Next-generation sequencing study reveals the broader variant spectrum of hereditary spastic paraplegia and related phenotypes

Elert‐Dobkowska, Ewelina; Stępniak, Iwona; Krysa, Wioletta; Ziora-Jakutowicz, Karolina; Rakowicz, Maria; Sobańska, Anna; Pilch, Jacek; Antczak-Marach, Dorota; Zaremba, Jacek; Sulek, Anna

doi:10.1007/s10048-019-00565-6

Cited by 42 publications

(33 citation statements)

References 54 publications

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“…GTPase-activating protein, was reported in hereditary spastic paraplegias (HSPs) [17] . It's interesting that mutations in gene of ITPR1, another Purkinje cell antigen, are also reported in HSPs [18] . Notably, the activity of some Rabs are regulated by calcium e ux [19] , as most of identi ed antigens that targeted by Purkinje cell antibodies are contributed in maintaining intracellular calcium homeostasis [20] , there may be potential functional relationship between them.…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Autoantibody to the Rab6A/Rab6B in Autoimmune Cerebellar Ataxia Associated with Sjogren’s Syndrome

Guo

Ren

Fan

et al. 2020

Preprint

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Background To report a novel autoantibody against Purkinje cell in a patient with autoimmune cerebellar ataxia (ACA) associated to Sjogren’s syndrome (SS).Methods The Patients on one centre with cerebellar ataxia of unknown cause, who were tested positive with tissue-based indirect immunofluorescence assay (TBA) on rat cerebellum sections and negative for comprehensive anti-neural autoantibodies panel, were investigated for novel autoantibody identification. Among them, one patient with comorbid ACA and SS was qualified for further exploration. His-immunoprecipitation (HIP) combined with mass spectrometric (MS) analysis was used to identify the target antigen, which was confirmed by recombinant cell based assay (CBA) and antibody neutralization experiments. Results TBA of the patient’s serum and cerebrospinal fluid (CSF) for autoantibody testing revealed binding of IgG antibody, mainly IgG1, to Purkinje cell and granular layer of rat cerebellum. Rab6A was identified as the autoantigen by MS and Western blot, subsequently verified by CBA with HEK293 cells expressing human Rab6A/Rab6B. Furthermore, recombinant human Rab6A/Rab6B protein to neutralize the autoantibodies’ tissue reaction was performed by a parallel confirmed approach.Conclusion Autoantibody against Rab6A/Rab6B may be a novel biomarker in diagnosis of ACA, especially in patients with comorbid ACA and SS. The role of the antibody in mechanism of ACA warrants further study.

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Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Autoantibody to the Rab6A/Rab6B in Autoimmune Cerebellar Ataxia Associated with Sjogren’s Syndrome

Guo

Ren

Fan

et al. 2020

Preprint

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“…Later on, an extensive research of 347 unrelated patients (80% Dutch) by clinical MPS detected 24 (6.9%) SPG30 cases with 20 different KIF1A mutations; in 11 families AD inheritance was confirmed, de novo origin of mutations was proven in 7 cases, and inheritance was not established in the remaining 6 patients [16]. The MPS panel screening in a group of 30 Polish HSP families, that have previously shown negative results of several target DNA tests, revealed one familial SPG30 case [23]. MPS in 55 Chinese HSP patients that have previously underwent MLPA screening unraveled 34 cases with SPG mutations with one SPG30 familial case [24].…”

Section: Discussionmentioning

confidence: 95%

“…Complicated familial cases have been already reported beyond our study. In some families, patients uniformly developed additional non-classical features, identical [23] or differing [12], in other cases 'pure' and complicated phenotypes were combined [10,13]. Altogether this points to the absence of strict 'genotype-phenotype' correlation in SPG30.…”

Section: Discussionmentioning

confidence: 99%

KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families

et al. 2020

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Background: Spastic paraplegia type 30 (SPG30) caused by KIF1A mutations was first reported in 2011 and was initially considered a very rare autosomal recessive (AR) form. In the last years, thanks to the development of massive parallel sequencing, SPG30 proved to be a rather common autosomal dominant (AD) form of familial or sporadic spastic paraplegia (SPG),, with a wide range of phenotypes: pure and complicated. The aim of our study is to detect AD SPG30 cases and to examine their molecular and clinical characteristics for the first time in the Russian population. Methods: Clinical, genealogical and molecular methods were used. Molecular methods included massive parallel sequencing (MPS) of custom panel 'spastic paraplegias' with 62 target genes complemented by familial Sanger sequencing. One case was detected by the whole-exome sequencing. Results: AD SPG30 was detected in 10 unrelated families, making it the 3rd (8.4%) most common SPG form in the cohort of 118 families. No AR SPG30 cases were detected. In total, 9 heterozygous KIF1A mutations were detected, with 4 novel and 5 known mutations. All the mutations were located within KIF1A motor domain. Six cases had pure phenotypes, of which 5 were familial, where 2 familial cases demonstrated incomplete penetrance, early onset and slow relatively benign SPG course. All 4 complicated cases were caused by novel mutations without familial history. The phenotypes varied from severe in two patients (e.g. lack of walking, pronounced mental retardation) to relatively mild non-disabling symptoms in two others. Conclusion: AD SPG30 is one of the most common forms of SPG in Russia, the disorder has pronounced clinical variability while pure familial cases represent a significant part.

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“…However, the SPG11 gene, comprising 40 exons and spanning 101 kilobases, have been discovered at least 127 mutations, distributing throughout theSPG11 gene without identi ed mutation hot spots [31]. Whole-exome capture by next generation sequencing provides a powerful and affordable mean to identify causative genes with less cost, more e ciency and accuracy [32]. SPG11 gene encodes endogenous expression of spatacsin, distributingin the neurons forming the corticospinal tract and corpus callosum, as well as in hippocampus, cerebellum, dentate nucleus and ponsin adult CNS [31].…”

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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Next-generation sequencing study reveals the broader variant spectrum of hereditary spastic paraplegia and related phenotypes

Cited by 42 publications

References 54 publications

WITHDRAWN: Autoantibody to the Rab6A/Rab6B in Autoimmune Cerebellar Ataxia Associated with Sjogren’s Syndrome

WITHDRAWN: Autoantibody to the Rab6A/Rab6B in Autoimmune Cerebellar Ataxia Associated with Sjogren’s Syndrome

KIF1A-related autosomal dominant spastic paraplegias (SPG30) in Russian families

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

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