Chronic Diarrhea and Juvenile Cataracts: Think Cerebrotendinous Xanthomatosis and Treat

Abstract

Cerebrotendinous xanthomatosis is an autosomal recessive disease of bile acid synthesis caused by 27-hydroxylase deficiency. Treatment with chenodeoxycholic acid normalizes cholestanol concentrations and abrogates progression of the disease. We present 4 patients with cerebrotendinous xanthomatosis within 1 family who were treated with chenodeoxycholic acid for 14 years. Two young sisters started treatment at the preclinical stage before the appearance of major symptoms. Their 2 older uncles, who had already developed the complete phenotypic form of cerebrotendinous xanthomatosis when diagnosed, commenced treatment at the same time as the sisters, thus establishing a natural control group. After 14 years of chenodeoxycholic acid therapy, the cholestanol levels of all 4 patients decreased to normal levels (<6 microg/mL). Both sisters remained asymptomatic. Only moderate improvement in symptoms was observed in their uncles. In this long-term study, prompt preclinical administration of chenodeoxycholic acid in early childhood completely prevented the cerebrotendinous xanthomatosis phenotype in 2 sisters. Pediatricians should be aware of this diagnostic possibility of cerebrotendinous xanthomatosis in children presenting with chronic diarrhea and juvenile cataracts. Prevention is particularly significant in light of the availability of early genetic diagnosis and the devastating effects of this illness if not treated.

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

“…Consistent with this, high CTX gene carrier frequencies have been reported for these populations (Berginer and Abeliovich 1981;Rosner et al 2009;Falik-Zaccai et al 2008) (Table 1). Genetic screening programs have been implemented in these communities at high risk for CTX (Falik-Zaccai et al 2008;Rosner et al 2009), enabling early identification and treatment of affected newborns, thereby preventing CTX symptoms in these individuals (Falik-Zaccai et al 2008;Berginer et al 2009). …”

“…Unexplained bilateral cataracts, particularly in children and adolescents, are a common manifestation that may be recognized by ophthalmologists (Cruysberg et al 1995). The combination of juvenile cataracts and chronic diarrhea is particularly noteworthy (Cruysberg et al 1991;Berginer et al 2009), as these are among the earliest signs and symptoms. In addition, psychiatric disturbances, including ADHD, irritability, aggression, or oppositional-defiant disorder, in children and adolescents should prompt further evaluation, especially in the context of consanguinity (Fraidakis 2013).…”

“…However, advanced symptoms that have been present for many years are unlikely to significantly improve (Berginer et al 2009). It reduces levels of circulating cholestanol, other sterols (e.g., lanosterol, campesterol, sitosterol), and bile acid precursors (e.g., 7-α-hydroxy-4-cholesten-3-one) (Berginer et al 1984;Kuriyama et al 1994;Salen et al 1975;Björkhem et al 1987;Mignarri et al 2016;DeBarber et al 2010); bile alcohol levels in plasma, bile, and urine (Batta et al 1987;Batta et al 2004); and cholic acid levels (Salen et al 1994).…”

“…Reprinted from De Stefano et al (2001) , with permission symptoms preventable, up to a point (Berginer et al 2015;Brienza et al 2015). Further, initiating treatment in patients who are diagnosed before the onset of clinical symptoms may be effective in preventing irreversible multiorgan damage and the onset of clinical symptoms (Berginer et al 2009). …”

“…Few specific adverse events or safety concerns have been reported for CTX patients treated with CDCA, with several reports indicating no adverse events (Berginer et al 1984;Berginer et al 2009). Hepatotoxicity has been specifically but rarely reported.…”