Ethylmalonic encephalopathy and liver transplantation: long-term outcome of the first treated patient

Abstract

Background Ethylmalonic encephalopathy (EE) is a severe intoxication-type metabolic disorder with multisystem clinical features and leading to early death. In 2014, based on the promising results obtained by liver-targeted gene therapy in Ethe1−/− mouse model, we successfully attempted liver transplantation in a 9-month-old EE girl. Here we report her long-term follow-up, lasting over 6 years, with a comprehensive evaluation of clinical, instrumental and biochemical assessments. Results Neurological signs initially reverted, with a clinical stabilization during the entire follow-up course. Accordingly, gross motor functions improved and then stabilized. Psychomotor evaluations documented an increasing communicative intent, the acquisition of new social skills and the capability to carry out simple orders. Neurophysiological assessments, which included EEG, VEP/ERG and BAEPs, remained unchanged. Brain MRI also stabilized, showing no further lesions and cerebral atrophy improvement. Compared to pre-transplant assessments, urinary ethylmalonic acid strikingly reduced, and plasma thiosulphate fully normalized. The child maintained good clinical conditions and never experienced metabolic crises nor epileptic seizures. Conclusions The long-term follow-up of the first EE transplanted patient demonstrates that liver transplantation stabilizes, or even improves, disease course, therefore representing a potentially elective option especially in early-diagnosed patients, such as those detected by newborn screening, before irreversible neurological damage occurs.

Current status and future directions of liver transplantation for metabolic liver disease in children

“…Case reports of experience with liver transplantation in MNGIE suggest rapid biochemical and clinical improvement in some children, implying a select group without significant neurological compromise may benefit 62,63 . Positive post‐OLT outcomes have also been described in ethylmalonic encephalopathy, suggesting a role for this approach early in infancy prior to evolution of irreversible neurological damage 64 …”

“…62,63 Positive post-OLT outcomes have also been described in ethylmalonic encephalopathy, suggesting a role for this approach early in infancy prior to evolution of irreversible neurological damage. 64 Ongoing experimental efforts to explore novel therapies, including gene therapy, may be key in future care of monogenic mitochondrial hepatopathies. 71 These may enable OLT to be a more viable option in future practice.…”

Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective

“…A single systemic injection of 4 × 10 13 viral genomes (vg)/kg of an ssAAV2/8 vector expressing the human hETHE1 cDNA under the liver-specific thyroxine-binding globulin (TBG) promoter in three weeks early symptomatic Ethe1 KO mice resulted in a marked amelioration of the phenotype and a robust prolongation of the mouse lifespan. This remarkable clinical result was associated with the partial or complete correction of the disease's main metabolic and biochemical indexes, including the EMA and thiosulfate levels in plasma and the COX activity in tissues [87] Living-donor orthotopic liver transplantation also resulted in an effective option to treat EE since the transplanted organ substituted the deficient ETHE1 enzyme and cleared the circulating toxic H 2 S [88][89][90]. These results proved the efficacy and safety of AAV2/8-mediated liver gene therapy for EE and similar conditions caused by the accumulation of toxic compounds in body fluids and tissues.…”

Gene therapy for mitochondrial disorders

“…An exception to this is mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) caused by biallelic pathogenic variants in TYMP where disease is in part due to harmful accumulation of thymidine (Thd) which can be cleared by enzyme replacement of the missing enzyme thymidine phosphorylase (TP) using allogeneic haematopoietic stem cell transplantation 26 . Furthermore, in some PMDs, for example, DGUOK deficiency, 27 TYMP deficiency, 28 and ETHE1 deficiency, 29 liver transplantation has had some success but does not correct disease in the brain 30 . Gene therapy has the potential to target several organs simultaneously including the CNS, making it attractive since PMDs typically involve several different organ systems.…”