Response to medical and a novel dietary treatment in newborn screen identified patients with ethylmalonic encephalopathy

Boyer, Monica; Sowa, Mary; Meo, Ivano Di; Eftekharian, Shaya S.; Steenari, Maija; Tiranti, Valeria; Abdenur, José E.

doi:10.1016/j.ymgme.2018.02.008

Cited by 31 publications

(29 citation statements)

References 13 publications

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“…EE is a fatal, progressive, multisystem recessive disorder of variable onset and severity; however, patients typically present in early infancy or childhood (Tiranti et al, ). Elevated C4 and C5 acylcarnitines may be detected if they are assessed by NBS, as they were in both patients herein presented and as previously reported in the literature (Boyer et al, ). Theoretically, if EE is potentially diagnosed before the onset of neonatal symptoms, early treatment may effectively alter the disease course and improve clinical outcome.…”

Section: Discussionsupporting

confidence: 86%

“…Furthermore, there is the potential of identifying patients with EE in infancy through NBS and to initiate treatment early in the disease course. The observations of clinical improvement in our patients who underwent liver transplantation serve to provide additional evidence to “validate this promising approach as standard of care for patients with EE” as suggested previously (Boyer et al, ) given the devastating natural history of EE and the lack of superior therapeutic options.…”

Section: Discussionmentioning

confidence: 99%

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Improved clinical outcome following liver transplant in patients with ethylmalonic encephalopathy

Tam

AlDhaheri

Mysore

et al. 2019

American J of Med Genetics Pt A

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Ethylmalonic encephalopathy (EE) is a rapidly progressive autosomal recessive mitochondrial disease caused by biallelic pathogenic variants in the ETHE1 gene that encodes the mitochondrial sulfur dioxygenase. It is characterized by neurodevelopmental delay and regression, pyramidal and extrapyramidal signs, recurrent petechiae, chronic diarrhea, and orthostatic acrocyanosis. Laboratory findings include elevated serum levels of lactate and C4-C5 acylcarnitines, and elevated urinary excretion of ethylmalonic acid and C4-C6 acylglycines, notably isobutyrylglycine and 2-methylbutyrylglycine. These findings are attributed to deficiency of the mitochondrial sulfur dioxygenase resulting in toxic accumulation of hydrogen sulfide metabolites in vascular endothelium and mucosal cells of the large intestine. Medical management has thus far been directed toward decreasing the accumulation of hydrogen sulfide metabolites using a combination of metronidazole and N-acetylcysteine. More recently, orthotopic liver transplant (OLT) has been reported as a new therapeutic option for EE. Here, we report two additional cases of EE who achieved psychomotor developmental improvement after 7-and 22-months following OLT. The second case serves as the longest developmental outcome follow-up reported, thus far, following OLT for EE. This report provides additional evidence to validate OLT as a promising therapeutic approach for what was considered to be a fatal disease. K E Y W O R D S ETHE1, ethylmalonic encephalopathy, hydrogen sulfide toxicity, mitochondrial sulfur dioxygenase, orthotopic liver transplant

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Improved clinical outcome following liver transplant in patients with ethylmalonic encephalopathy

Tam

AlDhaheri

Mysore

et al. 2019

American J of Med Genetics Pt A

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“…6 Diet restricted in sulfur-containing amino acids has been shown to improve the clinical outcome and biochemical markers. 7 The combined use of metronidazole and N-acetylcysteine has been used to control the H 2 S overload, the toxic mechanism implicated in patients with EE. 8 N-acetylcysteine acts as a physiologic acceptor of the sulfur atom of H 2 S while metronidazole reduces the sulfide producing bacterial load in the large intestine.…”

Section: Discussionmentioning

confidence: 99%

Child Neurology: Ethylmalonic encephalopathy

et al. 2020

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Ethylmalonic encephalopathy (EE; OMIM #602473) is an autosomal recessive disorder characterized by (1) progressive neurologic impairment, including global developmental delay with periods of regression during illness, progressive pyramidal and extrapyramidal signs, and seizures; and (2) generalized microvascular damage, including petechial purpura and chronic hemorrhagic diarrhea. It leads to premature death. EE is caused by mutations in ethylmalonic encephalopathy protein 1 (ETHE1), and more than 60 different mutations have been reported. 1,2 ETHE1 encodes a mitochondrial sulfur dioxygenase involved in the catabolism of hydrogen sulfide (H 2 S). 2 Impairment of sulfur dioxygenase leads to the accumulation of hydrogen sulfide and its derivatives (thiosulphate) in various body fluids and tissues. Higher concentration of H 2 S is toxic and induces direct damage to cell membranes. It inhibits cytochrome c oxidase (COX), increases lactic acid and short-chain acyl-COA dehydrogenase, and leads to elevation of ethyl malonate and C4/C5 acylcarnitine in muscle and brain. 2 We describe the clinical phenotype and MRI, pathologic, and biochemical findings of a patient with EE from India who had a novel homozygous c.493 G>C (p.D165H) variation in ETHE1.

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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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Response to medical and a novel dietary treatment in newborn screen identified patients with ethylmalonic encephalopathy

Cited by 31 publications

References 13 publications

Improved clinical outcome following liver transplant in patients with ethylmalonic encephalopathy

Improved clinical outcome following liver transplant in patients with ethylmalonic encephalopathy

Child Neurology: Ethylmalonic encephalopathy

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

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