Cerebrotendinous Xanthomatosis

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Continuing Education Activity

Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid storage disease associated with abnormally high cholestanol levels in the blood, accumulating in the nervous system and other organ systems. The cholestanol accumulates most notably in the brain, tendons, eyes, arteries and accounts for a broad spectrum of clinical manifestations. This activity reviews the evaluation and treatment of cerebrotendinous xanthomatosis and explains the interprofessional team's role in evaluating and treating patients with this condition.


  • Identify the etiology of cerebrotendinous xanthomatosis.
  • Outline the evaluation of cerebrotendinous xanthomatosis.
  • Review the management for patients with cerebrotendinous xanthomatosis.


Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease associated with abnormally high cholestanol levels in the blood that accumulates in the nervous system and other organ systems. The cholestanol accumulates most notably in the brain, tendons, eyes, arteries and accounts for a broad spectrum of clinical manifestations. The presentation may range from infantile-onset diarrhea, juvenile-onset cataracts, tendon xanthomas, and progressive neurologic impairments.

The neurologic manifestations are ample and may include ataxia, dystonia, epilepsy, intellectual disability, dementia, peripheral neuropathy, and parkinsonism. With the marked variability in clinical presentation, age of onset, and disease severity, CTX is often underdiagnosed. There is a median 16-year delay between the initial symptoms and diagnosis. As the clinical outcome and disease progression correlates with the initiation of chenodeoxycholic acid (CDCA) therapy, it is paramount for physicians to recognize and treat the pathology as early as possible.[1]


Cerebrotendinous xanthomatosis is caused by a mutation in the CYP27A1 gene. This gene encodes for sterol 27-hydroxylase, a mitochondrial enzyme responsible for bile acid synthesis. This enzyme's mutation decreases cholic acid and chenodeoxycholic acid, which upregulates 7α-hydroxy-4-cholesten-3-one, a precursor to cholestanol synthesis. Due to this mutation, cholesterol cannot be converted into bile acids and is subsequently converted into cholestanol and bile alcohol. A surplus of cholestanol subsequently leads to tissue deposition in various organs, yielding varied manifestations with multi-organ involvement.[2]

Research has demonstrated that as the blood-brain barrier is damaged during the process, cholestanol enters the brain and result in permanent cognitive impairments. Brain atrophy is commonly seen in patients with CTX, raising suspicion on whether cholestanol may have some role in increasing the apoptosis pathways.[3] Cholestanol has also been shown to deposit in bones, resulting in early osteoporosis and increased risk for pathological fractures.


CTX is considered a rare disease as there are only several hundred cases reported worldwide. Due to the variety of symptoms and delay in diagnosis, it is not surprising that CTX likely has a higher prevalence than reported. Older studies have suggested the prevalence of CTX in the USA among European ancestry is estimated to be 3 to 5 to 100,000 individuals.[4] The incidence among Americans is estimated at 1 in 72,000 to 1 in 150,000.[5] Considering the United States, with a population of over 320 million, the number of expected cases of CTX in the United States alone exceed the confirmed cases worldwide. A study was conducted investigating the Exome Aggregation Consortium cohort of 60,000 unrelated adults from global populations in 57 variants in CYP27A1 to determine the allele frequency. The estimated incidence of CTX was highest in South Asians and East Asians, followed by North Americans, Europeans, and Africans. Cases of CTX have been more commonly observed in women compared to men.


Histopathologic examination reveals that the tendon's dense connective tissue is replaced by an infiltrate of foamy histiocytes, multinucleated giant cells, and elongated cholesterol clefts. In the brain, demyelination, neuronal loss, lipid crystal clefts, perivascular macrophages, and reactive astrocytosis are commonly found. Primary axonal degeneration is found in peripheral nerves.

History and Physical

Patients with CTX often initially present with nonspecific findings. The symptoms typically appear in infancy, including intractable diarrhea, neonatal jaundice, or cholestasis. Some patients may develop chronic diarrhea through adulthood. In the first decade of life, patients with CTX may also report visual difficulty that is often attributed to juvenile-onset bilateral cataracts.[6] Tendon xanthomas may appear in the second or third decade of life, predominantly in the Achilles tendon, the extensor tendon of the elbow and hand, and the patellar tendon.[7] Less common non-neurologic findings include osteoporosis, premature atherosclerosis, and hypothyroidism. Psychiatric manifestations may be behavioral disorders, personality disorders, autism, or attentional deficits.[8]

Neurologic symptoms and signs typically manifest in the third decade of life and progressively worsen. The neurologic complications may vary; more predominant symptoms include extrapyramidal symptoms (dystonia and oromandibular dyskinesia), extensor plantar responses, spasticity, hyperreflexia, cerebellar signs (e.g., ataxia, nystagmus, and dysarthria), and peripheral neuropathy.[1] Some neurologic manifestations may emerge in adolescence or early adulthood, including developmental delays, cognitive impairment, intellectual disability, and learning difficulties. Other neurologic symptoms that are less common may manifest as dementia, epilepsy, and parkinsonism.


In general, biochemical testing is indicated when two of the four main symptoms are present in an individual. The four main clinical features that help clinicians diagnose CTX are infantile-onset diarrhea, childhood-onset cataract, adolescent to young adult-onset tendon xanthomas, and adult-onset progressive neurologic function.[9] The most common biochemical abnormality in patients suspected to have CTX is elevated serum plasma cholestanol levels (5-10x above normal limits). Patients with CTX typically have elevated plasma serum cholestanol levels, while plasma cholesterol concentration is normal or low. Other biochemical findings include increased bile alcohols in blood, urine, and plasma associated with a decreased biliary concentration of chenodeoxycholic acid. Increased plasma lactate concentration and cerebrospinal fluid (CSF) concentration of cholestanol and apolipoprotein B may be seen as well.

As CTX presentation varies significantly, neuroimaging and genetic testing are necessary to confirm the clinical suspicion. Molecular genetic testing is also used to evaluate for mutations of the CYP27A1 gene. Diagnostic imaging provides supplementary clinical information. Computed tomographic scan of the head and brain magnetic resonance imaging (MRI) may show bilateral focal cerebellar lesions or diffuse brain and cerebellar atrophy. Typical brain MRI findings of a patient with CTX may include white matter signal abnormalities, such as bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter.[10] Electrophysiological studies reveal decreased nerve conduction velocities and abnormal sensory, motor, visual, and brainstem evoked potentials.

Mignarri et al. created a suspicion index for early diagnosis of CTX. This diagnostic tool accurately identifies patients with CTX significantly earlier than previous studies; the investigators achieved a diagnostic age in their study of only 10.6 ± 9.8 years, which compares favorably to the previous average age at diagnosis of 35 years.[2]

Treatment / Management

Long-term treatment includes supplementation with CDCA.[11] As CTX stems from the inability to produce CDCA, supplementation of chenodeoxycholic acid normalizes bile acid synthesis, thus lowering the accumulation of plasma and CSF cholestanol levels. CDCA has a negative feedback effect, which reduces the synthesis of bile acid, which prevents the accumulation of cholestanol. The recommended dose of CDCA for adults is 250 mg three times a day and 15 mg/kg per day in three divided doses for children.[12]

Treatment in presymptomatic individuals appears to prevent clinical manifestations. Early treatment in symptomatic patients has shown to limit the progression and reverse neurologic deficits in some cases. Statin medications alone or in combination with CDCA have also been shown to decrease cholestanol concentration and improve neurologic clinical manifestation. As statins pose an increased risk of myopathy, coenzyme Q10 is taken concomitantly to improve muscle weakness.[10]

Patients are treated symptomatically for the neurologic and non-neurologic manifestations of CTX. Cataract extraction is a frequent procedure in these patients. Neurologic complications of epilepsy, spasticity, and parkinsonism are treated symptomatically. Calcium and vitamin D are supplemented for patients with osteoporosis.[13] Xanthomas may be surgically removed for cosmetic reasons.

Differential Diagnosis

  • Marinesco–Sjogren syndrome is an autosomal recessive disorder characterized by the triad of cerebellar ataxia, congenital cataract, and mental retardation that may resemble CTX. However, Marinesco-Sjogren syndrome does not present with intractable diarrhea and does not demonstrate an elevated level of cholestanol. The presence of tendon xanthomas is usually not associated with this disorder, although some case reports show this rare occurrence.[14] Patients with Marinesco-Sjogren syndrome more commonly present with short stature, muscular hypotonia, hypogonadism, peripheral neuropathy, skeletal deformities. Marinesco-Sjogren syndrome should be suspected in patients with the above findings with elevated serum creatinine kinase (2-4x upper normal limits) and an electromyogram showing myopathic findings only. A muscle biopsy would demonstrate variation in muscle fiber size, atrophic fibers, fatty replacement, and rimmed vacuole formation on light microscopy. Brain MRI would demonstrate cerebellar atrophy, usually more pronounced in the vermis than the hemispheres. The diagnosis is established in a proband of pathogenic variants of SIL1.
  • Sitosterolemia is a rare sterol storage disease characterized by tendon xanthomas, premature atherosclerosis, and hematologic disorders such as hemolytic anemia and thrombocytopenic purpura. Cataract development and neurologic diseases are not present, which may help differentiate from CTX. Treatment with ezetimibe and a low plant-sterol diet has been shown to improve cardiovascular and hematologic signs and promote xanthoma regression.[15]
  • Familial hypercholesterolemia is an autosomal dominant disorder that may also present with tendon xanthomas and a family history of premature atherosclerosis. Patients are diagnosed with the presence of elevated low-density lipid serum levels (>180mg/dL). Familial hypercholesterolemia is not associated with intractable diarrhea, cataract development, or neurologic symptoms.[16]


CTX is a progressive disease. If untreated, patients with CTX has a life expectancy into the fifth and sixth decades. However, with treatment, particularly before neurologic symptoms, patients with CTX are expected to have an average lifespan.[10]


If untreated, CTX may lead to several serious complications. Neurologic sequela of the disease is progressive, which includes epilepsy, peripheral neuropathy, ataxia, and dementia. Psychiatric complications include paranoid delusions, hallucinations, agitation, depression, all of which pose an increased risk for suicide attempts. Non-neurologic complications may include compression fractures, premature atherosclerosis resulting in myocardial infarction, and advanced aging.[10]


The following consultations are required:

  • Neurology
  • Psychiatry
  • Ophthalmology
  • Orthopedic surgery
  • Plastic surgery
  • Endocrinology
  • Gastroenterology
  • Genetics

Deterrence and Patient Education

The clinical course of CTX is progressive and potentially debilitating when left untreated. Given the wide variety of clinical manifestations and age of onset, CTX is often under-recognized and, therefore, not diagnosed for several years after clinical symptoms have emerged. Educating the patient, family, and healthcare providers is necessary to improve clinical suspicion and implement the appropriate treatment early in the clinical course. The mode of inheritance is also an essential factor that must be explained to parents. An autosomal recessive mode of inheritance requires both parents to be carriers, yielding a 25% chance for the offspring to have two homozygous recessive alleles.

Enhancing Healthcare Team Outcomes

As CTX is increasingly gaining recognition as an inborn error of metabolism, newborn screenings are currently being researched to assess their accuracy in identifying patients with CTX.[17] Early diagnosis would permit patients to start treatment before symptoms emerge, markedly impacting the patient and their families' quality of life. Patients diagnosed later in their clinical course have a median diagnosis delay of 16 years.

It is imperative to improve clinical suspicion among healthcare providers to intervene before the debilitating neurologic and non-neurologic sequela of the disease emerge. A suspicion index has already been created to help providers order the appropriate tests when patients and families note symptoms.[2] In addition to coordinating care among specialists (neurology, psychiatry, ophthalmology, orthopedic surgery, primary care, etc.), it would be paramount to collaborate with health-allied specialists such as nurses, therapists, psychologists to optimize patient function. There should also be more education for residents and fellows to approach a patient with more clinical vigilance and improve detection and treatment. [Level 5]

Article Details

Article Author

Bianca E. Carson

Article Editor:

Orlando De Jesus


10/31/2022 8:19:24 PM



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