Successful treatment of a patient with ethylmalonic encephalopathy by intravenous N-acetylcysteine

Kılıç, Mustafa; Dedeoğlu, Özge; Göçmen, Rahşan; Kesici, Selman; Yüksel, Deniz

doi:10.1007/s11011-016-9928-5

Cited by 18 publications

(8 citation statements)

References 21 publications

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“…Interestingly, the different ETHE1 deficient fibroblast cell lines showed some heterogenous alterations that could be at least partially explained by the different mutations. However, even different cell lines with the same mutation (ETHE1-1 and ETHE1-4) showed some variability in mitochondrial function, consistent with previous conclusions that there is no clear genotype-phenotype correlation in this disease 80–82 . The reasons for these variations and their correlation with clinical symptoms remain to be clarified, and may ultimately be useful for the identification of additional specific therapies.…”

Section: Discussionsupporting

confidence: 88%

“…These findings are particularly interesting since previous data showed that JP4-039 crosses brain-blood barrier in mice 78 and ETHE1 and MOCS1 deficiencies are inborn errors mainly characterized by neurological dysfunction. Furthermore, N -acetylcysteine, an antioxidant currently used to treat ETHE1 deficient patients 10,13,79,80 , did not affect superoxide levels, demonstrating the importance of mitochondrial targeting for the biological efficacy of free radical scavengers.…”

Section: Discussionmentioning

confidence: 96%

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ETHE1 and MOCS1 deficiencies: Disruption of mitochondrial bioenergetics, dynamics, redox homeostasis and endoplasmic reticulum-mitochondria crosstalk in patient fibroblasts

Grings

Seminotti

Karunanidhi

et al. 2019

Sci Rep

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Ethylmalonic encephalopathy protein 1 (ETHE1) and molybdenum cofactor (MoCo) deficiencies are hereditary disorders that affect the catabolism of sulfur-containing amino acids. ETHE1 deficiency is caused by mutations in the ETHE1 gene, while MoCo deficiency is due to mutations in one of three genes involved in MoCo biosynthesis ( MOCS1 , MOCS2 and GPHN ). Patients with both disorders exhibit abnormalities of the mitochondrial respiratory chain, among other biochemical findings. However, the pathophysiology of the defects has not been elucidated. To characterize cellular derangements, mitochondrial bioenergetics, dynamics, endoplasmic reticulum (ER)-mitochondria communication, superoxide production and apoptosis were evaluated in fibroblasts from four patients with ETHE1 deficiency and one with MOCS1 deficiency. The effect of JP4-039, a promising mitochondrial-targeted antioxidant, was also tested on cells. Our data show that mitochondrial respiration was decreased in all patient cell lines. ATP depletion and increased mitochondrial mass was identified in the same cells, while variable alterations in mitochondrial fusion and fission were seen. High superoxide levels were found in all cells and were decreased by treatment with JP4-039, while the respiratory chain activity was increased by this antioxidant in cells in which it was impaired. The content of VDAC1 and IP3R, proteins involved in ER-mitochondria communication, was decreased, while DDIT3, a marker of ER stress, and apoptosis were increased in all cell lines. These data demonstrate that previously unrecognized broad disturbances of cellular function are involved in the pathophysiology of ETHE1 and MOCS1 deficiencies, and that reduction of mitochondrial superoxide by JP4-039 is a promising strategy for adjuvant therapy of these disorders.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 96%

ETHE1 and MOCS1 deficiencies: Disruption of mitochondrial bioenergetics, dynamics, redox homeostasis and endoplasmic reticulum-mitochondria crosstalk in patient fibroblasts

Grings

Seminotti

Karunanidhi

et al. 2019

Sci Rep

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“…A resemblance of some EE biochemical features with ACADs and complex IV deficiency may have encouraged treatment with riboflavin. While some reports find no effect of riboflavin [98,[100][101][102][103][104][105][106][107], a number of reports suggest some level of positive effect [99,[108][109][110][111][112]. However, the therapeutic effect of riboflavin is difficult to interpret since most studies have used riboflavin in combination with other vitamins or cofactors.…”

Section: Ethylmalonic Encephalopathymentioning

confidence: 99%

Riboflavin Deficiency—Implications for General Human Health and Inborn Errors of Metabolism

Mosegaard

Dipace

Bross

et al. 2020

IJMS

126

103

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As an essential vitamin, the role of riboflavin in human diet and health is increasingly being highlighted. Insufficient dietary intake of riboflavin is often reported in nutritional surveys and population studies, even in non-developing countries with abundant sources of riboflavin-rich dietary products. A latent subclinical riboflavin deficiency can result in a significant clinical phenotype when combined with inborn genetic disturbances or environmental and physiological factors like infections, exercise, diet, aging and pregnancy. Riboflavin, and more importantly its derivatives, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), play a crucial role in essential cellular processes including mitochondrial energy metabolism, stress responses, vitamin and cofactor biogenesis, where they function as cofactors to ensure the catalytic activity and folding/stability of flavoenzymes. Numerous inborn errors of flavin metabolism and flavoenzyme function have been described, and supplementation with riboflavin has in many cases been shown to be lifesaving or to mitigate symptoms. This review discusses the environmental, physiological and genetic factors that affect cellular riboflavin status. We describe the crucial role of riboflavin for general human health, and the clear benefits of riboflavin treatment in patients with inborn errors of metabolism.

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“…Since the supplementation of NAC replenishes the intracellular pool of reduced glutathione, the sulfide is effectively buffered. NAC supplementation is currently used in patients with ethylmalonic encephalopathy [ 198 , 199 , 200 ], with encouraging results.…”

Section: “One-size-fits-all” Approachesmentioning

confidence: 99%

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

et al. 2020

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Primary mitochondrial diseases (PMD) refer to a group of severe, often inherited genetic conditions due to mutations in the mitochondrial genome or in the nuclear genes encoding for proteins involved in oxidative phosphorylation (OXPHOS). The mutations hamper the last step of aerobic metabolism, affecting the primary source of cellular ATP synthesis. Mitochondrial diseases are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. The limited information of the natural history, the limitations of currently available preclinical models, coupled with the large variability of phenotypical presentations of PMD patients, have strongly penalized the development of effective therapies. However, new therapeutic strategies have been emerging, often with promising preclinical and clinical results. Here we review the state of the art on experimental treatments for mitochondrial diseases, presenting “one-size-fits-all” approaches and precision medicine strategies. Finally, we propose novel perspective therapeutic plans, either based on preclinical studies or currently used for other genetic or metabolic diseases that could be transferred to PMD.

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Successful treatment of a patient with ethylmalonic encephalopathy by intravenous N-acetylcysteine

Cited by 18 publications

References 21 publications

ETHE1 and MOCS1 deficiencies: Disruption of mitochondrial bioenergetics, dynamics, redox homeostasis and endoplasmic reticulum-mitochondria crosstalk in patient fibroblasts

ETHE1 and MOCS1 deficiencies: Disruption of mitochondrial bioenergetics, dynamics, redox homeostasis and endoplasmic reticulum-mitochondria crosstalk in patient fibroblasts

Riboflavin Deficiency—Implications for General Human Health and Inborn Errors of Metabolism

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

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