Spastic ataxia comprises a heterogeneous group of neurodegenerative disorders characterized by ataxia and spastic paralysis, with onset and progression that vary by genetic variant.

Identifying CD99L2 as a disease-causing gene could enhance genetic diagnostics for rare movement disorders and illuminate the biological processes underlying neurodegeneration.

In this international collaboration, large-scale genetics were conducted in Tübingen, complemented by functional studies at Ruhr University Bochum.

A German-led study analyzed 2,811 individuals with ataxia, hereditary spastic paraplegia, and dystonia to identify harmful CD99L2 variants as a contributing cause of X-linked spastic ataxia.

This large cohort analysis identifies CD99L2 variants as the cause of X-linked spastic ataxia, resolving a previously unclear neurological disorder.

Disrupted CD99L2 production and its impaired interaction with CAPN1 due to disease-causing variants disrupt neuronal communication, providing a mechanism for movement-related symptoms.

The findings advocate for an integrated approach that combines genetic diagnostics with functional cellular studies to derive reliable disease mechanisms from genetic variants and improve genetic diagnosis for rare movement disorders.

The study emphasizes that merging genome-wide genetic testing with functional analyses is essential for understanding disease mechanisms in neurodegenerative conditions.

CD99L2, once mainly linked to immune functions, is shown to be essential for neural communication and normal neuronal signaling.

Published in Nature Communications, the work reveals CD99L2 acts as an activating partner for CAPN1, a calcium-dependent protease tied to neurodegenerative conditions, thereby linking immune-associated genes to neuronal signaling.

In spastic ataxia, movement coordination deficits and spasticity arise from damage in cerebellar and motor pathways, with variable clinical trajectories depending on the underlying variant.

The functional neuroscience work was led by Dr. Jonasz Weber and colleagues at Ruhr University Bochum, while the broader genetic analysis was conducted in Tübingen under Dr. Tobias Haack.