BRAT1-Associated Leukodystrophy Exacerbated by Classic Hodgkin Lymphoma-Directed Therapy

Area of Science:

• Neuroscience
• Genetics
• Oncology

Background:

• BRCA1-associated ataxia-telangiectasia-mutated activator-1 (BRAT1) is crucial for cell cycle surveillance and mitochondrial function.
• The clinical presentation and neuroimaging of adult-onset BRAT1 variants remain largely undescribed.

Observation:

• A 66-year-old man with Hodgkin lymphoma developed progressive cognitive and motor decline, with MRI showing white matter changes.
• Genetic testing revealed a pathogenic BRAT1 variant (c.294dupA; p.L99TfsX92), suggesting late-onset leukoencephalopathy.
• Chemotherapy for lymphoma led to rapid functional decline and worsening white matter abnormalities on MRI.

Findings:

• The patient's BRAT1 variant likely caused a progressive leukodystrophy.
• Chemotherapy-induced toxic leukoencephalopathy superimposed on the genetic condition.
• Mitochondrial energy deficiency was implicated in the neurological deterioration.

Implications:

• This case highlights the diagnostic challenges of leukodystrophies due to variable phenotypes and onset.
• BRAT1-associated leukodystrophy can be exacerbated by chemotherapy.
• Understanding mitochondrial dysfunction is critical for managing patients with genetic leukodystrophies and co-occurring conditions.