Prevalence and phenotype of the c.1529C&gt;T <scp>SPG</scp>7 variant in adult‐onset cerebellar ataxia in Italy

Mancini, Cecilia; Giorgio, Elisa; Rubegni, Anna; Pradotto, Luca; Bagnoli, Siro; Rubino, Elisa; Prontera, Paolo; Cavalieri, Simona; Gregorio, Eleonora Di; Ferrero, Marta; Pozzi, Elisa; Riberi, Evelise; Ferrero, Paula Gallego; Nigro, Pasquale; Mauro, Alessandro; Zibetti, Maurizio; Tessa, Alessandra; Barghigiani, Melissa; Antenora, Antonella; Sirchia, Fabio; Piacentini, Silvia; Silvestri, Gabriella; Michele, G. De; Filla, Alessandro; Orsi, Laura; Santorelli, Filippo M.; Brusco, Alfredo

doi:10.1111/ene.13768

Cited by 12 publications

(8 citation statements)

References 29 publications

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“…We found that p.Ala510Val homozygotes patients have a milder phenotype than compound heterozygotes, including a lower frequency of ptosis, bladder disorders, pyramidal signs (Babinski), and sensory signs . Unlike van Gassen and colleagues, we did not find a correlation between genotype and form of the disease, given that the same variant may cause pure and complex forms with a large phenotypic heterogeneity.…”

Section: Discussioncontrasting

confidence: 85%

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

et al. 2019

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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

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Section: Discussioncontrasting

confidence: 85%

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

et al. 2019

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“…Next, we tested the human SPG7_ del fibroblasts together with four SPG7 missense mutant cells [59] ( Fig. 1 G ), as well as fibroblasts deriving from non-SPG7 forms of HSP, i.e.…”

Section: Resultsmentioning

confidence: 99%

Impaired flickering of the permeability transition pore causes SPG7 spastic paraplegia

et al. 2020

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Background Mutations of the mitochondrial protein paraplegin cause hereditary spastic paraplegia type 7 (SPG7), a so-far untreatable degenerative disease of the upper motoneuron with still undefined pathomechanism. The intermittent mitochondrial permeability transition pore (mPTP) opening, called flickering, is an essential process that operates to maintain mitochondrial homeostasis by reducing intra-matrix Ca 2+ and reactive oxygen species (ROS) concentration, and is critical for efficient synaptic function. Methods We use a fluorescence-based approach to measure mPTP flickering in living cells and biochemical and molecular biology techniques to dissect the pathogenic mechanism of SPG7. In the SPG7 animal model we evaluate the potential improvement of the motor defect, neuroinflammation and neurodegeneration by means of an mPTP inducer, the benzodiazepine Bz-423. Findings We demonstrate that paraplegin is required for efficient transient opening of the mPTP, that is impaired in both SPG7 patients-derived fibroblasts and primary neurons from Spg7 −/− mice. We show that dysregulation of mPTP opening at the pre-synaptic terminal impairs neurotransmitter release leading to ineffective synaptic transmission. Lack of paraplegin impairs mPTP flickering by a mechanism involving increased expression and activity of sirtuin3, which promotes deacetylation of cyclophilin D, thus hampering mPTP opening. Pharmacological treatment with Bz-423, which bypasses the activity of CypD, normalizes synaptic transmission and rescues the motor impairment of the SPG7 mouse model. Interpretation mPTP targeting opens a new avenue for the potential therapy of this form of spastic paraplegia. Funding Telethon Foundation grant (TGMGCSBX16TT); Dept. of Defense, US Army, grant W81XWH-18–1–0001

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“…With regard to the recessive forms, our study confirmed that SPG11 is one of the most common AR HSP genes: indeed, together with those in CYP7B1 /SPG5, DDHD2 /SPG54, and FA2H /SPG35, mutations in SPG11 account for half of all AR cases. Finally, the relatively low frequency of mutations in SPG7 might be related to their study in a concurrent “ataxia-associated” NGS panel (54).…”

Section: Discussionmentioning

confidence: 99%

Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study

et al. 2018

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Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity—there are over 80 potential disease-associated genes—and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy.

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Prevalence and phenotype of the c.1529C>T SPG7 variant in adult‐onset cerebellar ataxia in Italy

Cited by 12 publications

References 29 publications

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

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

Impaired flickering of the permeability transition pore causes SPG7 spastic paraplegia

Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study

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