Dados do Trabalho

Título

ETHYLMALONIC ENCEPHALOPATHY (EE): DIFFERENTIAL DIAGNOSIS OF HEREDITARY SPASTIC PARAPARESIS.

Apresentação dos casos

Case report: Male patient, son of consanguineous parents. During early childhood, he had chronic diarrhea, resistant to nutritional therapy. Endoscopy, colonoscopy and gastric biopsy were carried out because of the suspicion of malabsorption syndrome. At the age of 12, he was evaluated by neurologist due to motor regression, difficulty walking and learning difficulties. On physical examination, he presented with lower limb spasticity and signs of pyramidal release, and was suspected of having Hereditary Spastic Paraparesis. Magnetic resonance imaging of the brain showed foci of nonspecific T2/Flair hyperintense signal in the caudate nucleus and putamen, bilaterally, which could be related to gliosis/myelinic rarefaction. A molecular test showed a homozygous variant classified as of uncertain significance, NM_014297.5: c.245C>A:p.(ALA82Glu), in exon 3 of the ETHE1 gene. Following this, organic acids were tested in the urine: a marked increase in ethylmalonic acid, a small increase in glycolic, 3-hydroxy-butyric, isobutyrylglycine and isovalerylglycine acids. Presence of methyl succinic acid. Acylcarnitine analysis and amino acid analysis normal. The diagnosis of Ethylmalonic Encephalopathy (EE) was confirmed. Treatment with Riboflavin and Coenzyme Q10 was started, and the clinical picture improved, with more sporadic episodes of diarrhea and progression of the spastic paraparesis stabilized.

Discussão

Discussion: EE is a rare, severe metabolic disorder caused by dysfunction of the ETHE1 protein, a mitochondrial dioxygenase involved in the detoxification of hydrogen sulfide (H2S). It is characterized by delayed or regressed neurodevelopment, associated with pyramidal and extrapyramidal signs and chronic diarrhea. In this case, the clinical picture resembled a complex form of spastic paraparesis with cognitive impairment. The diagnosis can be confirmed by molecular testing, but in this case it was necessary to carry out biochemical tests, as the variant identified was classified as VUS.

Comentários finais

We report a case of EE, with a milder phenotypic presentation and a variant of uncertain significance, in homozygosis, which was diagnosed after biochemical tests. His clinical condition stabilized with the use of Riboflavin and Coenzyme Q10, considering the mitochondrial pathophysiology. Thus, we can conclude that these findings expand the knowledge associated with EE.

Referências

Tiranti V, D'Adamo P, Briem E, Ferrari G, Mineri R, Lamantea E, Mandel H, Balestri P, Garcia-Silva MT, Vollmer B, Rinaldo P, Hahn SH, Leonard J, Rahman S, Dionisi-Vici C, Garavaglia B, Gasparini P, Zeviani M. Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein. Am J Hum Genet. 2004 Feb;74(2):239-52. doi: 10.1086/381653. Epub 2004 Jan 19. PMID: 14732903; PMCID: PMC1181922.

Ersoy M, Tiranti V, Zeviani M. Ethylmalonic encephalopathy: Clinical course and therapy response in an uncommon mild case with a severe ETHE1 mutation. Mol Genet Metab Rep. 2020 Aug 28;25:100641. doi: 10.1016/j.ymgmr.2020.100641. PMID: 32923369; PMCID: PMC7476058.

Di Meo I, Lamperti C, Tiranti V. Encefalopatia Etilmalônica. 21 de setembro de 2017. In: Adam MP, Feldman J, Mirzaa GM, et al., editores. GeneReviews® [Internet]. Seattle (WA): Universidade de Washington, Seattle; 1993-2024. Disponível em: https://www.ncbi.nlm.nih.gov/books/NBK453432/

Palavras Chave

inborn error of metabolism; Ethylmalonic encephalopathy; ETHE1 gene;