Identification of new mutations in the ETHE1 gene in a cohort of 14 patients presenting with ethylmalonic encephalopathy R Mineri, 1 M Rimoldi, 2 A B Burlina, 3 S Koskull, 4 C Perletti, 5 B Heese, 6 U von Do ¨beln, 7 P Mereghetti, 8 I Di Meo, 1 F Invernizzi, 1 M Zeviani, 1 G Uziel, 5 V Tiranti 1 1 Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Mitochondrial Disorders in Children, RCCS Foundation Neurological Institute C. Besta, Milan, Italy; 2 Unit of Biochemistry and Genetics, IRCCS Foundation Neurological Institute C. Besta, Milan, Italy; 3 Division of Metabolic Disorders, Department of Pediatrics, University Hospital, Padova, Italy; 4 Klinik fu ¨r Neuropa ¨diatrie, Behandlungszentrum Vogtareuth, Germany; 5 Unit of Child Neurology, IRCCS Foundation Neurological Institute C. Besta, Milan, Italy; 6 Division of Pediatric Genetics and Metabolism University of Florida, USA; 7 Centre for Inherited Metabolic Diseases, Karolinska University, Stockholm, Sweden; 8 Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan and Department of Chemistry, University of Sassari, Sassari Italy Correspondence to: Dr V Tiranti, Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute C. Besta, Via Temolo, 4, 20126 Milan, Italy; tiranti@istituto-besta.it Received 27 February 2008 Revised 2 April 2008 Accepted 3 April 2008 ABSTRACT Background: Ethylmalonic encephalopathy (EE) is a rare autosomal recessive metabolic disorder characterised by progressive encephalopathy, recurrent petechiae, acro- cyanosis and chronic diarrhoea, with a fatal outcome in early in life. Methods: 14 patients with EE were investigated for mutations in the ETHE1 gene. Results: Of the 14 patients, 5 were found to carry novel mutations. Conclusions: This work expands our knowledge of the causative mutations of EE. Ethylmalonic encephalopathy (EE; OMIM 602473) is a rare autosomal recessive metabolic disorder characterised by progressive encephalopathy, recur- rent petechiae, acrocyanosis and chronic diarrhoea, with a fatal outcome in early in life. The main neuropathological features of the disease are symmetrical necrotic lesions in the basal ganglia and brainstem, resembling Leigh syndrome (LS; OMIM 256000). Lactic acidosis, high levels of ethylmalonic acid (EMA) in urine, and high levels of C4 and C5 acylcarnitines in blood are the biochemical hallmarks of this disease. In addition, an isolated defect of cytochrome c oxidase is consistently present in the skeletal muscle. This disorder, mainly affecting children from the Mediterranean basin and the Arabian peninsula, is caused by mutations in the ETHE1 gene (chromosome 19q13.32) that codes for a mitochon- drial protein located into the matrix of the organelle. We have previously reported a series of 29 patients, presenting a fairly homogeneous clinical and biochemical presentation, in spite of a wide spectrum of ETHE1 mutations including missense, non-sense, frameshift and deletion of single exons or of the entire gene. We report the results of a mutational screening on 14 additional patients with EE, including 5 patients associated with new mutations. METHODS Patients Of the 14 new cases (7 male and 7 female patients) reported here, 2 were Italian, 4 Arab, 3 Turkish, 3 Hispanic and 2 of unknown origin. At the time of writing, 11 patients are now deceased; age of death ranged from 18 months to 3 years. Three patients are alive at 6 months, 7 years and 13 years, respectively. Five patients carried novel mutations and are described in more detail below, and some of their clinical and biochemical features are also sum- marised in table 1. Patient 1 This was the only affected child from allegedly non-consanguineous parents originating from two neighbouring small villages. Clinical onset occurred during the first year of life with frequent vomiting followed by several episodes of diarrhoea. Psychomotor delay was characterised by severe axial hypotonia with poor trunk control and striking proximal muscle weakness. The child later developed pyramidal signs, and distal acrocyanosis was noticed at 5 years of age. Laboratory findings showed increased urinary excretion of EMA (170 mmol/mol creatinine; normal value ,20). Serum lactate was slightly raised (2.67 mmol/l; normal value ,2). Serum butyrylcarnitine (C4) was slightly raised at one measurement and normal at the other. Brain MRI showed bilateral asymmetrical high T2-weighted signal intensity in the globus pallidus, capsula extrema and amygdala. An isolated partial defect of cytochrome c oxidase was detected in muscle (58% of the normal mean value), but was normal in myoblasts. This patient carries a new homozygous transition, c.586GRA, in the ETHE1 gene, leading to a p.D196N amino acid change in the ETHE1 protein sequence. Normal levels of ETHE1 cross-reacting material were present in mutant myoblasts (fig 1B). Patient 2 This child was born to healthy, non-consanguineous parents after a regular pregnancy and delivery. Another sibling was affected by early-onset encephalopathy with epileptic seizures and died at 7 months from severe lactic acidosis during an acute pulmonary infection, but the diagnosis remained undefined. Since the first weeks after birth, the patient had developed a progressive syndrome characterised by global hypotonia, pyramidal signs, psychomotor delay, difficulties in swallowing and poor growth. Lactic acidosis was detected at 2 months of age. The child later showed acrocyanosis, petechiae and diarrhoea. From 8 months of age, the child had several episodes of seizures due to drug-unresponsive partial epilepsy, and eventually died at 17 months from acute respiratory failure. Relevant laboratory Mutation report J Med Genet 2008;45:473–478. doi:10.1136/jmg.2008.058271 473 group.bmj.com on May 30, 2013 - Published by jmg.bmj.com Downloaded from