title: MtDNA mutations are a common cause of severe disease phenotypes in children with Leigh syndrome.
abstract: Leigh syndrome is a common clinical manifestation in children with mitochondrial disease and other types of inborn errors of metabolism. We characterised clinical symptoms, prognosis, respiratory chain function and performed extensive genetic analysis of 25 Swedish children suffering from Leigh syndrome with the aim to obtain insights into the molecular pathophysiology and to provide a rationale for genetic counselling. We reviewed the clinical history of all patients and used muscle biopsies in order to perform molecular, biochemical and genetic investigations, including sequencing the entire mitochondrial DNA (mtDNA), the mitochondrial DNA polymerase (POLGA) gene and the surfeit locus protein 1 (SURF1) gene. Respiratory chain enzyme activity measurements identified five patients with isolated complex I deficiency and five with combined enzyme deficiencies. No patient presented with isolated complex IV deficiency. Seven patients had a decreased ATP production rate. Extensive sequence analysis identified eight patients with pathogenic mtDNA mutations and one patient with mutations in POLGA. Mutations of mtDNA are a common cause of LS and mtDNA analysis should always be included in the diagnosis of LS patients, whereas SURF1 mutations are not a common cause of LS in Sweden. Unexpectedly, age of onset, clinical symptoms and prognosis did not reveal any clear differences in LS patients with mtDNA or nuclear DNA mutations.
authors.affiliation: Department of Clinical Sciences, Karolinska University Hospital, S-141 86 Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Naess
authors.forename: Christoph
authors.initials: C
authors.lastname: Freyer
authors.forename: Helene
authors.initials: H
authors.lastname: Bruhn
authors.forename: Rolf
authors.initials: R
authors.lastname: Wibom
authors.forename: Gunilla
authors.initials: G
authors.lastname: Malm
authors.forename: Inger
authors.initials: I
authors.lastname: Nennesmo
authors.forename: Ulrika
authors.initials: U
authors.lastname: von Döbeln
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D005260:Female; D005969:Glutamate Dehydrogenase / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007700:Kinetics; D007888:Leigh Disease / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D028361:Mitochondrial Diseases / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D016019:Survival Analysis
chemical_list: D004272:DNA, Mitochondrial; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C092928:Surf-1 protein; D000255:Adenosine Triphosphate; D005969:Glutamate Dehydrogenase; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human