a distinct clinical and genetic entity, named POLG1-associated encephalopathy. Case presentation We describe a 74 years old man carrying POLG1 mutations presenting with strokes, myopathy and ragged red fibers with some atypical aspects for MELAS such as late onset, lack of cerebral calcification and presence of frontal and occipital MRI lesions better consistent with the POLG associated-encephalopathy spectrum. Conclusion The lack of available data hampers a definite diagnosis in our patient as well as makes it difficult to compare MELAS, which is a clearly defined clinical syndrome, with POLG1-associated encephalopathy, which is so far a purely molecularly defined syndrome with a quite heterogeneous clinical picture. However, the present report contributes to expand the phenotypic spectrum of POLG1 mutations underlining the importance of searching POLG1 mutations in patients with mitochondrial signs and MELAS like phenotypes but negative for common mtDNA mutations.
    BMC Neurology 01/2013; 13(1):8. DOI:10.1186/1471-2377-13-8 · 2.04 Impact Factor
  • Source
    • "axia increase with age . Pathogenic POLG mutations have been reported presenting in similar ways to primary mitochondrial DNA disease [ such as MELAS , MERRF ( Myoclonic Epilepsy with Ragged Red Fibres ) , Kearns – Sayre Syndrome ] , reflecting without doubt the damaging effect of the impaired mitochondrial DNA polymerase on mito - chondrial DNA ( Deschauer et al . , 2007 ; Tzoulis and Bindoff , 2008 ; Bindoff , 2011 ) . However , some frequent mitochondrial DNA - related symptoms , such as diabetes mellitus , hearing loss or cardiomyopathy were infrequent in our cohort of patients with homozygous p . Ala467Thr . Cardiac abnormalities were only noted in two cases and were minor , which is in contrast wit"
    [Show abstract] [Hide abstract]
    ABSTRACT: Polymerase-γ (POLG) is a major human disease gene and may account for up to 25% of all mitochondrial diseases in the UK and in Italy. To date, >150 different pathogenic mutations have been described in POLG. Some mutations behave as both dominant and recessive alleles, but an autosomal recessive inheritance pattern is much more common. The most frequently detected pathogenic POLG mutation in the Caucasian population is c.1399G>A leading to a p.Ala467Thr missense mutation in the linker domain of the protein. Although many patients are homozygous for this mutation, clinical presentation is highly variable, ranging from childhood-onset Alpers-Huttenlocher syndrome to adult-onset sensory ataxic neuropathy dysarthria and ophthalmoparesis. The reasons for this are not clear, but familial clustering of phenotypes suggests that modifying factors may influence the clinical manifestation. In this study, we collected clinical, histological and biochemical data from 68 patients carrying the homozygous p.Ala467Thr mutation from eight diagnostic centres in Europe and the USA. We performed DNA analysis in 44 of these patients to search for a genetic modifier within POLG and flanking regions potentially involved in the regulation of gene expression, and extended our analysis to other genes affecting mitochondrial DNA maintenance (POLG2, PEO1 and ANT1). The clinical presentation included almost the entire phenotypic spectrum of all known POLG mutations. Interestingly, the clinical presentation was similar in siblings, implying a genetic basis for the phenotypic variability amongst homozygotes. However, the p.Ala467Thr allele was present on a shared haplotype in each affected individual, and there was no correlation between the clinical presentation and genetic variants in any of the analysed nuclear genes. Patients with mitochondrial DNA haplogroup U developed epilepsy significantly less frequently than patients with any other mitochondrial DNA haplotype. Epilepsy was reported significantly more frequently in females than in males, and also showed an association with one of the chromosomal markers defining the POLG haplotype. In conclusion, our clinical results show that the homozygous p.Ala467Thr POLG mutation does not cause discrete phenotypes, as previously suggested, but rather there is a continuum of clinical symptoms. Our results suggest that the mitochondrial DNA background plays an important role in modifying the disease phenotype but nuclear modifiers, epigenetic and environmental factors may also influence the severity of disease.
    Brain 12/2012; 135(Pt 12):3614-26. DOI:10.1093/brain/aws298 · 9.20 Impact Factor
  • Source
    • "They resemble true infarcts in that they are pan-necrotic and demonstrate profound neuronal cell loss, microvacuolation, gliosis and eosinophilia in surviving neurons but their topographical distribution does not follow the vascular territories of major cerebral arteries or border zones. Although stroke-like episodes are part of the clinical syndrome in MELAS (Pavlakis et al., 1984), more recently stroke-like episodes have been documented in patients harbouring the m.8344A4G mutation associated with myoclonic epilepsy ragged red fibres and autosomal recessive mutations in the POLG gene encoding for catalytic subunit of the polymerase gamma protein, which is responsible for mitochondrial DNA replication (Tanji et al., 2003; Deschauer et al., 2007). Regions of necrotic cortical lesions without clinical manifestation of stroke-like episodes has also been seen in POLG mutations typically confined to the posterior occipital lobe regions (Winterthun et al., 2005; Tzoulis et al., 2006, 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuropathological findings in mitochondrial DNA disease vary and are often dependent on the type of mitochondrial DNA defect. Many reports document neuronal cell loss, demyelination, gliosis and necrotic lesions in post-mortem material. However, previous studies highlight vascular abnormalities in patients harbouring mitochondrial DNA defects, particularly in those with the m.3243A>G mutation in whom stroke-like events are part of the mitochondrial encephalopathy lactic acidosis and stroke-like episodes syndrome. We investigated microangiopathic changes in the cerebellum of 16 genetically and clinically well-defined patients. Respiratory chain deficiency, high levels of mutated mitochondrial DNA and increased mitochondrial mass were present within the smooth muscle cells and endothelial cells comprising the vessel wall in patients. These changes were not limited to those harbouring the m.3243A>G mutation frequently associated with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, but were documented in patients harbouring m.8344A>G and autosomal recessive polymerase (DNA directed), gamma (POLG) mutations. In 8 of the 16 patients, multiple ischaemic-like lesions occurred in the cerebellar cortex suggestive of vascular smooth muscle cell dysfunction. Indeed, changes in vascular smooth muscle and endothelium distribution and cell size are indicative of vascular cell loss. We found evidence of blood-brain barrier breakdown characterized by plasma protein extravasation following fibrinogen and IgG immunohistochemistry. Reduced immunofluorescence was also observed using markers for endothelial tight junctions providing further evidence in support of blood-brain barrier breakdown. Understanding the structural and functional changes occurring in central nervous system microvessels in patients harbouring mitochondrial DNA defects will provide an important insight into mechanisms of neurodegeneration in mitochondrial DNA disease. Since therapeutic strategies targeting the central nervous system are limited, modulating vascular function presents an exciting opportunity to lessen the burden of disease in these patients.
    Brain 05/2012; 135(Pt 6):1736-50. DOI:10.1093/brain/aws110 · 9.20 Impact Factor
Show more