SPG6 (NIPA1 variant): A report of a case with early-onset complex hereditary spastic paraplegia and brief literature review

Spagnoli, Carlotta; Schiavoni, Silvia; Rizzi, Susanna; Salerno, Grazia Gabriella; Frattini, Daniele; Koskenvuo, Juha; Fusco, Carlo

doi:10.1016/j.jocn.2021.10.026

Cited by 11 publications

(17 citation statements)

References 21 publications

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“…The comorbidities included idiopathic generalized epilepsy (Svenstrup et al, 2011), polyneuropathy (Liu et al, 2008;Du et al, 2011), cognitive impairment (Martinez-Lage et al, 2012), ataxia (Kim et al, 2019), postural tremor (Svenstrup et al, 2011;Lu et al, 2018) and amyotrophic lateral sclerosis (ALS) (Tanti et al, 2020). Until now, epilepsy has been described in eight families with SPG6 (Reed et al, 2005;Svenstrup et al, 2011;Arkadir et al, 2014;Lu et al, 2018;Tanti et al, 2020;Fabbro et al, 2021;Spagnoli et al, 2021), including the first index patient in our study, who presented with a complicated form of HSP. Why NIPA1 mutation might cause epilepsy is unclear.…”

Section: Discussionmentioning

confidence: 81%

“…In our study, we identified the most common variant c.316G > A (p.G106R) in two unrelated patients. It has been discovered in more than 10 HSP families from China (Chen et al, 2005;Lu et al, 2018;Zhao et al, 2019), Britain (Reed et al, 2005), Brazil (Munhoz et al, 2006), Danmark (Svenstrup et al, 2011), Italy (Spagnoli et al, 2021), Korea (Kim et al, 2019) and America (Hedera 2013). Thus, it was considered to be a hotspot mutation of NIPA1 with the mechanism of DNA methylation in the coding regions (Beetz et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

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Clinical and Genetic Features of Chinese Patients With NIPA1-Related Hereditary Spastic Paraplegia Type 6

Jun

et al. 2022

Front. Genet.

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Background: Mutations in the NIPA1 gene cause hereditary spastic paraplegia (HSP) type 6 (SPG6), which is a rare type of HSP with a frequency of less than 1% in Europe. To date, less than 30 SPG6 families and limited NIPA1 mutations have been reported in different ethnic regions. The clinical features are variable.Methods: We screened for NIPA1 mutations by whole exome sequencing or next generation sequencing in 35 unrelated Chinese families with HSP. The clinical manifestations were evaluated.Results: Two variants of NIPA1 were identified in three index patients (3/35, 8.6%), two of whom carried a previously reported common variant c.316G > A (p.G106R), and the third patient harbored a novel likely pathogenic variant c.126C > G (p.N42K). Both variants were de novo in the three index patients. The phenotype was pure HSP in two patients and complicated HSP with epilepsy in the third one.Conclusion:NIPA1-related HSP is more common in China than it in Europe. Both pure and complicated form of HSP can be found. The variant c.316G > A is a hotspot mutation, and the novel variant c.126C > G expands the mutational spectrum. The phenomenon of de novo mutations in NIPA1 emphasizes the need to consider autosomal dominant HSP-related genes in sporadic patients.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Clinical and Genetic Features of Chinese Patients With NIPA1-Related Hereditary Spastic Paraplegia Type 6

Jun

et al. 2022

Front. Genet.

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“…Both mutations have been recognized as pathogenic mutations for SPG6 before. 10,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] The CADD v1.6 Phred scores of NIPA1 c.316G>A and c.316G>C were 28 and 27.9, respectively. Both MutationTaster and CADD predicted the two variants as disease-causing mutations.…”

Section: Resultsmentioning

confidence: 98%

“…One study reviewed and analyzed 110 genetically confirmed SPG6 cases and found 23% of the patients had complex HSP and 10% of the patients also had generalized epilepsy. 28 The additional neurological manifestations in SPG6 could be epilepsy, 10,14,20,24,27,28 ataxia, 24,25 cognitive impairment, 14,17,21 motor neuron disease, 27 and/or peripheral neuropathy. 18,19,21,24 Interestingly, SPG6 with complex HSP is usually caused by NIPA1 c.316G>A mutation, but may be infrequently found in patients with NIPA1 c.316G>C, c.134C>G (p.T45R), or c.249C>G (p.N83K) mutation, too.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we reviewed literature and found that epilepsy has been found in multiple individuals with the c.316G>A mutation but not in those with the c.316G>C mutation (Table S2). 10,[13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] Therefore, we wondered whether these two mutations might have different effects on the molecular mechanism. Since NIPA1 c.316G>A and c.316G>C are located in the exon-intron boundary region, we investigated whether these two mutations had different impacts on splicing utilizing a minigene assay.…”

Section: Nipa1 C316g>a and C316g>c Do Not Affect Splicingmentioning

confidence: 99%

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Clinical and genetic characterization of NIPA1 mutations in a Taiwanese cohort with hereditary spastic paraplegia

Fang

Chou

Hsu

et al. 2023

Ann Clin Transl Neurol

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Objective NIPA1 mutations have been implicated in hereditary spastic paraplegia (HSP) as the cause of spastic paraplegia type 6 (SPG6). The aim of this study was to investigate the clinical and genetic features of SPG6 in a Taiwanese HSP cohort. Methods We screened 242 unrelated Taiwanese patients with HSP for NIPA1 mutations. The clinical features of patients with a NIPA1 mutation were analyzed. Minigene‐based splicing assay, RT‐PCR analysis on the patients' RNA, and cell‐based protein expression study were utilized to assess the effects of the mutations on splicing and protein expression. Results Two patients were identified to carry a different heterozygous NIPA1 mutation. The two mutations, c.316G>A and c.316G>C, are located in the 3′ end of NIPA1 exon 3 near the exon–intron boundary and putatively lead to the same amino acid substitution, p.G106R. The patient harboring NIPA1 c.316G>A manifested spastic paraplegia, epilepsy and schizophrenia since age 17 years, whereas the individual carrying NIPA1 c.316G>C had pure HSP since age 12 years. We reviewed literature and found that epilepsy was present in multiple individuals with NIPA1 c.316G>A but none with NIPA1 c.316G>C. Functional studies demonstrated that both mutations did not affect splicing, but only the c.316G>A mutation was associated with a significantly reduced NIPA1 protein expression. Interpretation SPG6 accounted for 0.8% of HSP cases in the Taiwanese cohort. The NIPA1 c.316G>A and c.316G>C mutations are associated with adolescent‐onset complex and pure form HSP, respectively. The different effects on protein expression of the two mutations may be associated with their phenotypic discrepancy.

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Chromosome Microarray Analysis for the Investigation of Deletions in Pediatric Movement Disorders: A Systematic Review of the Literature

Soliani

Martín

Balsells³

et al. 2023

Movement Disord Clin Pract

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BackgroundBackground: Chromosome microarray analysis (CMA) can detect copy number variants (CNV) beyond the resolution of standard G-banded karyotyping. De novo or inherited microdeletions may cause autosomal dominant movement disorders. Objectives Objectives: The purpose of this study was to analyze the clinical characteristics, associated features, and genetic information of children with deletions in known genes that cause movement disorders and to make recommendations regarding the diagnostic application of CMA. Methods Methods: Clinical cases published in English were identified in scientific databases (PubMed, ClinVar, and DECIPHER) from January 1998 to July 2019 following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Cases with deletions or microdeletions greater than 300 kb were selected. Information collected included age, sex, movement disorders, associated features, and the size and location of the deletion. Duplications or microduplications were not included. ResultsResults: A total of 18.097 records were reviewed, and 171 individuals were identified. Ataxia (30.4%), stereotypies (23.9%), and dystonia (21%) were the most common movement disorders. A total of 16% of the patients demonstrated more than one movement disorder. The most common associated features were intellectual disability or developmental delay (78.9%) and facial dysmorphism (57.8%). The majority (77.7%) of microdeletions were smaller than 5 Mb. We find no correlation between movement disorders, their associated features, and the size of microdeletions. Conclusions Conclusions: Our results support the use of CMA as an investigational test in children with movement disorders. As the majority of identified articles were case reports and small case series (low quality), future efforts should focus on larger prospective studies to examine the causation of microdeletions in pediatric movement disorders.Movement disorders in children are divided into two categories: hyperkinetic and hypokinetic movements. Pediatric hyperkinetic movements (PMD) are defined and classified by the Taskforce on Childhood Movement Disorders as dystonia, chorea, athetosis, myoclonus, tremor, tics, and stereotypies. 1,2 Pediatric hypokinetic movements are characterized by a decrease in the number of movements and are also referred to as hypokineticrigid syndrome or parkinsonism. 3 In 2016, a new nomenclature

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SPG6 (NIPA1 variant): A report of a case with early-onset complex hereditary spastic paraplegia and brief literature review

Cited by 11 publications

References 21 publications

Clinical and Genetic Features of Chinese Patients With NIPA1-Related Hereditary Spastic Paraplegia Type 6

Clinical and Genetic Features of Chinese Patients With NIPA1-Related Hereditary Spastic Paraplegia Type 6

Clinical and genetic characterization of NIPA1 mutations in a Taiwanese cohort with hereditary spastic paraplegia

Chromosome Microarray Analysis for the Investigation of Deletions in Pediatric Movement Disorders: A Systematic Review of the Literature

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