KLHL11-IgG Paraneoplastic Neurologic Syndrome Across the Adult Lifespan: Clinical Spectrum and Cancer Associations
Marina Buciuc1, Nimalan Harinesan1, Yong Guo2, Haidara Kherbek1, Ehab Harahsheh1, Anastasia Zekeridou3, Andrew McKeon3, Eoin Flanagan3, Bardia Nourbakhsh4, Greer Waldrop5, Sepideh Mokhtari6, Rajesh Gupta7, Shannon Hinson2, Michael Wilson5, Sean Pittock3, Divyanshu Dubey3
1Neurology, 2Laboratory Medicine & Pathology, 3Neurology, Laboratory Medicine & Pathology, Mayo Clinic, 4Neurology, Johns Hopkins University, 5Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, 6Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, 7Division of Multiple Sclerosis and Neuroimmunology, Department of Neurology, University of Texas Health Science Center at Houston
Objective:
To characterize the clinical spectrum, cancer associations, and outcomes of Kelch-like protein 11 (KLHL11)-IgG–associated paraneoplastic neurologic syndrome (PNS) across the adult lifespan.
Background:
KLHL11-IgG is a rare antibody associated with paraneoplastic rhombencephalitis, classically described in young males with testicular seminoma. Emerging data suggest a broader age distribution and associations with non-testicular malignancies.
Design/Methods:
We conducted a multicenter retrospective observational study of KLHL11-IgG–positive patients. Demographic, clinical, imaging, and laboratory data were analyzed. Patients with symptom onset ≥50 years were classified as late-onset. LUZP4-IgG testing was performed using ELISA where available.
Results:
Eighty-eight patients were included (median age of onset 48 years [IQR 39–62], 89% male), of whom 41 (47%) with late-onset disease. Core clinical features reflected brainstem-cerebellar dysfunction, including ataxia (79%), diplopia (60%), vertigo (56%), nystagmus (52%), and dysarthria/dysphagia (49%). Additional manifestations included sensorineural hearing loss (37%), limbic encephalitis (20%), myelopathy (10%), and motor neuronopathy (8%). Male predominance was lower in late-onset cases (78% vs 98%, p=0.005). Both groups had high associations with malignancy (74% in late-onset vs 66% in younger cohorts). Younger patients almost exclusively had seminoma (94% vs 45%, p=0.0089), whereas non-testicular cancers were frequent in late-onset cases (16/28, 55%, most frequent were Merkel cell carcinoma. 4/16[25%] and prostate cancer 5/16 [31%]), and absent in younger patients (p<0.0001). Clinical presentation, immunotherapy response, and survival were similar between groups, with most patients experiencing persistent disability (mRS ≥3 in 77% at last follow-up). LUZP4-IgG was detected in 14/39 (36%) cases and was associated with seminoma/regressed testicular tumors (p=0.0283), with no cases identified in non-testicular cancers.
Conclusions:
KLHL11-IgG PNS presents with a characteristic rhombencephalitis-predominant syndrome across the adult lifespan and is associated with substantial long-term disability. While seminoma predominates in younger men, non-testicular malignancies are common in older patients. LUZP4-IgG appears specific to testicular germ cell tumor–related disease and is not associated with non-testicular cancers.
Generative AI Usage
No, did not use generative AI in the drafting or editing in this abstract.
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