Identifying High-Risk Neurological Phenotypes in Adult-Onset Monogenic Autoinflammatory Diseases: A Diagnostic Perspective for Neurologists

Monogenic autoinflammatory diseases are genetic disorders that result from mutations in a single gene, leading to dysregulation of the innate immune system and chronic inflammation. While these disorders often manifest in childhood, a significant subset of patients present with adult-onset symptoms, posing diagnostic challenges, particularly in the neurological domain. The recent systematic review by Silva et al. (2024) in BMC Neurology highlights critical neurological phenotypes that should raise suspicion of adult-onset monogenic autoinflammatory diseases, particularly in patients who present with unexplained inflammation, strokes, demyelinating lesions, or recurrent meningitis.

Background: Unrecognized Neurological Symptoms
The study emphasizes that neurologists often face delays in diagnosing autoinflammatory diseases due to the broad spectrum of neurological manifestations that can mimic more common conditions like multiple sclerosis (MS) or strokes. Early diagnosis is essential for initiating appropriate treatment, such as immunotherapy, which can prevent irreversible neurological damage. This systematic review analyzed case reports and case series focusing on the neurological symptoms of four prominent adult-onset autoinflammatory diseases: Familial Mediterranean Fever (FMF), Deficiency of Adenosine Deaminase 2 (DADA2), Cryopyrin-Associated Periodic Syndrome (CAPS), and Tumor Necrosis Factor Receptor-Associated Periodic Fever Syndrome (TRAPS).

Methods: A Focus on Neurological Phenotypes
Using a systematic search of PubMed, Embase, and Scopus, the authors identified 276 records, ultimately including 28 articles that met the criteria of reporting neurological symptoms in adult patients with monogenic autoinflammatory diseases. The review provides comprehensive data on clinical, laboratory, and radiological features, proposing the most prevalent neurological phenotypes associated with each disease.

Key Neurological Findings
Neurological symptoms often appear in adults after a median disease duration of five years, with some cases presenting neurological manifestations at disease onset. The following are the predominant neurological phenotypes identified:
DADA2: Stroke was the most common neurological manifestation, particularly small-vessel ischemic strokes, typically seen in the basal ganglia. DADA2 is characterized by increased macrophage activation and cytokine release, leading to vessel wall inflammation and a high risk of recurrent strokes.

FMF: Demyelinating lesions resembling MS were common in FMF patients, although they lacked some typical features of MS, such as cerebrospinal fluid (CSF) oligoclonal bands and female predominance. A third of the demyelinating cases did not meet the 2017 McDonald criteria for MS, indicating the need for neurologists to consider autoinflammatory diseases in patients with atypical MS presentations.

CAPS: Recurrent aseptic meningitis, often accompanied by leptomeningitis, was a hallmark feature. CAPS-related meningitis is thought to be driven by increased cytokine production, particularly interleukin-1β, which underscores the role of inflammation in these neurological presentations.

TRAPS: The review found insufficient data to characterize the neurological phenotypes of TRAPS due to a lack of detailed neuroimaging descriptions.

Diagnostic Implications for Neurologists
The findings of this review have significant implications for clinical practice, particularly in the neurology field. Neurologists should be vigilant when encountering young adult patients with neurological symptoms that do not fit conventional diagnostic categories. Red flags include:
Small-vessel ischemic strokes in patients with systemic inflammation, which should prompt consideration of DADA2.
Multiple sclerosis-like demyelinating lesions, particularly when accompanied by systemic inflammatory markers, should raise suspicion for FMF.
Recurrent or chronic aseptic meningitis, especially when neuroimaging reveals leptomeningeal involvement, may indicate CAPS.

Treatment Considerations
Timely recognition of these neurological phenotypes can significantly influence treatment outcomes. For instance, anti-tumor necrosis factor (TNF) therapy has been shown to reduce stroke recurrence and systemic inflammation in DADA2 patients. Similarly, treatments for FMF, such as colchicine or anti-interleukin-1 monoclonal antibodies, have been effective in preventing new demyelinating lesions.

Limitations and Future Directions The authors acknowledge several limitations in their study. Notably, some case reports did not include detailed genetic data, and the review may have introduced publication bias, as more severe neurological manifestations are likely to be published. Furthermore, the study design relied on case reports and case series, which may have led to an underrepresentation of certain phenotypes, particularly those related to TRAPS.

Future research should focus on prospective multicentric studies that include standardized neurological evaluations of patients with autoinflammatory diseases. This will allow for a more accurate characterization of the full spectrum of neurological manifestations and improve diagnostic algorithms.

Conclusion
Neurologists play a crucial role in the early diagnosis of monogenic autoinflammatory diseases, particularly when patients present with unusual neurological symptoms such as small-vessel strokes, demyelinating lesions, or recurrent aseptic meningitis. Recognizing these red flags and pursuing appropriate genetic testing can lead to timely interventions that prevent permanent neurological damage and improve patient outcomes.

References:
Silva GD, Mahler JV, da Silva Junior SRP, Mendonça LO, de Sá Barreto Lima PLG, Nóbrega PR, Kok F, Freua F. Identifying high-risk neurological phenotypes in adult-onset classic monogenic autoinflammatory diseases: when should neurologists consider testing? BMC Neurol. 2024 Apr 17;24(1):130. doi: 10.1186/s12883-024-03621-3. PMID: 38632524; PMCID: PMC11022464.