Hereditary spastic paraplegia (HSP) is a rare, but debilitating, disease. Those who are diagnosed with it – between two and 10 people per 100,000 – experience weakness, stiffness and contraction of the lower limbs, along with a range of possible incidental symptoms including eye issues, deafness, coordination problems and cognitive defects. And there are as many suspected causative genes for HSP as there are presentations of the disorder; over 70 “spastic gait genes” are known, along with others that produce similar phenotypes. But even the myriad genes aren’t enough to explain all cases of the disease, and many families exhibiting the HSP phenotype remain undiagnosed through generations. Recently, scientists at the Montreal Neurological Institute identified a new gene that could help diagnose patients with unexplained HSP symptoms.
“Our study shows that homozygous or compound heterozygous mutations in CAPN1 cause autosomal recessive HSP,” says Ziv Gan-Or, who led the study (1). “They are probably responsible for 1–2 percent of HSP patients. Although we cannot determine the exact mechanism, our results show that it is possibly related to the stabilization of microtubules.” But even without understanding the mechanism of disease, could the newly identified gene be useful in the clinic? “CAPN1 mutations can be immediately included in the panels of genes that are currently being sequenced in clinical lab tests,” Gan-Or says. “However, since we are the first to demonstrate a role for CAPN1 in HSP – and specifically for only four mutations in the gene – it is possible that such clinical tests will identify variants of unknown significance.” He advocates for more studies in different HSP cohorts in order to identify additional pathogenic CAPN1 variants, and suggests that the entire coding region and exon-intron boundaries of the gene should be fully sequenced in clinical tests. HSP is a very heterogeneous disease, and patients with mutations in the same gene can present with “pure” HSP (involvement of the lower limbs and bladder only), or with complex forms that include various other neurological symptoms. Most of the patients in the initial cohort of 20 families exhibited complex HSP with ataxia, but Gan-Or says it’s likely that other symptoms can occur in CAPN1-associated HSP. “There is no specific patient profile, so we recommend that every HSP patient with autosomal recessive inheritance, as well as single affected individuals in unaffected families, should be tested for biallelic CAPN1 mutations, regardless of the clinical presentation.” Some of the paper’s authors have already begun a more in-depth examination of the potential disease mechanism behind CAPN1 mutations. Gan-Or and his colleagues, on the other hand, are focused on identifying more genes that cause HSP. “Although more than 70 genetic loci are known to be involved, many families remain genetically undiagnosed – which means that other, still unknown genes are potentially involved.” Ultimately, their aim is to increase our overall genetic understanding of the disease to aid not only the diagnosis, but eventually also the treatment and counseling of patients and their families.
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References
- Z Gan-Or et al., “Mutations in CAPN1 cause autosomal-recessive hereditary spastic paraplegia”, Am J Hum Genet, 98, 1038–1046 (2016). PMID: 27153400.
