Case Series of Ethylmalonic Encephalopathy from Southern India

Abstract

Ethylmalonic encephalopathy is a rare neurometabolic disorder with central nervous system involvement and vasculopathy. It is presented in infancy with developmental delay, acrocyanosis, petechiae, chronic diarrhea, and early death. This was a retrospective study of confirmed cases of ethylmalonic aciduria from a tertiary care hospital over a period of 5 years from January 2015 to December 2020. Case details including analysis of clinical history, investigations, and outcomes are presented. Of six cases, male-to-female ratio was 4:2. Mean age of presentation was 35.5 months (range: 14–83 months). Consanguinity, global developmental delay, failure to thrive, skin rashes, microcephaly, hypotonia, and exaggerated deep tendon reflexes were observed in all cases. Chronic diarrhea was presented in five cases. The serum levels of C4 carnitine and urinary levels of ethylmalonic acid were increased in all cases. Magnetic resonance imaging (MRI) of the brain showed heterogenous bilateral symmetrical changes in the basal ganglia in five cases, and in one case, MRI could not be done. Genetic testing in two cases showed a homozygous variant in ETHE1 gene. Four children died, while the other two cases showed a decreased in recurrent encephalopathies and diarrhea after starting metronidazole. All children had global developmental delay, failure to thrive, skin rashes, central hypotonia, increased C4 carnitine levels in the serum, and increased ethylmalonic acid in the urine. Chronic diarrhea, acrocyanosis, and basal ganglia change in the MRI of the brain also give important clues for diagnosis. Metronidazole is useful in preventing recurrent episodes of encephalopathy.

Keywords

ethylmalonic aciduria - purpura - chronic diarrhea - petechiae - ETHE1 gene

Authors' Contributions

V. K. G. supervised, guided, and reviewed the manuscript. V. M. S. and S. K. S were involved in the management of the children and the preparation of manuscript. K. S., K. J., M. B., and R. C. were involved in the diagnosis of the children and the preparation of manuscript.

Publication History

Received: 22 May 2021

Accepted: 22 October 2021

Article published online:
06 December 2021

• References

• 1 Tiranti V, D'Adamo P, Briem E. et al. Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein. Am J Hum Genet 2004; 74 (02) 239-252
• 2 Kitzler TM, Gupta IR, Osterman B. et al. Acute and chronic management in an atypical case of ethylmalonic encephalopathy. JIMD Rep 2019; 45: 57-63
• 3 Pigeon N, Campeau PM, Cyr D, Lemieux B, Clarke JT. Clinical heterogeneity in ethylmalonic encephalopathy. J Child Neurol 2009; 24 (08) 991-996
• 4 McGowan KA, Nyhan WL, Barshop BA. et al. The role of methionine in ethylmalonic encephalopathy with petechiae. Arch Neurol 2004; 61 (04) 570-574
• 5 Papetti L, Garone G, Schettini L. et al. Severe early onset ethylmalonic encephalopathy with West syndrome. Metab Brain Dis 2015; 30 (06) 1537-1545
• 6 Dionisi-Vici C, Diodato D, Torre G. et al. Liver transplant in ethylmalonic encephalopathy: a new treatment for an otherwise fatal disease. Brain 2016; 139 (Pt 4): 1045-1051
• 7 Cavusoglu D, Hismi BO, Dundar NO. et al. An unusual cause of cavitating leukoencephalopathy: ethylmalonic encephalopathy. Acta Neurol Belg 2018; 118 (02) 309-312
• 8 Ozand PT, Rashed M, Millington DS. et al. Ethylmalonic aciduria: an organic acidemia with CNS involvement and vasculopathy. Brain Dev 1994; 16 (Suppl): 12-22
• 9 Debray FG, Morin C, Janvier A. et al. LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency. J Med Genet 2011; 48 (03) 183-189
• 10 Furuya H, Sugimura T, Yamada T, Hayashi K, Kobayashi T. A case of incomplete Kearns-Sayre syndrome with a stroke like episode [in Japanese]. Rinsho Shinkeigaku 1997; 37 (08) 680-684
• 11 Lam CW, Law CY, Siu WK. et al. Novel POLG mutation in a patient with sensory ataxia, neuropathy, ophthalmoparesis and stroke. Clin Chim Acta 2015; 448: 211-214
• 12 Tzoulis C, Henriksen E, Miletic H, Bindoff LA. No evidence of ischemia in stroke-like lesions of mitochondrial POLG encephalopathy. Mitochondrion 2017; 32: 10-15
• 13 Lim J, Shayota BJ, Lay E. et al. Acute strokelike presentation and long-term evolution of diffusion restriction pattern in ethylmalonic encephalopathy. J Child Neurol 2021; 36 (10) 841-852
• 14 Boyer M, Sowa M, Di Meo I. et al. Response to medical and a novel dietary treatment in newborn screen identified patients with ethylmalonic encephalopathy. Mol Genet Metab 2018; 124 (01) 57-63
• 15 Di Meo I, Lamperti C, Tiranti V. Ethylmalonic encephalopathy. In: Adam MP, Ardinger HH, Pagon RA. et al., eds. GeneReviews®. Seattle, WA: University of Washington; 1993-2021 [initial posting: September 21, 2017]
• 16 Tiranti V, Viscomi C, Hildebrandt T. et al. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat Med 2009; 15 (02) 200-205
• 17 Peake RWA, Rodan LH. Ethylmalonic aciduria in an infant with neurological and skin presentation. Clin Chem 2017; 63 (11) 1771-1773
• 18 Bijarnia-Mahay S, Gupta D, Shigematsu Y, Yamaguchi S, Saxena R, Verma IC. Ethylmalonic encephalopathy in an Indian boy. Indian Pediatr 2016; 53 (10) 914-916
• 19 Henriques BJ, Lucas TG, Rodrigues JV. et al. Ethylmalonic encephalopathy ETHE1 R163W/R163Q mutations alter protein stability and redox properties of the iron centre. PLoS One 2014; 9 (09) e107157
• 20 Amaral AU, Cecatto C, Busanello EN. et al. Ethylmalonic acid impairs brain mitochondrial succinate and malate transport. Mol Genet Metab 2012; 105 (01) 84-90
• 21 McHugh D, Cameron CA, Abdenur JE. et al. Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project. Genet Med 2011; 13 (03) 230-254
• 22 Grosso S, Mostardini R, Farnetani MA. et al. Ethylmalonic encephalopathy: further clinical and neuroradiological characterization. J Neurol 2002; 249 (10) 1446-1450
• 23 Mineri R, Rimoldi M, Burlina AB. et al. Identification of new mutations in the ETHE1 gene in a cohort of 14 patients presenting with ethylmalonic encephalopathy. J Med Genet 2008; 45 (07) 473-478
• 24 Satapathy K, Correa A, Kabra M. et al. Ethylmalonic encephalopathy masquerading as malabsorption syndrome - a case report. Meta Gene 2017; 13: 115-118
• 25 Govindaraj P, Parayil Sankaran B, Nagappa M. et al. Child neurology: ethylmalonic encephalopathy. Neurology 2020; 94 (12) e1336-e1339
• 26 Viscomi C, Burlina AB, Dweikat I. et al. Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy. Nat Med 2010; 16 (08) 869-871