Novel CAPN1 Mutations Extend the Phenotypic Heterogeneity in Combined Spastic Paraplegia and Ataxia

Overview

Journal Ann Clin Transl Neurol

Specialty Neurology

Date 2020 Aug 30

PMID 32860341

Citations 7

Authors

Lu-Lu Lai

Yi-Jun Chen

Yun-Lu Li

Xiao-Hong Lin

Meng-Wen Wang

En-Lin Dong

Ning Wang

Wan-Jin Chen

Xiang Lin

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

"Ear of the Lynx" Sign in Hereditary Spastic Paraplegia 76.

Lee M, Park H, Lee J, Lee J J Clin Neurol. 2025; 21(1):77-79.

PMID: 39778570 PMC: 11711263. DOI: 10.3988/jcn.2024.0234.

Three Iranian patients with rare subtypes of hereditary spastic paraplegia (HSP): SPG76, SPG56, and SPG69.

Sadr Z, Ghasemi A, Rohani M, Khorshid H, Habibi-Kavashkohie M, Mohammadi Y Neurogenetics. 2024; 26(1):12.

PMID: 39607444 DOI: 10.1007/s10048-024-00789-1.

Hereditary spastic paraplegia: Novel insights into the pathogenesis and management.

Awuah W, Tan J, Shkodina A, Ferreira T, Adebusoye F, Mazzoleni A SAGE Open Med. 2024; 12:20503121231221941.

PMID: 38162912 PMC: 10757446. DOI: 10.1177/20503121231221941.

Spastic paraplegia type 76 due to novel CAPN1 mutations: three case reports with literature review.

Zhu Z, Hou W, Cao Y, Zheng H, Tian W, Cao L Neurogenetics. 2023; 24(4):243-250.

PMID: 37468791 DOI: 10.1007/s10048-023-00726-8.

PLP1 gene mutations cause spastic paraplegia type 2 in three families.

Yao L, Zhu Z, Zhang C, Tian W, Cao L Ann Clin Transl Neurol. 2023; 10(3):328-338.

PMID: 36622199 PMC: 10014006. DOI: 10.1002/acn3.51722.

References

Rahimi Bidgoli M, Javanparast L, Rohani M, Najmabadi H, Zamani B, Alavi A . and hereditary spastic paraplegia: a novel variant in an Iranian family and overview of the genotype-phenotype correlation. Int J Neurosci. 2020; 131(10):962-974. DOI: 10.1080/00207454.2020.1763344. View

Travaglini L, Bellacchio E, Aiello C, Pro S, Bertini E, Nicita F . Expanding the clinical phenotype of CAPN1-associated mutations: A new case with congenital-onset pure spastic paraplegia. J Neurol Sci. 2017; 378:210-212. DOI: 10.1016/j.jns.2017.05.014. View

Tadic V, Klein C, Hinrichs F, Munchau A, Lohmann K, Bruggemann N . CAPN1 mutations are associated with a syndrome of combined spasticity and ataxia. J Neurol. 2017; 264(5):1008-1010. DOI: 10.1007/s00415-017-8464-5. View

Melo U, Freua F, Lynch D, Ripa B, Tenorio R, Saute J . Clinical aspects of hereditary spastic paraplegia 76 and novel CAPN1 mutations. Clin Genet. 2018; 94(5):482-483. DOI: 10.1111/cge.13428. View

Gan S, Zhao K, Wu Z, Wang N, Murong S . Chinese patients with Machado-Joseph disease presenting with complicated hereditary spastic paraplegia. Eur J Neurol. 2009; 16(8):953-6. DOI: 10.1111/j.1468-1331.2009.02639.x. View

Fink J . Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol. 2013; 126(3):307-28. PMC: 4045499. DOI: 10.1007/s00401-013-1115-8. View

Alkan C, Coe B, Eichler E . Genome structural variation discovery and genotyping. Nat Rev Genet. 2011; 12(5):363-76. PMC: 4108431. DOI: 10.1038/nrg2958. View

Chen Y, Wang M, Dong E, Lin X, Wang N, Zhang Z . Chinese patients with adrenoleukodystrophy and Zellweger spectrum disorder presenting with hereditary spastic paraplegia. Parkinsonism Relat Disord. 2019; 65:256-260. DOI: 10.1016/j.parkreldis.2019.06.008. View

Lu Y, Dong E, Yang W, Lai L, Lin X, Ma L . Generation of an integration-free induced pluripotent stem cell line, FJMUi001-A, from a hereditary spastic paraplegia patient carrying compound heterozygous p.P498L and p.R618W mutations in CAPN1 (SPG76). Stem Cell Res. 2019; 34:101354. DOI: 10.1016/j.scr.2018.11.015. View

10.

Kocoglu C, Gundogdu A, Kocaman G, Kahraman-Koytak P, Uluc K, Kiziltan G . Homozygous mutations causing a spastic-ataxia phenotype in 2 families. Neurol Genet. 2018; 4(1):e218. PMC: 5773845. DOI: 10.1212/NXG.0000000000000218. View

11.

Kim A, Kumar K, Davis R, Mallawaarachchi A, Gayevskiy V, Minoche A . Increased Diagnostic Yield of Spastic Paraplegia with or Without Cerebellar Ataxia Through Whole-Genome Sequencing. Cerebellum. 2019; 18(4):781-790. DOI: 10.1007/s12311-019-01038-0. View

12.

Wang Y, Hersheson J, Lopez D, Hammer M, Liu Y, Lee K . Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans. Cell Rep. 2016; 16(1):79-91. PMC: 4927383. DOI: 10.1016/j.celrep.2016.05.044. View

13.

Shetty A, Gan-Or Z, Ashtiani S, Ruskey J, van de Warrenburg B, Wassenberg T . CAPN1 mutations: Expanding the CAPN1-related phenotype: From hereditary spastic paraparesis to spastic ataxia. Eur J Med Genet. 2018; 62(12):103605. DOI: 10.1016/j.ejmg.2018.12.010. View

14.

Sorimachi H, Suzuki K . The structure of calpain. J Biochem. 2001; 129(5):653-64. DOI: 10.1093/oxfordjournals.jbchem.a002903. View

15.

Newton T, Allison R, Edgar J, Lumb J, Rodger C, Manna P . Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia. Brain. 2018; 141(5):1286-1299. PMC: 5917785. DOI: 10.1093/brain/awy034. View

16.

Lambe J, Monaghan B, Munteanu T, Redmond J . mutations broadening the hereditary spastic paraplegia/spinocerebellar ataxia phenotype. Pract Neurol. 2018; 18(5):369-372. DOI: 10.1136/practneurol-2017-001842. View

17.

Garcia-Berlanga J, Moscovich M, Palacios I, Banegas-Lagos A, Rojas-Martinez A, Martinez-Ramirez D . Variants as Cause of Hereditary Spastic Paraplegia Type 76. Case Rep Neurol Med. 2019; 2019:7615605. PMC: 6634065. DOI: 10.1155/2019/7615605. View

18.

Souza P, Silva L, Badia B, Farias I, Pinto W, Oliveira A . SPG76: An extremely rare hereditary spastic paraplegia with a new expanding complicated phenotype. Rev Neurol (Paris). 2019; 175(9):572-574. DOI: 10.1016/j.neurol.2019.01.397. View

19.

Shribman S, Reid E, Crosby A, Houlden H, Warner T . Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches. Lancet Neurol. 2019; 18(12):1136-1146. DOI: 10.1016/S1474-4422(19)30235-2. View

20.

Xia Z, Liu Z, Zhou X, Liu Z, Wang J, Hu Z . Mutation analysis of CAPN1 in Chinese populations with spastic paraplegia and related neurodegenerative diseases. J Neurol Sci. 2020; 411:116691. DOI: 10.1016/j.jns.2020.116691. View