Author Affiliations: Casey Eye Institute (Drs Monson and Stout) and Departments of Physiology and Pharmacology (Dr DeBarber), Ophthalmology (Dr Bock), Pediatrics (Drs Merkens and Steiner), and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Doernbecher Children's Hospital (Dr Steiner), Oregon Health & Science University, and Legacy Emanuel Hospital (Drs Bock and Anadiotis), Portland, and Eye Health Northwest, Oregon City (Dr Bock).
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder of bile acid synthesis.1 At least 50 different causative mutations have been identified in the CYP27A1 gene encoding for a sterol 27-hydroxylase important in bile acid synthesis.2 Sterol 27-hydroxylase deficiency leads to 5α-cholestanol accumulation in the blood and tissues of affected patients,1 including the brain, often leading to severe neurological dysfunction that can incapacitate patients by the fourth or fifth decade of life.1 Cerebrotendinous xanthomatosis generally presents clinically in the second or third decade; childhood signs and symptoms can include chronic diarrhea, juvenile cataracts, school failure,1,3 and xanthomas.1 Eighty-five percent of patients with CTX develop cataracts of multiple types,2 reported to occur as young as ages 5 to 6 years,1 with cataracts and chronic diarrhea commonly presenting before neurological disease.3 For this reason, and since diarrhea is nonspecific, the clinician may not consider a diagnosis of CTX when cataracts are identified.
Treatment for CTX is available in the form of chenodeoxycholic acid.1,4 The Food and Drug Administration recently reapproved chenodeoxycholic acid (Manchester Pharmaceuticals, Inc, Fort Collins, Colorado). Because treatment of CTX from the preclinical stage prevents the onset of disease complications,4 the value of an early diagnosis for this disorder cannot be overstated. We describe 2 cases of children with CTX enrolled in an institutional review board–approved study at Oregon Health & Science University with bilateral cataracts as as a presenting sign of disease.
A 9-year-old girl was referred to an ophthalmologist for decreased vision over several months. Her ocular history was unremarkable; a full ocular examination 2 years prior was normal. Family history was unremarkable. Her medical history was significant for diarrhea and nonverbal learning disorder. On examination, uncorrected distance visual acuity was 20/80 OU and uncorrected near acuity was 20/50 OU. Manifest refraction was 0.75 + 0.50 × 90 OU, with a corrected distance acuity of 20/60 OD and 20/80 OS. Complete dilated examination was remarkable for the presence of cataract in each eye, described as a diffuse nuclear haze on slitlamp examination, with mild posterior capsular opacification (Figure 1). Retroillumination highlighted posterior capsular findings (Figure 2). Sequential bilateral cataract surgery with intraocular lens placement resulted in a corrected visual acuity of 20/20 OU. A concurrent metabolic workup indicated her plasma 5α-cholestanol level was markedly elevated at 3.7 mg/dL (normal, <0.2 mg/dL1), suggestive of CTX. Urine testing confirmed CTX with an elevated concentration of bile alcohol glucuronides (30.1 μg/mL). Chenodeoxycholic acid treatment was initiated and diarrhea resolved within 1 month, with accompanying weight gain. Her plasma cholestanol concentration dropped to 0.5 mg/dL within 7 months and after 6 years of treatment was stable at less than 0.2 mg/dL. No further clinical symptoms of CTX developed.
Figure 1. Diffuse nuclear haze and posterior subcapsular capsule opacification in the right (A) and left (B) eye.
Figure 2. Posterior subcapsular opacification in the right (A) and left (B) eye.
An 11-year-old boy was referred to an ophthalmologist for cataract evaluation. High myopia was noted by a previous ophthalmologist at age 4 years. Family history was significant for high myopia and detached retina in the mother and grandmother. Medical history included diarrhea from infancy, delayed language, autism, and seizures. Examination was limited by cooperation; however, uncorrected distance visual acuity with both eyes open was at least 20/400 OU. Dilated examination revealed a refraction of −9.00 + 1.00 × 090 OD and −9.50 + 1.25 × 090 OS and was remarkable for bilateral cataracts. The lens opacities appeared visually significant with cortical flecks and distorted retinoscopic reflexes. Sequential bilateral cataract surgery was conducted with intraocular lens placement. The corrected visual acuity was 20/30 + 1 OD and 20/40 OS. Approximately 5 years later, the patient was screened for a cholesterol disorder. His plasma 5α-cholestanol concentration was elevated at 3.1 to 4.2 mg/dL, consistent with CTX. An elevated concentration of bile alcohol glucuronides in urine confirmed CTX. Diarrhea resolved within 1 month of initiating treatment. His plasma 5α-cholestanol concentration dropped to 0.6 mg/dL within 6 to 8 months. After 8 months of treatment, the patient remained intellectually impaired and continued to require an augmentative communication device. Although he still typed single words to express wishes and needs, his spoken vocabulary expanded modestly. His behavioral difficulties (making loud noises/head banging) also appeared to be subsiding.
The prevalence of CTX in the US population is estimated to be as high as 3 to 5 per 100 000,5 predicting a minimum number of 8400 affected individuals. Cerebrotendinous xanthomatosis is therefore almost certainly severely underdiagnosed, with treated patients in the United States numbering fewer than 100 (http://ctxinfo.org/). The 2 cases we describe illustrate typical presentations of CTX with bilateral cataracts and highlight the difficulty associated with diagnosing this disorder. Both patients were not diagnosed until several years after symptom onset. One patient was diagnosed shortly after cataracts were identified and, with treatment, has developed no further clinical symptoms of CTX. The other was not diagnosed until 5 years after cataract surgery and has significant neurological symptoms associated with disease progression, even after initiation of treatment. Unfortunately, treatment after many years of disease progression may not reverse the neurological deficit4 (though is still recommended).
We urge the ophthalmology community to inquire about diarrhea and developmental delay in all children and young adults with bilateral cataracts and to determine plasma sterol levels in patients with suspected disease or refer the patient to a metabolic disease specialist for evaluation for CTX. Timely diagnosis and treatment of CTX could prevent development of the severe neurological complications associated with this disorder.
Correspondence: Dr DeBarber, Oregon Health & Science University, Mail Code L334, 3181 SW Sam Jackson Park Rd, Portland, OR 97239 (firstname.lastname@example.org).
Author Contributions: Drs Monson and DeBarber contributed equally to this article.
Financial Disclosure: None reported.
Funding/Support: This work was supported by a training grant from the Sterol and Isoprenoid Diseases consortium (Dr DeBarber), which is a part of the National Institutes of Health Rare Diseases Clinical Research Network. Funding and/or programmatic support for this project was provided by grant 1U54HD061939 from The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Rare Diseases Research.
Monson DM, DeBarber AE, Bock CJ, Anadiotis G, Merkens LS, Steiner RD, Stout AU. Cerebrotendinous Xanthomatosis: A Treatable Disease With Juvenile Cataracts as a Presenting Sign. Arch Ophthalmol. 2011;129(8):1087-1088. doi:10.1001/archophthalmol.2011.219