CTX is a rare autosomal recessive inborn error of bile acid synthesis first reported by Von Bogaert in 1937. The disease is caused by mutation in gene CYP27A1 located on chromosome 2q33-qter leading to a lack of mitochondrial sterol 27-hydroxylase enzyme at the inner mitochondrial membrane in almost all cells of the body [7, 8]. Absence of sterol 27-hydroxylase enzyme activity causes deficiency of CDCA and cholic acid leading to a loss of feedback inhibition of rate-limiting enzyme cholesterol 7α-hydroxylase (CYP7A1) of bile synthesis, which results in excess production of cholestanol which gets deposited in various tissues [1–3].
The diagnosis is delayed due to subtle manifestations and the rarity of the disease [1]. The disease has multiorgan involvement such as bilateral premature cataracts, intractable childhood diarrhea, tendon xanthomas, neurological abnormalities, and premature atherosclerosis. The usual manifestations are due to deposition of excess cholestanol and cholesterol in the affected tissues [1, 3]. Our patient presented with bilateral tendo-Achilles tuberous xanthomas along with premature bilateral cataracts but no neurological abnormalities.
Familial hypercholesterolemia and sitosterolemia are the two important differential diagnoses of CTX. CTX is differentiated clinically from other disorders of lipid metabolism because of juvenile cataracts, progressive neurological symptoms, mild pulmonary insufficiency, and increased levels of cholestanol [9]. In the absence of tendinous xanthomas, CTX may be confused with Marinesco–Sjögren syndrome as it also presents with early age cataracts, cerebellar ataxia, neuromuscular weakness, and mental retardation but it can be differentiated from CTX by short stature, skeletal anomalies and hypergonadotropic hypogonadism [10, 11].
The laboratory findings include a normal or reduced serum cholesterol level, increased serum cholestanol, increased 7α-hydroxy-4-cholesten-3-one (7αC4), increased lathosterol, increased plant sterols (campesterol, sitosterol), increased serum and urinary bile acid alcohols but reduced serum CDCA and 27-hydroxycholesterol (27-OHC) [6]. Typical MRI findings are bilateral T2 and FLAIR hyperintense, nonhomogeneous signals in dentate nuclei and surrounding cerebellum. There are diffuse or focal white matter abnormalities along with cerebral and cerebellar atrophy [1, 3, 10]. MRS studies reveal increased lactate and lipid peaks in FLAIR sequence-hypointense lesions, and diffusely decreased NAA peaks. Microscopy reveals foamy cells admixed with inflammatory cells and giant cells surrounding cholesterol clefts [1]. These laboratory findings exactly correlate with those of our patient in the present discussion.
The treatment consists of replacement therapy, surgery and other symptomatic therapies. The replacement therapy can prevent or even reverse neurological complications and involves administration of bile acids such as CDCA, ursodeoxycholic acid, cholic acid, and taurocholic acid. Among these, CDCA is considered the drug of choice. Hydroxymethylglutaryl-CoA (HMG-CoA) synthase inhibitors are considered to enhance the effect of replacement therapy. Surgery may deteriorate gait imbalance and does not prevent neurological complications [1].