Researchers Link CD99L2 Gene to Rare Inherited Spastic Ataxia

Scientists in Germany have identified a previously overlooked gene linked to a rare inherited movement disorder, offering new insight into neurodegeneration. By studying the DNA of 2,811 patients, researchers connected damaging variants in the CD99L2 gene with X-linked spastic ataxia, a progressive condition affecting balance and muscle control.

The work, published in Nature Communications, may help resolve long-standing diagnostic mysteries for families affected by unexplained ataxia and hereditary spastic paraplegia. It also expands understanding of how genetic changes can disrupt nerve cell communication and contribute to complex neurological symptoms over time.

From immune gene to brain gene

Until now, CD99L2 was primarily associated with immune system function and had no established role in the nervous system. Using genome-wide sequencing and variant analysis, researchers identified recurring damaging changes in CD99L2 in several families showing X-linked patterns of spastic ataxia, linking the gene to the disorder.

Laboratory experiments using patient-derived cells showed that these variants impaired normal production of the CD99L2 protein. The findings indicated that CD99L2 is relevant not only to immune function but also to cellular processes involved in the nervous system.

How CD99L2 disrupts nerve signaling

Researchers at Ruhr University Bochum found that CD99L2 acts as an activating partner for CAPN1, a calcium-dependent protease already implicated in hereditary spastic paraplegia and ataxia. When CD99L2 is altered by damaging variants, CAPN1 activation is reduced, disrupting pathways involved in neuronal structure and signaling.

According to lead author Dr. Jonasz Weber, patient cells carrying CD99L2 variants showed disturbances in synaptic processes. These cellular abnormalities correspond with the neurological features observed in affected patients, including unsteady gait, muscle stiffness and difficulty coordinating voluntary movements.

The connection between CD99L2 and CAPN1 provides a potential explanation for how variants in a gene previously associated mainly with immune function can produce neurological symptoms.

Implications for diagnosis and treatment

Identifying CD99L2 as a gene associated with X-linked spastic ataxia expands the list of genetic causes known to underlie spastic ataxia and related neurological disorders. For patients whose condition remains genetically unexplained, including CD99L2 in diagnostic testing could improve the chances of identifying a molecular cause.

There is currently no cure for X-linked spastic ataxia. However, understanding the CD99L2–CAPN1 pathway gives researchers another biological mechanism to investigate when developing potential treatments.

By identifying where cellular signaling is disrupted, scientists can explore whether future approaches might restore or compensate for the affected function in neurons. Such possibilities remain subjects for further research rather than currently available treatments.

Spastic ataxia and broader research

Spastic ataxia describes a group of rare neurodegenerative disorders characterized by both ataxia, involving impaired coordination and balance, and spasticity, which causes increased muscle tone and stiffness. These symptoms are associated with dysfunction affecting the cerebellum and motor pathways in the brain and spinal cord.

Symptoms can begin during childhood or adulthood, and progression can vary considerably between patients, complicating clinical diagnosis. The Tübingen-based team led by Dr. Tobias Haack coordinated the large-scale sequencing work designed to capture this genetic diversity, while functional studies in Bochum investigated how CD99L2 variants affect neuronal processes.

The research demonstrates how combining large-scale genetic diagnostics with cellular experiments can help uncover the biological basis of rare neurological disorders that previously lacked a molecular explanation.

As additional disease-associated genes are identified, genetic testing may provide more families with clearer diagnoses and a better understanding of the conditions affecting them. In the longer term, identifying the molecular pathways involved could also help researchers investigate more precise approaches to treating these rare disorders.