Long-Term Treatment of Cerebrotendinous Xanthomatosis with Chenodeoxycholic Acid

Abstract

We studied the effect of chenodeoxycholic acid in 17 patients with cerebrotendinous xanthomatosis. Before treatment, all subjects were symptomatic, with Achilles tendon xanthomas (in 15 of 17), cataracts (in 12 of 17), dementia (in 13 of 17), pyramidal-tract signs (in all 17), cerebellar dysfunction (in 13 of 17), mild peripheral neuropathy (in 7 of 17), electroencephalographic abnormalities (in 10 of 13), and abnormal cerebral computerized axial tomographic scans (in 10 of 12). After at least one year of chenodeoxycholic acid treatment (750 mg per day), dementia cleared in 10 subjects, and pyramidal and cerebellar signs disappeared in 5 and improved in another 8. Peripheral neuropathy was no longer detected in six. The electroencephalogram became normal in five and showed fewer abnormalities in another three subjects. Cerebral computerized axial tomographic scans improved in seven patients; the changes included the disappearance of a cerebellar xanthoma in one case. Concomitantly, mean plasma cholestanol levels declined threefold, and abnormal bile acid synthesis was suppressed. We conclude that long-term therapy with chenodeoxycholic acid may correct the biochemical abnormalities and arrest and possibly reverse the progression of cerebrotendinous xanthomatosis.

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

“…Chronic, unexplained, and often intractable diarrhea with onset in infancy or childhood is common and a key symptom associated with CTX and may persist into adulthood in some patients (Verrips et al 2000c;Mignarri et al 2014;Degos et al 2016). Cataracts and tendon xanthomas reflect the accumulation of cholestanol and cholesterol in the affected tissues; although both are common, they do not occur in all patients (Berginer et al 1984;Verrips et al 1999aVerrips et al , 2000cMoghadasian et al 2002). Bilateral cataracts associated with CTX typically develop during childhood, sometimes preceding xanthomas and neurologic symptoms, but may also be seen in adults (Verrips et al 2000c;Moghadasian 2004;Degos et al 2016).…”

“…Xanthomas also may begin to develop in childhood or adolescence and progressively enlarge over time (Moghadasian 2004;Berginer et al 2015;Saute et al 2015). Tendon xanthomas most often affect the Achilles tendon, although xanthomas may also develop on the fingers, tibial tuberosities, triceps, and plantar surfaces of the feet (Berginer et al 1984;Moghadasian 2004;Berginer et al 2015;Varman et al 2016). Tuberous xanthomas located subcutaneously in the elbows, knees, and hands may also develop (Berginer et al 2015), as well as xanthomas in the brain (Brienza et al 2015;Bhattacharyya et al 2007).…”

“…Increased peaks of choline on MR spectroscopy (MRS) have also been observed and may be useful to monitor response to therapy (Degos et al 2016); abnormal lipid peaks have also been detected on MRS, although their clinical significance is uncertain (Embirucu et al 2010). Reported computed tomography (CT) abnormalities include cerebellar white matter hypodensities above and below the tentorium (Berginer et al 1984;Waterreus et al 1987). EEG abnormalities are common and may be characterized by diffuse irregular slow theta and delta activity with frequent sharp wave discharges; however, these abnormalities are not unique to CTX (Waterreus et al 1987;Berginer et al 1984;Berginer et al 1982;Tokimura et al 1992).…”

“…Following the discovery that the biliary bile acid composition of patients with CTX is abnormal, with a virtual absence of CDCA (Salen 1971), administration of CDCA orally was evaluated and shown to correct the biochemical abnormalities and improve clinical symptoms in 17 patients with CTX (Berginer et al 1984). Alternative treatments have been examined, including hydrophilic bile acids (Batta et al 2004;Koopman et al 1985), cholestyramine (Batta et al 2004), clofibrate (Salen and Grundy 1973), statins (alone or in combination with CDCA) (Peynet et al 1991;Salen et al 1994;Verrips et al 1999b), and LDL apheresis (Mimura et al 1993;Dotti et al 2004), but have generally shown limited efficacy in inhibiting abnormal bile acid synthesis, reducing and maintaining reduced cholestanol levels, and/or demonstrating significant clinical improvement.…”

“…CDCA reduces abnormal bile acid synthesis via direct inhibition of the cholesterol 7α-hydroxylase enzyme (CYP7A1; EC 1.14.14.23) and via negative feedback on cholesterol biosynthesis (Berginer et al 1984;Salen et al 1975). Specifically, it inhibits CYP7A1 through a pathway mediated by nuclear receptor farnesoid X receptor (FXR) (Ellis et al 2003).…”