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

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.

• Authors: Beatriz De la Casa-Fages, Gorka Fernández-Eulate, Josep Gamez, Raúl Barahona-Hernando, Germán Morís, María García-Barcina, Jon Infante, Miren Zulaica, Uxoa Fernández-Pelayo, Mikel Muñoz-Oreja, Miguel Urtasun, Ander Olaskoaga, Victoria Zelaya, Ivonne Jericó, Raquel Saez-Villaverde, Irene Catalina, Emma Sola, Elena Martínez-Sáez, Aurora Pujol, Montserrat Ruiz, Agatha Schlüter, Antonella Spinazzola, Jose Luis Muñoz-Blanco, Francisco Grandas, Ian Holt, Victoria Álvarez, Adolfo López de Munaín
• Journal: Movement disorders : official journal of the Movement Disorder Society (Mov Disord) Vol. 34 Issue 10 Pg. 1547-1561 (10 2019) ISSN: 1531-8257 [Electronic] United States
• PMID: 31433872 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 International Parkinson and Movement Disorder Society.

Chemical References

• DNA, Mitochondrial

Topics

• Adolescent
• Adult
• Child
• DNA, Mitochondrial (genetics)
• Female
• Humans
• Male
• Middle Aged
• Mitochondria (genetics)
• Mitochondrial Diseases (genetics)
• Mutation (genetics)
• Paraplegia (genetics)
• Parkinsonian Disorders (genetics)
• Phenotype
• Spastic Paraplegia, Hereditary (genetics)
• Young Adult