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Ethylmalonic Aciduria in an Infant with Neurological and Skin Presentation.


A 2-year-old female was investigated for developmental delay, hypotonia, and infantile spasms, the latter of which began at approximately 10 months of age. On examination, widespread petechiae located over pressure points and retinal vessel tortuosity were notable. The initial electroencephalogram demonstrated a disorganized, high-amplitude background and multifocal, interictal epileptiform discharges consistent with hypsarrhythmia. She was treated with vigabatrin with excellent clinical and electrophysiologic response. Repeat electroencephalogram demonstrated only left temporal sharp waves and focal slowing. A magnetic resonance imaging scan demonstrated volume loss and increased T2 signal in the periventricular white matter and dorsal brainstem, and abnormal foci of increased T2 signal in the basal ganglia bilaterally with decreased diffusion. Spectroscopy demonstrated a lactate peak. A mitochondrial disorder was initially suspected. Routine biochemistry testing revealed a mild metabolic acidosis (plasma total C[O.sub.2], 20 mmol/L; reference interval, 22-30) and moderately increased plasma lactate of 3.1 mmol/L (reference interval 0.5-2.2). A urine specimen was collected for organic acid analysis by gas chromatography--mass spectrometry. The results are shown in Fig. 1.


This patient has ethylmalonic encephalopathy (EE) [3], a severe disorder affecting mitochondria and blood vessels that typically presents with central nervous system disease, gastrointestinal dysfunction, retinal vessel tortuosity, petechiae, orthostatic acrocyanosis, and the production of ethylmalonic acid (EMA). First described in a neonate with hypotonia who subsequently developed a severe pyramidal disorder, EE was initially labeled as a branched-chain acyl-CoA dehydrogenase defect (1). In the years since, the cause of EE has been determined as mutations in ETHE1, a gene encoding a mitochondrial dioxygenase involved in hydrogen sulfide ([H.sub.2]S) detoxification.

The major biochemical hallmark of EE is the production of EMA in urine. Ethylmalonic aciduria is also associated with several other conditions, including short-chain acyl-CoA dehydrogenase deficiency, multiple acyl-CoA dehydrogenase deficiency, and Jamaican vomiting sickness. In EE, the production of EMA is often accompanied by lactic acid, 2-methylsuccinic acid, and branched-chain 4- and 5-carbon acylglycines, isobutyrylglycine, and isovalerylglycine (Fig. 1). In this case, EMA excretion was in excess of 299 mg/g creatinine (reference interval 0.5-20.0). The source of EMA and additional metabolites has long been the subject of substantial debate. This has been partly elucidated by loading and restriction studies using isoleucine, methionine, and lipids (2). Such studies have concluded that multiple pathways are affected, although it remains unclear as to the extent of their involvement. It is universally accepted that [H.sub.2]S toxicity is the underlying cause of the problems in each of these affected pathways (Fig. 2). EMA is produced in response to isoleucine loading, with concomitant increases of urine 2-methylsuccinnic and 2-ethylhydracrylic acids. In this mechanism, EMA is produced via the R-pathway of isoleucine catabolism, involving the racemization of 2-keto-3-methylvaleric acid (from S to R form), followed by conversion to EMA via 2-methylbutyryl-CoA and 2-ethyl-3-hydroxypropionyl-CoA (2-ethyl-3-hydroxypropionic acid, noted in Fig. 1). The production of [H.sub.2]S likely causes selective inhibition of several short-chain acyl-CoA dehydrogenases, including isobutyryl-CoA and isovaleryl-CoA dehydrogenases, resulting in the production of isobutyrylglycine and isovalerylglycine, respectively. The isoleucine catabolic enzyme 2-methyl branched-chain acyl-CoA dehydrogenase is also affected, which may result in excretion of 2-methylbutyrylglycine. It is also likely that [H.sub.2]S disrupts fatty acid oxidation through inhibition of butyryl-CoA dehydrogenase. EMA may be formed via carboxylation of accumulated butyryl-CoA, catalyzed by propionyl-CoA carboxylase. The presence of methylsuccinic acid was also noted, likely produced from ethylmalonyl-CoA.

The clinical features in EE, such as recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea, are attributed to the accumulation of sulfide compounds in blood vessels. The neurological features are most likely related to the mitochondrial toxicity of the sulfide compounds (3).

EE may be diagnosed through newborn screening programs by detection of increased C4 acylcarnitine concentrations. As a result of butyryl-CoA dehydrogenase inhibition, there is accumulation of butyryl-CoA and isobutyryl-CoA, which conjugate with carnitine to produce butyrylcarnitine and isobutyrylcarnitine, respectively. The accumulation of isovaleryl-CoA results in the formation of isovalerylcarnitine (C5 acylcarnitine), which may also be increased. In this case, the disorder was not detected by newborn screening, and plasma acylcarnitine analysis at the time ofclinical presentation revealed only a mild increase in C4 of 1.69 [micro]mol/L (reference interval <1.05).

Molecular analysis of the ETHE1 gene showed the patient was homozygous for the pathogenic variant, c.488G>A (p.Arg163Gln). She was started on dual therapy with oral metronidazole and N-acetylcysteine, which has been proposed as an effective therapy (4). Metronidazole decreases exogenous [H.sub.2]S production by intestinal flora, and N-acetylcysteine replenishes intramitochondrial glutathione stores in an effort to neutralize the oxidative injury from [H.sub.2]S accumulation. It was also recommended that she avoid nonsteroidal antiinflammatory drugs given increased bleeding risk.

Reproduced with permission from Roy Peake, PhD.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.


(1.) Burlina A, Zacchello F, Dionisi-Vici C, Bertini E, Sabetta G, Bennett MJ, et al. New clinical phenotype of branched-chain acyl-CoA oxidation defect. Lancet 1991;338:1522-3.

(2.) Barth M, Ottolenghi C, HubertL, Chretien D, Serre V, Gobin S, et al. Multiplesources of metabolic disturbance in ETHEI-related ethylmalonic encephalopathy. J Inherit Metab Dis 33(Suppl 3):S443-53,2010.

(3.) Tiranti V, Viscomi C, Hildebrandt T, Di Meo I, Mineri R, Tiveron C, et al. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat Med 2009;15:200-5.

(4.) Viscomi C, Burlina AB, Dweikat I, Savoiardo M, Lamperti C, Hildebrandt T, et al. Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy. Nat Med 2010;16:869-71.

Roy W.A. Peake [1] * and Lance H. Rodan [2]

[1] Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA; [2] Division of Genetics and Metabolism and Department of Neurology, Boston Children's Hospital, Boston, MA.

* Address correspondence to this author at: Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115. Fax 617-730-0383; e-mail

Received July 12, 2017; accepted August 4, 2017.

DOI: 10.1373/clinchem.2017.279497

[3] Nonstandard abbreviations: EE, ethylmalonic encephalopathy; EMA, ethylmalonic acid.

Caption: Fig. 1. Organic acids analysis of patient urine using gas chromatography-mass spectrometry. Urine organic acids were extracted into ethyl acetate/ether and converted to trimethylsilyl derivatives prior to analysis using a GC 6890N/MS 5975 system equipped with a DB-1 column (Agilent).

Caption: Fig. 2. Metabolic pathways involved in ethylmalonic encephalopathy.
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Title Annotation:the Clinical Chemist: Genetic Metabolic Series
Author:Peake, Roy W.A.; Rodan, Lance H.
Publication:Clinical Chemistry
Article Type:Clinical report
Date:Nov 1, 2017
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