title: Ndufs4 related Leigh syndrome: A case report and review of the literature.
abstract: The genetic causes of Leigh syndrome are heterogeneous, with a poor correlation between the phenotype and genotype. Here, we present a patient with an NDUFS4 mutation to expand the clinical and biochemical spectrum of the disease. A combined defect in the CoQ, PDH and RCC activities in our patient was due to an inappropriate assembly of the RCC complex I (CI), which was confirmed using Blue-Native polyacrylamide gel electrophoresis (BN-PAGE) analysis. Targeted exome sequencing analysis allowed for the genetic diagnosis of this patient. We reviewed 198 patients with 24 different genetic defects causing RCC I deficiency and compared them to 22 NDUFS4 patients. We concluded that NDUFS4-related Leigh syndrome is invariably linked to an early onset severe phenotype that results in early death. Some data, including the clinical phenotype, neuroimaging and biochemical findings, can guide the genetic study in patients with RCC I deficiency.
authors.affiliation: Division of Child Neurology, Sant Joan de Déu Hospital, University of Barcelona, Spain; Division of Child Neurology, Fundación Hospital Asilo de Granollers, Barcelona, Spain.
authors.forename: Juan Darío
authors.initials: JD
authors.lastname: Ortigoza-Escobar
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Centro de Biología Molecular Severo Ochoa CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, IDIPAZ, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Oyarzabal
authors.affiliation: Division of Biochemistry, Sant Joan de Déu Hospital, University of Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Montero
authors.affiliation: Division of Biochemistry, Sant Joan de Déu Hospital, University of Barcelona, Spain; Center for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Artuch
authors.affiliation: Pathology, Sant Joan de Déu Hospital, University of Barcelona, Spain; Center for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Jou
authors.affiliation: Pathology, Sant Joan de Déu Hospital, University of Barcelona, Spain; Center for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Jiménez
authors.affiliation: Division of Inborn Errors of Metabolism-IBC, Department of Biochemistry and Molecular Genetics, Hospital Clinic, Barcelona, Spain; Center for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Gort
authors.affiliation: Division of Inborn Errors of Metabolism-IBC, Department of Biochemistry and Molecular Genetics, Hospital Clinic, Barcelona, Spain; Consejo Superior de Investigaciones Científicas (CSIC), ISCIII, Spain; Center for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Paz
authors.initials: P
authors.lastname: Briones
authors.affiliation: Radiology, Sant Joan de Déu Hospital, University of Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Muchart
authors.affiliation: Universidad de Zaragoza, ISCIII, Spain; Center for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: López-Gallardo
authors.affiliation: Universidad de Zaragoza, ISCIII, Spain; Center for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Emperador
authors.affiliation: Universidad de Zaragoza, ISCIII, Spain; Center for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Eduardo Ruiz
authors.initials: ER
authors.lastname: Pesini
authors.affiliation: Universidad de Zaragoza, ISCIII, Spain; Center for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Montoya
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Centro de Biología Molecular Severo Ochoa CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, IDIPAZ, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Centro de Biología Molecular Severo Ochoa CSIC-UAM, Departamento de Biología Molecular, Universidad Autónoma de Madrid, IDIPAZ, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Rodríguez-Pombo
authors.affiliation: Division of Child Neurology, Sant Joan de Déu Hospital, University of Barcelona, Spain; Center for the Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain. Electronic address: bperez@hsjdbcn.org.
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez-Dueñas
mesh_terms: D042967:Electron Transport Complex I; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007888:Leigh Disease / Q000175:diagnosis*; D009245:NADH Dehydrogenase / Q000172:deficiency*; D014451:Ubiquinone / Q000172:deficiency
chemical_list: D014451:Ubiquinone; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C427643:NDUFS4 protein, human
keywords: BN-PAGE; Leigh syndrome; NDUFS4; Next generation sequencing; Respiratory chain complex I