Biochemical and clinical response to a sulfur-restricted diet in ethylmalonic encephalopathy.

Introduction: Ethylmalonic encephalopathy (EE) is an often-severe inborn error of metabolism caused by biallelic variants in the Methods: We performed an open-label, single-arm study to evaluate the effects of dietary intervention with a methionine and cysteine restricted diet (20-30 mg/kg/day) on biochemical parameters and overall clinical trajectory in three patients with molecularly confirmed ethylmalonic encephalopathy (two with attenuated phenotypes, one classically affected). All three patients were receiving a combination of medical therapy with metronidazole and NAC and were status-post OLT at the time of diet initiation. Plasma butyrylcarnitine (C4) levels were measured at diagnosis, serially following initiation of medical therapy and OLT, and at regular follow-up visits in a metabolic clinic after diet initiation. Additionally, we obtained untargeted metabolomics studies and directly evaluated ethylmalonate, butyrylcarnitine, isobutyrylcarnitine, isovalerylcarnitine, 2-methylbutyrylcarnitine, glutarylcarnitine, and methylsuccinate levels in the pre- OLT/medical therapy, post- OLT/medical therapy, and post- sulfur-restricted diet states. Results: We observed a 20-38 % reduction in plasma C4 levels in all three patients following OLT and combination medical therapy with NAC and metronidazole. An 8-10 % reduction in C4 was observed following the introduction of dietary therapy in the two patients with attenuated phenotypes and an 82 % increase in C4 was seen in the patient with the classical phenotype. The metabolic profile as assessed by untargeted metabolomics analysis was largely unchanged in the pre-OLT/medical therapy, post-OLT/medical therapy, and post-diet states. Conclusions: The modest biochemical response to a sulfur-restricted diet observed in our cohort likely reflects the relatively minor contribution of endogenous sulfur-containing amino acid catabolism to overall H