Nogueira, CéliaNesti, ClaudiaMeschini, Maria ChiaraCarrozzo, RosalbaBarros, JoseSá, Maria JoséAzevedo, LuisaVilarinho, LauraSantorelli, Filippo2013-02-062013-02-062012-11http://hdl.handle.net/10400.18/1194Publicado em: Livro de abstracts do congresso LIMPE_DISMOV 2012Introduction: Defects of mitochondrial complex III (CIII) are a relatively rare cause of mitochondrial dysfunction. The complex catalyzes the electron transfer from reduced coenzyme Q to cytochrome c and is composed of 11 subunits, one of which (MT-CYB) is mtDNA encoded. Mutations in MT-CYB and in assembly factor BCS1L account for the vast majority of cases with low CIII, and are associated with a wide range of neurological disorders. The gene coding for human tetratricopeptide 19 (TTC19) produces a poorly characterized protein thought to be involved in the correct assembly of CIII. Recently, mutations in TTC19 have been described in three unrelated Italian kindred in association with a severe neurodegenerative disease. Objectives: We studied a consanguineous Portuguese family where a severe neurometabolic disorder occurred in four siblings (three men and one woman) in association with a slowly progressive disorder characterized by dystonia of hands and feet, ataxic gait, severe olivo-ponto-cerebellar atrophy documented at brain MRI, and relentless psychiatric manifestations. Variability in age at onset and disease course was observed. Methods: The enzymatic activity of CIII was determined in muscle using a reported spectrophotometric method. Sequence analysis of genomic DNA was performed to identify disease-causing mutations in TTC19. Immunodetection analysis in muscle homogenate and skin fibroblasts allowed the detection of the amount TTC19 protein using a commercially available anti-TTC19 antibody. Results: In this family, we identified a novel homozygous TTC19 mutation predicting frameshift and early protein truncation. The mutation was heterozygous in parents and healthy siblings, and it was absent in ethnically-matched controls. The protein was undetectable in tissues by Western blot analyses. Conclusion: This is the fourth kindred presenting mutations in TTC19. The clinical phenotype of such condition is severe, embraces neurological and psychiatric symptoms, and represents a further example of autosomal recessive ataxia of metabolic origin.engCIIIAtaxiaDoenças Genéticasconference object