%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.