Localized cerebral energy failure in DNA polymerase gamma-associated encephalopathy syndromes

Abstract

Mutations in the catalytic subunit of the mitochondrial DNA-polymerase gamma cause a wide spectrum of clinical disease ranging from infantile hepato-encephalopathy to juvenile/adult-onset spinocerebellar ataxia and late onset progressive external ophthalmoplegia. Several of these syndromes are associated with an encephalopathy that characteristically shows episodes of rapid neurological deterioration and the development of acute cerebral lesions. The purpose of this study was to investigate the nature, distribution and natural evolution of central nervous system lesions in polymerase gamma associated encephalopathy focusing particularly on lesions identified by magnetic resonance imaging. We compared radiological, electrophysiological and pathological findings where available to study potential mechanisms underlying the episodes of exacerbation and acute cerebral lesions. We studied a total of 112 magnetic resonance tomographies and 11 computed tomographies in 32 patients with polymerase gamma-encephalopathy, including multiple serial examinations performed during both the chronic and acute phases of the disease and, in several cases, magnetic resonance spectroscopy and serial diffusion weighted studies. Data from imaging, electroencephalography and post-mortem examination were compared in order to study the underlying disease process. Our findings show that magnetic resonance imaging in polymerase gamma-related encephalopathies has high sensitivity and can identify patterns that are specific for individual syndromes. One form of chronic polymerase gamma-encephalopathy, that is associated with the c.1399G > A and c.2243G > C mutations, is characterized by progressive cerebral and cerebellar atrophy and focal lesions of the thalamus, deep cerebellar structures and medulla oblongata. Acute encephalopathies, both infantile and later onset, show similar pictures with cortical stroke-like lesions occurring during episodes of exacerbation. These lesions can occur both with and without electroencephalographic evidence of concurrent epileptic activity, and have diffusion, spectroscopic and histological profiles strongly suggestive of neuronal energy failure. We suggest therefore that both infantile and later onset polymerase gamma related encephalopathies are part of a continuum.

A diagnostic flow chart forPOLG-related diseases based on signs sensitivity and specificity

“…By contrast brain imaging was not directly informative for the diagnosis of POLG- related disease. Cerebellar hemispheric white matter hyperintensities, previously associated with POLG -related diseases,31 33 were found in only four patients. Of note they may also be encountered with single mtDNA deletion 34…”

Energy failure in multiple sclerosis and its investigation using MR techniques

“…Increased energy consumption or decreased oxygen availability shifts catabolism from the mitochondrial oxidative pathway to anaerobic glycolysis, leading to lactate accumulation. Increase in lactate is seen using MR spectroscopy in patients with mitochondrial mutations [45, 83,84], following severe hypoxia [46, 55] and following ischaemic stroke [48,54]. Elevated lactate is also seen in Parkinson's disease [85] gliomas [86], following acute traumatic brain injury [87], and in reversible lesions associated with status epilepticus [88].…”

Number of CAG repeats in POLG1 and its association with Parkinson disease in the Norwegian population

“…We know that pathogenic POLG1 mutations lead to the accumulation of somatic mtDNA mutations in postmitotic tissue, including the brain (Hakonen et al, 2008;Zsurka et al, 2008), and that these cause mitochondrial dysfunction and cell death. These events may, moreover, be focal and show organ and tissue specificity (Tzoulis et al, 2010). In addition, studies have (Anvret et al, 2010;Eerola et al, 2010;Hudson et al, 2009;Luoma et al, 2007;Taanman and Schapira, 2005;Tiangyou et al, 2006).…”