Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood
Por:
Baide-Mairena H, Gaudó P, Marti-Sanchez L, Emperador S, Sánchez-Montanez A, Alonso-Luengo O, Correa M, Grau AM, Ortigoza-Escobar JD, Artuch-Iriberri R, Vázquez E, Del Toro M, Garrido-Pérez N, Ruiz-Pesini E, Montoya C, Bayona-Bafaluy MP and Pérez-Dueñas B
Publicada:
1 mar 2019
Ahead of Print:
5 ene 2019
Resumen:
Aim: To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations.
Method: A multi-gene panel of childhood-onset basal ganglia neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts.
Results: Three siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Brain magnetic resonance showed symmetric and bilateral cytotoxic lesions in the putamen and proliferation of the lenticular-striate arteries, latter spreading to the caudate and progressing to cavitation and volume loss. We identified a frameshift novel change (c.554_558delTTCTT; p.Tyr187AsnfsTer65) and a pathogenic missense change (c.371T > C; p.Ile124Thr) in the NDUFAF6 gene, which segregated with an autosomal recessive inheritance within the family. Patient mutations were associated with the absence of the NDUFAF6 protein and reduced activity and assembly of mature complex I in fibroblasts. By functional complementation assay, the mutant phenotype was rescued by the canonical version of the NDUFAF6. A literature review of 14 NDUFAF6 patients showed a consistent phenotype of an early childhood insidious onset neurological regression with prominent dystonia associated with basal ganglia degeneration and long survival.
Interpretation: NDUFAF6-related Leigh syndrome is a relevant cause of childhood onset dystonia and isolated bilateral striatal necrosis. By genetic complementation, we could demonstrate the pathogenicity of novel genetic variants in NDUFAF6.
Filiaciones:
Baide-Mairena H:
Department of Child Neurology, Hospital Vall d'Hebron - Institut de Recerca (VHIR), Barcelona, Spain
Faculty of Medicine, Universitat Autónoma de Barcelona, Unitat Docent Vall d'Hebrón, Spain
Gaudó P:
Departament of Biochemistry, Molecular and Cellular Biology, Zaragoza University-Sanitary Research Institute of Aragon (IIS-Aragón), Zaragoza, Spain
Marti-Sanchez L:
Clinical Biochemistry Institut de Recerca - Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Emperador S:
Departament of Biochemistry, Molecular and Cellular Biology, Zaragoza University-Sanitary Research Institute of Aragon (IIS-Aragón), Zaragoza, Spain
CIBERER, Centro de Investigaciones Biomédicas en Red de Enfermedades Raras, Madrid, Spain
Sánchez-Montanez A:
Neuroradiology Hospital Vall d'Hebron - Institut de Recerca (VHIR), Barcelona, Spain
Alonso-Luengo O:
Department of Pediatrics, University Hospital Virgen del Rocío, Sevilla, Spain
Correa M:
Department of Child Neurology, Hospital Vall d'Hebron - Institut de Recerca (VHIR), Barcelona, Spain
Grau AM:
Department of Child Neurology, Hospital Vall d'Hebron - Institut de Recerca (VHIR), Barcelona, Spain
Ortigoza-Escobar JD:
Department of Child Neurology Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Artuch-Iriberri R:
Clinical Biochemistry Institut de Recerca - Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain
Vázquez E:
Neuroradiology Hospital Vall d'Hebron - Institut de Recerca (VHIR), Barcelona, Spain
Del Toro M:
Department of Child Neurology, Hospital Vall d'Hebron - Institut de Recerca (VHIR), Barcelona, Spain
Garrido-Pérez N:
Departament of Biochemistry, Molecular and Cellular Biology, Zaragoza University-Sanitary Research Institute of Aragon (IIS-Aragón), Zaragoza, Spain
Ruiz-Pesini E:
Departament of Biochemistry, Molecular and Cellular Biology, Zaragoza University-Sanitary Research Institute of Aragon (IIS-Aragón), Zaragoza, Spain
Montoya C:
Departament of Biochemistry, Molecular and Cellular Biology, Zaragoza University-Sanitary Research Institute of Aragon (IIS-Aragón), Zaragoza, Spain
CIBERER, Centro de Investigaciones Biomédicas en Red de Enfermedades Raras, Madrid, Spain
Bayona-Bafaluy MP:
Departament of Biochemistry, Molecular and Cellular Biology, Zaragoza University-Sanitary Research Institute of Aragon (IIS-Aragón), Zaragoza, Spain
CIBERER, Centro de Investigaciones Biomédicas en Red de Enfermedades Raras, Madrid, Spain
Pérez-Dueñas B:
Department of Child Neurology, Hospital Vall d'Hebron - Institut de Recerca (VHIR), Barcelona, Spain
CIBERER, Centro de Investigaciones Biomédicas en Red de Enfermedades Raras, Madrid, Spain
Faculty of Medicine, Universitat Autónoma de Barcelona, Unitat Docent Vall d'Hebrón, Spain
Green Accepted
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