Fanconi Anemia Associated Neurological Syndrome – Phenotyping and Immune Profiling of a Novel Condition
Prashanth Ramachandran1, Bryan Smith2, Darshan Pandya2, Greer Waldrop3, Ariane Soldatos2, Yair Mina4, Kelsey Zorn3, Samuel Pleasure3, Camilo Toro2, Avindra Nath2, Michael Wilson3, Eunike Velleuer5
1University of Melbourne, 2National Institutes of Health, 3University of CA San Francisco, 4Tel Aviv Medical Center, 5University of Düsseldorf
Objective:
To present a detailed overview of the clinical presentation, radiological findings, and underlying pathology of Fanconi Anemia Associated Neurological Syndrome (FANS).
Background:
FANS is a recently identified condition that affects a subset of patients with Fanconi Anemia and results in significant disability. The etiology remains unknown and there is currently no effective treatment.
Design/Methods:
A total of 16 patients, 6 from the US and 10 from Europe, were studied. Clinical and radiological phenotyping was performed. Two patients underwent brain biopsy and one underwent autopsy, while three consented to research based peripheral blood and cerebrospinal fluid profiling. A variety of analytical techniques were used, including single cell and bulk RNA-Sequencing, metagenomic sequencing, rodent brain staining, flow cytometry, 81-plex cytokine analysis, Optical coherence tomography angiography (OCT-A) and Phage Immuno Precipitation Sequencing (PhIP-Seq).
Results:
FANS presents as a spectrum of progressive neurological condition with superimposed attacks, including hemiparesis, spasticity, cerebellar symptoms, and seizures. 70% of patients showed evidence of retinal vasculopathy on fluorescein angiogram. MRI revealed small, persistently enhancing lesions, predominantly in the cerebellum, with an accumulation of lesions over time. These lesions demonstrate central T1 hypointensity. A subset of FANS patients present with large pseudo-tumor-like lesions with severe vasogenic edema. Brain biopsy shows central gliosis, necrosis, and macrophage infiltration with severe vasculopathy. Research testing demonstrated a lack of inflammation, except for mild elevations in IL-6. Broad immunosuppression did not effectively treat the disease.
Conclusions:
FANS is a progressive neurological condition caused by brain and retinal small vessel vasculopathy, and phenotypically carries a striking resemblance to Retinal Vasculopathy with Cerebral Leukoencephalopathy, another genetic condition related to DNA damage and repair. Extensive investigations have failed to demonstrate a clear inflammatory cause. Further research is needed in this field.