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
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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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    • "In a series of patients with different mitochondrial defects and ataxia, a high proportion of cerebellar neurons had complex I deficiency and only a small fraction of these neurons demonstrated COX down-regulation. These studies also showed that there is a progression of respiratory chain deficiency in the patients and COX down-regulation appears later in the course of disease (Lax et al., 2012). Deficiency of COX was strongly correlated with cell loss, implying that COX is essential to neuronal viability. "
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