Although very heterogeneous, some diseases share the characteristic of being rare. For this very reason, the last day of February (this year, February 28) marks Rare Disease Day, which aims to promote information and awareness about these conditions.
On the occasion of this day, we interviewed Dr. Yuri Matteo Falzone, neurologist at the Neurology Unit of IRCCS San Raffaele Hospital in Milan and research associate in the Neuromuscular Repair lab, to explore the epidemiological and clinical features of a rare disease: Stiff Person Syndrome.

Origins and symptoms of an “ultra-rare” disease

The Stiff Person Syndrome (SPS) is an extremely rare condition. With an estimated prevalence of about one case per million individuals, SPS falls into the category of ultra-rare diseases. It predominantly affects women (with a ratio of approximately 3:1) and typically has an onset between the ages of 20 and 50.

From an etiological standpoint, SPS is primarily an autoimmune condition, meaning that the immune system, which normally protects the body from pathogens such as harmful viruses and bacteria, mistakenly attacks the body itself. Only a small percentage of cases are paraneoplastic.

At the biological level, SPS is characterized by the production of antibodies against the enzyme GAD (glutamic acid decarboxylase), a protein essential to produce GABA. When anti-GAD antibodies reduce GABA levels, the nervous system loses part of its ability to restrain the muscles, which consequently tend to contract more than normal and struggle to relax, causing stiffness and spasms.

“The result of this biological mechanism is therefore marked muscle hyperexcitability: the muscles become excessively reactive and may contract rigidly or involuntarily,” explains Dr. Falzone, adding: “thus, in its classic form, the disease manifests as muscle stiffness, mainly involving the axial musculature – that is, the trunk muscles that support and move the spine – particularly the paravertebral muscles alongside the spine, as well as the proximal muscles of the limbs.”

“This stiffness can be so intense as to cause pain and very painful muscle spasms, as well as loss of muscle control, leading to sudden falls and trauma,” the doctor adds.

There are also some less frequent clinical variants of the syndrome. These include stiff limb syndrome (SLS), often paraneoplastic in nature, in which symptoms affect only one limb, and progressive encephalomyelitis with rigidity and myoclonus (PERM), characterized by widespread stiffness, sudden muscle contractions, and focal neurological signs—that is, abnormalities affecting specific areas of the nervous system.

Diagnosis and treatment

Due to its rarity and complexity, Stiff Person Syndrome is often diagnosed with years of delay. Initial suspicion arises from the symptoms reported by the patient and is confirmed by the presence of specific antibodies, particularly anti-GAD antibodies, as well as by neurophysiological evaluation through electromyography. This test measures the electrical activity of muscles by inserting a small needle into them; in this syndrome, it reveals continuous and simultaneous activation of agonist and antagonist muscles, which is responsible for the characteristic spasms.

To date, there is no definitive cure capable of healing Stiff Person Syndrome; treatment approaches are aimed at improving the patient’s quality of life and slowing disease progression.
As Dr. Falzone explains, therapy is structured around two different approaches:

• Symptomatic treatment, aimed at relieving the most evident symptoms, such as painful spasms, using medications like benzodiazepines and muscle relaxants;
• Etiological treatment, which targets the autoimmune cause of the disease by using corticosteroids, immunoglobulins, and plasmapheresis to modulate immune system activity, as well as immunosuppressive drugs such as rituximab to reduce the immune system’s attack on the muscles.

“Unfortunately, there is currently no definitive cure,” Falzone comments, “but research, although limited by the rarity of the disease, is also exploring drugs approved for other autoimmune conditions, with the aim of finding a targeted therapy.”

In fact, the use of therapeutic targets already developed for other autoimmune diseases could also represent an important opportunity for Stiff Person Syndrome. For example, neonatal Fc receptor (FcRn) inhibitors might be of particular interest. Although FcRn is not directly involved in the pathogenesis of the disease, it regulates the half-life of immunoglobulin G; its blockade promotes the degradation of circulating IgG, including pathogenic antibodies. As Dr. Falzone clarifies, this approach partly mirrors the rationale behind plasmapheresis, a treatment already considered in the clinical cases of SPS.

Even highly innovative strategies, such as CAR-T therapies, may represent an area of potential interest, especially in patients who are refractory to conventional treatments. “Expanding and analyzing different therapeutic options is crucial, considering that in some cases the disease can be extremely disabling and difficult to manage,” Falzone states.

Awareness and dialogue

Even in the absence of true cognitive impairments directly caused by the disease, the psychological impact of SPS is often profound. “Living with a chronic condition marked by painful spasms and traumatic events such as falls, dislocations, and fractures exposes many patients to high levels of anxiety and depression, also fueled by the constant fear that these episodes may recur,” explains Falzone.

In this complex context, consultation with experienced specialists plays a central role. “The rarity of the condition makes it essential to rely on referral centers and multidisciplinary expertise,” the doctor notes, concluding: “an approach open to dialogue and referral not only makes it possible to explore all available therapeutic options, but also reduces the risk of diagnostic delays, offering patients care that is more informed and better suited to the complexity of the disease.”

Published on: 27/02/2026

Written by: Andrea Iotti