A case of Cerebrotendinous Xanthomatosis with spinal cord involvement and without tendon xanthomas: identification of a new mutation of the CYP27A1 gene

Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive defect of the alternative pathway of bile acid biosynthesis, due to the deficiency of mitochondrial cytochrome P450 sterol 27-hydroxylase enzyme encoded by CYP27A1. The deficit of sterol 27-hydroxylase raises cholestanol in plasma and tissues of affected patients. Although there is a marked variability of signs, symptoms, severity and age of onset, the main clinical manifestations of CTX include chronic diarrhea, bilateral cataract, tendon xanthomas and neurological dysfunction. Herein, we report the clinical, biochemical and molecular characterization of a Caucasian female affected by CTX diagnosed at 28 years. The patient's clinical history revealed neurological and behavioral manifestations already at fifth year of life, following by bilateral cataract and chronic diarrhea without xanthomas. At diagnosis, an involvement of the cervical spinal cord was also observed on MRI. Sterols profile analysis in plasma and red blood cell membranes showed very high cholestanol levels. CYP27A1 sequencing revealed a new variant (e.g., c.850_854delinsCTC) at homozygous status. The follow-up after 5 months of chenodeoxycholic acid treatment showed a decrease of plasma cholestanol of 64%. After 1 year, the patient showed normalization of bowel function, reduction of risk of falls, improvement of cognitive function although brain and spine MRI and other instrumental examinations remained unchanged. This case highlights the variability of the CTX phenotype that makes it difficult to reach an early diagnosis. Biochemical and/or molecular screening of CTX should be taken into account to early start the pharmacological treatment limiting neurological damages.