Ethylmalonic Encephalopathy Is Caused by Mutations in ETHE1, a Gene Encoding a Mitochondrial Matrix Protein

Valeria Tiranti, Pio D'Adamo, Egill Briem, Gianfrancesco Ferrari, Rossana Mineri, Eleonora Lamantea, Hanna Mandel, Paolo Balestri, Maria Teresa Garcia-Silva, Brigitte Vollmer, Piero Rinaldo, Si Houn Hahn, James Leonard, Shamima Rahman, Carlo Dionisi-Vici, Barbara Garavaglia, Paolo Gasparini, Massimo Zeviani

Research output: Contribution to journalArticlepeer-review


Ethylmalonic encephalopathy (EE) is a devastating infantile metabolic disorder affecting the brain, gastrointestinal tract, and peripheral vessels. High levels of ethylmalonic acid are detected in the body fluids, and cytochrome c oxidase activity is decreased in skeletal muscle. By use of a combination of homozygosity mapping, integration of physical and functional genomic data sets, and mutational screening, we identified GenBank D83198 as the gene responsible for EE. We also demonstrated that the D83198 protein product is targeted to mitochondria and internalized into the matrix after energy-dependent cleavage of a short leader peptide. The gene had previously been known as "HSCO" (for hepatoma subtracted clone one). However, given its role in EE, the name of the gene has been changed to "ETHE1." The severe consequences of its malfunctioning indicate an important role of the ETHE1 gene product in mitochondrial homeostasis and energy metabolism.

Original languageEnglish
Pages (from-to)239-252
Number of pages14
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - Feb 2004

ASJC Scopus subject areas

  • Genetics

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