Association of Early-Onset Spasticity and Risk for Cognitive Impairment With Mutations at Amino Acid 499 in SPAST

Hereditary spastic paraplegia is a phenotypically and genetically heterogeneous group of neurodegenerative disorders characterized by lower extremity weakness and spasticity. Spastic paraplegia 4 (SPG4), caused by heterozygous mutations in the gene SPAST, typically causes a late-onset, uncomplicated form of hereditary spastic paraplegia in affected individuals. Additional clinical features in SPG4 have been reported on occasion, but no genotype-phenotype correlation has been established. Through targeted clinical testing, we identified 2 unrelated female patients with the same de novo p.Arg499His mutation in SPAST. Both patients presented with early-onset spasticity resulting in delayed motor milestones, which led to a diagnosis of cerebral palsy in one child and tethered cord in the other. Review of the literature identified several patients with mutations at amino acid 499 and early-onset symptoms associated with a risk of cognitive impairment. Early and accurate diagnosis of children with early-onset spasticity is important for informed prognosis and genetic counselling.

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A heterozygous mutation in the CCDC88C gene likely causes early-onset pure hereditary spastic paraplegia: a case report

BMC Neurology ◽

10.1186/s12883-021-02113-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ashraf Yahia ◽

Zhefan Stephen Chen ◽

Ammar E. Ahmed ◽

Sara Emad ◽

Rawaa Adil ◽

...

Keyword(s):

Hereditary Spastic Paraplegia ◽

Early Onset ◽

Late Onset ◽

In Silico Analysis ◽

Spinocerebellar Ataxia Type ◽

Heterozygous Mutation ◽

Spastic Paraplegia ◽

Case Presentation ◽

293 Cells ◽

Extrapyramidal Signs

Abstract Background CCDC88C is a ubiquitously expressed protein with multiple functions, including roles in cell polarity and the development of dendrites in the nervous system. Bi-allelic mutations in the CCDC88C gene cause autosomal recessive congenital hydrocephalus (OMIM #236600). Studies recently linked heterozygous mutations in CCDC88C to the development of the late-onset spinocerebellar ataxia type 40 (OMIM #616053). Case presentation A 48-year-old Sudanese female presented with pure early onset hereditary spastic paraplegia. Exome sequencing, in-silico analysis, and Sanger sequencing identified the heterozygous NM_001080414.4:c.1993G > A (p.E665K) variant in CCDC88C as a potential cause of her illness. To explore the pathogenicity of the NM_001080414.4:c.1993G > A (p.E665K) variant, we expressed it in human embryonic kidney 293 cells and assessed its effects on apoptosis. In our experiment, NM_001080414.4:c.1993G > A (p.E665K) induced JNK hyper-phosphorylation and enhanced apoptosis. In contrast to previous reports, our patient developed neurological symptoms in early childhood and showed neither features of cerebellar ataxia, extrapyramidal signs, nor evidence of intellectual involvement. Conclusion We, herein, heighlighted the possibility of extending the phenotype associated with variants in CCDC88C to include early-onset pure hereditary spastic paraplegia.

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Mild cognitive impairment in novel SPG11 mutation-related sporadic hereditary spastic paraplegia with thin corpus callosum: case series

BMC Neurology ◽

10.1186/s12883-020-02040-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chuan Li ◽

Qi Yan ◽

Feng-ju Duan ◽

Chao Zhao ◽

Zhuo Zhang ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Corpus Callosum ◽

Hereditary Spastic Paraplegia ◽

Late Onset ◽

Case Series ◽

Spastic Paraplegia ◽

Thin Corpus Callosum ◽

Modeling Analysis ◽

Multiple Domains

Abstract 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 many instances of sporadic late-onset HSP-TCC cases with a 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 HSP-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 executive function, delayed recall, abstraction and language. Conclusions The results expand the mutational spectrum of SPG11-associated HSP-TCC from sporadic cases, and confirm MCI with combination of decreased MoCA and normal MMSE assessment, suggesting that clinicians should consider doing a MoCA to detect MCI in patients with HSP, particularly those with HSP-TCC.

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

10.21203/rs.3.rs-60928/v1 ◽

2020 ◽

Author(s):

Chuan Li ◽

Qi Yan ◽

Feng-ju Duan ◽

Chao Zhao ◽

Zhuo Zhang ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Corpus Callosum ◽

Hereditary Spastic Paraplegia ◽

Late Onset ◽

Spastic Paraplegia ◽

Thin Corpus Callosum ◽

Modeling Analysis ◽

Sporadic Cases ◽

Multiple Domains

Abstract 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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Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

European Journal of Human Genetics ◽

10.1038/s41431-020-00720-w ◽

2020 ◽

Vol 28 (12) ◽

pp. 1763-1768

Author(s):

Thomas Bourinaris ◽

◽

Damian Smedley ◽

Valentina Cipriani ◽

Isabella Sheikh ◽

...

Keyword(s):

Hereditary Spastic Paraplegia ◽

De Novo ◽

Age At Onset ◽

Genetic Diagnosis ◽

Spastic Paraplegia ◽

Sequencing Data ◽

Juvenile Form ◽

Pathogenic Variants ◽

Degenerative Disorders ◽

Significant Gene

AbstractHereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

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Abstract 15169: De Novo Variants of USP10 in Early Onset Bicuspid Aortic Valve Disease

Circulation ◽

10.1161/circ.142.suppl_3.15169 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Siddharth K Prakash ◽

Angela T Yetman ◽

Hector I Michelena ◽

Malenka M Bissell ◽

Yuli Y Kim ◽

...

Keyword(s):

Aortic Valve ◽

Bicuspid Aortic Valve ◽

Early Onset ◽

Rare Variants ◽

De Novo ◽

Late Onset ◽

Copy Number Variants ◽

Aortic Aneurysms ◽

Thoracic Aortic Aneurysms ◽

Aortic Dissections

Introduction: Bicuspid Aortic Valve (BAV), the most common congenital heart defect, is a major cause of aortic regurgitation or stenosis requiring valve replacement and thoracic aortic aneurysms predisposing to acute aortic dissections (TAD). The spectrum of BAV ranges from severe early onset valve and aortic complications to sporadic late onset disease. Hypothesis: Early onset BAV (EBAV) cases with valve or aortic complications that require intervention prior to age 30 are enriched for rare genetic variants that cause BAV and TAD. Methods: We performed whole exome sequencing of 147 EBAV cases in 141 families who were enrolled in the UTHealth Bicuspid Aortic Valve Research Registry. Candidate variants in the EBAV cohort (26% female, mean age 18, 44% with TAD) were compared to unselected controls from the Genome Aggregation Database (gnoMAD) and the Database of Genotypes and Phenotypes (dbGAP). We considered variants with minor allele frequencies (MAF) < 1%, Combined Annotation Dependent Depletion (CADD) scores > 25, and damaging (Polyphen-2) or deleterious (SIFT) functional prediction scores. Genomic copy number variants (CNVs) were detected using CoNIFER and prioritized when deletions involved genes with probability of loss intolerance (pLI) > 0.9. Variants were validated using quantitative PCR or Sanger sequencing. Results: We identified 6 rare variants of USP10 in 6 EBAV families (4% of cohort): 4 CNVs (2 duplications and 2 deletions) that are rare in dbGAP controls (4 in 15,414) and 2 deleterious rare missense variants (MAF<5x10 -5 in gnoMAD). Two of the 4 CNVs were de novo events in trios. In contrast, rare deleterious variants of the known causal BAV genes NOTCH1 (1), ROBO4 (1), GATA4 (1), GATA5 (1), and SMAD6 (4) were found in 7 total families. USP10 encodes a ubiquitin peptidase that is required for endothelial Notch signaling during vascular development. Conclusions: We identified rare and de novo variants of USP10 that implicate USP10 as a new candidate gene for BAV.

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