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. 2019 Oct;34(10):1547-1561.
doi: 10.1002/mds.27812. Epub 2019 Aug 21.

Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism

Beatriz De la Casa-Fages  1   2   3 , Gorka Fernández-Eulate  4   5 , Josep Gamez  6   7 , Raúl Barahona-Hernando  1   8   9 , Germán Morís  10   11 , María García-Barcina  12 , Jon Infante  13   14 , Miren Zulaica  5   14 , Uxoa Fernández-Pelayo  5 , Mikel Muñoz-Oreja  5 , Miguel Urtasun  4 , Ander Olaskoaga  15 , Victoria Zelaya  16 , Ivonne Jericó  17 , Raquel Saez-Villaverde  18 , Irene Catalina  1   8 , Emma Sola  19 , Elena Martínez-Sáez  20   21 , Aurora Pujol  22   23   24 , Montserrat Ruiz  22   24 , Agatha Schlüter  22   24 , Antonella Spinazzola  25   26 , Jose Luis Muñoz-Blanco  1   3   8 , Francisco Grandas  1   2   3 , Ian Holt  5   27 , Victoria Álvarez  10   28 , Adolfo López de Munaín  4   5   29   30
Affiliations

Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism

Beatriz De la Casa-Fages et al. Mov Disord. 2019 Oct.

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. © 2019 International Parkinson and Movement Disorder Society.

Keywords: SPG7 gene; hereditary spastic paraplegia; mitochondria; parkinsonism; pathogenic genetic variants.

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References

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