Cerebrotendinous Xanthomatosis (CTX)

Information: Cerebrotendinous Xanthomatosis, Van Bogaert–Scherer–Epstein syndrome

Rare autosomal recessive lipid storage disease.
Abnormal cholestanol accumulation in the nervous system and other organ systems.
Clinical manifestations: Brain, tendons, eyes, arteries.
Spectrum of presentations: Infantile diarrhea, cataracts, tendon xanthomas, progressive neurologic impairments.
Neurologic manifestations: Ataxia, dystonia, epilepsy, dementia, etc.
Diagnostic delay: Median of 16 years.
Early intervention with chenodeoxycholic acid (CDCA) critical for prognosis.

Mutation in CYP27A1 gene encoding sterol 27-hydroxylase.
- Defective bile acid synthesis → Accumulation of cholestanol.
- Impacts cholesterol conversion → Multi-organ involvement.
Neurologic impact linked to blood-brain barrier damage and cholestanol deposition.

Rare, underdiagnosed condition.
Global prevalence estimates:
- U.S.: ~1 in 72,000 to 1 in 150,000.
- Higher prevalence in South Asians and East Asians.
Gender bias: More common in women.

Tendon histology: Foamy histiocytes, multinucleated giant cells, cholesterol clefts.
Brain findings: Demyelination, neuronal loss, lipid clefts, reactive astrocytosis.
Peripheral nerves: Axonal degeneration.

Infancy:
- Intractable diarrhea.
- Neonatal jaundice/cholestasis.
Childhood:
- Juvenile cataracts.
- Developmental delays, cognitive issues.
Adolescence/Adulthood:
- Tendon xanthomas (Achilles, patellar, hand extensor tendons).
- Progressive neurologic symptoms (e.g., spasticity, ataxia, dystonia).
Non-neurologic findings:
- Premature atherosclerosis, osteoporosis, hypothyroidism.
- Psychiatric issues: Behavioral disorders, personality changes.

Biochemical testing:
- Elevated serum cholestanol (5-10x normal).
- Increased bile alcohols in blood/urine.
- Normal/low plasma cholesterol.
Neuroimaging:
- Brain MRI: White matter hyperintensities, cerebellar atrophy, dentate nuclei hyperintensity.
Genetic testing:
- CYP27A1 mutation confirmation.
Electrophysiology:
- Abnormal sensory, motor, visual evoked potentials.

Early diagnosis possible when specific combinations of symptoms are present (Mignarri et al., 2014).

Suspicion Index in Cerebrotendinous Xanthomatosis (CTX):

Category	Clinical Features	Score
Neurological Symptoms	Progressive ataxia, cognitive decline, seizures, spasticity, peripheral neuropathy	2-3
Tendon Xanthomas	Tendon swelling or firm nodules, typically Achilles tendon	2-3
Juvenile Cataracts	Early onset of cataracts, often bilateral	2-3
Diarrhea	Chronic, unexplained diarrhea in childhood	1-2
Skeletal Abnormalities	Osteoporosis or fractures at a young age	1-2
Cholestasis in Infancy	Prolonged jaundice or neonatal cholestasis	2
Family History	Relatives with CTX, early cataracts, xanthomas, or neurological symptoms	1-2
Biochemical Markers	Elevated plasma cholestanol, bile alcohols, or abnormal sterol profile	3-4

Low Suspicion (0-4 points): CTX unlikely but may require further assessment if symptoms persist.
Moderate Suspicion (5-8 points): Investigate further with plasma cholestanol and genetic testing.
High Suspicion (9+ points): Strongly consider CTX; initiate confirmatory testing and treatment immediately.

Mechanism:
- Restores bile acid synthesis.
- Lowers plasma and CSF cholestanol levels.
Dosage:
- Adults: 250 mg TID.
- Children: 15 mg/kg/day in 3 doses.
Prevents progression and reverses early symptoms.

Statins (with coenzyme Q10 for myopathy prevention).
Symptomatic treatments:
- Epilepsy, spasticity, parkinsonism.
- Cataract surgery.
- Calcium/vitamin D for osteoporosis.
Xanthoma excision (cosmetic reasons).

Marinesco–Sjogren syndrome:
- Similar features but lacks diarrhea and elevated cholestanol.
- Additional findings: Short stature, skeletal abnormalities.
Sitosterolemia:
- Tendon xanthomas, no cataracts or neurologic issues.
- Treatment: Ezetimibe, low plant-sterol diet.
Familial hypercholesterolemia:
- Elevated LDL, no cataracts or diarrhea.

Required Consultations:
- Neurology, Psychiatry, Ophthalmology, Orthopedic surgery, Genetics.
Coordination with allied health professionals:
- Nurses, therapists, psychologists.
Family education: Autosomal recessive inheritance, early treatment benefits.