Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Shribman, Samuel; Reid, Evan; Crosby, Andrew H.; Houlden, Henry; Warner, Thomas T.

doi:10.1016/s1474-4422(19)30235-2

Cited by 215 publications

(233 citation statements)

References 115 publications

(141 reference statements)

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“…1,2 Historically, HSP is distinguished as pure or complicated forms on the basis of clinical grounds. 3 Pure form HSP shows predominant spasticity and weakness restricted to the lower limbs, and often presents hypertonia, hyperreflexia, and Babinski sign. In addition, bladder dysfunction and sensory disturbance are also frequently reported in the pure form.…”

Section: Introductionmentioning

confidence: 99%

“…4 Notably, it has been proposed that many autosomal recessive HSP genes remain unidentified. 3 Recently, loss-of-function mutations in the CAPN1 gene have been described as causative for spastic paraplegia 76 (SPG76). 5 CAPN1 encodes a neutral calcium-activated protease known as calpain-1 protein, which is involved in processes of synaptic plasticity, neuronal migration, neuronal maintenance and necrosis, among others.…”

Section: Introductionmentioning

confidence: 99%

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Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

Lai

Chen

et al. 2020

Ann Clin Transl Neurol

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Objective: Recessive mutations in the CAPN1 gene have recently been identified in spastic paraplegia 76 (SPG76), a complex hereditary spastic paraplegia (HSP) that is combined with cerebellar ataxia, resulting in an ataxia-spasticity disease spectrum. This study aims to assess the influence of CAPN1 variants on the occurrence of SPG76 and identify factors potentially contributing to phenotypic heterogeneity. Methods: We screened a cohort of 240 unrelated HSP families for variants in CAPN1 using high-throughput sequencing analysis. We described in detail the clinical and genetic features of the SPG76 patients in our cohort and summarized all reported cases. Results: Six unreported CAPN1-associated families containing eight patients with or without cerebellar ataxia were found in our cohort of HSP cases. These patients carried three previously reported homozygous truncating mutations (p.V64Gfs*103, c.759+1G>A, and p.R285*), and three additional novel compound heterozygous missense mutations (p.R481Q, p.P498L, and p.R618W). Lower limbs spasticity, hyperreflexia, and Babinski signs developed in about 94% of patients, with ataxia developing in 63% of cases. In total, 33 pathogenic mutations were distributed along the three reported functional domains of calpain-1 protein, encoded by CAPN1, with no hotspot region. A comparison of gender distribution between the two groups indicated that female SPG76 patients were significantly more likely to present with complicated HSP than male patients (P = 0.015). Interpretation: Our study supports the clinically heterogeneous inter-and intra-family variability of SPG76 patients, and demonstrates that gender and calpain-1 linker structure may contribute to clinical heterogeneity in SPG76 cases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

Lai

Chen

et al. 2020

Ann Clin Transl Neurol

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“…Loss of spatacsin function may affect axonal transport, contributing to the degeneration of the corticospinal tract and corpus callosum in HSP [33]. More recently, loss of spatacsin has also been demonstrated to be pivotal for autophagic lysosome reformation, and resulted in depletion of free lysosomes, accumulation of autolysosomes or lipids in lysosomes, and neuronal degeneration [34]. As shown in our study, we have reported four sporadic spastic paraplegias with TCC cases, and found novel SPG11 mutations in each patient by next generation sequencing.…”

Section: Discussionmentioning

confidence: 99%

Mild Cognitive Impairment in novel SPG11 Mutation-Related Sporadic Hereditary Spastic Paraplegia with Thin Corpus Callosum

Yan

Duan

et al. 2020

Preprint

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Background: SPG11 mutation-related autosomal recessive hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) is the most common cause in complicated forms of HSP, usually presenting comprehensive mental retardation on early-onset stage preceding spastic paraplegias in childhood. However, there are still lots of sporadic late-onset HSP-TCC cases with negative family history, and potential mild cognitive deficits in multiple domains may be easily neglected and inaccurately described. Methods: In this study, we performed next generation sequencing in four sporadic late-onset patients with spastic paraplegia and thin corpus callosum (TCC), and combined Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) to evaluate cognition of the patients. Results: By evolutionary conservation and structural modeling analysis, we have revealed 4 novel pathogenic SPG11 mutations, and firstly confirmed mild cognitive impairment (MCI) with normal MMSE scores (≥27) and decreased MoCA scores (<26) in these SPG11 mutation-related HSP-TCC patients, predominantly presenting impairment of visuoexecutive function, delayed recall, abstraction and language correlated with prefrontal deficits.Conclusions: The results expand the mutational spectrum of SPG11-associated HSP-TCC from sporadic cases, and confirm MCI characterized with dysfunction of prefrontal lobe in SPG11-related HSP-TCC, which should be paid more attention by neurologists.

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“…To date, it clearly emerged that HSP, HA, ASS, and other neurological disorders are part of a continuum of overlapping clinical conditions. For instance, the clinical overlap of HSP with HA or intellectual/ developmental disability is not new and so it is the overlap with the mechanisms involved in more common neurological conditions including amyotrophic lateral sclerosis, multiple sclerosis, Parkinson disease, and dementias (Patten et al, 2014;Parodi et al, 2017;Boutry et al, 2019b;Shribman et al, 2019). Since HSP and ASS are a group of disorders characterized by high genetic diversity, researchers have widely exploited the zebrafish as an in vivo model system of these pathologies.…”

Section: Conclusion and Future Applicationsmentioning

confidence: 99%

Swimming in Deep Water: Zebrafish Modeling of Complicated Forms of Hereditary Spastic Paraplegia and Spastic Ataxia

et al. 2019

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Hereditary spastic paraplegia (HSP) and hereditary ataxia (HA) are two groups of disorders characterized, respectively, by progressive dysfunction or degeneration of the pyramidal tracts (HSP) and of the Purkinje cells and spinocerebellar tracts (HA). Although HSP and HA are generally shown to have distinct clinical-genetic profiles, in several cases the clinical presentation, the causative genes, and the cellular pathways and mechanisms involved overlap between the two forms. Genetic analyses in humans in combination with in vitro and in vivo studies using model systems have greatly expanded our knowledge of spinocerebellar degenerative disorders. In this review, we focus on the zebrafish (Danio rerio), a vertebrate model widely used in biomedical research since its overall nervous system organization is similar to that of humans. A critical analysis of the literature suggests that zebrafish could serve as a powerful experimental tool for molecular and genetic dissection of both HA and HSP. The zebrafish, found to be very useful for demonstrating the causal relationship between defect and mutation, also offers a useful platform to exploit for the development of therapies.

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Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

Cited by 215 publications

References 115 publications

Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

Mild Cognitive Impairment in novel SPG11 Mutation-Related Sporadic Hereditary Spastic Paraplegia with Thin Corpus Callosum

Swimming in Deep Water: Zebrafish Modeling of Complicated Forms of Hereditary Spastic Paraplegia and Spastic Ataxia

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