Cerebrotendinous Xanthomatosis: A Treatable Disease with Juvenile Cataracts as a Presenting Sign

Introduction

Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive disorder of bile acid synthesis¹. At least 50 different causative mutations have been identified in the CYP27A1 gene encoding for a sterol 27-hydroxylase important in bile acid synthesis². Sterol 27-hydroxylase deficiency leads to 5α-cholestanol accumulation in the blood and tissues of affected patients¹, including brain, often leading to severe neurological dysfunction that can incapacitate patients by the 4^th–5^th decade of life¹. CTX generally presents clinically in the 2^nd–3^rd decade; childhood signs and symptoms can include chronic diarrhea, juvenile cataracts, school failure^1,3, and potentially xanthomas¹. Eighty-five percent of CTX patients develop cataracts of multiple types², reported to occur as young as age 5–6 years¹, with cataracts and chronic diarrhea commonly presenting before neurologic disease³. For this reason, and since diarrhea is non-specific, the clinician may not consider a diagnosis of CTX when cataracts are identified.

Treatment for CTX is available in the form of chenodeoxycholic acid (CDCA)^1,4. The FDA recently reapproved CDCA (Manchester Pharmaceuticals, Inc). As treatment of CTX from the preclinical stage prevents the onset of disease complications⁴, the value of early diagnosis for this disorder cannot be overstated. We describe two cases of CTX affected children enrolled in an IRB approved study at OHSU with bilateral cataracts as presenting signs of disease.

Case 1

A 9 year old female was referred to an ophthalmologist for decreased vision over several months. Past ocular history was unremarkable; full ocular exam 2 years prior was normal. Family history was unremarkable. Past medical history was significant for diarrhea and nonverbal learning disorder. On examination uncorrected distance visual acuity was 20/80 and uncorrected near acuity was 20/50 in each eye. Manifest refraction was 0.75+0.50X90 in each eye, with corrected distance acuity of 20/60 in the right and 20/80 in the left. Complete dilated exam was remarkable for the presence of cataract in each eye and described as a diffuse nuclear haze on slit lamp 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 in each eye. A metabolic workup indicated plasma 5α-cholestanol was markedly elevated at 3.7 mg/dl (normal < 0.2 mg/dl¹), suggestive of CTX. Urine testing confirmed CTX with elevated bile alcohol glucuronides present (30.1 μg/ml). CDCA treatment was initiated and diarrhea resolved within one month, with accompanying weight gain. Plasma cholestanol dropped to 0.5 mg/dl within 7 months and after 6 years of treatment is currently stable at <0.2 mg/dl. No further clinical symptoms of CTX have developed.

Figure 1.

Diffuse nuclear haze and posterior sub capsular capsule opacification in right (A) and left (B) eye.

Figure 2.

Posterior sub capsular opacification in right (A) and left (B) eye.

Case 2

An 11 year old male was referred to an ophthalmologist for cataract evaluation. High myopia was noted by a previous ophthalmologist at age 4. Family history was significant for high myopia and detached retina in mother and grandmother. Medical history included diarrhea from infancy, delayed language, autism, and seizures. Examination was limited by cooperation; however uncorrected distance visual acuity was at least 20/400 with both eyes open. Dilated examination revealed a refraction of −9.00 +1.00X090 in the right eye, and −9.50+1.25X090 in the left 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 in the right and 20/40 in the left eye. Approximately 5 years later the patient was screened for a cholesterol disorder. Plasma 5α-cholestanol was elevated at 3.1–4.2 mg/dl, consistent with CTX. Elevated bile alcohol glucuronides in urine confirmed CTX. Diarrhea resolved within one month of initiating treatment. Plasma 5α-cholestanol dropped to 0.6 mg/dl within 6–8 months. After 8 months of treatment, the patient remains intellectually impaired, and continues to require an augmentative communication device. Although he still types single words to express wishes and needs, his spoken vocabulary has expanded modestly. His behavioral difficulties (making loud noises/head banging) also appear to be subsiding.

Comment

The prevalence of CTX in the US population is estimated to be as high as 3 to 5 per 100,000⁵, predicting a minimum number of 8,400 affected individuals. CTX is therefore almost certainly severely under diagnosed with known patients in the US numbering less than 100 (http://ctxinfo.org/ accessed 5.24.2010). The two 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 suffers 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 sequealae⁴ (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 suspect patients 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.