Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome
Tóm tắt
Leigh syndrome (LS) is a rare heterogeneous progressive neurodegenerative disorder usually presenting in infancy or early childhood. Clinical presentation is variable and includes psychomotor delay or regression, acute neurological or acidotic episodes, hypotonia, ataxia, spasticity, movement disorders, and corresponding anomalies of the basal ganglia and brain stem on magnetic resonance imaging. To date, 35 genes have been associated with LS, mostly involved in mitochondrial respiratory chain function and encoded in either nuclear or mitochondrial DNA. We used whole-exome sequencing to identify disease-causing variants in four patients with basal ganglia abnormalities and clinical presentations consistent with LS. Compound heterozygote variants in ECHS1, encoding the enzyme enoyl-CoA hydratase were identified. One missense variant (p.Thr180Ala) was common to all four patients and the haplotype surrounding this variant was also shared, suggesting a common ancestor of French-Canadian origin. Rare mutations in ECHS1 as well as in HIBCH, the enzyme downstream in the valine degradation pathway, have been associated with LS or LS-like disorders. A clear clinical overlap is observed between our patients and the reported cases with ECHS1 or HIBCH deficiency. The main clinical features observed in our cohort are T2-hyperintense signal in the globus pallidus and putamen, failure to thrive, developmental delay or regression, and nystagmus. Respiratory chain studies are not strikingly abnormal in our patients: one patient had a mild reduction of complex I and III and another of complex IV. The identification of four additional patients with mutations in ECHS1 highlights the emerging importance of this pathway in LS.
Từ khóa
Tài liệu tham khảo
Aulbert W, Weigt-Usinger K, Thiels C, Kohler C, Vorgerd M, Schreiner A, Hoffjan S, Rothoeft T, Wortmann SB, Heyer CM, Podskarbi T, Lucke T (2014) Long survival in Leigh syndrome: new cases and review of literature. Neuropediatrics 45:346–353. doi:10.1055/s-0034-1383823
Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J (2011) Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 12:745–755. doi:10.1038/nrg3031
Boycott KM, Vanstone MR, Bulman DE, MacKenzie AE (2013) Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat Rev Genet 14:681–691. doi:10.1038/nrg3555
Buhas D, Bernard G, Fukao T, Decarie JC, Chouinard S, Mitchell GA (2013) A treatable new cause of chorea: beta-ketothiolase deficiency. Mov Disord 28:1054–1056. doi:10.1002/mds.25538
Chinnery PF (2000) Mitochondrial disorders overview. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews® [Internet]. University of Washington, Seattle, WA, 1993–2015
Fahiminiya S, Majewski J, Al-Jallad H, Moffatt P, Mort J, Glorieux FH, Roschger P, Klaushofer K, Rauch F (2014) Osteoporosis caused by mutations in PLS3: clinical and bone tissue characteristics. J Bone Miner Res 29:1805–1814. doi:10.1002/jbmr.2208
Ferdinandusse S, Waterham HR, Heales SJ, Brown GK, Hargreaves IP, Taanman JW, Gunny R, Abulhoul L, Wanders RJ, Clayton PT, Leonard JV, Rahman S (2013) HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase. Orphanet J Rare Dis 8:188. doi:10.1186/1750-1172-8-188
Haack TB, Jackson CB, Murayama K, Kremer LS, Schaller A, Kotzaeridou U, de Vries MC, Schottmann G, Santra S, Buchner B, Wieland T, Graf E, Freisinger P, Eggimann S, Ohtake A, Okazaki Y, Kohda M, Kishita Y, Tokuzawa Y, Sauer S, Memari Y, Kolb-Kokocinski A, Durbin R, Hasselmann O, Cremer K, Albrecht B, Wieczorek D, Engels H, Hahn D, Zink AM, Alston CL, Taylor RW, Rodenburg RJ, Trollmann R, Sperl W, Strom TM, Hoffmann GF, Mayr JA, Meitinger T, Bolognini R, Schuelke M, Nuoffer JM, Kolker S, Prokisch H, Klopstock T (2015) Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement. Ann Clin Transl Neurol 2:492–509. doi:10.1002/acn3.189
Jellinger K, Seitelberger F (1970) Subacute necrotizing encephalomyelopathy (LEIGH). Ergeb Inn Med Kinderheilkd 29:155–219
Jordan DM, Ramensky VE, Sunyaev SR (2010) Human allelic variation: perspective from protein function, structure, and evolution. Curr Opin Struct Biol 20:342–350. doi:10.1016/j.sbi.2010.03.006
Loupatty FJ, Clayton PT, Ruiter JP, Ofman R, Ijlst L, Brown GK, Thorburn DR, Harris RA, Duran M, Desousa C, Krywawych S, Heales SJ, Wanders RJ (2007) Mutations in the gene encoding 3-hydroxyisobutyryl-CoA hydrolase results in progressive infantile neurodegeneration. Am J Hum Genet 80:195–199. doi:10.1086/510725
McKelvie P, Infeld B, Marotta R, Chin J, Thorburn D, Collins S (2012) Late-adult onset Leigh syndrome. J Clin Neurosci 19:195–202. doi:10.1016/j.jocn.2011.09.009
Mitchell GA, Gauthier N, Lesimple A, Wang SP, Mamer O, Qureshi I (2008) Hereditary and acquired diseases of acyl-coenzyme A metabolism. Mol Genet Metab 94:4–15. doi:10.1016/j.ymgme.2007.12.005
Perelman DLN (2000) Requirements for branched chain amino acids and their interactions in the nematode Caenorhabditis elegans. Nematology 2:6
Peters H, Buck N, Wanders R, Ruiter J, Waterham H, Koster J, Yaplito-Lee J, Ferdinandusse S, Pitt J (2014) ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism. Brain 137:2903–2908. doi:10.1093/brain/awu216
Reuter MS, Sass JO, Leis T, Kohler J, Mayr JA, Feichtinger RG, Rauh M, Schanze I, Bahr L, Trollmann R, Uebe S, Ekici AB, Reis A (2014) HIBCH deficiency in a patient with phenotypic characteristics of mitochondrial disorders. Am J Med Genet A 164:3162–3169. doi:10.1002/ajmg.a.36766
Ruhoy IS, Saneto RP (2014) The genetics of Leigh syndrome and its implications for clinical practice and risk management. Appl Clin Genet 7:221–234. doi:10.2147/TACG.S46176
Sakai C, Yamaguchi S, Sasaki M, Miyamoto Y, Matsushima Y, Goto YI (2014) ECHS1 mutations cause combined respiratory chain deficiency resulting in Leigh syndrome. Hum Mutat. doi:10.1002/humu.22730
Shrikhande DY, Kalakoti P, Syed MM, Ahya K, Singh G (2010) A rare mitochondrial disorder: Leigh syndrome—a case report. Ital J Pediatr 36:62. doi:10.1186/1824-7288-36-62
Thorburn DR, Rahman S (2003) Mitochondrial DNA-associated Leigh syndrome and NARP. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews® [Internet]. University of Washington, Seattle, WA, 1993–2015
Wanders RJ, Duran M, Loupatty FJ (2012) Enzymology of the branched-chain amino acid oxidation disorders: the valine pathway. J Inherit Metab Dis 35:5–12. doi:10.1007/s10545-010-9236-x