Cortical Damage Associated With Cognitive and Motor Impairment in Hereditary Spastic Paraplegia: Evidence of a Novel SPAST Mutation

Lin, Jianzhong; Zheng, Honghua; Ma, Qin; Wang, Chen; Fan, Liping; Wu, Hanming; Wang, Danni; Zhang, Jiaxing; Zhan, Yihong

doi:10.3389/fneur.2020.00399

Cited by 9 publications

(10 citation statements)

References 34 publications

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“…In this work, a novel data-driven multivariate approach was applied to investigate brain damage pattern in HSP subtypes. It was found that patients with SPG4 and SPG5 shared a similar WM damage pattern in which GM volume reductions in these brain regions have been reported in SPG4 patients [3,[5][6][7][8]. At network level, these cortical regions mainly belong to the dorsal attention network [22].…”

Section: Discussionmentioning

confidence: 70%

“…Amongst the genetic subtypes of HSPs, spastic paraplegia type 4 (SPG4) caused by mutations in the SPAST gene is the most common form of autosomal dominant HSP involving impaired axonal transport, whilst spastic paraplegia type 5 (SPG5) caused by mutations in the CYP7B1 gene is an autosomal recessive form of HSP involving abnormalities in lipid metabolism [1]. Previous neuroimaging studies have reported brain structural alteration in both SPG4 and SPG5 [3][4][5][6][7][8][9][10][11]. Although both HSP subtypes were characterized by widespread white matter (WM) involvement, inconsistent results in grey matter (GM) alterations have been reported in these studies [5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

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Relationship between brain white matter damage and grey matter atrophy in hereditary spastic paraplegia types 4 and 5

Tu,

Liu,

Fan

et al. 2024

Euro J of Neurology

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Background and purposeWhite matter (WM) damage is the main target of hereditary spastic paraplegia (HSP), but mounting evidence indicates that genotype‐specific grey matter (GM) damage is not uncommon. Our aim was to identify and compare brain GM and WM damage patterns in HSP subtypes and investigate how gene expression contributes to these patterns, and explore the relationship between GM and WM damage.MethodsIn this prospective single‐centre cohort study from 2019 to 2022, HSP patients and controls underwent magnetic resonance imaging evaluations. The alterations of GM and WM patterns were compared between groups by applying a source‐based morphometry approach. Spearman rank correlation was used to explore the associations between gene expression and GM atrophy patterns in HSP subtypes. Mediation analysis was conducted to investigate the interplay between GM and WM damage.ResultsTwenty‐one spastic paraplegia type 4 (SPG4) patients (mean age 50.7 years ± 12.0 SD, 15 men), 21 spastic paraplegia type 5 (SPG5) patients (mean age 29.1 years ± 12.8 SD, 14 men) and 42 controls (sex‐ and age‐matched) were evaluated. Compared to controls, SPG4 and SPG5 showed similar WM damage but different GM atrophy patterns. GM atrophy patterns in SPG4 and SPG5 were correlated with corresponding gene expression (ρ = 0.30, p = 0.008, ρ = 0.40, p < 0.001, respectively). Mediation analysis indicated that GM atrophy patterns were mediated by WM damage in HSP.ConclusionsGrey matter atrophy patterns were distinct between SPG4 and SPG5 and were not only secondary to WM damage but also associated with disease‐related gene expression.Clinical trial registration no. NCT04006418.

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Section: Discussionmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Relationship between brain white matter damage and grey matter atrophy in hereditary spastic paraplegia types 4 and 5

Tu,

Liu,

Fan

et al. 2024

Euro J of Neurology

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“…A study of HSP in SPG4 patients found that the disease duration was negatively correlated with cortical thickness and the Montreal Cognitive Assessment score. 20 An Italian pilot study similarly found a significant correlation between the SPRS score and disease duration (β=0.408, p <0.01). 26 In contrast to the general conception that neurodegenerative disease are more progressed when symptoms begin to appear earlier, our results showed that a later age at onset significantly affected the disease severity and ambulatory dysfunction.…”

Section: Discussionmentioning

confidence: 84%

“…Abnormal brain MRI was positively correlated with disability severity, and cortical thickness was negatively correlated with SPRS scores. 19 20 In a large German HSP cohort, the presence of complicating features was associated with greater disease severity. 12 Furthermore, the health-related quality of life was reduced in patients with complicated HSP.…”

Section: Discussionmentioning

confidence: 99%

Hereditary Spastic Paraplegia in Koreans: Clinical Characteristics and Factors Influencing the Disease Severity

Geol

Kim

et al. 2022

J Clin Neurol

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Background and Purpose Hereditary spastic paraplegia (HSP) progresses over time and is associated with locomotive dysfunction. Understanding the factors affecting disease severity and locomotive function is important in HSP. This study investigated the factors influencing disease severity and ambulation status of HSP. Methods We consecutively enrolled 109 Korean patients (64 males, and 45 females)from 84 families with a clinical diagnosis of HSP. HSP was primarily diagnosed based on clinical criteria including clinical findings, family history, and supported by genetic studies. Epidemiological and clinical features of the patients were analyzed, and the Spastic Paraplegia Rating Scale (SPRS) score and ambulatory status were used to evaluate disease severity. Results Ninety-two (84.4%) patients had pure HSP, and 55 (50.4%) had a dominant family history. Thirty-one (28.4%) patients required a mobility aid for locomotion. A Kaplan-Meier analysis showed that HSP patients lost their independent gait ability after a median disease duration of 34 years. Those with an age at onset of ≤18 years had a longer median independent walking time. Pure HSP is characterized by predominant bilateral lower extremity weakness and spasticity, whereas complicated HSP presents more complex neurological findings such as ocular and bulbar symptoms, ataxia, and cognitive impairment. Complicated HSP was significantly correlated with the SPRS mobility score (β=3.70, 95% confidence interval=0.45–6.94). The age at onset and disease duration were significantly correlated with disease severity, and they were significant predictors of the use of a mobility aid ( p <0.05). Conclusions These findings suggest that a later age at onset and longer disease duration are significant factors affecting the disease severity and ambulatory function in patients with HSP. These findings can help clinicians to identify subjects at risk of locomotive impairment.

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“…This may be a consequence of the patient's condition worsening with age. 35 Although white matter lesions have been reported to be associated with motor disability in SPG4 patients, 36 , 37 the white matter changes in patients IV:10 and IV:12 may be a physiological change that is common in older individuals without clinical significance. 38 Therefore, long‐term follow‐up studies focusing on these patients are warranted.…”

Section: Discussionmentioning

confidence: 99%

A Novel SPAST Mutation Results in Spastin Accumulation and Defects in Microtubule Dynamics

Chen

Yao³

et al. 2021

Movement Disorders

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Background Haploinsufficiency is widely accepted as the pathogenic mechanism of spastic paraplegia type 4 (SPG4). However, there are some cases that cannot be explained by reduced function of the spastin protein encoded by SPAST . Objectives To identify the causative gene of autosomal dominant hereditary spastic paraplegia in three large Chinese families and explore the pathological mechanism of a spastin variant. Methods Three large Chinese hereditary spastic paraplegia families with a total of 247 individuals (67 patients) were investigated, of whom 59 members were recruited to the study. Genetic testing was performed to identify the causative gene. Western blotting and immunofluorescence were used to analyze the effects of the mutant proteins in vitro. Results In the three hereditary spastic paraplegia families, of whom three index cases were misdiagnosed as other types of neurological diseases, a novel c.985dupA (p.Met329Asnfs*3) variant in SPAST was identified and was shown to cosegregate with the phenotype in the three families. The c.985dupA mutation produced two truncated mutants (mutant M1 and M87 isoforms) that accumulated to a higher level than their wild‐type counterparts. Furthermore, the mutant M1 isoform heavily decorated the microtubules and rendered them resistant to depolymerization. In contrast, the mutant M87 isoform was diffusely localized in both the nucleus and the cytoplasm, could not decorate microtubules, and was not able to promote microtubule disassembly. Conclusions SPAST mutations leading to premature stop codons do not always act through haploinsufficiency. The truncated spastin may damage the corticospinal tracts through an isoform‐specific toxic effect.

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Cortical Damage Associated With Cognitive and Motor Impairment in Hereditary Spastic Paraplegia: Evidence of a Novel SPAST Mutation

Cited by 9 publications

References 34 publications

Relationship between brain white matter damage and grey matter atrophy in hereditary spastic paraplegia types 4 and 5

Relationship between brain white matter damage and grey matter atrophy in hereditary spastic paraplegia types 4 and 5

Hereditary Spastic Paraplegia in Koreans: Clinical Characteristics and Factors Influencing the Disease Severity

A Novel SPAST Mutation Results in Spastin Accumulation and Defects in Microtubule Dynamics

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