Sulthiame impairs mitochondrial function in vitro and may trigger onset of visual loss in Leber hereditary optic neuropathy
Abstract Background Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder and characterized by acute or subacute painless visual loss. Environmental factors reported to trigger visual loss in LHON mutation carriers include smoking, heavy intake of alcohol, raised intraoc...
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doaj-f2ed60a7286945d8b7912beced21838e2021-02-07T12:10:59ZengBMCOrphanet Journal of Rare Diseases1750-11722021-02-011611810.1186/s13023-021-01690-ySulthiame impairs mitochondrial function in vitro and may trigger onset of visual loss in Leber hereditary optic neuropathyMarie-Christine Reinert0David Pacheu-Grau1Claudia B. Catarino2Thomas Klopstock3Andreas Ohlenbusch4Michael Schittkowski5Ekkehard Wilichowski6Peter Rehling7Knut Brockmann8Division of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, University Medical Center GöttingenDepartment of Cellular Biochemistry, University Medical Center GöttingenDepartment of Neurology, Friedrich-Baur-Institute, University Hospital, LMU MunichDepartment of Neurology, Friedrich-Baur-Institute, University Hospital, LMU MunichDivision of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, University Medical Center GöttingenDepartment of Ophthalmology, Section for Strabismus, Neuroophthalmology and Oculoplastics, University Medical Center GöttingenDivision of Pediatric Neurology, Department of Pediatrics and Adolescent Medicine, University Medical Center GöttingenDepartment of Cellular Biochemistry, University Medical Center GöttingenInterdisciplinary Pediatric Center for Children With Developmental Disabilities and Severe Chronic Disorders, University Medical Center GöttingenAbstract Background Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder and characterized by acute or subacute painless visual loss. Environmental factors reported to trigger visual loss in LHON mutation carriers include smoking, heavy intake of alcohol, raised intraocular pressure, and some drugs, including several carbonic anhydrase inhibitors. The antiepileptic drug sulthiame (STM) is effective especially in focal seizures, particularly in benign epilepsy of childhood with centrotemporal spikes, and widely used in pediatric epileptology. STM is a sulfonamide derivate and an inhibitor of mammalian carbonic anhydrase isoforms I–XIV. Results We describe two unrelated patients, an 8-year-old girl and an 11-year-old boy, with cryptogenic focal epilepsy, who suffered binocular (subject #1) or monocular (subject #2) visual loss in close temporal connection with starting antiepileptic pharmacotherapy with STM. In both subjects, visual loss was due to LHON. We used real-time respirometry in fibroblasts derived from LHON patients carrying the same mitochondrial mutations as our two subjects to investigate the effect of STM on oxidative phosphorylation. Oxygen consumption rate in fibroblasts from a healthy control was not impaired by STM compared with a vehicle control. In contrast, fibroblasts carrying the m.14484T>C or the m.3460G>A LHON mutation displayed a drastic reduction of the respiration rate when treated with STM compared to vehicle control. Conclusions Our observations point to a causal relationship between STM treatment and onset or worsening of visual failure in two subjects with LHON rather than pure coincidence. We conclude that antiepileptic medication with STM may pose a risk for visual loss in LHON mutation carriers and should be avoided in these patients.https://doi.org/10.1186/s13023-021-01690-ySulthiameCarbonic anhydrase inhibitorAdverse effectsLeber hereditary optic neuropathyLHONOxygen consumption rate |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marie-Christine Reinert David Pacheu-Grau Claudia B. Catarino Thomas Klopstock Andreas Ohlenbusch Michael Schittkowski Ekkehard Wilichowski Peter Rehling Knut Brockmann |
spellingShingle |
Marie-Christine Reinert David Pacheu-Grau Claudia B. Catarino Thomas Klopstock Andreas Ohlenbusch Michael Schittkowski Ekkehard Wilichowski Peter Rehling Knut Brockmann Sulthiame impairs mitochondrial function in vitro and may trigger onset of visual loss in Leber hereditary optic neuropathy Orphanet Journal of Rare Diseases Sulthiame Carbonic anhydrase inhibitor Adverse effects Leber hereditary optic neuropathy LHON Oxygen consumption rate |
author_facet |
Marie-Christine Reinert David Pacheu-Grau Claudia B. Catarino Thomas Klopstock Andreas Ohlenbusch Michael Schittkowski Ekkehard Wilichowski Peter Rehling Knut Brockmann |
author_sort |
Marie-Christine Reinert |
title |
Sulthiame impairs mitochondrial function in vitro and may trigger onset of visual loss in Leber hereditary optic neuropathy |
title_short |
Sulthiame impairs mitochondrial function in vitro and may trigger onset of visual loss in Leber hereditary optic neuropathy |
title_full |
Sulthiame impairs mitochondrial function in vitro and may trigger onset of visual loss in Leber hereditary optic neuropathy |
title_fullStr |
Sulthiame impairs mitochondrial function in vitro and may trigger onset of visual loss in Leber hereditary optic neuropathy |
title_full_unstemmed |
Sulthiame impairs mitochondrial function in vitro and may trigger onset of visual loss in Leber hereditary optic neuropathy |
title_sort |
sulthiame impairs mitochondrial function in vitro and may trigger onset of visual loss in leber hereditary optic neuropathy |
publisher |
BMC |
series |
Orphanet Journal of Rare Diseases |
issn |
1750-1172 |
publishDate |
2021-02-01 |
description |
Abstract Background Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder and characterized by acute or subacute painless visual loss. Environmental factors reported to trigger visual loss in LHON mutation carriers include smoking, heavy intake of alcohol, raised intraocular pressure, and some drugs, including several carbonic anhydrase inhibitors. The antiepileptic drug sulthiame (STM) is effective especially in focal seizures, particularly in benign epilepsy of childhood with centrotemporal spikes, and widely used in pediatric epileptology. STM is a sulfonamide derivate and an inhibitor of mammalian carbonic anhydrase isoforms I–XIV. Results We describe two unrelated patients, an 8-year-old girl and an 11-year-old boy, with cryptogenic focal epilepsy, who suffered binocular (subject #1) or monocular (subject #2) visual loss in close temporal connection with starting antiepileptic pharmacotherapy with STM. In both subjects, visual loss was due to LHON. We used real-time respirometry in fibroblasts derived from LHON patients carrying the same mitochondrial mutations as our two subjects to investigate the effect of STM on oxidative phosphorylation. Oxygen consumption rate in fibroblasts from a healthy control was not impaired by STM compared with a vehicle control. In contrast, fibroblasts carrying the m.14484T>C or the m.3460G>A LHON mutation displayed a drastic reduction of the respiration rate when treated with STM compared to vehicle control. Conclusions Our observations point to a causal relationship between STM treatment and onset or worsening of visual failure in two subjects with LHON rather than pure coincidence. We conclude that antiepileptic medication with STM may pose a risk for visual loss in LHON mutation carriers and should be avoided in these patients. |
topic |
Sulthiame Carbonic anhydrase inhibitor Adverse effects Leber hereditary optic neuropathy LHON Oxygen consumption rate |
url |
https://doi.org/10.1186/s13023-021-01690-y |
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