Ferrari, G. et al. Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. Brain 128, 723-731

Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, National Institute of Neurology, Milano, Italy.
Brain (Impact Factor: 9.2). 05/2005; 128(Pt 4):723-31. DOI: 10.1093/brain/awh410
Source: PubMed


We studied nine infant patients with a combination of progressive neurological and hepatic failure. Eight children, including two sibling pairs and four singletons, were affected by Alpers' hepatopathic poliodystrophy. A ninth baby patient suffered of a severe floppy infant syndrome associated with liver failure. Analysis of POLG1, the gene encoding the catalytic subunit of mitochondrial DNA polymerase, revealed that all the patients carried different allelic mutations in this gene. POLG1 is a major disease gene in mitochondrial disorders. Mutations in this gene can be associated with multiple deletions, depletion or point mutations of mitochondrial DNA (mtDNA). In turn, these different molecular phenotypes dictate an extremely heterogeneous spectrum of clinical outcomes, ranging from adult-onset progressive ophthalmoplegia to juvenile ataxic syndromes with epilepsy, to rapidly fatal hepatocerebral presentations, including Alpers' syndrome.

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    • "MNGIE (serious systemic manifestations) PDH1A, POLG1, MELAS (neuronal or cortical mantle involvement) [11] [12]. Succinate Dehydrogenase deficiency Complex I deficiency such as NDUFS1, NUBPL Mitochondrial aminoacyl-tRNA synthetases including FARS2 ( "
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    ABSTRACT: An approved definition of the term leukodystrophy does not currently exist. The lack of a precise case definition hampers efforts to study the epidemiology and the relevance of genetic white matter disorders to public health. Thirteen experts at multiple institutions participated in iterative consensus building surveys to achieve definition and classification of disorders as leukodystrophies using a modified Delphi approach. A case definition for the leukodystrophies was achieved, and a total of 30 disorders were classified under this definition. In addition, a separate set of disorders with heritable white matter abnormalities but not meeting criteria for leukodystrophy, due to presumed primary neuronal involvement and prominent systemic manifestations, was classified as genetic leukoencephalopathies (gLE). A case definition of leukodystrophies and classification of heritable white matter disorders will permit more detailed epidemiologic studies of these disorders. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jan 2015 · Molecular Genetics and Metabolism
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    • "Ataxia is a frequent manifestation of mitochondrial diseases, but is often associated with other neurological and systemic signs in the context of peculiar syndromes: this makes MIRAS difficult to diagnose, since it may present as pure ataxia and resemble other more common ARCAs. However, correct diagnosis of MIRAS is important for two main reasons: first, treatment with coenzyme Q10 may provide a symptomatic benefit in mitochondrial disorders; [7] second, POLG1-mutated patients may develop epilepsy at any stage of the disease , and their valproate treatment can lead to acute liver damage requiring liver transplantation [8]. In light of these points, we suggest to consider mutations c.1399G NA (A467T) and c.2243G NC (W748S) of POLG1 in ARCAs with sensory axonal neuropathy and absence of cerebellar atrophy, once FA and AVED have been excluded. "

    Full-text · Article · Jan 2015 · Journal of the Neurological Sciences
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    • "Multiple mtDNA deletions affecting between ∼20 and 50% of mtDNA molecules have been identified,12–15 but whether this level of mtDNA deletion alone is sufficient to cause respiratory dysfunction and neuronal death remains unclear.17 Both normal and mildly decreased (70–75% of control) mtDNA copy number have been found in brain homogenate,12,13,16,18 and 1 study in neurons from the dorsal root ganglia of a single patient15 has reported clear mtDNA depletion (∼50% of controls). Accumulation of mtDNA point mutations has been shown in skeletal muscle of patients with POLG disease using an ultradeep resequencing-by-synthesis (UDS) assay,19,20 whereas no increase in mtDNA point mutations was detected in another study in brain.12 "
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    ABSTRACT: Objective Polymerase gamma (POLG) mutations are a common cause of mitochondrial disease and have also been linked to neurodegeneration and aging. We studied the molecular mechanisms underlying POLG-related neurodegeneration using post-mortem tissue from a large number of patients.Methods Clinical information was available from all subjects. Formalin-fixed and frozen brain tissue from 15 patients and 23 controls were studied employing a combination of histopathology, immunohistochemistry and molecular studies of microdissected neurons.ResultsThe primary consequence of POLG mutation in neurons is mitochondrial DNA depletion. This was already present in infants with little evidence of neuronal loss or mitochondrial dysfunction. With longer disease duration, we found an additional, progressive accumulation of mitochondrial DNA deletions and point mutations accompanied by increasing numbers of complex I deficient neurons. Progressive neurodegeneration primarily affected the cerebellar systems and dopaminergic cells of the substantia nigra. Superimposed on this chronic process were acute, focal cortical lesions that correlated with epileptogenic foci and which showed massive neuronal loss.InterpretationPOLG mutations appear to compromise neuronal respiration via a combination of early and stable depletion and a progressive somatic mutagenesis of the mitochondrial genome. This leads to two distinct, but overlapping biological processes: a chronic neurodegeneration reflected clinically by progressive ataxia and cognitive impairment, and an acute focal neuronal necrosis that appears related to the presence of epileptic seizures. Our findings offer an explanation of the acute-on-chronic clinical course of this common mitochondrial encephalopathy. ANN NEUROL 2014. © 2014 American Neurological Association
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