Cerebellar Ataxia in Patients With Mitochondrial DNA Disease

Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.
Journal of Neuropathology and Experimental Neurology (Impact Factor: 3.8). 02/2012; 71(2):148-61. DOI: 10.1097/NEN.0b013e318244477d
Source: PubMed


Cerebellar ataxia is a prominent clinical symptom in patients with mitochondrial DNA (mtDNA) disease. This is often progressive with onset in young adulthood. We performed a detailed neuropathologic investigation of the olivary-cerebellum in 14 genetically and clinically well-defined patients with mtDNA disease. Quantitative neuropathologic investigation showed varying levels of loss of Purkinje cells and neurons of the dentate nucleus and inferior olivary nuclei. Typically, focal Purkinje cell loss was present in patients with the m.3243A>G mutation caused by the presence of microinfarcts, with relative preservation of neuronal cell populations in the olivary and dentate nuclei. In contrast, patients with the m.8344A>G mutation or recessive POLG mutations showed extensive and global neuronal cell loss in all 3 olivary-cerebellum areas examined. Molecular analysis of mutated mtDNA heteroplasmy levels revealed that neuronal cell loss occurred independently of the level of mutated mtDNA present within surviving neurons. High levels of neuronal respiratory chain deficiency, particularly of complex I, were detected in surviving cells; levels of deficiency were greater in regions with extensive cell loss. We found a relationship between respiratory deficiency and neuronal cell density, indicating that neuronal cell death correlates with respiratory deficiency. These findings highlight the vulnerability of the olivary-cerebellum to mtDNA defects.

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Available from: Victoria Nesbitt, Jan 14, 2014
    • "Pol γA, the catalytic core of the enzyme, is encoded by the nuclear POLG1 gene. Mutations of this gene are associated with multiple deletions and/or depletion of mtDNA, which may lead to impaired energy production in the mitochondria and the so-called POLG syndromes [1]. Since the discovery of the gene in 1996, more than 100 pathogenic mutations have been linked to a wide range of nonneurological and neurological disorders. "
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    ABSTRACT: Polymerase γ (POLG) is the enzyme responsible for the replication and maintenance of mitochondrial DNA (mtDNA). Mutations in the POLG1 gene can lead to mitochondrial dysfunction, producing a wide range of neurological and non-neurological phenotypes. Neurological manifestations include ataxia, muscular weakness, epilepsy, progressive external ophthalmoplegia (PEO), ptosis, neuropathy, psychiatric disorders and, more rarely, parkinsonism. We present the case of an 80-year old female patient with a history of PEO, ptosis, childish behaviour, obsessive disorder, cognitive decline, and parkinsonism. A comprehensive study showed striatal dopamine deficiency on DaT Scan and ragged red fibres as evidenced by Gomori staining in a biopsy of the biceps brachii. Multiple deletions of mtDNA were detected, and sequencing of the POLG1 gene identified a novel substitution, 2834A>T, in exon 18, changing the p.His945Leu amino acid. In silico analysis using PolyPhen-2 ( predicted that this change is probably damaging, with a score of 1.0 (0-1). Copyright © 2015 Elsevier B.V. All rights reserved.
    No preview · Article · Feb 2015 · Journal of the Neurological Sciences
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    • "A preferential involvement of the cerebellum has been reported in secondary mitochondrial dysfunction (Montero et al., 2007). In the classic mitochondrial disorders, cerebellar involvement is frequently reported and cerebellar atrophy might even be the primary neuroradiological finding (reviewed in Lax et al., 2012). Basal ganglia structures including the caudate are also among the most frequently affected brain regions in mitochondrial disorders (Haas and Dietrich, 2004; Friedman et al., 2010) and can be combined with atrophy of the cerebellum (Delonlay et al., 2013). "
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    • "ear to be particularly susceptible to mtDNA mutation . For example , the m . 8344 A . G mutation disrupts function of Purkinje cells and neurons in the dentate nucleus and inferior olivary nuclei of the cerebellum ( Mancuso et al . , 2013 ) . Cerebellar ataxia is a prominent clinical feature of mtDNA disease and often pro - gressively gets worse ( Lax et al . , 2012 ) . Here , several of our patients showed signs of cerebellar atrophy and were ataxic , and on testing were impaired in processing speed and motor control . In addition to the cerebellum , reduced cerebral glucose uptake in occipital and temporal regions has been found in mitochondrial disorders ( Molnar et al . , 2000 ) . Further , les"
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    ABSTRACT: Mutations in the mitochondrial genome can impair normal metabolic function in the central nervous system (CNS) where cellular energy demand is high. Primary mitochondrial DNA (mtDNA) mutations have been linked to several mitochondrial disorders that have comorbid psychiatric, neurologic, and cognitive sequelae. Here, we present a series of cases with primary mtDNA mutations who were genotyped and evaluated across a common neuropsychological battery. Nineteen patients with mtDNA mutations were genotyped and clinically and cognitively evaluated. Pronounced deficits in nonverbal/visuoperceptual reasoning, verbal recall, semantic word generativity, and processing speed were evident and consistent with a “mitochondrial dementia” that has been posited. However, variation in cognitive performance was noteworthy, suggesting that the phenotypic landscape of cognition linked to primary mtDNA mutations is heterogeneous. Our patients with mtDNA mutations evidenced cognitive deficits quite similar to those commonly seen in Alzheimer's disease and could have clinical relevance to the evaluation of dementia.
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