CAPN1 and hereditary spastic paraplegia: a novel variant in an Iranian family and overview of the genotype-phenotype correlation

Abstract

Purpose

SPG76 is one of the rare forms of hereditary spastic paraplegia (HSP) which causes by mutations in the CAPN1 gene. The mode of inheritance of SPG76 is autosomal recessive (AR) and so far, only 24 families and 25 mutations in this gene have been reported worldwide. These mutations have been associated with a spectrum of disorders from pure HSP to spastic ataxia. HSP genetically is one of the most heterogeneous neurological disorders and to date, 79 types of HSP (SPG1-SPG79) have been identified, however, it has been suggested that many HSP-genes, particularly in AR-HSPs, remained unknown. AR-HSPs clinically overlap with other neurodegenerative disorders, making an accurate diagnosis of the disease difficult. Therefore, in addition to clinical examination, a high throughout genetic method like whole exome sequencing (WES) may be necessary for the diagnosis of this type of neurodegenerative disorders.

Methods and Results

Herein, we present the clinical features and results of WES in the first Iranian family with a novel CAPN1 variant, c.C853T:p.R285* and pure HSP.

Conclusion

Some of the previous studies have mentioned that the “spasticity-ataxia phenotype might be conducted to the diagnosis of SPG76” but recently the number of pure HSP patients with CAPN1 mutation is increasing. The present study also expands the mutation spectrum of pure CAPN1-related SPG76; emphasizing that CAPN1 screening is required in both pure HSP and spasticity-ataxia phenotypes. As noted in some other literature, we suggest the clinical spectrum of this disorder to be considered as “CAPN1-associated neurodegeneration”.

Keywords:

• Hereditary spastic paraplegia
• HSP
• CAPN1
• Whole exome sequencing (WES)
• SPG76

Disclosure statement

All authors claim absence of financial interests and absence of conflicts of interest.

Author’s roles

Mohammad Masoud Rahimi Bidgoli and Leila Javanparast: analysis of exome sequencing data, mutation screening of CAPN1; Hossein Najmabadi: Advisors of MMRB and LJ; Babak Zamani: clinical evaluations and editing of manuscript; Mohammad Rohani: clinical evaluations, writing and editing of manuscript; Afagh Alavi: designed and supervised the research and wrote the manuscript. All authors read and approved the final version of manuscript.

Ethical standards

All participants, after being informed of the nature of the research, consented to participate. This research was performed in accordance with the Declaration of Helsinki and with approval of the ethics board of the University of Social Welfare and Rehabilitation Sciences.

Additional information

Funding

We acknowledge the Iran National Institute for Medical Research Development (NIMAD; grant number 963846) and the University of Social Welfare and Rehabilitation Sciences (USWR; grant number 97/ت/1969) for funding the research and thank the patients and their family members for participating in the study.