Cerebrotendinous xanthomatosis (CTX) is a rare inborn bile acid synthesis disorder. It is caused by CYP27A1mutations, which result in a deficiency of one key enzyme in the cholesterol metabolic pathway. The result is almost complete inhibition of chenodeoxycholic acid (CDCA) production, and to a lesser extent, of cholic acids. The lack of these products means that the body, feeling their deficiency, drives the metabolic pathway to further their production. Unfortunately, as a result, intermediate products of the path that cannot be converted to their final form due to an inactive enzyme undergo emergency metabolism. That leads to creating many products toxic to cells, including cholestanol.
The disease is inherited regardless of gender, and for symptoms to develop, both copies of the CYP27A1gene must be affected (autosomal recessive inheritance).
The incidence of CTX remains an estimate only. The most extensive population-based study to date predicted that incidence would be 1:134,970 in Europeans, 1:263,222 in Africans, 1:71,677 in Americans, 1:64,267 East Asians, and 1:36,072 in South Asians. Even though CTX is a disease accompanying the patient from birth, the diagnosis is most often made in patients' the early 30s. Based on the available reports, it seems that the disease is not more frequent or clinically different for genders (there are only slight differences in the presence of specific symptoms). However, differences in clinical manifestations are observed between the Asian and non-Asian populations. The overall clinical course of CTX remains highly different between individuals. This often causes that the correct diagnosis is associated with a significant delay, on average 15-25 years.
The determination of the metabolic block has led to developing an effective, targeted substitution therapy with CDCA.
Despite the broad clinical manifestations of the disease, we can distinguish certain groups of symptoms based on their potential period of onset. For example, cholestatic jaundice, cataracts, and diarrhea are the triad of symptoms that can happen in the first years of life. They may also be accompanied by a delay in the child's psychomotor development, and in some cases, epilepsy. Other manifestations like tendon xanthomas, balance disorders, sensory deficits, muscle stiffness, or osteoporosis occur mainly at the earliest in adolescence.
CYP27A1