Understanding the Disease
Hereditary Spastic Paraplegia Type 76 (SPG76) is an ultra-rare genetic neurological disorder caused by mutations in the CAPN1 gene. It progressively affects movement, and there are currently no approved treatments.
CAPN1 encodes calpain-1, a calcium-activated enzyme essential for neuronal health and synaptic function. In SPG76, both copies of the gene carry loss-of-function mutations, meaning the body produces little or no functional calpain-1. Without this enzyme, a related protein — calpain-2 — operates without its natural counterbalance, contributing to progressive neuronal damage.
SPG76 typically presents in early adulthood with progressive lower-limb spasticity and difficulty walking. Additional features may include cerebellar ataxia (impaired coordination and balance), sensory neuropathy, and upper-limb hyperreflexia. Symptoms vary between individuals, but the condition is progressive — mobility generally declines over time.
SPG76 follows an autosomal recessive inheritance pattern. Both parents must carry one copy of the mutated CAPN1 gene to have a child with the condition. Carriers — people with one working copy and one mutated copy — are clinically unaffected, which is why most families have no prior history of the disease.
Because SPG76 is so rare, diagnosis typically requires genetic testing — most often whole exome sequencing (WES). Many patients experience a long diagnostic odyssey, seeing multiple specialists and undergoing extensive testing before the genetic cause is identified.
How SPG76 Was Discovered
SPG76 was first described in 2016. Dr. Ziv Gan-Or was first author of the study that linked the CAPN1 gene to hereditary spastic paraplegia and gave the condition its name, SPG76 (Gan-Or et al., American Journal of Human Genetics, 2016). The same year, Dr. Michel Baudry's group showed that loss of CAPN1 causes ataxia in mice and in people (Wang et al., Cell Reports, 2016). Both are among the researchers we collaborate with.
Natural History
A natural history study follows how a disease develops over time across many people — when symptoms start, how they change, and how quickly. For a disease as rare as SPG76, no single clinic sees enough people to answer those questions, so researchers combine information from doctors around the world.
Knowing how SPG76 progresses without treatment is what will let future studies tell whether a treatment slows or halts it. Read about the natural history collaboration.
How Rare Is SPG76?
There are approximately 100 confirmed cases worldwide, with many more suspected undiagnosed. Because a diagnosis needs genetic testing, many people living with hereditary spastic paraplegia may not yet know which form they have.
SPG76 is one of approximately 25–30 autosomal recessive HSP subtypes that share a similar therapeutic profile — small genes, loss-of-function mechanisms, unaffected carriers. Treatments developed for SPG76 could establish a reusable platform applicable across this entire family of related conditions, multiplying the impact of every research dollar.