title: Phenotypic variation of TTC19-deficient mitochondrial complex III deficiency: a case report and literature review.
abstract: Isolated mitochondrial respiratory chain complex III deficiency has been described in a heterogeneous group of clinical presentations in children and adults. It has been associated with mutations in MT-CYB, the only mitochondrial DNA encoded subunit, as well as in nine nuclear genes described thus far: BCS1L, TTC19, UQCRB, UQCRQ, UQCRC2, CYC1, UQCC2, LYRM7, and UQCC3. BCS1L, TTC19, UQCC2, LYRM7, and UQCC3 are complex III assembly factors. We report on an 8-year-old girl born to consanguineous Iraqi parents presenting with slowly progressive encephalomyopathy, severe failure to thrive, significant delays in verbal and communicative skills and bilateral retinal cherry red spots on fundoscopy. SNP array identified multiple regions of homozygosity involving 7.5% of the genome. Mutations in the TTC19 gene are known to cause complex III deficiency and TTC19 was located within the regions of homozygosity. Sequencing of TTC19 revealed a homozygous nonsense mutation at exon 6 (c.937C > T; p.Q313X). We reviewed the phenotypes and genotypes of all 11 patients with TTC19 mutations leading to complex III deficiency (including our case). The consistent features noted are progressive neurodegeneration with Leigh-like brain MRI abnormalities. Significant variability was observed however with the age of symptom onset and rate of disease progression. The bilateral retinal cherry red spots and failure to thrive observed in our patient are unique features, which have not been described, in previously reported patients with TTC19 mutations. Interestingly, all reported TTC19 mutations are nonsense mutations. The severity of clinical manifestations however does not specifically correlate with the residual complex III enzyme activities.
authors.affiliation: SA Pathology, Women's and Children's Hospital, North Adelaide, Australia.|Department of Paediatrics, University of Adelaide, North Adelaide, Australia.
authors.forename: Dylan A
authors.initials: DA
authors.lastname: Mordaunt
authors.affiliation: SA Pathology, Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Jolley
authors.affiliation: SA Pathology, Women's and Children's Hospital, North Adelaide, Australia.|Metabolic Unit, Princess Margaret Hospital for Children, Subiaco, Australia.|School of Paediatrics and Child Health, The University of Western Australia, Perth, Australia.
authors.forename: Shanti
authors.initials: S
authors.lastname: Balasubramaniam
authors.affiliation: Murdoch Childrens Research Institute and Victorian Clinical Genetics Service, The Royal Children's Hospital, Parkville, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: Murdoch Childrens Research Institute and Victorian Clinical Genetics Service, The Royal Children's Hospital, Parkville, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, Australia.
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Mountford
authors.affiliation: Murdoch Childrens Research Institute and Victorian Clinical Genetics Service, The Royal Children's Hospital, Parkville, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, Australia.
authors.forename: Alison G
authors.initials: AG
authors.lastname: Compton
authors.affiliation: SA Pathology, Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Jillian
authors.initials: J
authors.lastname: Nicholl
authors.affiliation: SA Pathology, Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Manton
authors.affiliation: Department of Neurology, Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Damian
authors.initials: D
authors.lastname: Clark
authors.affiliation: SA Pathology, Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Drago
authors.initials: D
authors.lastname: Bratkovic
authors.affiliation: SA Pathology, Women's and Children's Hospital, North Adelaide, Australia.|Department of Paediatrics, University of Adelaide, North Adelaide, Australia.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Friend
authors.affiliation: SA Pathology, Women's and Children's Hospital, North Adelaide, Australia.
authors.forename: Sui
authors.initials: S
authors.lastname: Yu
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D018389:Codon, Nonsense; D003241:Consanguinity; D018450:Disease Progression; D014450:Electron Transport Complex III / Q000172:deficiency* / Q000235:genetics; D005183:Failure to Thrive / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007223:Infant; D007805:Language Development Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D024101:Mitochondrial Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012160:Retina / Q000378:metabolism / Q000473:pathology
chemical_list: D018389:Codon, Nonsense; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C557528:TTC19 protein, human; D014450:Electron Transport Complex III
keywords: TTC19; cytochrome bc1 complex; mitochondrial complex III; mitochondrial encephalomyopathy; ubiquinol-cytochrome c oxidoreductase