Ethylmalonic Encephalopathy: Clinical and Biochemical Observations

Abstract

Ethylmalonic encephalopathy (EE) is a rare, recently defined inborn error of metabolism which affects the brain, gastrointestinal system and peripheral blood vessels and is characterized by a unique constellation of clinical and biochemical features. A 7-month-old male, who presented with psychomotor retardation, chronic diarrhea and relapsing petechiae is described with the objective of highlighting the biochemical and neuroradiological features of this disorder as well as the effect of high-dose riboflavin therapy. Urinary organic acid analysis revealed markedly increased excretion of ethylmalonic acid, isobutyrylglycine, 2-methylbutyrylglycine and isovalerylglycine. Acylcarnitine analysis in dried blood spots showed increased butyrylcarnitine. Short-chain acyl-CoA dehydrogenase (SCAD) activity in muscle was normal as were mitochondrial OXPHOS enzyme activities in cultured skin fibroblasts. In skeletal muscle the catalytic activity of complex II was decreased. Brain MRI revealed bilateral and symmetrical atrophy in the fronto-temporal areas, massive enlargement of the subarachnoid spaces and hyperdensities on T (2) sequences of the basal ganglia. Mutation analysis of the ETHE1 gene demonstrated homozygosity for the Arg163Gly mutation, confirming the diagnosis of EE at a molecular level. On repeat MRI, a significant deterioration was seen, correlating well with the clinical deterioration of the patient.

Ethylmalonic encephalopathy associated with respiratory failure

“…The symptoms of EE usually become apparent at birth or in the first few months of life and progressively become worse. The symptoms include developmental retardation, hypotonia, abnormal movements in the arms and legs, seizures, petechiae, cyanosis, acrocyanosis (blue color in hands and feet due to low blood oxygen concentration), and chronic diarrhea (1,2,5). The present case had developmental retardation, hypotonia, exanthematous skin lesions, acrocyanosis and chronic diarrhea.…”

“…EE is an autosomal recessive disease caused by ETHE1 gene (chromosome 19q13) mutations and manifests itself with nervous system, gastrointestinal system and blood vessel abnormalities (1,5). Genetic testing is of great importance since a healthy "carrier" couple with mutation in a single allele in ETHE1 gene has a risk by 25% in each pregnancy (2,5).…”

“…Lactic acidemia is defined as increased acylcarnitine concentration in serum and ethylmalonic acid and ethylmalonic acid derivatives in the urine and ethylmalonic aciduria. Ethylmalonic aciduria is certainly accompanied by encephalopathy (1,2). EE, which shows autosomal recessive inheritance, has been demonstrated in animal experiments that inhibited mitochondrial kinase activity, although its underlying mechanism is undefined.…”

Autoimmune Thyroiditis, Pernicious Anaemia, Vitiligo and Scleroatrophic Lichen in a Boy with Short-Chain AcylCoA Dehydrogenase Deficiency

“…The enzyme deficiency in SCAD causes an alteration of the β-oxidation cycle that leads to increased urinary excretion of ethylmalonic acid and high levels of butyryl-carnitine in plasma (C4), which are metabolic biomarkers of this disease [13]. Molecular analysis and low enzymatic activity of SCAD in skin fibroblasts or muscle confirms the diagnosis.…”

Altered Sulfide (H2S) Metabolism in Ethylmalonic Encephalopathy

“…Mutations in the ETHE1 gene have been found in 32 patients affected by EE worldwide (Di Rocco et al 2006;Merinero et al 2006;Zafeiriou et al 2007;Mineri et al 2008). A total of 18 nonsense (Tiranti et al 2004Merinero et al 2006) and nine missense (Tiranti et al 2004Di Rocco et al 2006;Zafeiriou et al 2007) mutations has so far been described. To date, a total of 70 mutant patients have been identified in our laboratory (V Tiranti and M Zeviani, unpubl.).…”