Cholestatic jaundice
Scientific reports indicate the occurrence of prolonged neonatal jaundice or cholestasis in newborns. It may therefore be the first symptom of the disease. Some retrospective studies have found that 8-16% of CTX patients had neonatal cholestatic jaundice. However, this relatively low number of descriptions is caused most likely by four independent mechanisms. Firstly, some individual variations in the inborn serum cholesterol levels could impact overall neonatal cholic acids synthesis rates. Secondly, cholestatic jaundice is self-limiting in some cases, and no additional diagnostic studies are done. Thirdly, some cases are severe and fatal, thus not reported. Lastly, but probably not less important, the medical history of adult patients usually doesn’t contain reliable information about the first years of life. These examples could partially explain why cholestasis is not adequately reported in CTX patients.
Cataract
CTX patients present a high occurrence of idiopathic bilateral cataracts. Studies report its incidence of 75-80%. It is probably slightly more common in women. Cataracts can occur as early as in the first years of life. When considering most of the reports, it would seem that it is mainly diagnosed around 17. However, some develop cataracts only in late adulthood. An interesting report of cohort screening of 170 patients with juvenile-onset idiopathic bilateral cataracts showed that as many as 1.8% of these patients were diagnosed with CTX. Therefore, it seems that CTX should be included in the permanent differential diagnosis standard in people developing cataracts before 30.
Tendon xanthomas
They manifest as enlargement and swelling of the tendon area, commonly of the Achilles tendon. However, they were also reported in patellar and elbow tendons. Xanthomas are found mostly after 20, being a rare finding in a pediatric population. This clinical manifestation is more likely to occur in a non-Asian population (89%) than in an Asian population (63%). Unfortunately, it is not clear why such differences are present. We also need to remember that tendon xanthomas can be found in other syndromes (familial hypercholesterolemia, sitosterolemia, primary biliary cholangitis). It should also be noted that treatment with CDCA does not reduce the of already developed xanthomas in most cases. Still, it inhibits their development and recurrence after surgical removal.
Diarrhea
Chronic diarrhea belongs to the group of symptoms that may appear in the neonatal period. What’s more, it may also be the only symptom of the disease over a long period. Thus this clinical manifestation may be overlooked since a patient who has been used to this type of bowel movement for many years may not report it as disturbing. Less frequently, chronic diarrhea may not appear until adulthood. Another problem is the fundamental discrepancies in assessing the frequency of this symptom depending on the research. That is why we can find information about chronic diarrhea incidence from 20-80%. However, if a distinction is made between the non-Asian and Asian populations, the occurrence of the symptom can be assessed as 60-92% and 4-23%, respectively. Therefore, chronic diarrhea can be expected more often in patients of non-Asian origin. It is also a symptom that disappears quickly in many patients after starting treatment. Investigations of gastrointestinal tract in CTX patients did not reveal any abnormal results.
Cognitive impairment and psychiatric manifestations
Intellectual disability is one of the most common symptoms. It is a trait of CTX in about 70% of cases. Usually, it present along with developmental delay, but sometimes it can take the form of early dementia. Other manifestations that nearly half of the CTX patients face are behavioral and psychiatric symptoms. Reports have shown that the behavioral changes take mostly a form of aggressivity, irritability, and agitation. Such symptoms in pediatric cases led to attention deficit hyperactivity disorder or autism spectrum disorder diagnosis. Unfortunately, only with proper treatment of underlying disease could these behavioral changes be resolved. Other relatively common psychiatric symptoms are depression and anxiety. At last, in rare cases, psychotic symptoms in CTX were the cause of schizophrenia diagnosis.
Epilepsy
It is not a common manifestation in the disease course, with incidence reported 10-32% (rather near the lower spectrum). Usually, seizures start at a young age, but they can also occur in adulthood like other signs. Morphology of episodes tends to be primarily generalized tonic-clonic, less often myoclonic. Epilepsy in CTX patients is almost always accompanied by some degree of intellectual disability. We have not come across a case of a patient in whom epilepsy would be the only symptom. If such situations exist, they are incidental.
Fortunately, in many known cases, CTX treatment also resolved seizures. Others responded quite well to classical anticonvulsants. However, some studies showed that abnormal EEG recordings were present even in patients without clinical symptoms. The reported incidence was 60-77%.
Ataxia, spastic paraparesis and speech impairment
Cerebellar symptoms in CTX patients can manifest as truncal and limb ataxia, speech impairment, or nystagmus. In some cases, studies report pyramidal manifestations - spasticity, pyramidal signs like the Babinski sign. Very often, cerebellar and pyramidal symptoms overlap and occur mainly after 30-40, leading to unsteady gait. The incidence of those symptoms differs in studies, but mostly it is over 60%. Speech impairment can be found in 19-36% of CTX patients in the form of dysarthria or slurred speech. Unfortunately, with disease progression, it can turn into dysphagia.
Polyneuropathy
About half of CTX patients will develop clinical or electrophysiological signs of polyneuropathy. Both the etiology and nature of neuropathy are still investigated. Thus, currently, most useful is probably the proposed division into three types of CTX polyneuropathy: axonal, myelinated, and mixed. In several reports, pathological changes registered in ENG studies weren’t accompanied by clinical signs. Therefore, the absence of symptoms should not lead us to assume that peripheral nerves have no developing pathology.
Parkinsonism
Parkinsonism is a rare symptom in CTX patients, occurring in approximately 10%. However, this is one of those situations where a rare sign should get more of our attention. Most commonly, symptoms of parkinsonism begin around the age of 40. Moreover, in some cases, it is the first and only symptom of the underlying disease. Therefore, CTX should be considered in the differential diagnosis of rare causes of early onset parkinsonism. Unfortunately, in cases of developed parkinsonism, CDCA treatment is seldom successful, and the L-dopa effectiveness is ambiguous.
Early osteoporosis and skeletal deformities
CTX patients may present with repeated fractures due to underlying early osteoporosis. However, the cause of this manifestation is not clear. Especially that in CTX osteoporotic patients, the plasma calcium, phosphate, and 25-OHD levels are usually reported as within the normal range. Diagnosis is made by evaluation of bone mineral density. Osteoporosis incidence is around 23%, probably occurring around 1.5 times more often in women. Another bone-related problem is skeletal deformities. The most prevalent is kyphosis and pes cavus. The latter is probably underdiagnosed, but it can be found in 40% of CTX patients (more commonly males).
Dysmorphic features
Dysmorphic features among CTX patients appear to be reported less frequently than their actual occurrence. Thus our data comes actually from sporadic reports. Among them, short stature and elongated face are most frequent. However, it seems somewhat inappropriate to talk about frequency in such a small group. Other incidental reports describe the high-arched palate, gingival hyperplasia, macrocephaly, turricephaly, camptodactyly, syndactyly.
CYP27A1