%0 Journal Article %T Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism. %A De la Casa-Fages B %A Fernández-Eulate G %A Gamez J %A Barahona-Hernando R %A Morís G %A García-Barcina M %A Infante J %A Zulaica M %A Fernández-Pelayo U %A Muñoz-Oreja M %A Urtasun M %A Olaskoaga A %A Zelaya V %A Jericó I %A Saez-Villaverde R %A Catalina I %A Sola E %A Martínez-Sáez E %A Pujol A %A Ruiz M %A Schlüter A %A Spinazzola A %A Muñoz-Blanco JL %A Grandas F %A Holt I %A Álvarez V %A López de Munaín A %J Mov Disord %V 34 %N 10 %D 10 2019 %M 31433872 %F 9.698 %R 10.1002/mds.27812 %X 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.
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.
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.
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).
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. © 2019 International Parkinson and Movement Disorder Society.