CAPN1 – Autosomal Recessive Spastic Paraplegia Type 76

CAPN1 encodes the cysteine protease calpain-1, and biallelic loss-of-function variants cause autosomal recessive spastic paraplegia type 76 (SPG76), a complex hereditary spastic paraplegia with pyramidal and cerebellar involvement. SPG76 manifests with progressive lower limb spasticity, dysarthria, ataxia, and lower limb muscle weakness, often accompanied by variable cerebellar atrophy on MRI.

1 Assess Clinical Validity

Strong clinical validity is supported by 21 novel probands from two European centers with CAPN1 variants, confirmed by segregation and functional assays (PMID:33486633). Additional familial co-segregation in Iranian and consanguineous pedigrees further substantiates the gene–disease link. No conflicting evidence has been reported to date.

2 Genetic Evidence

SPG76 is inherited in an autosomal recessive manner. Nine truncating and six missense CAPN1 variants have been identified across at least nine unrelated families, with compound heterozygosity or homozygosity demonstrating full segregation in affected sibships (PMID:33486633; PMID:32352326). The variant spectrum is enriched for protein-truncating changes, while missense alleles often correlate with earlier onset.

3 Functional Evidence

Functional studies of patient-derived cells and heterologous models show that truncating variants lead to loss of calpain-1 protease activity and mislocalization, and missense changes diminish enzyme function and downstream signaling (PMID:35126465; PMID:37468791). These concordant experimental results recapitulate axonal degeneration and support a loss-of-function mechanism.

4 Integration and Clinical Utility

The genetic and functional data integrate to define CAPN1 as a definitive cause of SPG76, with robust segregation, phenotype correlation, and mechanistic evidence. CAPN1 testing should be included in diagnostic gene panels for hereditary spastic paraplegia and spastic ataxia, facilitating early diagnosis and genetic counseling.

Key Take-home: CAPN1 loss-of-function variants reliably cause SPG76, and clinical testing has high utility for patients with early-adult onset spasticity and ataxia.

References

• Neurogenetics • 2021 • Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations PMID:33486633
• The International Journal of Neuroscience • 2021 • CAPN1 and hereditary spastic paraplegia: a novel variant in an Iranian family and overview of the genotype-phenotype correlation PMID:32352326
• Frontiers in Genetics • 2021 • A Compound Heterozygous Mutation in Calpain 1 Identifies a New Genetic Cause for Spinal Muscular Atrophy Type 4 (SMA4) PMID:35126465
• Neurogenetics • 2023 • Spastic paraplegia type 76 due to novel CAPN1 mutations: three case reports with literature review PMID:37468791

Evidence Based Scoring (AI generated)