Abstract Details

Title Fanconi Anemia Associated Neurological Syndrome – Phenotyping and Immune Profiling of a Novel Condition

Topic General Neurology

Presentation(s) P8 - Poster Session 8 (5:30 PM-6:30 PM)

Poster/Presentation
Number 4-004

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.

Authors/Disclosures
Prashanth S. Ramachandran, Jr., MBBS (Royal Melbourne Hospital) PRESENTER	Dr. Ramachandran has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Ramachandran has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merk. Dr. Ramachandran has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche.
Bryan Smith, MD (DC VA Neurology 3BW)	Dr. Smith has nothing to disclose.
Darshan Pandya, MD	Dr. Pandya has nothing to disclose.
Greer Waldrop, MD (UCSF)	Dr. Waldrop has nothing to disclose.
Ariane Soldatos, MD, FAAN	Dr. Soldatos has nothing to disclose.
Yair Mina, MD (NIH)	Dr. Mina has nothing to disclose.
Kelsey Zorn	Ms. Zorn has nothing to disclose.
Samuel Pleasure, MD, PhD (UCSF)	Dr. Pleasure has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for JAMA Neurology. The institution of Dr. Pleasure has received research support from NINDS, NIMH, NIDA, National MS Society, Brain Research Foundation, John Merck Fund, Whitehall Foundation, Lupus Research Association, Juvenile Diabetes Research Foundation.
Camilo Toro, MD, FAAN (NIH)	Dr. Toro has received personal compensation in the range of $100,000-$499,999 for serving as a TORO with NIH/IRP.
Avindra Nath, MD, MBBS, FAAN (National Institutes of Health)	The institution of Dr. Nath has received research support from National Institutes of Health. The institution of Dr. Nath has received research support from Target ALS. Dr. Nath has received intellectual property interests from a discovery or technology relating to health care.
Michael R. Wilson, MD, FAAN (University of California San Francisco)	Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer. Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ouro Medicines. Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vertex Pharmaceuticals. Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Indapta Therapeutics. Dr. Wilson has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Delve Bio. Dr. Wilson has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Cambridge Medical Experts. Dr. Wilson has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Dunham Hallmark. Dr. Wilson has stock in Delve Bio. The institution of Dr. Wilson has received research support from Genentech / Roche. The institution of Dr. Wilson has received research support from NIH. The institution of Dr. Wilson has received research support from Novartis. The institution of Dr. Wilson has received research support from National Multiple Sclerosis Society. The institution of Dr. Wilson has received research support from Fanconi Anemia Research Foundation. The institution of Dr. Wilson has received research support from Department of Defense. The institution of Dr. Wilson has received research support from Chan Zuckerberg Initiative. The institution of Dr. Wilson has received research support from Kyverna Therapeutics. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received personal compensation in the range of $10,000-$49,999 for serving as a Expert Witness with US Dept of Justice.
Eunike Velleuer (University of Düsseldorf)	No disclosure on file

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