Posted - December 2019 in Research Highlights
Parkinsonism and a potential eye movement biomarker
Large study expands knowledge of SPG7 with Parkinsonism found in 20%
This large study of people with SPG7 in Spain has resulted in a significant expansion of knowledge of this HSP type, with impairment of mitochondrial function universal and Parkinsonism as a not uncommon related effect.
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 SPG7 gene. Mean age at onset was 40 years (range, 12-63); 63% of SPG7 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 SPG7 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.
SOURCE: Mov Disord. 2019 Aug 21. doi: 10.1002/mds.27812. [Epub ahead of print] © 2019 International Parkinson and Movement Disorder Society. PMID: 31433872
Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism.
De la Casa-Fages B1,2,3, Fernández-Eulate G4,5, Gamez J6,7, Barahona-Hernando R1,8,9, Morís G10,11, García-Barcina M12, Infante J13,14, Zulaica M5,14, Fernández-Pelayo U5, Muñoz-Oreja M5, Urtasun M4, Olaskoaga A15, Zelaya V16, Jericó I17, Saez-Villaverde R18, Catalina I1,8, Sola E19, Martínez-Sáez E20,21, Pujol A22,23,24, Ruiz M22,24, Schlüter A22,24, Spinazzola A25,26, Muñoz-Blanco JL1,3,8, Grandas F1,2,3, Holt I5,27, Álvarez V10,28, López de Munaín A4,5,29,30.
1 Department of Neurology, Hospital General Universitario Gregorio Marañon, Madrid, Spain.
2 Movement Disorders Unit, National Referral Center for rare diseases with Movement Disorders (CSUR), Hospital General Universitario Gregorio Marañon, Madrid, Spain.
3 Neurosciences Area, Instituto Investigacion Sanitaria Gregorio Marañon, Madrid, Spain.
4 Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain.
5 Department of Neurosciences, Instituto Biodonostia, San Sebastian, Spain.
6 Department of Neurology, Hospital General Universitari Vall d’Hebron-UAB-VHIR, Barcelona, Spain.
7 European Reference Network on Rare Neurological Diseases (ERN-RND), Hospital General Universitari Vall d’Hebron-UAB, Barcelona, Spain.
8 ALS-Neuromuscular Unit, Hospital General Universitario Gregorio Marañon, Madrid, Spain.
9 Department of Neurology, Hospital Ruber Juan Bravo, Grupo Quironsalud, Madrid, Spain.
10 Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
11 Department of Neurology, Hospital Universitario Central de Asturias, Oviedo, Spain.
12 Genetics Unit, Hospital Universitario Basurto, Bilbao, Spain.
13 Department of Neurology, Hospital Universitario Marques de Valdecilla-IDIVAL, University of Cantabria, Santander, Spain.
14 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Institute Carlos III, Spain.
15 Hospital de Zumarraga, Zumarraga, Spain.
16 Department of Pathology, Complejo Hospitalario de Navarra, Pamplona, Spain.
17 Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Spain.
18 Department of Genetics, Hospital Universitario Donostia, San Sebastian, Spain.
19 Department of Pathology, Hospital General Universitario Gregorio Marañon, Madrid, Spain.
20 Department of Pathology, Hospital General Universitari Vall d’Hebron-UAB-VHIR, Barcelona, Spain.
21 Department of Medicine, UAB, Barcelona, Spain.
22 Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain.
23 Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain.
24 Center for Biomedical Research on Rare Diseases (CIBERER), Institute Carlos III, Madrid, Spain.
25 Department of Clinical Movement Neurosciences, UCL Queen Square Institute of Neurology, Royal Free Campus, London, United Kingdom.
26 MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, United Kingdom.
27 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
28 Genetics Laboratory, AGC Medicine Laboratory, Hospital Universitario Central de Asturias, Oviedo, Spain.
29 Department of Neurosciences UPV/EHU, San Sebastian, Spain.
30 Ciberned, Ministry of Science, Innovation and Universities, Madrid, Spain.
Eye movement disorder in SPG7 HSP
Characteristic may be a valuable biomarker
Anecdotal oculomotor disturbances have been described in spastic paraplegia type 7 (SPG7). We investigated oculomotor and vestibular dysfunction in five patients with genetically verified SPG7. All five patients exhibited significantly slower velocities of vertical saccades compared to controls, but significantly faster than in progressive supranuclear palsy, with upward saccades being particularly affected. Horizontal saccades, cerebellar oculomotor markers, and vestibuloocular reflex seem to be variably affected.
Thus, albeit subclinical in some cases, slowing of the vertical saccades may belong to the phenotype of SPG7 and may serve as a valuable biomarker for differentiation from spastic ataxias and atypical parkinsonism.
SOURCE: Ann Clin Transl Neurol. 2019 Oct;6(10):2127-2132. doi: 10.1002/acn3.50907. Epub 2019 Oct 10. © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. PMID: 31602813
Slowed vertical saccades as a hallmark of hereditary spastic paraplegia type 7.
1 Department of Neurology, Medical University of Vienna, Vienna, Austria.