Beatriz De la Casa-Fages1,2,3, Gorka Fernández-Eulate4,5, Josep Gamez6,7, Raúl Barahona-Hernando1,8,9, Germán Morís10,11, María García-Barcina12, Jon Infante13,14, Miren Zulaica5,14, Uxoa Fernández-Pelayo5, Mikel Muñoz-Oreja5, Miguel Urtasun4, Ander Olaskoaga15, Victoria Zelaya16, Ivonne Jericó17, Raquel Saez-Villaverde18, Irene Catalina1,8, Emma Sola19, Elena Martínez-Sáez20,21, Aurora Pujol22,23,24, Montserrat Ruiz22,24, Agatha Schlüter22,24, Antonella Spinazzola25,26, Jose Luis Muñoz-Blanco1,3,8, Francisco Grandas1,2,3, Ian Holt5,27, Victoria Álvarez10,28, Adolfo López de Munaín4,5,29,30. 1. Department of Neurology, Hospital General Universitario Gregorio Marañon, Madrid, Spain. 2. Movement Disorders Unit, National Referral Center for rare diseases with Movement Disorders (CSUR), Hospital General Universitario Gregorio Marañon, Madrid, Spain. 3. Neurosciences Area, Instituto Investigacion Sanitaria Gregorio Marañon, Madrid, Spain. 4. Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain. 5. Department of Neurosciences, Instituto Biodonostia, San Sebastian, Spain. 6. Department of Neurology, Hospital General Universitari Vall d'Hebron-UAB-VHIR, Barcelona, Spain. 7. European Reference Network on Rare Neurological Diseases (ERN-RND), Hospital General Universitari Vall d'Hebron-UAB, Barcelona, Spain. 8. ALS-Neuromuscular Unit, Hospital General Universitario Gregorio Marañon, Madrid, Spain. 9. Department of Neurology, Hospital Ruber Juan Bravo, Grupo Quironsalud, Madrid, Spain. 10. Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain. 11. Department of Neurology, Hospital Universitario Central de Asturias, Oviedo, Spain. 12. Genetics Unit, Hospital Universitario Basurto, Bilbao, Spain. 13. Department of Neurology, Hospital Universitario Marques de Valdecilla-IDIVAL, University of Cantabria, Santander, Spain. 14. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Institute Carlos III, Spain. 15. Hospital de Zumarraga, Zumarraga, Spain. 16. Department of Pathology, Complejo Hospitalario de Navarra, Pamplona, Spain. 17. Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Spain. 18. Department of Genetics, Hospital Universitario Donostia, San Sebastian, Spain. 19. Department of Pathology, Hospital General Universitario Gregorio Marañon, Madrid, Spain. 20. Department of Pathology, Hospital General Universitari Vall d'Hebron-UAB-VHIR, Barcelona, Spain. 21. Department of Medicine, UAB, Barcelona, Spain. 22. Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. 23. Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain. 24. Center for Biomedical Research on Rare Diseases (CIBERER), Institute Carlos III, Madrid, Spain. 25. Department of Clinical Movement Neurosciences, UCL Queen Square Institute of Neurology, Royal Free Campus, London, United Kingdom. 26. MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom. 27. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. 28. Genetics Laboratory, AGC Medicine Laboratory, Hospital Universitario Central de Asturias, Oviedo, Spain. 29. Department of Neurosciences UPV/EHU, San Sebastian, Spain. 30. Ciberned, Ministry of Science, Innovation and Universities, Madrid, Spain.
Abstract
BACKGROUND: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA. OBJECTIVES: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients. METHODS: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction. RESULTS: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001). CONCLUSIONS: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families.
BACKGROUND: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA. OBJECTIVES: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients. METHODS: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction. RESULTS: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001). CONCLUSIONS:Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families.
Authors: Michel Sáenz-Farret; Anthony E Lang; Lorraine Kalia; Inês Cunha; Mário Sousa; Greg Kuhlman; Christos Ganos; Renato P Munhoz; Alfonso Fasano; Carlos Eduardo Piña-Avilés; Carlos Zúñiga-Ramírez Journal: Mov Disord Clin Pract Date: 2022-04-01
Authors: T Bogdan; T Wirth; A Iosif; A Schalk; S Montaut; C Bonnard; G Carre; O Lagha-Boukbiza; C Reschwein; E Albugues; S Demuth; H Landsberger; M Einsiedler; T Parratte; A Nguyen; F Lamy; H Durand; P Fahrer; P Voulleminot; K Bigaut; J B Chanson; G Nicolas; J Chelly; C Cazeneuve; M Koenig; C Bund; I J Namer; S Kremer; N Calmels; C Tranchant; M Anheim Journal: J Neurol Date: 2022-07-23 Impact factor: 6.682
Authors: Shaun Martin; Stefanie Smolders; Peter Vangheluwe; Christine Van Broeckhoven; Chris Van den Haute; Bavo Heeman; Sarah van Veen; David Crosiers; Igor Beletchi; Aline Verstraeten; Helena Gossye; Géraldine Gelders; Philippe Pals; Norin Nabil Hamouda; Sebastiaan Engelborghs; Jean-Jacques Martin; Jan Eggermont; Peter Paul De Deyn; Patrick Cras; Veerle Baekelandt Journal: Acta Neuropathol Date: 2020-03-14 Impact factor: 17.088
Authors: V Montano; D Orsucci; V Carelli; C La Morgia; M L Valentino; C Lamperti; S Marchet; O Musumeci; A Toscano; G Primiano; F M Santorelli; C Ticci; M Filosto; A Rubegni; T Mongini; P Tonin; S Servidei; R Ceravolo; G Siciliano; Michelangelo Mancuso Journal: J Neurol Date: 2021-07-14 Impact factor: 4.849