Progressive cerebral poliodystrophy - Alpers' disease: Disorganized giant neuronal mitochondria on electron microscopy

Sandbank, U.; Lerman, Pinchas

doi:10.1136/jnnp.35.6.749

Cited by 55 publications

(11 citation statements)

References 21 publications

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“…Both Leigh's and Alpers' disease have CNS lesions with gliosis, spongiosis, necrosis, or capillary proliferation (Pincus, 1972;Montpetit et al, 1971;Jellinger and Seitelberger, 1970;Greenhouse and Neubuerger, 1964;Egger et al, 1987;Sandbank and Lerman, 1972). Neuropathologically, the primary point of differentiation between Leigh's disease and Alpers' disease is the severity of involvement of certain brain regions (Table I).…”

Section: Alpers' Disease (Progressive Infantile Poliodystrophy)mentioning

confidence: 97%

Oxidative Phosphorylation Diseases

Shoffner

Wallace

1990

Advances in Human Genetics

246

157

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Section: Alpers' Disease (Progressive Infantile Poliodystrophy)mentioning

confidence: 97%

Oxidative Phosphorylation Diseases

Shoffner

Wallace

1990

Advances in Human Genetics

246

157

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“…7 However, the confirmation of diagnosis still relies on genetic analysis, and several mutations related to AHS have been uncovered, 5 among which p.A467T and p.W748S are the most common. Although it has been accepted that AHS is an inherited mitochondrial disorder since the disorder was first described in 1972, 8 the downstream mechanisms of AHS remain elusive and no effective clinical treatment is available.…”

mentioning

confidence: 99%

Valproic acid‐induced hepatotoxicity in alpers syndrome is associated with mitochondrial permeability transition pore opening‐dependent apoptotic sensitivity in an induced pluripotent stem cell model

Guo

Ying

et al. 2015

Hepatology

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Valproic acid (VPA) is widely used to treat epilepsy, migraine, chronic headache, bipolar disorder, and as adjuvant chemotherapy, but potentially causes idiosyncratic liver injury. Alpers-Huttenlocher syndrome (AHS), a neurometabolic disorder caused by mutations in mitochondrial DNA polymerase gamma (POLG), is associated with an increased risk of developing fatal VPA hepatotoxicity. However, the mechanistic link of this clinical mystery remains unknown. Here, fibroblasts from 2 AHS patients were reprogrammed to induced pluripotent stem cells (iPSCs) and then differentiated to hepatocyte-like cells (AHS iPSCs-Hep). Both AHS iPSCs-Hep are more sensitive to VPA-induced mitochondrial-dependent apoptosis than controls, showing more activated caspase-9 and cytochrome c release. Strikingly, levels of both soluble and oligomeric optic atrophy 1, which together keep cristae junctions tight, are reduced in AHS iPSCs-Hep. Furthermore, POLG mutation cells show reduced POLG expression, mitochondrial DNA (mtDNA) amount, mitochondrial adenosine triphosphate production, as well as abnormal mitochondrial ultrastructure after differentiation to hepatocyte-like cells. Superoxide flashes, spontaneous bursts of superoxide generation, caused by opening of the mitochondrial permeability transition pore (mPTP), occur more frequently in AHS iPSCs-Hep. Moreover, the mPTP inhibitor, cyclosporine A, rescues VPA-induced apoptotic sensitivity in AHS iPSCs-Hep. This result suggests that targeting mPTP opening could be an effective method to prevent hepatotoxicity by VPA in AHS patients. In addition, carnitine or N-acetylcysteine, which has been used in the treatment of VPAinduced hepatotoxicity, is able to rescue VPA-induced apoptotic sensitivity in AHS iPSCs-Hep. Conclusion: AHS iPSCs-Hep are more sensitive to the VPA-induced mitochondrial-dependent apoptotic pathway, and this effect is mediated by mPTP opening. Toxicity models in genetic diseases using iPSCs enable the evaluation of drugs for therapeutic targets. (HEPATOLOGY 2015;61:1730-1739

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“…It is unfortunate that no ultrastructural clues exist in the present series, since without electron microscope studies the presence of various forms of inclusion bodies and virus-like particles (Bubis et al, 1972), as well as mitochondrial abnormalities (Suzuki and Rapin, 1969;Sandbank and Lerman, 1972), would be missed. We would certainly advocate ultrastructural examination if not culture studies in future biopsies.…”

Section: Discussionmentioning

confidence: 77%