This is the first real-life prospective cohort studying the value of systematic plasma cholestanol analysis at the moment of juvenile-onset unexplained bilateral cataract diagnosis and before the onset of neurological disease. 1/30 patients (3.3%) was diagnosed with CTX, and had no other symptom of the disease, aside from a personal history of chronic diarrhea in childhood, which can go undetected if not asked directly.
A previous study analyzing plasma cholestanol levels retrospectively in patients with juvenile-onset bilateral cataracts selected from records, reported a prevalence of 1.8% (3/170 patients) , and other epidemiological studies in patients with childhood-onset bilateral cataracts have shown a prevalence of 2–3.7% [6,7,8]. In these studies, cholestanol was analyzed years after cataract diagnosis, once the full CTX phenotype is present and cholestanol levels may not be similar to those at cataract diagnosis. Nevertheless, the rate of CTX diagnosis in patients with bilateral cataracts is high considering the rarity of the disease.
Although descriptions of the cataracts in CTX are largely lacking, four reports also showed posterior subcapsular cataracts with particular fleck-like opacities in patients with CTX [5, 9,10,11], as was the case in our CTX patient (Fig. 1). The reliability of this particular cataract morphology as a clinical biomarker of CTX should be further studied. Another frequent cause of juvenile posterior cataracts and neurological disease is myotonic dystrophy type 1 (DM1) or Steinert’s disease, however, patients with DM1 frequently show a “Christmas tree” morphology of the cataract , which differs from the above mentioned fleck-like opacities in CTX patients (Fig. 1). Inborn errors of metabolism other than CTX causing pediatric cataracts are congenital galactosemia, galactokinase deficiency and Wilson’s disease . In congenital galactosemia, cataract is usually associated with several gastro-intestinal symptoms, and Wilson’s disease frequently associates hepatic manifestations. However, in galactokinase deficiency the cataract may be the only consistent abnormality , as it can also be the case in CTX at the moment of cataract diagnosis. Other non-metabolic genetic diseases of bilateral cataracts as well as acquired causes should be searched for , guided by a complete ophthalmological and general examination.
As mentioned, chronic diarrhea in CTX can be easily missed during a clinical consultation, as there is no malabsorption or growth retardation and may improve with time. Furthermore, bilateral cataracts can be the sole manifestation of CTX for several years, however, treatment should be initiated as soon as possible. Therefore, even in the absence of chronic diarrhea, neurodevelopmental disorders and fleck-like opacities (which probably increase the likelihood of diagnosing a patient with CTX), patients with juvenile-onset bilateral cataracts should undergo plasma cholestanol analysis.
Patients with bilateral cataracts showed more frequently moderate elevations of cholestanol levels than a control pediatric population (17.2 vs. 4.2%), which are much lower than the levels usually seen in newly diagnosed CTX patients. This could suggest that moderately elevated cholestanol may build up early in the lens and be a risk factor for juvenile cataract development . Age and total cholesterol influence cholestanol levels [16, 17], however in the present study, they do not seem to account for the differing proportion of patients with high cholestanol between cohorts. Nevertheless, differences in sample size may have biased our results and therefore further studies looking specifically for this issue should be undertaken. Whether heterozygous variant in the CYP27A1 gene may lead to bilateral cataracts without the full CTX phenotype, as reported here for one patient, needs further examination. Alternatively, other genetic variations outside CYP27A1 gene but in genes involved in bile acids synthesis may account for a moderate increase in plasma cholestanol and be a risk factor for juvenile cataract. Finally, we cannot exclude that among the four non-genotyped patients with moderate elevation of cholestanol, some may have an undiagnosed CTX, although it seems unlikely given the very moderate elevation of plasma cholestanol levels. As this study was part of a real-life clinical scenario, we had some missing data including the lack of global CYP27A1 genotyping. However, the prospective nature of the study reduces selection biases, including recall bias, and has allowed to compile clinical and biochemical data not frequently assessed at the moment of cataract diagnosis.