Spastic paraplegia type 31: A novel REEP1 splice site donor variant and expansion of the phenotype variability

Kamada, Masaki; Kawarai, Toshitaka; Miyamoto, Ryosuke; Kawakita, R.; Tojima, Yuki; Montecchiani, Celeste; D'Onofrio, Laura; Caltagirone, Carlo; Orlacchio, Antonio; Kaji, Ryuji

doi:10.1016/j.parkreldis.2017.10.012

Cited by 12 publications

(5 citation statements)

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“…In line with previous study, the SPG4 family in present study showed genetic anticipation, with a decreased age at onset and increased severity in successive generations. In addition to SPG4, genetic anticipation has also been reported in other types of HPS, such as SPG3 and SPG31 (Kamada et al, 2018;Ming, 2007;Rodrigues et al, 2020). There may be other environmental and genetic modifiers influencing phenotype variability.…”

Section: Discussionmentioning

confidence: 93%

The investigation of genetic and clinical features in patients with hereditary spastic paraplegia in central‐Southern China

Wang

Zhang

et al. 2021

Molec Gen & Gen Med

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Section: Discussionmentioning

confidence: 93%

The investigation of genetic and clinical features in patients with hereditary spastic paraplegia in central‐Southern China

Wang

Zhang

et al. 2021

Molec Gen & Gen Med

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“…Remarkably, the only patient (IIII:2) in the fourth generation was younger at onset and had a more severe gait disturbance accompanied by mental impairment than the previous generations. In addition to SPG4, genetic anticipation have also been reported in other types of HPS, such as SPG3 (11) and SPG31 (12). There may be other environmental and genetic modi ers in uencing phenotype variability.…”

Section: Discussionmentioning

confidence: 95%

The Investigation of Genetic and Clinical Features in Patients with Hereditary Spastic Paraplegia in Central-Southern China

Wang

Zhang

et al. 2020

Preprint

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Objective Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative disorders. We describe the genetic and clinical features of a cohort of five HSP families from central-southern China. Methods Using targeted exome-sequencing technology, we investigated the genetic and clinical features in five HSP families. We review the clinical histories of these patients as well as the molecular and functional characterization of the associated gene variants. We also performed functional analyse of an intron variant of SPAST in vitro.Results We identified a known SPAST mutation (p.Pro435Leu) in a family with autosomal dominant HSP (AD-HSP) and four novel variants in three HSP families and a sporadic case. These identified four novel variants include a SPG11 nonsense variant (p.Val1979Ter), two B4GALNT1 variants (p.Ser475Phe and c.1002+2T>G), and a splicing site variant in SPAST (c.1245+5G>A). Minigene analysis of the SPAST splicing variant（c.1245+5G>A）revealed that the mutation resulted in mRNAs with a loss of exon 9. The SPG4 family carrying SPAST c.1245+5G>A exhibited obviously genetic anticipation, with a decreased age at onset and increased severity in successive generations. The proband with p.Val1979Ter variant in SPG11 showed characteristic clinical feature of early-onset, severe spasticity, and corpus callosum atrophy which were highly suggestive of the diagnosis of SPG11-associated HSP. Conclusions Our findings strongly support variable phenotype of B4GALNT1-related SPG26 and also expand the clinical and mutation spectrum of HSP caused by mutations in SPG4, SPG11, and B4GALNT1. These results will help to improve the efficiency of early diagnosis in patients clinically suspected of HSP.

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“…The literature search also showed anticipation might rarely be observed in some other subtypes of AD-HSP, including a few SPG3A (with mutations in ATL1) 53 and SPG31 (with mutations in REEP1) 54 families. Although anticipation may be observed in other subtypes of HSP, it seems SPAST will be the first candidate gene in families who present autosomal dominant inheritance, the pure form of disease as well as anticipation.…”

Section: Discussionmentioning

confidence: 96%

Anticipation Can Be More Common in Hereditary Spastic Paraplegia with SPAST Mutations Than It Appears

Hashemi

Hajati

Davarzani

et al. 2021

Can. J. Neurol. Sci.

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Background and objective: Hereditary spastic paraplegia (HSP) is a heterogeneous neurodegenerative disorder with lower-limb spasticity and weakness. Different patterns of inheritance have been identified in HSP. Most autosomal-dominant HSPs (AD-HSPs) are associated with mutations of the SPAST gene (SPG4), leading to a pure form of HSP with variable age-at-onset (AAO). Anticipation, an earlier onset of disease, as well as aggravation of symptoms in successive generations, may be correlated to SPG4. Herein, we suggested that anticipation might be a relatively common finding in SPG4 families. Methods: Whole-exome sequencing was done on DNA of 14 unrelated Iranian AD-HSP probands. Data were analyzed, and candidate variants were PCR-amplified and sequenced by the Sanger method, subsequently checked in family members to co-segregation analysis. Multiplex ligation-dependent probe amplification (MLPA) was done for seven probands. Clinical features of the probands were recorded, and the probable anticipation was checked in these families. Other previous reported SPG4 families were investigated to anticipation. Results: Our findings showed that SPG4 was the common subtype of HSP; three families carried variants in the KIF5A, ATL1, and MFN2 genes, while five families harbored mutations in the SPAST gene. Clinical features of only SPG4 families indicated decreasing AAO in affected individuals of the successive generations, and this difference was significant (p-value <0.05). Conclusion: It seems SPAST will be the first candidate gene in families that manifests a pure form of AD-HSP and anticipation. Therefore, it may be a powerful situation of genotype–phenotype correlation. However, the underlying mechanism of anticipation in these families is not clear yet.

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Spastic paraplegia type 31: A novel REEP1 splice site donor variant and expansion of the phenotype variability

Cited by 12 publications

References 11 publications

The investigation of genetic and clinical features in patients with hereditary spastic paraplegia in central‐Southern China

The investigation of genetic and clinical features in patients with hereditary spastic paraplegia in central‐Southern China

The Investigation of Genetic and Clinical Features in Patients with Hereditary Spastic Paraplegia in Central-Southern China

Anticipation Can Be More Common in Hereditary Spastic Paraplegia with SPAST Mutations Than It Appears

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