469 - The "X" Factor: A Case Report of Spinal Xanthomatosis Leading to Spastic Paraparesis

Case Diagnosis: Cerebrotendinous Xanthomatosis (CTX) presenting as spastic paraparesis.

Case Description: A previously healthy 25-year-old female presented with 14 months of tremors and weakness primarily in her legs. Additional symptoms included bilateral foot drop, ataxia, and urinary urgency. Initial radiologic, electrodiagnostic, and laboratory workup found no abnormalities. She was diagnosed with a functional movement disorder and treated with physical therapy, psychotherapy, oral antispasticity medications, and an SSRI. A second opinion noted evidence of hypertonia, clonus, and hyperreflexia, with distinct corticospinal tracts on MRI, leading to expanded testing. Genetic analysis revealed a heterozygous CYP27A1 pathogenic mutation for CTX and another variant of unknown significance. Further assessment in our ALS clinic confirmed the diagnosis of CTX. Intrathecal baclofen improved the leg spasticity, and chenodiol replacement therapy was initiated for CTX.

Discussions: CTX is a rare autosomal recessive bile acid metabolism disorder caused by CYP27A1 gene mutations. CYP27A1 codes for sterol 27-hydroxylase in the cholesterol metabolism pathway. Defects increase blood cholestanol levels classically presenting with infantile diarrhea, childhood cataracts, adolescent tendon xanthomas, and adulthood neurologic dysfunction. A rare variant of CTX leads to progressive spastic paraparesis secondary to spinal xanthomatosis. Chenodiol bypasses sterol 27-hydroxylase, decreases cholestanol, stabilizes disease progression, and improves symptoms. Over 140 mutations are known to cause CTX. This patient had one pathogenic variant and another of unknown significance, potentially suggesting a novel pathogenic variant or a symptomatic carrier.

Conclusions: This patient had an atypical presentation for a rare inborn bile acid metabolism disorder. Once her upper motor neuron findings were identified, differential diagnosis included hereditary spastic paraplegia, and primary lateral sclerosis. Diagnostic studies subsequently identified CTX. This case highlights an atypical presentation of a rare metabolic disorder to increase awareness of the disease, raise clinical suspicion when addressing patients with new onset spastic paraparesis, and report a potential novel pathogenic variant or symptomatic heterozygote for CTX.