Heidy Baide-Mairena1, Paula Gaudó2, Laura Marti-Sánchez3, Sonia Emperador4, Angel Sánchez-Montanez5, Olga Alonso-Luengo6, Marta Correa7, Anna Marcè Grau7, Juan Darío Ortigoza-Escobar8, Rafael Artuch3, Elida Vázquez5, Mireia Del Toro7, Nuria Garrido-Pérez2, Eduardo Ruiz-Pesini2, Julio Montoya4, María Pilar Bayona-Bafaluy4, Belén Pérez-Dueñas9. 1. 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. 2. Departament of Biochemistry, Molecular and Cellular Biology, Zaragoza University-Sanitary Research Institute of Aragon (IIS-Aragón), Zaragoza, Spain. 3. Clinical Biochemistry Institut de Recerca - Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain. 4. 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. 5. Neuroradiology Hospital Vall d'Hebron - Institut de Recerca (VHIR), Barcelona, Spain. 6. Department of Pediatrics, University Hospital Virgen del Rocío, Sevilla, Spain. 7. Department of Child Neurology, Hospital Vall d'Hebron - Institut de Recerca (VHIR), Barcelona, Spain. 8. Department of Child Neurology Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain. 9. 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. Electronic address: belen.perez@vhir.org.
Abstract
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.
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 NDUFAF6patients 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.
Authors: Thomas Johnstone; Jennifer Wang; Daron Ross; Nicholas Balanda; Yan Huang; Rena Godfrey; Catherine Groden; Brandon R Barton; William Gahl; Camilo Toro; May Christine V Malicdan Journal: Mol Genet Metab Date: 2020-10-14 Impact factor: 4.797