title: Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype.
abstract: BACKGROUND
  TTC19 deficiency is a progressive neurodegenerative disease associated with isolated mitochondrial respiratory chain (MRC) complex III deficiency and loss-of-function mutations in the TT19 gene in the few patients reported so far.
  
  
  METHODS
  We performed exome sequencing and selective mutational analysis of TTC19, respectively, in patients from three unrelated families presenting with initially unspecific clinical signs of muscular hypotonia and global developmental delay followed by regression, ataxia, loss of speech, and rapid neurological deterioration. One patient showed severe lactic acidosis at the neonatal age and during intercurrent illness.
  
  
  RESULTS
  We identified homozygous mutations in all three index cases, in two families novel missense mutations (c.544 T > C/p.Leu185Pro; c.917 T > C/p.Leu324Pro). The younger sister of the severely affected patient 3 showed only mild delay of motor skills and muscular hypotonia so far but is also homozygous for the same mutation. Notably, one patient revealed normal activities of MRC complex III in two independent muscle biopsies. Neuroimaging of the severely affected patients demonstrated lesions in putamen and caudate nuclei, cerebellar atrophy, and the unusual finding of hypertrophic olivary nuclei degeneration. Reviewing the literature revealed striking similarities regarding neuroimaging and clinical course in pediatric patients with TTC19 deficiency: patterns consistent with Leigh or Leigh-like syndrome were found in almost all, hypertrophic olivary nucleus degeneration in all patients reported so far. The clinical course in pediatric patients is characterized by an initially unspecific developmental delay, followed by regression, progressive signs and symptoms of cerebellar, basal ganglia and brainstem affection, especially loss of speech and ataxia. Subsequently, neurological deterioration leading to a vegetative state occurs.
  
  
  CONCLUSIONS
  Our findings add to the phenotypic, genetic, and biochemical spectrum of TTC19 deficiency. However, TTC19 deficient patients do show characteristic clinical and neuroimaging features, which may facilitate diagnosis of this yet rare disorder. Normal MRC complex III activity does not exclude the diagnosis.
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020, Salzburg, Austria. j.koch@salk.at.
authors.forename: Johannes
authors.initials: J
authors.lastname: Koch
authors.affiliation: Department of Pediatrics Kreisklinken Reutlingen, Steinenbergstr. 31, 72764, Reutlingen, Germany. freisinger_p@klin-rt.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Freisinger
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020, Salzburg, Austria. r.feichtinger@salk.at.
authors.forename: René G
authors.initials: RG
authors.lastname: Feichtinger
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020, Salzburg, Austria. f.zimmermann@salk.at.
authors.forename: Franz A
authors.initials: FA
authors.lastname: Zimmermann
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020, Salzburg, Austria. c.rauscher@salk.at.
authors.forename: Christian
authors.initials: C
authors.lastname: Rauscher
authors.affiliation: Department of Pediatrics, Krankenhaus der Barmherzigen Brueder, Esterhazystr. 26, 7000, Eisenstadt, Austria. wagentristl@gmx.at.
authors.forename: Hans P
authors.initials: HP
authors.lastname: Wagentristl
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. vassiliki.konstantopoulou@meduniwien.ac.at.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Konstantopoulou
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. rainer.seidl@meduniwien.ac.at.
authors.forename: Rainer
authors.initials: R
authors.lastname: Seidl
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany. tobias.haack@helmholtz-muenchen.de.|Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Trogerstr. 32/3, 81675, Munich, Germany. tobias.haack@helmholtz-muenchen.de.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany. prokisch@helmholtz-muenchen.de.|Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Trogerstr. 32/3, 81675, Munich, Germany. prokisch@helmholtz-muenchen.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Trogerstr. 32/3, 81675, Munich, Germany. uwe.ahting@humangenetik.med.tum.de.
authors.forename: Uwe
authors.initials: U
authors.lastname: Ahting
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020, Salzburg, Austria. w.sperl@salk.at.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sperl
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020, Salzburg, Austria. h.mayr@salk.at.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Mayr
authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg, Muellner Hauptstr. 48, 5020, Salzburg, Austria. esther.maier@med.uni-muenchen.de.|Present affiliation: Dr. von Hauner Children's Hospital, University of Munich, Lindwurmstr. 4, 80337, Munich, Germany. esther.maier@med.uni-muenchen.de.
authors.forename: Esther M
authors.initials: EM
authors.lastname: Maier
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D003001:Cloning, Molecular; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C557528:TTC19 protein, human