Case report: Cerebrotendinous xanthomatosis with a novel mutation in the CYP27A1 gene mimicking behavioral variant frontotemporal dementia

**Background:** Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease caused by mutations in the CYP27A1 gene, leading to impaired bile acid synthesis and accumulation of cholesterol and cholestanol. Classic symptoms include premature cataracts, chronic diarrhea, and intellectual disability in childhood and adolescence. This report presents a unique case of CTX presenting with behavioral variant frontotemporal dementia (bvFTD) in a middle-aged woman.

**Methods:** A 60-year-old woman presented with a 4-year history of progressive behavioral and personality changes, including disinhibition, compulsive behavior, apathy, and dietary changes. Neuropsychological testing, brain imaging (MRI, spectroscopy, amyloid PET), physical examination, and biochemical and genetic analyses were performed. Serum cholestanol and 7α,12α-dihydroxycholest-4-en-3-one levels were measured, and whole exome sequencing of the CYP27A1 gene was conducted. The patient was treated with chenodeoxycholic acid (750 mg/day).

**Key Results:** The patient's Mini-Mental State Examination score was 22, and clinical dementia rating was 1. Initial brain spectroscopy showed hypoperfusion in bilateral frontal and right temporal lobes, and FLAIR images showed periventricular white matter changes. Four years later, FLAIR images revealed symmetrical high signals in the bilateral dentate nuclei of the cerebellum. Physical examination revealed xanthomas on the dorsum of both hands and Achilles tendons. Serum cholestanol was elevated at 12.4 mg/L (normal ≤6.0), and 7α,12α-dihydroxycholest-4-en-3-one was 0.485 nmol/mL (normal ≤0.100). Genetic testing identified a novel likely pathogenic variant (c.1001T>A, p.Met334Lys) and a known pathogenic variant (c.1420C>T, p.Arg474Trp) in the CYP27A1 gene, confirmed to be in trans. After 8 months of treatment with chenodeoxycholic acid, the patient showed decreased disinhibition and improvements in visuospatial function, memory, frontal/executive function, general cognition, and global severity scales.

**Clinical Implications:** This case demonstrates that CTX can present with an unusual bvFTD phenotype in middle age, without classic premature symptoms. The identification of a novel likely pathogenic variant expands the genetic spectrum of CTX. Early diagnosis is crucial because treatment with chenodeoxycholic acid can reverse metabolic abnormalities and prevent or ameliorate neurological dysfunction. Clinicians should consider CTX in patients with progressive dementia and xanthomas, even in the absence of typical early-life symptoms.