Alterations of oligodendrocytes and demyelination in the spinal cord of patients with mitochondrial encephalomyopathy

doi:10.1016/0022-510X(88)90004-4

Journal of the Neurological Sciences

Volume 86, Issue 1, August 1988, Pages 19-29

https://doi.org/10.1016/0022-510X(88)90004-4 Get rights and content

Abstract

The spinal cords of 2 autopsied patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) were examined. Histologically, the spinal cords showed a spongy state due to the presence of distended myelinated fibers with enlarged periaxonal spaces. Ultrastructurally, the affected fibers showed extensive microvacuolation of the inner myelin sheath with occasional vesicular changes. The presence of macrophages near the degenerated myelin was a frequent finding. The stripping of myelin lamellae by macrophage was observed, with frequent appearance of denuded axons. Furthermore, prominent morphological changes were observed in oligodendrocytes. These findings indicate that demyelination, probably secondary to the degeneration of oligodendrocytes, occurs in the spinal cord of MELAS.

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Cited by (12)

Magnetic resonance imaging correlates of genetically characterized patients with mitochondrial disorders: A study from south India
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Citation Excerpt :
Spinal cord degeneration confined to posterior column is also seen in POLG1 related disorders and has been supported by histopathological studies (Hopkins et al., 2010; Lax et al., 2012a). Spinal cord pathology is also reported in patients with mitochondrial myopathy encephalopathy, lactic acidosis and stroke like episode syndrome (Ohara et al., 1988). Spinal cords showed spongy state due to the presence of distended myelinated fibers with enlarged periaxonal spaces.
Large studies analyzing magnetic resonance imaging correlates in different genotypes of mitochondrial disorders are far and few. This study sought to analyze the pattern of magnetic resonance imaging findings in a cohort of genetically characterized patients with mitochondrial disorders.
The study cohort included 33 patients (age range 18 months–50 years, M:F — 0.9:1) with definite mitochondrial disorders seen over a period of 8 yrs. (2006–2013). Their MR imaging findings were analyzed retrospectively.
The patients were classified into three groups according to the genotype, Mitochondrial point mutations and deletions (n = 21), SURF1 mutations (n = 7) and POLG1 (n = 5). The major findings included cerebellar atrophy (51.4%), cerebral atrophy (24.2%), signal changes in basal ganglia (45.7%), brainstem (34.2%) & white matter (18.1%) and stroke like lesions (25.7%). Spinal cord imaging showed signal changes in 4/6 patients. Analysis of the special sequences revealed, basal ganglia mineralization (7/22), lactate peak on magnetic resonance spectrometry (10/15), and diffusion restriction (6/22). Follow-up images in six patients showed that the findings are dynamic. Comparison of the magnetic resonance imaging findings in the three groups showed that cerebral atrophy and cerebellar atrophy, cortical signal changes and basal ganglia mineralization were seen mostly in patients with mitochondrial mutation. Brainstem signal changes with or without striatal lesions were characteristically noted in SURF1 group. There was no consistent imaging pattern in POLG1 group.
Magnetic resonance imaging findings in mitochondrial disorders are heterogeneous. Definite differences were noted in the frequency of anatomical involvement in the three groups. Familiarity with the imaging findings in different genotypes of mitochondrial disorders along with careful analysis of the family history, clinical presentation, biochemical findings, histochemical and structural analysis will help the physician for targeted metabolic and genetic testing.
Mitochondrial diseases part I: Mouse models of OXPHOS deficiencies caused by defects in respiratory complex subunits or assembly factors
2015, Mitochondrion
Citation Excerpt :
However, there are studies indicating that myelinating cells are sensitive to mitochondrial defects. In fact, demyelination has been reported in patients with MELAS (Ohara et al., 1988; Rusanen et al., 1995), Leber's Hereditary Optic Neuropathy (Kovacs et al., 2005), Friedreich's Ataxia (Carelli et al., 2002) and Dominant Optic Atrophy (Johnston et al., 1979). In addition, cultured rat or human oligodendrocytes increase mitochondrial function during differentiation and the differentiated cells become more sensitive to rotenone (Schoenfeld et al., 2010).
Mitochondrial disorders are the most common inborn errors of metabolism affecting the oxidative phosphorylation system (OXPHOS). Because of the poor knowledge of the pathogenic mechanisms, a cure for these disorders is still unavailable and all the treatments currently in use are supportive more than curative. Therefore, in the past decade a great variety of mouse models have been developed to assess the in vivo function of several mitochondrial proteins involved in human diseases. Due to the genetic and physiological similarity to humans, mice represent reliable models to study the pathogenic mechanisms of mitochondrial disorders and are precious to test new therapeutic approaches. Here we summarize the features of several mouse models of mitochondrial diseases directly related to defects in subunits of the OXPHOS complexes or in assembly factors. We discuss how these models recapitulate many human conditions and how they have contributed to the understanding of mitochondrial function in health and disease.
Oligodendroglial differentiation induces mitochondrial genes and inhibition of mitochondrial function represses oligodendroglial differentiation
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Demyelination occurs in multiple inherited mitochondrial diseases. We studied which genes were induced as a consequence of differentiation in rodent and human oligodendroglia. Cholesterol, myelin and mitochondrial genes were significantly increased with oligodendroglial differentiation. Mitochondrial DNA content per cell and acetyl CoA-related transcripts increased significantly; thus, the large buildup of cholesterol necessary for myelination appears to require mitochondrial production of acetyl-CoA. Oligodendroglia were treated with low doses of the mitochondrial inhibitor rotenone to test the dependence of differentiation on mitochondrial function. Undifferentiated cells were resistant to rotenone, whereas differentiating cells were much more sensitive. Very low doses of rotenone that did not affect viability or ATP synthesis still inhibited differentiation, as measured by reduced levels of the myelin transcripts 2′,3′-Cyclic Nucleotide-3′-Phosphodiesterase and Myelin Basic Protein. Thus, mitochondrial transcripts and mtDNA are amplified during oligodendroglial differentiation, and differentiating oligodendroglia are especially sensitive to mitochondrial inhibition, suggesting mechanisms for demyelination observed in mitochondrial disease.
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^∗: Present address: The Third Department of Internal Medicine, Shinshu University, School of Medicine, Asahi 3-1-1, Matsumoto 390, Japan.

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Alterations of oligodendrocytes and demyelination in the spinal cord of patients with mitochondrial encephalomyopathy

Abstract

J. Neurol. Sci.

J. Neurol. Sci.

J. Neurol. Sci.

J. Neurol. Sci.

Pathology of experimental spinal cord trauma. II. Ultrastructure of axons and myelin

Lab. Invest.

Observation on oligodendrocyte degeneration, the resolution of status spongiosus and remyelination in cuprizone intoxication in mice

J. Neurocytol.

Primary demyelination in Theiler's virus infection

An ultrastructural study

Lab. Invest.

Familial poliodystrophy, mitochondrial myopathy, and lactate acidemia

Arch. Neurol.

A possible mechanism of demyelination in the Syrian hamster with hindleg paralysis

Lab. Invest.

Chemical injury of the spinal cord of the rabbit after intracisternal injection of gentamicin

An ultrastructural study

J. Neuropathol. Exp. Neurol.

Mitochondrial encephalomyopathy with lactate-pyruvate elevation and brain infarctions

Neurology

Demyelination and remyelination in experimental allergic encephalomyelitis

Further electron microscopic observations

J. Neuropathol. Exp. Neurol.