%0 Journal Article %A De la Casa-Fages, Beatriz %A Fernández-Eulate, Gorka %A Gamez, Josep %A Barahona-Hernando, Raúl %A Morís, Germán %A García-Barcina, María %A Infante, Jon %A Zulaica, Miren %A Fernández-Pelayo, Uxoa %A Muñoz-Oreja, Mikel %A Urtasun, Miguel %A Olaskoaga, Ander %A Zelaya, Victoria %A Jericó, Ivonne %A Saez-Villaverde, Raquel %A Catalina, Irene %A Sola Vendrell, Emma %A Martínez-Sáez, Elena %A Pujol, Aurora %A Ruiz, Montserrat %A Schlüter, Agatha %A Spinazzola, Antonella %A Muñoz-Blanco, Jose Luis %A Holt, Ian %A Álvarez, Victoria %A López de Munaín, Adolfo %A Grandas Pérez, Francisco Javier %T Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism %D 2019 %@ 1547-1561 %U https://hdl.handle.net/20.500.14352/100492 %X BackgroundPathogenic 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.ObjectivesTo better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients.MethodsGenetic 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.ResultsThirty-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).ConclusionsParkinsonism 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. %~