Prevalence of Cerebrotendinous Xanthomatosis Among Patients Diagnosed With Acquired Juvenile-Onset Idiopathic Bilateral Cataracts

Abstract

IMPORTANCE Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive bile acid synthesis disorder caused by mutations in CYP27A1, the gene encoding sterol 27-hydroxylase, which results in elevated levels of plasma cholestanol and urinary bile alcohols. Clinical symptoms and signs may include early-onset chronic diarrhea, juvenile-onset bilateral cataracts, cholestatic jaundice, tendon xanthomas, and progressive neurological deterioration. Although initiation of treatment at a young age can prevent disease complications, diagnosis often occurs after the onset of permanent neurologic damage. Strategies are needed to facilitate early diagnosis. OBJECTIVE To evaluate the prevalence of CTX in a patient population diagnosed with early-onset idiopathic bilateral cataracts. DESIGN, SETTING, AND PARTICIPANTS This interim analysis of the Cerebrotendinous Xanthomatosis Prevalence Study was conducted in 26 active US sites from November 2015 to June 2017. The study included patients diagnosed as having idiopathic bilateral cataracts from ages 2 to 21 years. Potentially eligible study participants were identified through retrospective medical record review or on receiving care for cataracts at an active site. Data were analyzed from July 2017 to October 2018. MAIN OUTCOMES AND MEASURES Measurement of plasma cholestanol levels and optional urine bile alcohol screening were performed. A plasma cholestanol concentration of 0.4 mg/dL or greater or a positive urine bile alcohol result prompted CYP27A1 genetic testing to confirm the diagnosis of CTX. RESULTS Of 170 tested patients, 88 (51.8%) were male, and the median (range) age was 10 (2-49) years. A total of 3 patients (1.8%) had biochemical and genetic confirmation of newly diagnosed CTX (plasma cholestanol level greater than 1.0 mg/dL, positive urine bile alcohol result, and disease-causative mutations in CYP27A1). The mean (range) age at cataract diagnosis for patients with CTX was 12 (8-16) years. Reported symptoms included abnormal gait or balance (n = 3), learning disability (n = 2), cognitive decline (n = 2), seizures (n = 2), frequent bone fractures (n = 2), and chronic diarrhea (n = 1). CONCLUSIONS AND RELEVANCE To date, 1.8% of patients in this study were diagnosed as having CTX, which is approximately 500-fold the currently estimated prevalence of CTX in the general population (3 to 5 per 100 000). These data suggest that juvenile-onset idiopathic bilateral cataracts may be useful as a screening marker for CTX and that ophthalmologists can play an important role in facilitating early identification of this condition.

Spinal cerebrotendinous xanthomatosis: A case report and literature review

“…Pediatricians and ophthalmologists play key roles in CTX diagnosis as neonatal diarrhea and juvenile cataracts are frequently the first symptoms observed in CTX. Prevalence of CTX in patients with bilateral juvenile-onset cataracts is estimated to 1.8% - 4% [ 33 , 34 ]. When present, tendinous xanthomas, although also found in familial hypercholesterolemia and sitosterolemia, might be an important diagnostic clue for dermatologists.…”

Emerging Trends and Research Foci in Cataract Genes: A Bibliometric and Visualized Study

“…In the present study, We further used CiteSpace to capture the burst keywords. Two frontiers of related research were found as follows: cerebrotendinous xanthomatosis (2017–2019) (Tibrewal et al, 2017 ; Freedman et al, 2019 ), oxidative stress (2017–2019) (Zoric et al, 2008 ; Petrou and Terzidaki, 2017 ), and these key words cover the research frontier of the current topic.…”

“…Within this study population, the CTX gene was about 500-fold the presently estimated its prevalence in human (3 to 5/100 000). The data suggested that idiopathic, early-onset, and bilateral cataracts could be a screening tool for CTX for early identification (Freedman et al, 2019 ). Tibrewal et al previously reported the case of a child who presented with bilateral cataracts, which led to a diagnosis of CTX.…”

Cerebrotendinous Xanthomatosis: Molecular Pathogenesis, Clinical Spectrum, Diagnosis, and Disease-Modifying Treatments

“…Early onset of cataracts is uncommon and therefore, juvenile cataracts are arguably an important cue for early diagnosis of CTX. A screening for CTX among 170 patients with idiopathic bilateral cataracts diagnosed between the ages of 2 and 21 years identified 3 cases 57) .…”

“…Inborn errors of bile acid metabolism including CTX lead to neonatal cholestasis or hepatitis 144,145) , which can be the first manifestation in this disease. In patients with juvenile bilateral cataracts and/or progressive mental deterioration, CTX should be considered 2,57) . When xanthomas are evident, differential diagnosis includes familial hypercholesterolemia (FH) and sitosterolemia.…”