Motor system abnormalities in hereditary spastic paraparesis type 4 (SPG4) depend on the type of mutation in the spastin gene

Bönsch, Dominikus; Schwindt, Adam R.; Navratil, P; Palm, Daniel; Neumann, C.; Klimpe, S.; Schickel, J.; Hazan, Jamilé; Weiller, Cornelius; Deufel, Thomas; Liepert, Joachim

doi:10.1136/jnnp.74.8.1109

Cited by 25 publications

(17 citation statements)

References 17 publications

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“…CMCT calculation method was specified for 24/32 papers; 11 papers used the F-wave method, 11 papers used the spinal stimulation method and 2 studies used both methods (23, 24). Two studies used the F-wave method, however detailed a different peripheral motor conduction time calculation formula to previously published guidelines (13, 16, 25).…”

Section: Resultsmentioning

confidence: 99%

Motor Evoked Potentials in Hereditary Spastic Paraplegia—A Systematic Review

Siow

Smail

et al. 2019

Front. Neurol.

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Background: Hereditary Spastic Paraplegia (HSP) is a slowly progressive neurodegenerative disorder with no disease modifying treatment. Potential therapeutic approaches are emerging and large-scale clinical drug trials for patients with HSP are imminent. A sensitive biomarker to measure the drug efficacy in these trials is required. Motor evoked potentials (MEPs) are a potential biomarker for HSP as they assess the central motor pathways and can be standardized with set protocols and guidelines.Objectives: We performed a systematic review to investigate the utility of MEPs as a diagnostic and disease severity biomarker for HSP.Search Methods: Systematic searches of PubMed, Embase, Medline, and Scopus were performed.Selection Criteria: Studies reporting on central motor conduction time measured with MEPs in adult and pediatric patients with HSP were included. We excluded studies in non-HSP patient cohorts, not in English, not original research, and unpublished journal articles.Data Collection and analysis: Search results were de-duplicated and screened according to the inclusion and exclusion criteria. The included papers were reviewed independently by two reviewers and data was collected on patient cohorts, test methods, results, and study quality. Results were analyzed using descriptive methods.Results: Of the 882 search results, 32 studies were included in the review. The most common finding was absent or prolonged lower limb (LL) central motor conduction time (CMCT) in patients with HSP (78% of patients studied). Quality assessment revealed variability in study methodology and reporting of results. Variations included patient cohorts of various genotypes as well as variations in equipment and techniques used. Aside from CMCT, none of the MEP parameter measures correlated with disease severity and many did not show significant difference between HSP patients and controls.Conclusion: Systematic review of MEP studies in HSP patient cohorts demonstrated mixed findings. Lower limb CMCT was the most promising parameter in terms of differentiating HSP patients from controls, with one study demonstrating a weak correlation with clinical disease severity. It is possible that the lack of consistency in study methodologies and small patient cohorts have contributed to the variable findings. A longitudinal study of MEPs in a large cohort of HSP patients with the same genotype will help clarify the utility of MEPs as a biomarker for disease severity and use in clinical trials.

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Section: Resultsmentioning

confidence: 99%

Motor Evoked Potentials in Hereditary Spastic Paraplegia—A Systematic Review

Siow

Smail

et al. 2019

Front. Neurol.

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“…The affected women on the other hand, presented normal CMCTs even in affected legs, which is consistent with axonal disease of the pyramidal tract. The molecular mechanisms that induce axonal involvement are poorly understood and may differ among mutations 12. Axonal dysfunctions could result from biological and biochemical changes in axons, such as an impairment of fine regulation of the microtubule cytoskeleton in long axons, an altered microtubule metabolism, or defects in synaptic growth and neurotransmission 13–15.…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic study of a large SPG4 Italian family

et al. 2005

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A novel SPG4 906delT frame-shift mutation in exon 6 was identified in a large Italian family with an autosomal dominant form of hereditary spastic paraplegia (ADHSP). Intrafamilial phenotypic variations observed in the pedigree included spasticity and additional clinical features, such as peripheral sensory-motor neuropathy, cognitive impairment, and urological dysfunction. Severe clinical features were found predominantly in the men who were affected, and there was no statistically significant correlation of disability and time since onset of symptoms, suggesting the existence of other genetic/nongenetic modifier(s), including gender.

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“…9 Spastin appears to interact with atlastin-1 (encoded by SPG3A ) and receptor expression enhancing protein 1 (encoded by REEP1 ); haploinsufficiency of these proteins leads to SPG3A and SPG31, respectively, two other types of AD-HSP. 10 Though convincing genotype-phenotype correlations for SPAST mutations in SPG4 have been alternately reported 11–13 and discounted, 14,15 point mutations and indels tend to cluster in the sequences coding for the AAA domain, MIT (microtubule interacting and trafficking) domain, MTBD (microtubule-binding domain), and a yet-undefined region (residues 228–269) of spastin. 16 Several sequence variants within SPAST (reviewed in 17 ) and one in heat shock 60kDa protein 1 (chaperonin) ( HSPD1 ; the gene associated with SPG13) 18 have been proposed to be modifiers of the SPG4 phenotype.…”

Section: Introductionmentioning

confidence: 99%

Alu-specific microhomology-mediated deletion of the final exon of SPAST in three unrelated subjects with hereditary spastic paraplegia

Boone

Liu

Zhang

et al. 2011

Genetics in Medicine

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Purpose Autosomal dominant spastic paraplegia, type 4 (SPG4), a debilitating disorder of progressive spasticity and weakness of the lower limbs, results from heterozygous mutations in the SPAST gene. The full spectrum of SPAST mutations causing SPG4 and their mechanisms of formation remain to be determined. Methods We used multiplex ligation-dependent probe amplification, locus-specific array comparative genomic hybridization, and breakpoint DNA sequencing to identify and describe genomic rearrangements in three patients with a clinical presentation of hereditary spastic paraplegia. Results We describe three SPG4 patients with intragenic rearrangements in SPAST; all specifically delete the final exon, exon 17. Breakpoint sequence analyses provide evidence for Alu-specific microhomology-mediated deletion as the mechanism of exon loss; one complex rearrangement apparently occurred by multiple Alu-facilitated template switches. Conclusion We hypothesize that the high concentration of Alu family members in the introns and flanking sequence of SPAST may predispose to intragenic rearrangements. Thus, Alu-specific microhomology-mediated intragenic rearrangements in SPAST may be a common cause of SPG4. Furthermore, we propose that genomic deletions encompassing the final exon of SPAST may affect expression of SLC30A6, the most proximal downstream locus and a gene that has been implicated in the pathogenesis of Alzheimer disease, potentially explaining recent reports of dementia in selected SPG4 patients.

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Motor system abnormalities in hereditary spastic paraparesis type 4 (SPG4) depend on the type of mutation in the spastin gene

Cited by 25 publications

References 17 publications

Motor Evoked Potentials in Hereditary Spastic Paraplegia—A Systematic Review

Motor Evoked Potentials in Hereditary Spastic Paraplegia—A Systematic Review

Clinical and genetic study of a large SPG4 Italian family

Alu-specific microhomology-mediated deletion of the final exon of SPAST in three unrelated subjects with hereditary spastic paraplegia

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