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10.1136/Jmg.2005.036210 J Med Genet: First Published As 10.1136/Jmg.2005.036210 on 23 September 2005

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10.1136/Jmg.2005.036210 J Med Genet: First Published As 10.1136/Jmg.2005.036210 on 23 September 2005 JMG Online First, published on September 23, 2005 as 10.1136/jmg.2005.036210 J Med Genet: first published as 10.1136/jmg.2005.036210 on 23 September 2005. Downloaded from ETHE1 mutations are specific to Ethylmalonic Encephalopathy V. Tiranti1*, E. Briem 1*, E. Lamantea1, R. Mineri1, E. Papaleo2, L. De Gioia2, F. Forlani3, P. Rinaldo4, P. Dickson5, B. Abu-Libdeh6, L. Cindro-Heberle7, M. Owaidha8, R.M. Jack9, E. Christensen10, A. Burlina11, M. Zeviani1 1Unit of Molecular Neurogenetics – Pierfranco and Luisa Mariani Center for the Study of Children’s Mitochondrial Disorders, National Neurological Institute “C. Besta”, Milan, Italy; 2Department of Biotechnology and Biosciences. University of Milan-Bicocca, Italy; 3Dipartimento di Scienze Molecolari Agro-Alimentari, Facoltà di Agraria, State University of Milan, Italy; 4Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Biochemical Genetics Laboratory, Rochester, MN, USA; 5Harbor-UCLA Medical Center, Division of Medical Genetics, Torrance, CA, USA; 6Makassed Hospital, Mount of Olives, Jerusalem, Israel; 7Paediatric Neurology Unit, Al Sabah Hospital, Kuwait; 8Al-Jahra Hospital, Kuwait; 9Biochemical Genetics lab, Children’s Hospital, Sand Point Way NE, Seattle, WA USA: 10Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark; 11Division of Inborn Metabolic Diseases, Department of Pediatrics, University of Padua, Italy Correspondence to: Massimo Zeviani, MD, PhD Unit of Molecular Neurogenetics National Neurological Institute “Carlo Besta” Via Temolo 4, 20133 Milan, Italy FAX +39-02-23942619 Phone +39-02-23942630 E-mail: [email protected] [email protected] http://jmg.bmj.com/ URL: www.mitopedia.org *The first two authors should be regarded as joint First Authors. on September 24, 2021 by guest. Protected copyright. Key Words: ETHE1, HSCO, mitochondria, metabolic disorders, ethylmalonic aciduria, ethylamalonic encephalopathy, metallo-beta-lactamase Database information: ETHE1 (OMIM#608451) EE (OMIM#602473) H.sapiens Ethe1 (Swiss Prot code O95571) H. sapiens ethylmalonic encephalopathy 1 ETHE1, mRNA (NM_014297) H. sapiens acyl-Coenzyme A dehydrogenase, short/branched chain mRNA (NM_000017) - 1 - Copyright Article author (or their employer) 2005. Produced by BMJ Publishing Group Ltd under licence. J Med Genet: first published as 10.1136/jmg.2005.036210 on 23 September 2005. Downloaded from ABSTRACT Introduction: Mutations in ETHE1, a gene located on chromosome 19q13, have recently been identified in patients affected by Ethylmalonic Encephalopathy (EE). EE is a devastating infantile metabolic disorder, characterized by widespread lesions in the brain, hyperlactic acidemia, petechiae, orthostatic acrocyanosis and ethylmalonic aciduria (EMA). However, the 625G>A SNP in the gene encoding the short-chain acylCoA dehydrogenase (SCAD) was previously proposed as a co-factor in the etiology of EE and other EMA syndromes. We present here a systematic investigation on the distribution and characterization of ETHE1 mutations and of the 625G>A SNP in a large cohort of EE and non-EE EMA patients. We also propose a structural 3D model of Ethe1p which can shed some light about the function of this protein. Methods: A total of 29 patients with typical EE and11 with non-EE EMA were considered in this study. The following methods were used in our investigation: (a) automated nucleotide sequence analysis of the ETHE1 gene, (b) SNP analysis of SCAD, (c) western-blot analysis using an antibody specific to Ethe1 protein (Ethe1p), (d) two dimension blue-native electrophoresis (2D-BNE) and (e) a series of software packages for the computational simulation of 3D structures of polypeptides. Results: Frameshift, stop, splice site and missense mutations of ETHE1 were detected in all the typical EE patients. Western-blot analysis indicated that some of the missense mutations are associated with the presence of the Ethe1p protein, suggesting that the corresponding wild-type aminoacid residues have a catalytic function. No ETHE1 mutations were identified in non-EE EMA patients. 2D-BNE experiments indicated that Ethe1p works as a supramolecular, presumably homo-dimeric, complex, and our 3D-model suggests that Ethe1p is likely to be a mitochondrial matrix thioesterase acting on a still unknown substrate. Finally, SNP analysis in our patients ruled out a pathogenic role of SCAD variants in EE, but did show a highly significant prevalence of the 625A alleles in non-EE EMA patients. http://jmg.bmj.com/ on September 24, 2021 by guest. Protected copyright. - 2 - J Med Genet: first published as 10.1136/jmg.2005.036210 on 23 September 2005. Downloaded from INTRODUCTION Ethylmalonic encephalopathy (EE) (OMIM 602473) is an autosomal recessive disorder originally reported in Italian families and predominantly affecting children of Mediterranean or Arab descent. EE is characterized by psychomotor regression and generalized hypotonia, later evolving into spastic tetraparesis, dystonia and eventually global neurological failure (1). MRI examination shows the presence of symmetric and asymmetric “patchy” lesions, distributed in the deep grey structures of the brain, including the brainstem, thalamus and corpus striatum (2, 3). The encephalopathy is typically accompanied by widespread lesions of the small blood vessels, causing showers of petechiae, especially during intercurrent infections, easy bruising, and orthostatic acrocyanosis. Chronic diarrhoea is another prominent feature of EE. The course is relentlessly progressive and usually leads to death within the first decade of life. From a biochemical point of view, EE is characterized by persistent lactic acidemia, a reduction in the activity of mitochondrial respiratory complex IV in skeletal muscle, and markedly elevated excretion of ethylmalonic and methylsuccinic acid in urine (4). Ethylmalonic acid is believed to derive from the carboxylation of butyryl-CoA, as a consequence of disorders of the mitochondrial β- oxidation of fatty acids, or from 2-ethylmalonic-semialdehyde, as a consequence of the R-pathway catabolism of isoleucine (5). The differential diagnosis of EE is with other known causes of persistent ethylmalonic aciduria (EMA), including deficiency of short-chain acyl-CoA dehydrogenase (SCAD), Glutaric acidemia type 2, and Jamaican vomiting sickness. In addition, Gregersen et al (6) reported that, in several patients, mild ethylmalonic aciduria (EMA) was associated with a predominance of the 625A allele, vs. the 625G allele, of a single-nucleotide polymorphism (SNP), in the gene encoding the short-chain acyl-CoA dehydrogenase (SCAD). We present here a study on the prevalence of both ETHE1 (MIM#608451) mutations and SCAD 625G>A SNP alleles in patients with EE and non-EE EMA. To gain insight into the pathogenetic mechanisms of mutations, the Ethe1 protein (Ethe1p) mutant variants http://jmg.bmj.com/ were further investigated by immunoassay and 3-dimension (3D) modelling. on September 24, 2021 by guest. Protected copyright. - 3 - J Med Genet: first published as 10.1136/jmg.2005.036210 on 23 September 2005. Downloaded from PATIENTS Table 1 lists the genetic findings and the clinical information obtained for our patients. Among the 40 EMA patients enrolled in this study, a first group of 29 unrelated subjects was classified as having EE. The inclusion criteria for the diagnosis of EE were: (1) early-onset progressive encephalopathy with symmetrical lesions in the basal ganglia and brainstem; (2) vasculopathic petechiae and orthostatic acrocyanosis; (3) chronic diarrhoea, and (4) EMA. The latter was usually associated with methyl- succinic aciduria, excretion of C4 acylglycines, C4 acylcarnitines and lactic acidosis. With a few exceptions, most of the 29 EE patients were of Arabic or Mediterranean origin. Seventeen of them have already been reported elsewhere (3). Unfortunately, for some of these patients the clinical and laboratory information is not complete. For instance, although the available clinical records reported in each and every case elevated levels of urinary EMA and methyl-succinic acid, the exact values were missing for several patients. Eleven other patients were referred to us as presenting an infantile encephalopathy or encephalomyopathy consistently associated with EMA. In these patients the urinary excretion of methyl-succinic acid was normal. In three of them the acyl-carnitine profile was available in the clinical records and resulted as normal (see Table I). Again, most of these patients died several years ago and the clinical information that we were able to obtain is incomplete (see Table I). The neurological features were more heterogeneous in this group of patients than in the EE group. In addition, in none of these patients were the typical extra-neurological EE hallmark features ever found; for instance, vascular purpura, orthostatic acrocyanosis, and chronic diarrhoea were notably absent. The age of onset varied from birth to childhood. Additional signs were reported in some patients, including facial dysmorphism, agenesis of corpus callosum, mid-brain calcifications, and brain atrophy (Table I). They were referred to us as non-typical cases, and were classified by us as having non-EE EMA. When available, the quantitative values of EMA in both cohorts were extremely http://jmg.bmj.com/ variable, ranging from 45 to 730 mg/g creatinine. In 9 cases the ethnic origin was known (3 Italians, 4 Turks, 1 Arab, and 1 Chinese). Mitochondrial β-oxidation of fatty acids was analysed fluorimetrically in fibroblasts
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