Ethylmalonic Encephalopathy

Abstract

Ethylmalonic encephalopathy is a severe mitochondrial disease of early infancy clinically characterised by a combination of developmental delay, progressive pyramidal signs and vascular lesions including petechial purpura, orthostatic acrocyanosis and chronic hemorrhagic diarrhoea. Biochemical hallmarks of the disease are persistently high levels of lactate, and C4–C5-acylcarnitines in blood, markedly elevated urinary excretion of methylsuccinic and ethylmalonic (EMA) acids and defective cytochrome c oxidase (COX) in the muscles. The corresponding gene was named ETHE1 and mutation analysis including nonsense and missense mutations, frameshift and deletion of single exons or of the entire gene have been reported. The prognosis of the disease is poor but combined treatment with metronidazole, N-acetylcysteine and coenzyme Q10 resulted in disappearance of diarrhoea, petechial showers and acrocyanosis. Ethylmalonic encephalopathy, first described by Burlina et al. 1991, is a severe mitochondrial disease due to mutations in the ETHE1 gene (MIM ≠ 608451). Clinically it is characterised by a combination of symptoms including developmental delay, progressive pyramidal signs, vascular lesions including petechial purpura, orthostatic acrocyanosis and chronic hemorrhagic diarrhoea. The clinical condition is quite homogeneous but a broad clinical spectrum of severity has been described. The prognosis is poor with half of the patients dying within the first 2 years of life from metabolic decompensation. Brain MRI reveals symmetric patchy signals in basal ganglia, periventricular white matter and dentate nuclei, along with brain and spinal cord malformations. Biochemical hallmarks of the disease are persistently high levels of lactate, C4–C5-acylcarnitines in blood, markedly elevated urinary excretion of methylsuccinic and ethylmalonic acids and defective COX in the muscles and brain but not in cultured skin fibroblasts. The pathogenic mechanisms underlying the clinical and biochemical abnormalities are the main consequence of ETHE1 impairment. The main consequence of ETHE1 loss is the accumulation of hydrogen sulphide (H₂S), a product of intestinal anaerobes and, in trace amount, tissues. Increased concentration of sulphide in tissues (i.e. colonic mucosae, muscle and brain) causes rapid inhibition of COX activity and long-term degradation of COX subunits. In addition, H₂S blocks short-chain fatty acid oxidation by inhibiting the activity of short-chain acyl CoA dehydrogenase (and possibly other beta-oxidation enzymes as well), which explains the accumulation of EMA. Furthermore, H₂S has vasoactive and vasotoxic effects, which in turn explain the vascular lesions in the skin and, possibly, other organs. Combined treatment with metronidazole, N-acetylcysteine and coenzyme Q10 resulted in some neurological improvement, disappearance of diarrhoea, petechial showers and acrocyanosis. Further opportunities for therapy will include transplantation of hemopoietic stem cells and adeno-associated virus mediated gene therapy.