Abstract
BackgroundEthylmalonic 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.ResultsNeurological 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.ConclusionsThe 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.
Highlights
Ethylmalonic encephalopathy (EE) is a severe intoxication-type metabolic disorder with multisystem clinical features and leading to early death
H2S accumulation exerts an inhibitory effect on several mitochondrial enzymes, including cytochrome C oxidase (COX) and short chain acyl-CoA dehydrogenase (SCAD), explaining the characteristic biochemical abnormalities [3, 4]
Secondary COX deficiency mainly affects energetic metabolism in brain and muscle, causing lactic acidosis, stroke-like encephalopathic crises, epileptic seizures and myopathy [8], while SCAD inhibition causes the elevation of ethylmalonic acid and of C4and C5- acyl-carnitine esters [1, 2]
Summary
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 We report her long-term follow-up, lasting over 6 years, with a comprehensive evaluation of clinical, instrumental and biochemical assessments. Few studies reported the potential beneficial effects of a combined treatment with N-acetylcysteine (NAC), metronidazole (MTZ), and the dietary restriction of the sulphur containing aminoacid methionine in decreasing serum thiosulphate and ameliorating the clinical course (Table 1) [9,10,11] These approaches have a limited impact on the natural disease history in patients with severe EE [12]. A spectrum of clinical severity exists in EE, which includes, beside the severe form presenting with multisystem clinical features and leading to early death, a handful of cases with an “atypical” mild phenotype, characterized by pyramidal dysfunction, minor cognitive involvement, no systemic signs and longer survival [13,14,15]
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