Approximately 100 confirmed cases.
Zero approved treatments.
The SPG76 Research Foundation funds preclinical and translational research to develop the first disease-modifying treatment for Hereditary Spastic Paraplegia Type 76, an ultra-rare neurological disorder caused by mutations in the CAPN1 gene.
Understanding the Disease
What Is SPG76?
Hereditary Spastic Paraplegia Type 76 is an ultra-rare genetic neurological disorder caused by mutations in the CAPN1 gene. It progressively affects movement, and there are currently no disease-modifying treatments.
The Gene
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.
Symptoms
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.
Inheritance
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.
Diagnosis
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. The CAPN1 gene was first linked to HSP in 2016.
Our Mission
Patient-Led. Research-Focused.
The SPG76 Research Foundation is a patient-led nonprofit organization — 501(c)(3) formation in progress — dedicated to funding preclinical and translational research aimed at developing the first disease-modifying treatment for SPG76.
We don't conduct research. We fund it — directing resources to academic institutions and investigators working to understand and treat this disease. Every dollar raised supports scientific work at established research programs.
The Founder's Story
Our founder's symptoms began in August 2014 — subtle changes in balance and gait that gradually worsened. An initial clinical diagnosis of hereditary spastic paraplegia came in March 2016, but genetic testing at that time came back negative. The reason: the gene responsible for SPG76 had not yet been discovered. It was identified by researchers later that same year.
What followed was a years-long diagnostic odyssey — spinal taps, brain MRIs, repeat evaluations, and no clear answers. A whole exome sequencing test was ordered in November 2018, requiring blood samples from the patient and saliva samples from both parents. The confirmed SPG76 diagnosis arrived in February 2019.
That experience — the uncertainty, the years without answers, and the eventual discovery that approximately 100 people worldwide share this confirmed diagnosis, with many more suspected undiagnosed — is what drives this foundation. No one should have to navigate this alone, and no disease should go without research simply because it's rare.
The Science
A Therapeutic Opportunity
SPG76 has several features that make it a strong candidate for therapeutic development. The CAPN1 gene is relatively small — its coding sequence fits well within the packaging limits of gene therapy delivery vehicles. The disease follows a straightforward loss-of-function mechanism: both copies of the gene are broken, and carriers with one working copy are completely healthy. This means even partial restoration of calpain-1 function could be therapeutic.
Importantly, approximately 50–60% of the gene therapy development pathway has already been solved by active programs targeting other hereditary spastic paraplegia subtypes. SPG76 can build on their infrastructure, regulatory precedents, and delivery methods rather than starting from scratch.
Track 1
Gene Replacement Therapy
Because SPG76 results from loss of a functional gene, the therapeutic strategy is conceptually direct: deliver a working copy of CAPN1 to affected neurons. No toxic protein needs to be silenced — only a missing one restored. Active preclinical research programs at academic institutions are working to advance this approach toward eventual clinical testing.
Track 2
Pharmacological Intervention
In parallel with gene therapy, researchers are investigating targeted pharmacological approaches. The loss of calpain-1 leaves calpain-2 — a closely related enzyme with opposing biological effects — unopposed. Selective inhibition of calpain-2 may restore the natural balance and protect neurons from ongoing damage. Early preclinical work in animal models is underway at multiple institutions.
Beyond SPG76: A Platform for Rare Disease
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.
Patient Network
You Are Not Alone
With approximately 100 confirmed cases worldwide and many more suspected undiagnosed, receiving an SPG76 diagnosis can feel isolating. But you are part of a small, growing community — and connecting with each other matters more than most people realize.
Every patient who comes forward strengthens the case for research funding, accelerates clinical trial planning, and helps build the natural history data that regulatory agencies require before approving treatments. Your participation has direct scientific value.
Whether you were diagnosed recently or years ago, whether your symptoms are mild or advanced — we want to hear from you.
Your privacy is important to us. All information you share is kept confidential and will only be used to connect you with relevant research opportunities and community updates. We will never share your personal information without your explicit consent. See our Privacy Policy for details.
Get Involved
Help Move This Forward
There are several ways to support SPG76 research — whether you're a donor, a researcher, or someone who simply wants to help spread the word.
Donate
All funds raised support preclinical and translational research at academic institutions. Contact us to learn about our current research programs and how your contribution would be directed.
Contact Us to Donate501(c)(3) formation in progress · EIN pending
contact@spg76research.org
Share
Many people with SPG76 remain undiagnosed or don't know this foundation exists. If you know someone with unexplained progressive spasticity, ataxia, or a rare neurological condition — sharing this website could change their life and strengthen our research efforts.
Collaborate
If you are a researcher, clinician, or institution interested in SPG76 or related hereditary spastic paraplegias — we'd like to hear from you. We are actively building collaborations across multiple academic centers and welcome new scientific partnerships.
Contact for Collaboration