CSF Anti-DAGLA Autoantibodies Identified as Potential Biomarker of Rapidly Progressive Cerebellitis

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A recent study recognized anti-DAGLA autoantibodies in the cerebrospinal fluid of a small group of patients, suggesting that it could be a potential biomarker for diagnosing cerebellar ataxia.

Kurt-Wolfram Sühs, MD  (Credit: Hannover Medical School)

Kurt-Wolfram Sühs, MD

(Credit: Hannover Medical School)

In a small-scale study published in the Journal of Neurology, Neurosurgery & Psychiatry, investigators identified diacylglycerol lipase alpha (DAGLA) as the autoantibody target in 4 patients with rapid progressive disabling cerebellar ataxia. Thus, researchers proposed that anti-DAGLA autoantibodies detected in the cerebrospinal fluid (CSF) with a characteristic tissue indirect immunofluorescence assay (IIFA) pattern represent novel biomarkers for rapidly progressive cerebellitis and should be considered when diagnosing patients with this disease.1

The study aimed to investigate the clinical, imaging, and fluid biomarker charcteristics of 4 patients with DAGLA-autoantibody-associated cerebellitis. In these 4 patients, researchers confirmed DAGLA as the target antigen by performing competitive inhibition experiments and DAGLA-specific recombinant cell-based IIFA (RC-IIFA).

In RC-IIFA, investigators observed serum reactivity against DAGLA in 17 of the disease controls (n = 101), including those with different clinical phenotypes than the indexed patients, and in 1 of the healthy donors (n = 102). During epitope characterization, results showed that 17 of the anti-DAGLA-positive control sera (n = 18) reacted with a C-terminal intracellular DAGLA 583-1042 fragment, while the CSF samples of the index patients targeted a conformational epitope between amino acid 1 and 157.

Top Clinical Takeaways

  • Early detection of anti-DAGLA autoantibodies in cerebrospinal fluid may be crucial for diagnosing progressive cerebellitis and initiating prompt treatment.
  • Recognition of conformational epitopes in anti-DAGLA autoantibodies underscored the importance of tailored immunotherapies for neurological disorders.
  • Further research with larger patient cohorts is needed to validate the diagnostic significance of anti-DAGLA autoantibodies and optimize treatment protocols.

"Based on these observations and the high inflammatory changes at disease onset it might be possible that earlier diagnosis and more aggressive and prolonged immunotherapy at the beginning could have had a more beneficial, long-term effect and might have ameliorated irreversible cerebellar destruction,” senior author Kurt-Wolfram Sühs, MD, consultant neurologist in the department of neurology at Hannover Medical School in Germany, and colleagues wrote.1

READ MORE: Negative Myoclonus Associated With Severe Motor Implications in Progressive Myoclonus Ataxia

Investigators subjected the samples of serum and CSF from the index patients to comprehensive autoantibody screening by IIFA between April 2022 and February 2023. Researchers used immunoprecipitation, mass spectrometry, and recombinant protein assays to identify the autoantigen among the patients. In addition, authors assessed sera from patients with various neurological symptoms and a similar tissue staining pattern as the index patient samples, and healthy donors in RC-IIFA with the identified protein. Investigators then performed epitope characterization of all positive samples through ELISA, immunoblot, immunoprecipitation and RC-IIFA using different DAGLA fragments as previously described.2

All the index participants were aged between 18 and 34 years, relatively young, and experienced pronounced gait ataxia, dysarthria, and visual impairments. Authors noted that paraclinical hallmarks in the early stage of disease among these patients included inflammatory CSF changes and cerebellar cortex hyperintensity in MRI. Notably, after 6 months, severe cerebellar atrophy developed in only 3 out of the 4 patients. Investigators also noted that all patient samples displayed the same unclassified IgG reactivity with the cerebellar molecular layer.

“In the clinical routine it might become challenging to differentiate these 2 groups of anti-DAGLA autoantibodies. Therefore, we recommend for the diagnostic workup, to consider only anti-DAGLA autoantibodies detected in tissue-IIFA-positive CSF samples as a marker for a new form of progressive cerebellitis, particularly, in combination with CSF pleocytosis and signs of intrathecal autoantibody synthesis,” Sühs et al noted.1 “Screening for anti-DAGLA autoantibodies should be performed using RC-IIFA with DAGLA full length protein. Positive CSF samples should be confirmed by RC-IIFA with the DAGLA 1–582 variant.”

This study's limitation is the small sample size of patients since investigators could not estimate the incidence of the disease. Furthermore, authors noted the limitation of the small amount of CSF samples that were available from the 4 index patients and 5 disease controls with anti-DAGLA autoantibodies present in serum. Researchers recommended that future research with well-characterized patient cohorts with paired serum/CSF samples is needed to validate the results that anti-DAGLA autoantibodies detected in cerebellitis patients recognize conformational epitopes.

“The identification of anti-DAGLA-associated cerebellitis seems important for several reasons. Without the autoantibody detection, an infectious cause of the disease might initially be assumed, which might delay immunosuppressive treatment. A rapid diagnosis and early, aggressive and prolonged immunotherapy might help to prevent severe neurological sequelae, as the disease progresses rapidly, and neuronal cell loss cannot be restored,” Sühs et al noted.1

REFERENCES
1. Miske R, Scharf M, Borowski K, et al. Identification of DAGLA as an autoantibody target in cerebellar ataxia. J Neurol Neurosurg Psychiatry. Published online April 25, 2024. doi:10.1136/jnnp-2024-333458
2. Miske R, Scharf M, Stark P, et al. Autoantibodies Against the Purkinje Cell Protein RGS8 in Paraneoplastic Cerebellar Syndrome. Neurol Neuroimmunol Neuroinflamm. 2021;8(3):e987. Published 2021 Mar 29. doi:10.1212/NXI.0000000000000987
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