Abstract Details

Title BRAT1 Associated Leukodystrophy exacerbated by Lymphoma directed Chemotherapy

Topic Neuro-oncology

Presentation(s) P13 - Poster Session 13 (8:00 AM-9:00 AM)

Poster/Presentation
Number 4-005

Background

Leukodystrophies are inherited white matter disorders. BRCA1-associated ATM activator 1, encoded by the BRAT1 gene, is responsible for cell cycle surveillance and mitochondrial function. Previously described BRAT1 mutations result in childhood lethal rigidity and multifocal seizure syndrome. To our knowledge, the clinical phenotype of adult-onset cognitive and motor decline associated with BRAT1 leukodystrophy has not been previously described.

Objective To describe a case of progressive leukodystrophy in an adult patient with BRAT1 mutation.

Design/Methods NA

Results A 66-year-old-man with a recent diagnosis of classical Hodgkin Lymphoma was referred to neuro-oncology for cognitive and motor decline and advanced cerebral white matter changes. He received no prior systemic chemotherapy or CNS radiotherapy. His relevant medical history was significant for prolonged aseptic meningitis secondary to Bactrim. Neurological exam revealed global weakness, broad-based gait, and bilateral extensor plantar responses. Brain MRI revealed periventricular, deep, and subcortical white matter T2/FLAIR hyperintensities without contrast enhancement. CSF studies were unremarkable. GeneDX genetic leukodystrophy panel conduction revealed pathogenic mutation (c.294dupA; p.L99TfsX92) resulting in a truncated protein and a BRAT1 variant of uncertain significance (c.746A>G; p.E249G). Presumptive diagnosis of late-onset leukoencephalopathy secondary to BRAT1 mutation was made. The patient began chemotherapy and had a precipitous functional decline. Compared to pre-chemotherapy imaging, metabolic imaging showed response after three cycles of chemotherapy; however, repeat brain MRI showed worsening white matter abnormalities. Adaptative chemotherapy was started, but he continued to decline. The patient died six months after a urological procedure complicated by urosepsis and cardiac arrest.

Conclusions Given the variability in phenotypes and clinical onset, leukodystrophies can be a diagnostic challenge. Our patient’s decline was likely due to genetic leukodystrophy exacerbated by chemotherapy, and his ultimate demise was secondary to mitochondrial energy deficit secondary to BRAT1 mutation. Further research is needed on the treatment of curable malignancies minimizing exacerbation of underlying leukodystrophy.

Authors/Disclosures
Sara Hooshmand, MD (Mayo Clinic) PRESENTER	Dr. Hooshmand has nothing to disclose.
	No disclosure on file
Michael W. Ruff, MD (Mayo Clinic)	Dr. Ruff has received intellectual property interests from a discovery or technology relating to health care.