Improved clinical outcome following liver transplant in patients with ethylmalonic encephalopathy

Abstract

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

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

“…LT rapidly normalized serum levels of toxic nucleosides in a 25-year-old MNGIE patient, and his conditions were stable after 400 days of follow-up [ 395 ]. LT also resulted in an effective option to treat ethylmalonic encephalopathy due to mutation in ETHE1 gene [ 396 , 397 ], since the replaced organ can substitute the deficient ETHE1 enzyme and clear the toxic H 2 S that accumulate in this disorder, constituting a feasible therapeutic option in patients. Patients showed progressive improvement of the neurological functions and normalization or amelioration of the biochemical abnormalities [ 396 , 397 ].…”

“…LT also resulted in an effective option to treat ethylmalonic encephalopathy due to mutation in ETHE1 gene [ 396 , 397 ], since the replaced organ can substitute the deficient ETHE1 enzyme and clear the toxic H 2 S that accumulate in this disorder, constituting a feasible therapeutic option in patients. Patients showed progressive improvement of the neurological functions and normalization or amelioration of the biochemical abnormalities [ 396 , 397 ]. However, the decision to perform LT remains difficult because neurological manifestations may worsen despite their absence before the transplant [ 398 ].…”

Novel Compound Heterozygous Variants of ETHE1 Causing Ethylmalonic Encephalopathy in a Chinese Patient: A Case Report

“…Dual treatment caused marked improvement in 5 EE patients, almost without side effects as follows: body weight increased; diarrhea occurred less frequently; petechiae, acrocyanosis and seizures decreased or disappeared; hypotonia showed marked improvement; and plasma EMA significantly decreased in all 5 affected children. In addition, liver transplantation is considered as a viable therapeutic option for EE (Dionisi-Vici et al, 2016;Tam et al, 2019). Although only 3 EE patients achieved psychomotor developmental improvement and marked reversion of biochemical abnormalities after liver transplantation, their outcomes support the promising approach as a standard treatment for EE.…”

Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures

“…Interestingly, untargeted metabolomics profiling (Kennedy et al, ; Miller et al, ) performed on Patient 1 revealed elevated lactate, fumarate and glutarate, which indicate perturbation in energy metabolism secondary to mitochondrial dysfunction further providing functional evidence for the pathogenicity of the variant identified in COX4I1 . Evidence of mitochondrial dysfunction by the use of untargeted metabolomics analysis in CSF and plasma may provide functional validation for variants of unknown significance observed in nuclear genes associated with mitochondrial disease, providing semi‐quantitative values for TCA cycle intermediates and altered lipid metabolism as a consequence of abnormal mitochondrial function (Esterhuizen, Van Der Westhuizen, & Louw, ; Shayota et al, ; Tam et al, ).…”