Clinical aspects of hereditary spastic paraplegia 76 and novel <i>CAPN1</i> mutations

Melo, Uirá Souto; Freua, Fernando; Lynch, David S.; Ripa, B.D.; Tenório, Renata Barreto; Saute, Jonas Alex Morales; Leite, Felipe de Souza; Kitajima, João Paulo; Houlden, Henry; Zatz, Mayana; Kok, Fernando

doi:10.1111/cge.13428

Cited by 8 publications

(8 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5,15,18 Comprehensive analysis of all available clinical information for our cohort combined with that available in previous studies showed that lower limb spasticity, manifesting as stiffness, hyperreflexia, and Babinski signs, developed in about 94% of patients, followed by ataxia, dysarthria, and cerebellar atrophy. 5,6,[11][12][13][14][15][16][17][18][19][20][21][22][23][24] Meanwhile, the clinical overlap is extensive between complicated form HSP and HSP mimic diseases (e.g., adrenoleukodystrophy, spinocerebellar ataxia type 3, etc.). 30,31 Remarkably, the variability and fluidity of the ataxia-spasticity disease spectrum suggest that spastic paraplegia and ataxia share not only overlapping phenotypes and causal genes, but also disease-specific underlying mechanisms (e.g., common cellular pathways or regulatory networks, etc.).…”

Section: Discussionmentioning

confidence: 84%

“…The combination of our cohort with the other previously reported cases resulted in a total of 35 pedigrees, which included 67 SPG76‐affected individuals that carried a total of 33 homozygous or compound heterozygous CAPN1 mutations among them 5,6,11‐24 . These mutations were distributed along the entire CAPN1 locus with no exon‐associated hotspot (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…A combined total of 33 rare CAPN1 mutations were detected between our cohort and previously reported cases. 5,6,[11][12][13][14][15][16][17][18][19][20][21][22][23][24] Notably, seven mutations (c.182_183insC, c.759+1G>A, c.853C>T, c.1015C>T, c.1142C>T, c.1176G>A, and c.1534C>T) were shared in ≥2 pedigrees, and in particular the nonsense mutation c.1176G>A (p.W392*) was most prevalent, recorded in four pedigrees.…”

Section: Discussionmentioning

confidence: 99%

“…9 Even though mutations in CAPN1 were initially associated with cerebellar ataxia in dogs and humans, 6,10 as well as in human complicated form HSP presented with any of ataxia, dysarthria and amyotrophy, 5 reports of pure form HSP patients with CAPN1 mutations are increasing. [11][12][13][14][15][16][17][18][19][20][21][22][23][24] Given this broad range of symptoms and contributing factors, it remains an ongoing challenge to find a specific, reliable correlation between genotype and phenotype for this disease complex.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Lai

Chen

et al. 2020

Ann Clin Transl Neurol

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Lai

Chen

et al. 2020

Ann Clin Transl Neurol

View full text Add to dashboard Cite

show abstract

“…In 2016, mutations of CAPN1 [c.884G > C (p.R295P), c.1579C > T (p.Q527*), c.406delC (p.P136Rfs*40) and c.1605 + 5G > A] were identified in three AR inherited HSP pedigrees for the first time [7]. Subsequently, other homozygous or compound-heterozygous mutations of CAPN1 were reported in other groups [11–17].…”

Section: Introductionmentioning

confidence: 99%

Two novel homozygous mutations of CAPN1 in Chinese patients with hereditary spastic paraplegia and literatures review

Peng

Sun

Quan

et al. 2019

Orphanet J Rare Dis

View full text Add to dashboard Cite

Background Hereditary spastic paraplegias (HSP) are of great clinical and genetic heterogeneity. According to the clinical features, HSP can be divided into pure or complicated subtypes which combined with other neurological symptoms including cerebellar ataxia. Up to date, 78 loci or genes have been implicated in HSP. CAPN1 was a novel gene detected recently for spastic paraplegia 76 (SPG76). Methods Patients referred to our clinic with spastic or spastic-ataxic gait were collected. Genetic testing of the probands were performed by target sequencing of a panel containing over 4000 known virulence genes. And the candidate mutations were further confirmed by polymerase chain reaction (PCR) and Sanger sequencing. The clinical materials of these patients were demonstrated retrospectively. Results Two Chinese patients, both from consanguineous families, each carried a novel homozygous mutation of CAPN1 , p.R48X and p.R339X. The male proband presented pure HSP subtype while the female proband presented complicated HSP symptoms with cerebellar ataxia. We then reviewed all the literatures of HSP patients carrying CAPN1 mutations and summarized the molecular spectrum and clinical characteristics of CAPN1 -related SPG76. Conclusion These two SPG76 patients carrying CAPN1 mutations were the first reported in China. By reviewing the clinical manifestations of SPG76 patients, we validated the “spastic-ataxia” phenotype and emphasized the association between spasticity and ataxia, indicating the importance of CAPN1 screening in HSP patients.

show abstract

Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations

et al. 2021

View full text Add to dashboard Cite

Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.

show abstract

Clinical aspects of hereditary spastic paraplegia 76 and novel CAPN1 mutations

Cited by 8 publications

References 5 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

Two novel homozygous mutations of CAPN1 in Chinese patients with hereditary spastic paraplegia and literatures review

Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations

Contact Info

Product

Resources

About