SPG76: An extremely rare hereditary spastic paraplegia with a new expanding complicated phenotype

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

“…Among them, the three homozygous variants (c.182_183insC (p.V64Gfs * 103) in Families 1 and 4, c.759+1G>A in Family 3, and c.853C>T (p.R285 * ) in Family 5) were found to be known truncating mutations, 6,11,21 while the three compound heterozygous variants ((c.1442G>A (p.R481Q) in Family 6, c.1493C>T (p.P498L) in Families 2 and 6, and c.1852C> T (p.R618W) in Family 2) were defined as novel, likely‐pathogenic missense mutations. A combined total of 33 rare CAPN1 mutations were detected between our cohort and previously reported cases 5,6,11‐24 . 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.…”

“…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.…”

“…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.…”

“…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.).…”

“…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.…”