Clinical relevance and neurophysiological correlates of spasticity in cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disease due to defective activity of sterol 27-hydroxylase, with plasma and tissue cholestanol storage. Clinical phenotype is characterized by both systemic manifestations and neurological signs. Therapy with chenodeoxycholic acid (CDCA) suppresses abnormal bile acid synthesis. The purpose of the study was to assess the frequency and clinical relevance of spasticity in the CTX phenotype and to study the usefulness of transcranial magnetic stimulation (TMS) in detecting corticospinal tract damage and monitoring the effects of replacement therapy. Twenty-four CTX patients underwent clinical evaluation including general disability scores, pyramidal and cerebellar function scales, assessment of serum cholestanol and TMS. Nine patients who started CDCA therapy at baseline received clinical and neurophysiological follow up. All patients showed signs of pyramidal damage which were relevant for clinical disability in 18 out of 24 cases (75%), resulting in spastic paraparesis. TMS revealed corticospinal alterations even in subjects with mild clinical signs of corticospinal tract involvement. After CDCA treatment, serum cholestanol decreased to normal concentrations in all patients. Clinical picture was unchanged in seven out of nine cases; in two others pyramidal signs disappeared. A reduction in abnormal neurophysiological parameters was found. Spastic paraparesis is the most frequent and relevant neurological feature in CTX patients. Replacement treatment with CDCA can prevent the progression of pyramidal damage, especially if started early in the course of the disease. TMS represents a sensitive indicator of corticospinal tract dysfunction and subclinical improvements in pyramidal function after CDCA therapy.