Cerebrotendinous xanthomatosis

Mendelian MONDO:0008948 Pathograph 66 Inborn error of bile acid synthesis Leukodystrophy

Cerebrotendinous xanthomatosis is an autosomal recessive inborn error of bile acid synthesis caused by biallelic pathogenic variants in CYP27A1, encoding mitochondrial sterol 27-hydroxylase. Loss of CYP27A1 activity impairs cholesterol side-chain oxidation and chenodeoxycholic acid synthesis, leading to compensatory sterol precursor metabolism, elevated cholestanol and bile alcohols, sterol deposition in the central nervous system and tendons, and multisystem disease that includes early ocular involvement. Core manifestations include infantile diarrhea or neonatal cholestasis, juvenile cataracts, tendon xanthomas, progressive neurologic dysfunction, peripheral neuropathy, pyramidal and cerebellar signs, psychiatric features, seizures, and treatability with chenodeoxycholic acid when diagnosed early.

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Mappings

MONDO

MONDO:0008948 cerebrotendinous xanthomatosis

Orphanet ORPHA:909 lists MONDO:0008948 as an exact cross-reference for cerebrotendinous xanthomatosis.

📘

Definitions

Orphanet cerebrotendinous xanthomatosis definition

An anomaly of bile acid synthesis with neonatal cholestasis, childhood-onset cataract, tendon and brain xanthomata, and adult-onset neurologic dysfunction.

OTHER

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"anomaly of bile acid synthesis characterized by neonatal cholestasis"

Orphanet defines CTX as a bile acid synthesis anomaly with the major clinical sequence.

👪

Inheritance

Autosomal recessive inheritance HP:0000007

Cerebrotendinous xanthomatosis is inherited in an autosomal recessive pattern.

Autosomal recessive inheritance

Show evidence (2 references)

ORPHA:909 SUPPORT Other

"Autosomal recessive"

Orphanet records autosomal recessive inheritance.

PMID:20301583 SUPPORT Other

"CTX is inherited in an autosomal recessive manner."

GeneReviews confirms autosomal recessive inheritance.

⚙

Pathophysiology

CYP27A1 sterol 27-hydroxylase deficiency

CYP27A1 pathogenic variants reduce mitochondrial sterol 27-hydroxylase activity, disrupting cholesterol side-chain oxidation, a key step in bile acid synthesis.

hepatocyte link

CYP27A1 link

bile acid biosynthetic process link ↓ DECREASED cholesterol catabolic process link ↓ DECREASED

steroid hydroxylase activity link ↓ DECREASED

mitochondrion link

Downstream

Chenodeoxycholic acid deficiency and disinhibited bile acid precursor synthesis Loss of sterol 27-hydroxylase reduces chenodeoxycholic acid synthesis.

Abnormal enzyme/coenzyme activity CYP27A1 loss causes deficient sterol 27-hydroxylase activity.

Show evidence (2 references)

PMID:20494109 SUPPORT Other

"accumulation of cholesterol and cholestanol in brain and tendons caused by a mutation in the sterol 27-hydroxylase gene"

Review identifies CYP27A1/sterol 27-hydroxylase mutation as the upstream bile-acid synthesis defect.

PMID:4031069 SUPPORT Human Clinical

"To examine the defect in side-chain oxidation during the formation of bile acids"

Human biochemical study supports defective sterol side-chain oxidation in bile-acid formation.

Chenodeoxycholic acid deficiency and disinhibited bile acid precursor synthesis

Reduced chenodeoxycholic acid synthesis weakens bile-acid feedback control over cholesterol 7-alpha-hydroxylase, increasing production of upstream bile acid precursors.

hepatocyte link

bile acid biosynthetic process link ⚠ ABNORMAL

Downstream

Cholestanol and bile alcohol accumulation Excess bile-acid precursors are converted into cholestanol and bile alcohols.

Chenodeoxycholic acid Reduced CYP27A1-dependent bile-acid synthesis lowers chenodeoxycholic acid.

Prolonged neonatal jaundice Infantile bile-acid synthetic failure can present as neonatal cholestasis or prolonged jaundice.

Show evidence (2 references)

PMID:4031069 SUPPORT Human Clinical

"depressed primary bile acid synthesis in cerebrotendinous xanthomatosis with a reduction in chenodeoxycholic acid formation"

Biochemical study supports reduced CDCA formation.

PMID:20494109 SUPPORT Other

"The gene defect leads to reduced bile acid synthesis with a compensatory increase in the activity of the rate-limiting enzyme in bile acid synthesis"

Review supports disinhibition of the rate-limiting bile-acid synthesis step.

Cholestanol and bile alcohol accumulation

Abnormal sterol precursor flux causes high plasma and tissue cholestanol and increased bile alcohols and glyconjugates, the major biochemical signature that distinguishes CTX from other xanthoma disorders.

cholesterol metabolic process link ⚠ ABNORMAL

Downstream

Plasma and tissue cholestanol Abnormal sterol metabolism produces elevated plasma and tissue cholestanol.

Bile alcohols and glyconjugates CYP27A1 deficiency increases bile alcohols and their glyconjugates.

Sterol deposition in tendons Elevated cholestanol and cholesterol deposit in tendon tissue.

CNS sterol deposition and white-matter injury Cholestanol and sterol precursor accumulation injures brain white matter and neural structures.

Peripheral nerve involvement Accumulated cholestanol in neuronal membranes is modeled as an upstream metabolic driver of the peripheral neuropathy branch observed in CTX.

Ocular cholestanol deposition and cataractogenesis Multisystemic cholestanol deposition includes the eye and contributes to early cataract disease.

Skeletal, bone-density, and appendicular involvement CTX can include bone and appendicular involvement; cached evidence does not resolve the intermediate mechanism linking sterol storage to osteoporosis and distal morphology findings.

Chronic diarrhea Bile-acid synthetic failure and abnormal sterol metabolism contribute to early gastrointestinal disease.

Show evidence (2 references)

PMID:20301583 SUPPORT Other

"high plasma and tissue cholestanol concentration"

GeneReviews identifies high plasma and tissue cholestanol as a defining biochemical abnormality.

PMID:20494109 SUPPORT Other

"This leads to a marked accumulation of 7alpha-hydroxylated bile acid precursors, in particular 7alpha-hydroxy-4-cholesten-3-one."

Review explains conversion of bile-acid precursors into cholestanol.

Sterol deposition in tendons

Cholestanol and cholesterol accumulation in tendon tissue causes tendon xanthomas and Achilles tendon abnormalities.

lipid storage link ↑ INCREASED

tendon link

Downstream

Tendon xanthomatosis Sterol accumulation in tendons causes xanthomatous enlargement.

Abnormality of the Achilles tendon Achilles tendon involvement is a characteristic tendon xanthoma location.

Show evidence (2 references)

PMID:23759795 SUPPORT Other

"accumulation of cholesterol and cholestanol in brain and tendons caused by a mutation in the sterol 27-hydroxylase gene (CYP27A1)."

Review links CYP27A1 loss to sterol accumulation in tendons and brain.

PMID:20301583 SUPPORT Other

"adolescent- to young adult-onset tendon xanthomas"

GeneReviews identifies tendon xanthomas as a core manifestation.

Skeletal, bone-density, and appendicular involvement

CTX includes bone-density loss and distal appendicular findings in the curated phenotype record. These are modeled as a conservative branch from systemic sterol accumulation because the cached evidence supports the manifestations but not a single resolved mechanism.

Downstream

Osteoporosis Bone involvement and surveillance-relevant bone-density loss are captured as osteoporosis.

Abnormal finger morphology Orphanet records frequent finger morphology abnormalities, but the intermediate mechanism is unresolved.

Abnormal tibia morphology Orphanet records frequent tibial morphology abnormalities, but the intermediate mechanism is unresolved.

Abnormality of the plantar skin of foot Orphanet records frequent plantar skin involvement, but the intermediate mechanism is unresolved.

Show evidence (2 references)

PMID:20301583 SUPPORT Other

"Xanthomas have been reported in the lung, bones, and central nervous system."

GeneReviews notes that xanthomas can involve bone in CTX.

ORPHA:909 SUPPORT Other

"HP:0000939 | Osteoporosis | Frequent"

Orphanet reports osteoporosis as a frequent CTX phenotype.

CNS sterol deposition and white-matter injury

Cholestanol and precursor accumulation in brain tissue is associated with white-matter lesions, vacuolation, cerebellar and pyramidal tract disease, cognitive decline, psychiatric manifestations, seizures, and extrapyramidal signs.

neuron link oligodendrocyte link

cholesterol metabolic process link ⚠ ABNORMAL

central nervous system link

Downstream

Cerebellar, corticospinal, and bulbar pathway dysfunction CNS sterol deposition and white-matter injury involve cerebellar and long-tract pathways.

Extrapyramidal and neuropsychiatric involvement Progressive CNS disease includes extrapyramidal, cognitive, and psychiatric manifestations.

CTX neuronal axonopathy Patient-derived neuronal models show CTX-associated biochemical changes and axonal defects.

Cognitive impairment Progressive CNS injury causes cognitive decline and dementia.

Ataxia Cerebellar involvement produces ataxia and gait disturbance.

Spasticity Pyramidal tract involvement produces spasticity and hyperreflexia.

Seizure Progressive brain involvement can cause seizures.

Hyperintensity of cerebral white matter on MRI White-matter injury is visible on MRI.

Abnormal auditory evoked potentials CNS pathway involvement can be detected as abnormal auditory evoked potentials.

Abnormality of somatosensory evoked potentials CNS and sensory pathway involvement can be detected as abnormal somatosensory evoked potentials.

Show evidence (2 references)

PMID:23759795 SUPPORT Other

"CTX patients with white matter lesions and vacuolation are described."

Review supports white-matter injury and vacuolation as brain pathology in CTX.

PMID:20301583 SUPPORT Other

"progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures)"

GeneReviews links CTX to the major progressive neurologic manifestations.

Ocular cholestanol deposition and cataractogenesis

Multisystemic cholestanol deposition includes the eye, and CTX commonly presents with childhood cataracts and visual impairment.

eye link

Downstream

Juvenile cataract Ocular sterol deposition is associated with early cataract formation.

Visual impairment Childhood cataracts can reduce vision.

Optic neuropathy Ocular and visual pathway involvement includes optic neuropathy.

Optic disc pallor Optic disc pallor is modeled as optic pathway involvement.

Abnormality of visual evoked potentials Visual pathway involvement can be detected as abnormal visual evoked potentials.

Abnormal retinal vascular morphology Retinal vascular abnormalities are modeled under ocular involvement.

Show evidence (2 references)

DOI:10.1186/s13023-025-03889-9 SUPPORT Other

"leading to multisystemic cholestanol deposition in membranes, including those of neurons, smooth muscle cells, tendons, and the eye."

Review supports eye involvement as part of multisystemic cholestanol deposition.

PMID:20301583 SUPPORT Other

"cataracts are the first finding, often appearing in the first decade of life."

GeneReviews supports early cataract as a major ocular manifestation.

Cerebellar, corticospinal, and bulbar pathway dysfunction

Progressive CNS involvement affects cerebellar, corticospinal, and bulbar motor pathways, producing ataxia, spastic paraparesis, dysarthria, pyramidal signs, and characteristic cerebellar/dentate-region MRI abnormalities.

cerebellum link corticospinal tract link

Downstream

Ataxia Cerebellar involvement produces ataxia.

Nystagmus Cerebellar and ocular-motor pathway involvement can produce nystagmus.

Gait disturbance Cerebellar and long-tract involvement impair gait.

Dysarthria Cerebellar and bulbar involvement can produce dysarthria.

Spasticity Corticospinal tract involvement produces spasticity.

Hyperreflexia Corticospinal tract involvement produces hyperreflexia.

Abnormal pyramidal sign Corticospinal tract dysfunction produces pyramidal signs.

Babinski sign Corticospinal tract dysfunction can cause Babinski signs.

Paraparesis Spastic paraparesis reflects corticospinal pathway involvement.

Abnormal cerebellum morphology Cerebellar involvement is reflected in cerebellar imaging abnormalities.

Abnormality of the dentate nucleus Dentate nucleus involvement is a characteristic MRI abnormality.

Abnormal cerebellar peduncle morphology Cerebellar tract disease can involve the cerebellar peduncles.

Abnormal motor evoked potentials Corticospinal pathway involvement can be detected as abnormal motor evoked potentials.

Show evidence (4 references)

PMID:20301583 SUPPORT Other

"Pyramidal signs (i.e., spasticity)"

GeneReviews supports pyramidal and cerebellar pathway involvement.

PMID:33313117 SUPPORT Human Clinical

"Cognitive decline, spastic paraplegia, cerebellar ataxia"

Clinical series supports corticospinal, cerebellar, and bulbar motor manifestations.

PMID:33313117 SUPPORT Human Clinical

"bulbar palsy"

Clinical series supports bulbar motor involvement in CTX.

+ 1 more reference

Extrapyramidal and neuropsychiatric involvement

Progressive CNS disease also involves extrapyramidal and neuropsychiatric systems, producing dystonia, atypical parkinsonism, cognitive decline, behavioral change, and depression.

central nervous system link

Downstream

Dystonia Extrapyramidal involvement produces dystonia.

Parkinsonism Extrapyramidal involvement can produce atypical parkinsonism.

Abnormality of extrapyramidal motor function Extrapyramidal system involvement causes abnormal extrapyramidal motor function.

Abnormal globus pallidus morphology Globus pallidus abnormalities are modeled under the extrapyramidal/basal ganglia branch.

Orofacial dyskinesia Extrapyramidal motor involvement can include orofacial dyskinesia.

Atypical behavior Neuropsychiatric involvement can cause behavioral change.

Depression Neuropsychiatric involvement can include depression.

Cognitive impairment Progressive CNS involvement causes cognitive decline.

Intellectual disability CTX neurologic involvement can include intellectual disability.

Neurodevelopmental delay Early neurologic involvement can include developmental delay.

Specific learning disability Cognitive and neurodevelopmental involvement can include learning disability.

Progressive psychomotor deterioration Progressive CNS disease drives psychomotor deterioration.

Show evidence (2 references)

PMID:20301583 SUPPORT Other

"progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures)"

GeneReviews supports extrapyramidal, cognitive, and psychiatric manifestations.

DOI:10.3389/fneur.2022.1049850 SUPPORT Other

"Cerebellar ataxia, peripheral neuropathy, spastic paraparesis, epilepsy, parkinsonism, cognitive decline, intellectual disability, and neuropsychiatric disturbances represent some of the most common neurological signs observed in this condition."

Practice review summarizes common neurologic and neuropsychiatric manifestations.

CTX neuronal axonopathy

Patient-derived cortical projection neurons recapitulate CTX biochemical abnormalities and axonal defects, providing a cellular bridge from bile-acid pathway disruption to progressive long-tract and peripheral neurologic disease.

neuron link

Show evidence (1 reference)

DOI:10.1186/s13023-023-02666-w SUPPORT In Vitro

"CTX and SPG5 patient iPSC-derived cortical PNs recapitulated several disease-specific biochemical changes and axonal defects of both diseases."

Patient-derived cortical projection neuron model supports CTX-associated axonal defects.

Peripheral nerve involvement

CTX can cause a sensorimotor peripheral neuropathy with demyelinating and axonal features, contributing to decreased nerve conduction velocity, distal amyotrophy, pes cavus, and gait impairment.

neuron link myelinating Schwann cell link

nerve conduction link ↓ DECREASED

Downstream

Peripheral neuropathy Peripheral nerve injury causes clinical neuropathy.

Decreased nerve conduction velocity Demyelinating neuropathy slows nerve conduction.

Distal amyotrophy Chronic peripheral nerve injury can cause distal amyotrophy.

Pes cavus Chronic peripheral neuropathy can contribute to pes cavus.

Gait disturbance Peripheral neuropathy contributes to gait impairment.

Show evidence (3 references)

PMID:33313117 SUPPORT Human Clinical

"Peripheral neuropathy was predominant sensorimotor demyelinating type"

Clinical-neurophysiology study supports demyelinating peripheral neuropathy in CTX.

PMID:33313117 SUPPORT Human Clinical

"Demyelinating and axonal degeneration tend to exist in severe neuropathy."

Study supports both demyelinating and axonal neuropathy mechanisms.

DOI:10.1186/s13023-023-02666-w SUPPORT In Vitro

"CTX and SPG5 patient iPSC-derived cortical PNs recapitulated several disease-specific biochemical changes and axonal defects of both diseases."

Patient-derived cortical projection neuron models support CTX-associated neuronal axonal defects.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Digestive 2

Chronic diarrhea Frequent (79-30%) Chronic diarrhea (HP:0002028)

Show evidence (2 references)

ORPHA:909 SUPPORT Other

"HP:0002028 | Chronic diarrhea | Frequent"

Orphanet reports chronic diarrhea as frequent.

PMID:20301583 SUPPORT Other

"infantile-onset diarrhea"

GeneReviews identifies infantile-onset diarrhea as a core clinical characteristic.

Prolonged neonatal jaundice Occasional (29-5%) Prolonged neonatal jaundice (HP:0006579)

Show evidence (2 references)

ORPHA:909 SUPPORT Other

"HP:0006579 | Prolonged neonatal jaundice | Occasional"

Orphanet reports prolonged neonatal jaundice as occasional.

PMID:33414089 SUPPORT Human Clinical

"consider the possibility of CTX caused by CYP27A1 gene variants for infants with cholestasis."

Infant cohort supports cholestasis as an early presentation of CYP27A1-related CTX.

Eye 2

Visual impairment Very frequent (99-80%) Visual impairment (HP:0000505)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0000505 | Visual impairment | Very frequent"

Orphanet reports visual impairment as very frequent.

Nystagmus Frequent (79-30%) Nystagmus (HP:0000639)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0000639 | Nystagmus | Frequent"

Orphanet reports nystagmus as frequent.

Integument 1

Tendon xanthomatosis Frequent (79-30%) Tendon xanthomatosis (HP:0010874)

Show evidence (2 references)

ORPHA:909 SUPPORT Other

"HP:0010874 | Tendon xanthomatosis | Frequent"

Orphanet reports tendon xanthomatosis as frequent.

PMID:20301583 SUPPORT Other

"tendon xanthomas"

GeneReviews identifies tendon xanthomas as a core clinical feature.

Limbs 1

Pes cavus Frequent (79-30%) Pes cavus (HP:0001761)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0001761 | Pes cavus | Frequent"

Orphanet reports pes cavus as frequent.

Musculoskeletal 2

Spasticity Frequent (79-30%) Spasticity (HP:0001257)

Show evidence (2 references)

ORPHA:909 SUPPORT Other

"HP:0001257 | Spasticity | Frequent"

Orphanet reports spasticity as frequent.

PMID:20301583 SUPPORT Other

"Pyramidal signs (i.e., spasticity)"

GeneReviews identifies spasticity as a common pyramidal sign.

Osteoporosis Frequent (79-30%) Osteoporosis (HP:0000939)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0000939 | Osteoporosis | Frequent"

Orphanet reports osteoporosis as frequent.

Nervous System 15

Cognitive impairment Frequent (79-30%) Cognitive impairment (HP:0100543)

Show evidence (2 references)

ORPHA:909 SUPPORT Other

"HP:0100543 | Cognitive impairment | Frequent"

Orphanet reports cognitive impairment as frequent.

PMID:20301583 SUPPORT Other

"dementia with slow deterioration in intellectual abilities"

GeneReviews supports progressive cognitive decline.

Intellectual disability Frequent (79-30%) Intellectual disability (HP:0001249)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0001249 | Intellectual disability | Frequent"

Orphanet reports intellectual disability as frequent.

Neurodevelopmental delay Frequent (79-30%) Neurodevelopmental delay (HP:0012758)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0012758 | Neurodevelopmental delay | Frequent"

Orphanet reports neurodevelopmental delay as frequent.

Ataxia Frequent (79-30%) Ataxia (HP:0001251)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0001251 | Ataxia | Frequent"

Orphanet reports ataxia as frequent.

Gait disturbance Frequent (79-30%) Gait disturbance (HP:0001288)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0001288 | Gait disturbance | Frequent"

Orphanet reports gait disturbance as frequent.

Hyperreflexia Frequent (79-30%) Hyperreflexia (HP:0001347)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0001347 | Hyperreflexia | Frequent"

Orphanet reports hyperreflexia as frequent.

Dysarthria Frequent (79-30%) Dysarthria (HP:0001260)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0001260 | Dysarthria | Frequent"

Orphanet reports dysarthria as frequent.

Dystonia Frequent (79-30%) Dystonia (HP:0001332)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0001332 | Dystonia | Frequent"

Orphanet reports dystonia as frequent.

Parkinsonism Occasional (29-5%) Parkinsonism (HP:0001300)

Show evidence (2 references)

ORPHA:909 SUPPORT Other

"HP:0001300 | Parkinsonism | Occasional"

Orphanet reports parkinsonism as occasional.

PMID:20301583 SUPPORT Other

"atypical parkinsonism"

GeneReviews includes atypical parkinsonism among neurologic manifestations.

Seizure Frequent (79-30%) Seizure (HP:0001250)

Show evidence (2 references)

ORPHA:909 SUPPORT Other

"HP:0001250 | Seizure | Frequent"

Orphanet reports seizures as frequent.

PMID:20301583 SUPPORT Other

"peripheral neuropathy, and seizures"

GeneReviews includes seizures among neurologic manifestations.

Peripheral neuropathy Frequent (79-30%) Peripheral neuropathy (HP:0009830)

Show evidence (2 references)

ORPHA:909 SUPPORT Other

"HP:0009830 | Peripheral neuropathy | Frequent"

Orphanet reports peripheral neuropathy as frequent.

PMID:33313117 SUPPORT Human Clinical

"Peripheral neuropathy was predominant sensorimotor demyelinating type"

Clinical-neurophysiology study supports peripheral neuropathy in CTX.

Hyperintensity of cerebral white matter on MRI Frequent (79-30%) Hyperintensity of cerebral white matter on MRI (HP:0030890)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0030890 | Hyperintensity of cerebral white matter on MRI | Frequent"

Orphanet reports cerebral white matter hyperintensity as frequent.

Atypical behavior Frequent (79-30%) Atypical behavior (HP:0000708)

Show evidence (2 references)

ORPHA:909 SUPPORT Other

"HP:0000708 | Atypical behavior | Frequent"

Orphanet reports atypical behavior as frequent.

PMID:20301583 SUPPORT Other

"Neuropsychiatric symptoms such as behavioral changes"

GeneReviews supports behavioral and psychiatric manifestations.

Depression Occasional (29-5%) Depression (HP:0000716)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0000716 | Depression | Occasional"

Orphanet reports depression as occasional.

Abnormal globus pallidus morphology Frequent (79-30%) Abnormal globus pallidus morphology (HP:0002453)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0002453 | Abnormal globus pallidus morphology | Frequent"

Orphanet reports abnormal globus pallidus morphology as frequent.

Other 25

Juvenile cataract Very frequent (99-80%) Juvenile cataract (HP:0001118)

Show evidence (2 references)

ORPHA:909 SUPPORT Other

"HP:0001118 | Juvenile cataract | Very frequent"

Orphanet reports juvenile cataract as very frequent.

PMID:20301583 SUPPORT Other

"childhood-onset cataract"

GeneReviews identifies childhood-onset cataract as a core clinical characteristic.

Optic neuropathy Frequent (79-30%) Optic neuropathy (HP:0001138)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0001138 | Optic neuropathy | Frequent"

Orphanet reports optic neuropathy as frequent.

Abnormality of the Achilles tendon Frequent (79-30%) Abnormal Achilles tendon morphology (HP:0005109)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0005109 | Abnormality of the Achilles tendon | Frequent"

Orphanet reports Achilles tendon abnormality as frequent.

Decreased nerve conduction velocity Frequent (79-30%) Decreased nerve conduction velocity (HP:0000762)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0000762 | Decreased nerve conduction velocity | Frequent"

Orphanet reports decreased nerve conduction velocity as frequent.

Distal amyotrophy Frequent (79-30%) Distal amyotrophy (HP:0003693)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0003693 | Distal amyotrophy | Frequent"

Orphanet reports distal amyotrophy as frequent.

Abnormal cerebellum morphology Frequent (79-30%) Abnormal cerebellum morphology (HP:0001317)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0001317 | Abnormal cerebellum morphology | Frequent"

Orphanet reports abnormal cerebellum morphology as frequent.

Abnormality of the dentate nucleus Occasional (29-5%) Abnormal dentate nucleus morphology (HP:0100321)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0100321 | Abnormality of the dentate nucleus | Occasional"

Orphanet reports dentate nucleus abnormality as occasional.

Abnormal enzyme/coenzyme activity Very frequent (99-80%) Abnormal circulating enzyme concentration or activity (HP:0012379)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0012379 | Abnormal enzyme/coenzyme activity | Very frequent"

Orphanet reports abnormal enzyme/coenzyme activity as very frequent.

Optic disc pallor Frequent (79-30%) Optic disc pallor (HP:0000543)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0000543 | Optic disc pallor | Frequent"

Orphanet reports optic disc pallor as frequent.

Abnormality of visual evoked potentials Frequent (79-30%) Abnormality of visual evoked potentials (HP:0000649)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0000649 | Abnormality of visual evoked potentials | Frequent"

Orphanet reports abnormal visual evoked potentials as frequent.

Abnormal retinal vascular morphology Frequent (79-30%) Abnormal retinal vascular morphology (HP:0008046)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0008046 | Abnormal retinal vascular morphology | Frequent"

Orphanet reports abnormal retinal vascular morphology as frequent.

Specific learning disability Frequent (79-30%) Specific learning disability (HP:0001328)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0001328 | Specific learning disability | Frequent"

Orphanet reports specific learning disability as frequent.

Progressive psychomotor deterioration Frequent (79-30%) Progressive psychomotor deterioration (HP:0007272)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0007272 | Progressive psychomotor deterioration | Frequent"

Orphanet reports progressive psychomotor deterioration as frequent.

Abnormality of extrapyramidal motor function Frequent (79-30%) Abnormality of extrapyramidal motor function (HP:0002071)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0002071 | Abnormality of extrapyramidal motor function | Frequent"

Orphanet reports abnormal extrapyramidal motor function as frequent.

Orofacial dyskinesia Frequent (79-30%) Orofacial dyskinesia (HP:0002310)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0002310 | Orofacial dyskinesia | Frequent"

Orphanet reports orofacial dyskinesia as frequent.

Paraparesis Frequent (79-30%) Paraparesis (HP:0002385)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0002385 | Paraparesis | Frequent"

Orphanet reports paraparesis as frequent.

Abnormal pyramidal sign Frequent (79-30%) Abnormal pyramidal sign (HP:0007256)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0007256 | Abnormal pyramidal sign | Frequent"

Orphanet reports abnormal pyramidal sign as frequent.

Babinski sign Frequent (79-30%) Babinski sign (HP:0003487)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0003487 | Babinski sign | Frequent"

Orphanet reports Babinski sign as frequent.

Abnormal auditory evoked potentials Frequent (79-30%) Abnormal auditory evoked potentials (HP:0006958)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0006958 | Abnormal auditory evoked potentials | Frequent"

Orphanet reports abnormal auditory evoked potentials as frequent.

Abnormality of somatosensory evoked potentials Frequent (79-30%) Abnormality of somatosensory evoked potentials (HP:0007377)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0007377 | Abnormality of somatosensory evoked potentials | Frequent"

Orphanet reports abnormal somatosensory evoked potentials as frequent.

Abnormal motor evoked potentials Frequent (79-30%) Abnormal motor evoked potentials (HP:0012896)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0012896 | Abnormal motor evoked potentials | Frequent"

Orphanet reports abnormal motor evoked potentials as frequent.

Abnormal cerebellar peduncle morphology Frequent (79-30%) Abnormal cerebellar peduncle morphology (HP:0011931)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0011931 | Abnormality of the cerebellar peduncle | Frequent"

Orphanet reports abnormal cerebellar peduncle morphology as frequent.

Abnormal finger morphology Frequent (79-30%) Abnormal finger morphology (HP:0001167)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0001167 | Abnormality of finger | Frequent"

Orphanet reports abnormality of finger as frequent.

Abnormal tibia morphology Frequent (79-30%) Abnormal tibia morphology (HP:0002992)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0002992 | Abnormality of tibia morphology | Frequent"

Orphanet reports abnormality of tibia morphology as frequent.

Abnormality of the plantar skin of foot Frequent (79-30%) Abnormality of the plantar skin of foot (HP:0100872)

Show evidence (1 reference)

ORPHA:909 SUPPORT Other

"HP:0100872 | Abnormality of the plantar skin of foot | Frequent"

Orphanet reports abnormality of the plantar skin of foot as frequent.

🧬

Genetic Associations

CYP27A1 (Causal loss-of-function variant)

Show evidence (3 references)

PMID:20301583 SUPPORT Other

"biallelic pathogenic variants in CYP27A1 identified by molecular genetic testing"

GeneReviews identifies biallelic CYP27A1 pathogenic variants as diagnostic.

ORPHA:909 SUPPORT Other

"CYP27A1 | cytochrome P450 family 27 subfamily A member 1 | hgnc:2605 | Disease-causing germline mutation(s) in"

Orphanet lists CYP27A1 as the disease-causing gene.

CGGV:assertion_84f4b8c1-a978-49ab-a21c-578e5d4fcdec-2024-09-23T160000.000Z SUPPORT Other

ClinGen classifies the CYP27A1-cerebrotendinous xanthomatosis gene-disease relationship as definitive with autosomal recessive inheritance.

💊

Treatments

Chenodeoxycholic acid

Action: Pharmacotherapy NCIT:C15986

Agent: chenodeoxycholic acid ↗

Long-term chenodeoxycholic acid is targeted replacement/suppression therapy that normalizes cholestanol biochemistry and is most neurologically protective when started before advanced neurologic damage.

Mechanism Target:

RESTORES Chenodeoxycholic acid deficiency and disinhibited bile acid precursor synthesis — CDCA restores bile-acid feedback and normalizes excessive precursor synthesis.

Show evidence (2 references)

PMID:20494109 SUPPORT Other

"The activity of cholesterol 7alpha-hydroxylase is normalized by treatment with bile acids."

Review supports bile-acid therapy as feedback correction of the upstream metabolic defect.

DOI:10.1186/s13023-023-02666-w SUPPORT In Vitro

"the bile acid chenodeoxycholic acid (CDCA) effectively mitigated the biochemical alterations and rescued axonal degeneration in patient iPSC-derived neurons."

Patient-derived neuronal model supports CDCA mitigation of CTX-relevant biochemical and axonal abnormalities.

INHIBITS Cholestanol and bile alcohol accumulation — CDCA suppresses the accumulated cholestanol biochemical signature downstream of CYP27A1 deficiency.

Show evidence (1 reference)

PMID:20301583 SUPPORT Other

"Long-term treatment with chenodeoxycholic acid (CDCA) normalizes plasma and cerebrospinal fluid concentration of cholestanol"

GeneReviews supports CDCA lowering the accumulated cholestanol marker.

MODULATES CTX neuronal axonopathy — CDCA mitigates CTX-relevant biochemical abnormalities and axonal degeneration in patient-derived neurons.

Show evidence (1 reference)

DOI:10.1186/s13023-023-02666-w SUPPORT In Vitro

"the bile acid chenodeoxycholic acid (CDCA) effectively mitigated the biochemical alterations and rescued axonal degeneration in patient iPSC-derived neurons."

Patient-derived neuronal model supports CDCA rescue of axonal degeneration.

Show evidence (2 references)

PMID:20301583 SUPPORT Other

"Long-term treatment with chenodeoxycholic acid (CDCA) normalizes plasma and cerebrospinal fluid concentration of cholestanol"

GeneReviews supports CDCA as targeted therapy that normalizes cholestanol.

PMID:23673909 SUPPORT Human Clinical

"preventing neurological damage and deterioration in CTX."

Long-term cohort supports early CDCA therapy to prevent neurologic damage.

Cholic acid

Action: Pharmacotherapy NCIT:C15986

Agent: cholic acid ↗

Cholic acid is an alternative bile-acid therapy reported to lower cholestanol and improve neurologic symptoms in limited experience.

Mechanism Target:

RESTORES Chenodeoxycholic acid deficiency and disinhibited bile acid precursor synthesis — Cholic acid provides bile-acid feedback when CDCA is not tolerated.

Show evidence (1 reference)

DOI:10.1186/s13023-025-03889-9 SUPPORT Other

"CA reduced cholestanol levels in CSF and blood while also reducing bile acid synthesis and excretion of bile alcohols in the urine."

Review supports cholic acid reducing bile-acid synthesis output and bile alcohol excretion.

INHIBITS Cholestanol and bile alcohol accumulation — Cholic acid lowers cholestanol and bile-alcohol biochemical abnormalities.

Show evidence (1 reference)

DOI:10.1186/s13023-025-03889-9 SUPPORT Other

"CA reduced cholestanol levels in CSF and blood while also reducing bile acid synthesis and excretion of bile alcohols in the urine."

Review supports cholic acid lowering cholestanol and urinary bile alcohol excretion.

Show evidence (1 reference)

PMID:20301583 PARTIAL Other

"Cholic acid treatment decreases cholestanol levels and improves neurologic symptoms"

GeneReviews supports cholic acid as a limited-experience alternative.

HMG-CoA reductase inhibitor therapy

Action: Pharmacotherapy NCIT:C15986

Agent: HMG-CoA reductase inhibitor ↗

Statin-class HMG-CoA reductase inhibitors can be used alone or with CDCA to decrease cholestanol concentration and improve clinical signs, but require caution because GeneReviews notes potential muscle damage.

Mechanism Target:

INHIBITS Cholestanol and bile alcohol accumulation — Statin therapy decreases cholestanol concentration but does not correct the primary CYP27A1 defect.

Show evidence (1 reference)

PMID:20301583 PARTIAL Other

"Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase alone or in combination with CDCA are also effective in decreasing cholestanol concentration and improving clinical signs; however, they may induce muscle damage."

GeneReviews supports statin-class therapy as a cholestanol-lowering adjunct while noting toxicity concerns.

Show evidence (1 reference)

PMID:20301583 PARTIAL Other

GeneReviews supports statins as adjunct/second-line biochemical therapy while noting myopathy risk.

Multidisciplinary supportive care

Action: supportive care MAXO:0000950

Supportive management addresses cataracts, epilepsy, spasticity, parkinsonism, neuropsychiatric symptoms, gait impairment, osteoporosis, and surveillance of neurologic, cardiac, and bone complications.

Target Phenotypes: Juvenile cataract ↗ Seizure ↗ Spasticity ↗

Show evidence (2 references)

PMID:20301583 SUPPORT Other

"Cataract extraction is typically required in at least one eye by age 50 years."

GeneReviews supports cataract-directed supportive intervention.

PMID:20301583 SUPPORT Other

"Epilepsy, spasticity, and parkinsonism are treated symptomatically."

GeneReviews supports symptomatic neurologic management.

🔬

Biochemical Markers

Plasma and tissue cholestanol (Elevated)

Context: Defining biochemical abnormality used diagnostically and for monitoring response.

Pathograph Readouts

Readout Of Cholestanol and bile alcohol accumulation Positive Diagnostic

Elevated plasma or tissue cholestanol reports the sterol-accumulation branch caused by CYP27A1 deficiency.

Show evidence (1 reference)

PMID:20301583 SUPPORT Other

"high plasma and tissue cholestanol concentration"

GeneReviews identifies high plasma and tissue cholestanol as a defining CTX biochemical abnormality.

Show evidence (1 reference)

PMID:20301583 SUPPORT Other

"high plasma and tissue cholestanol concentration"

GeneReviews identifies elevated cholestanol as a distinguishing biochemical abnormality.

Chenodeoxycholic acid (Decreased)

Context: Primary bile acid deficiency caused by impaired CYP27A1-dependent synthesis.

Pathograph Readouts

Readout Of Chenodeoxycholic acid deficiency and disinhibited bile acid precursor synthesis Negative Diagnostic

Decreased chenodeoxycholic acid reports impaired CYP27A1-dependent primary bile-acid synthesis.

Show evidence (1 reference)

PMID:20301583 SUPPORT Other

"decreased chenodeoxycholic acid (CDCA)"

GeneReviews identifies decreased CDCA as part of the diagnostic biochemical profile.

Show evidence (1 reference)

PMID:20301583 SUPPORT Other

"decreased chenodeoxycholic acid (CDCA)"

GeneReviews identifies decreased CDCA as part of the CTX biochemical profile.

Bile alcohols and glyconjugates (Elevated)

Context: Abnormal bile acid pathway intermediates accumulate when CYP27A1 activity is deficient.

Pathograph Readouts

Readout Of Cholestanol and bile alcohol accumulation Positive Diagnostic

Elevated bile alcohols and glyconjugates report abnormal bile-acid precursor metabolism in CTX.

Show evidence (1 reference)

PMID:20301583 SUPPORT Other

"increased concentration of bile alcohols and their glyconjugates"

GeneReviews identifies elevated bile alcohols and glyconjugates as part of the CTX biochemical profile.

Show evidence (1 reference)

PMID:20301583 SUPPORT Other

"increased concentration of bile alcohols and their glyconjugates"

GeneReviews identifies elevated bile alcohols and glyconjugates.

🔬

Clinical Trials

NCT04270682 PHASE_III COMPLETED

RESTORE was an interventional phase 3 study of chenodeoxycholic acid in adult and pediatric patients with cerebrotendinous xanthomatosis, including randomized placebo-withdrawal and pediatric open-label dose-titration cohorts.

Show evidence (1 reference)

clinicaltrials:NCT04270682 SUPPORT Human Clinical

"a randomized double-blind crossover (placebo withdrawal with rescue) study"

ClinicalTrials.gov documents a completed phase 3 CDCA study in CTX.

NCT02638220 NOT_APPLICABLE COMPLETED

Observational multicenter prevalence study that screened children and young adults with early-onset idiopathic bilateral cataracts for CTX, reflecting a cataract-first disease-detection strategy.

Target Phenotypes: Juvenile cataract ↗

Show evidence (1 reference)

clinicaltrials:NCT02638220 SUPPORT Human Clinical

"pediatric cataract evaluation and treatment is a promising avenue for disease detection and prevention."

ClinicalTrials.gov documents CTX screening among patients with early-onset idiopathic bilateral cataracts.

{ }

Source YAML

click to show

name: Cerebrotendinous xanthomatosis
category: Mendelian
creation_date: '2026-05-03T19:07:11Z'
updated_date: '2026-05-21T21:06:27Z'
synonyms:
- CTX
- Sterol 27-hydroxylase deficiency
description: >
  Cerebrotendinous xanthomatosis is an autosomal recessive inborn error of bile
  acid synthesis caused by biallelic pathogenic variants in CYP27A1, encoding
  mitochondrial sterol 27-hydroxylase. Loss of CYP27A1 activity impairs
  cholesterol side-chain oxidation and chenodeoxycholic acid synthesis, leading
  to compensatory sterol precursor metabolism, elevated cholestanol and bile
  alcohols, sterol deposition in the central nervous system and tendons, and
  multisystem disease that includes early ocular involvement. Core
  manifestations include infantile
  diarrhea or neonatal cholestasis, juvenile cataracts, tendon xanthomas,
  progressive neurologic dysfunction, peripheral neuropathy, pyramidal and
  cerebellar signs, psychiatric features, seizures, and treatability with
  chenodeoxycholic acid when diagnosed early.
disease_term:
  preferred_term: Cerebrotendinous xanthomatosis
  term:
    id: MONDO:0008948
    label: cerebrotendinous xanthomatosis
parents:
- Inborn error of bile acid synthesis
- Leukodystrophy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008948
      label: cerebrotendinous xanthomatosis
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:909
    mapping_justification: >
      Orphanet ORPHA:909 lists MONDO:0008948 as an exact cross-reference for
      cerebrotendinous xanthomatosis.
external_assertions:
- name: Orphanet cerebrotendinous xanthomatosis record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:909
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=909
  description: >
    Orphanet's ORPHA:909 structured record for cerebrotendinous xanthomatosis
    provides the exact MONDO and OMIM mappings, autosomal recessive inheritance,
    definition, CYP27A1 disease-gene assertion, epidemiology, and HPO
    annotations used in this curation.
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0008948 | Exact"
    explanation: Orphanet maps ORPHA:909 exactly to the MONDO identifier used here.
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:213700 | Exact"
    explanation: Orphanet lists OMIM:213700 as an exact external cross-reference.
definitions:
- name: Orphanet cerebrotendinous xanthomatosis definition
  definition_type: OTHER
  description: >
    An anomaly of bile acid synthesis with neonatal cholestasis, childhood-onset
    cataract, tendon and brain xanthomata, and adult-onset neurologic
    dysfunction.
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "anomaly of bile acid synthesis characterized by neonatal cholestasis"
    explanation: Orphanet defines CTX as a bile acid synthesis anomaly with the major clinical sequence.
inheritance:
- name: Autosomal recessive inheritance
  description: Cerebrotendinous xanthomatosis is inherited in an autosomal recessive pattern.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CTX is inherited in an autosomal recessive manner."
    explanation: GeneReviews confirms autosomal recessive inheritance.
prevalence:
- population: Worldwide
  percentage: Unknown
  notes: >
    Orphanet records worldwide point prevalence as unknown, with higher point
    prevalence bands reported in the United States and specific populations.
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Unknown | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet records worldwide point prevalence as unknown.
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | United States | Point prevalence | PMID:16157755"
    explanation: Orphanet cites a United States point-prevalence band from the Lorincz study.
progression:
- phase: Early systemic presentation
  age_range: Infancy to childhood
  notes: >
    Chronic diarrhea and neonatal cholestasis can be the earliest signs, and
    cataracts commonly appear in childhood before tendon xanthomas and
    progressive neurologic disease become obvious.
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Chronic diarrhea from infancy and/or neonatal cholestasis may be the earliest clinical manifestation."
    explanation: GeneReviews identifies early gastrointestinal and hepatic manifestations.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "cataracts are the first finding, often appearing in the first decade of life."
    explanation: GeneReviews supports childhood cataracts as an early feature.
- phase: Tendon xanthoma and neurologic progression
  age_range: Adolescence to adulthood
  notes: >
    Tendon xanthomas typically emerge in adolescence or young adulthood, while
    progressive cognitive, psychiatric, pyramidal, cerebellar, extrapyramidal,
    peripheral nerve, and seizure manifestations usually drive later disability.
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Xanthomas appear in the second or third decade"
    explanation: GeneReviews supports the typical age range for tendon xanthoma emergence.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "adult-onset progressive neurologic dysfunction"
    explanation: GeneReviews supports later neurologic progression.
genetic:
- name: CYP27A1
  association: Causal loss-of-function variant
  gene_term:
    preferred_term: CYP27A1
    term:
      id: hgnc:2605
      label: CYP27A1
  notes: >
    Biallelic pathogenic variants in CYP27A1 impair mitochondrial sterol
    27-hydroxylase activity. The Orphanet structured record identifies CYP27A1
    germline variants as disease-causing.
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "biallelic pathogenic variants in CYP27A1 identified by molecular genetic testing"
    explanation: GeneReviews identifies biallelic CYP27A1 pathogenic variants as diagnostic.
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CYP27A1 | cytochrome P450 family 27 subfamily A member 1 | hgnc:2605 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists CYP27A1 as the disease-causing gene.
  - reference: CGGV:assertion_84f4b8c1-a978-49ab-a21c-578e5d4fcdec-2024-09-23T160000.000Z
    reference_title: "CYP27A1 / cerebrotendinous xanthomatosis (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CYP27A1 | HGNC:2605 | cerebrotendinous xanthomatosis | MONDO:0008948 | AR | Definitive"
    explanation: ClinGen classifies the CYP27A1-cerebrotendinous xanthomatosis gene-disease relationship as definitive with autosomal recessive inheritance.
pathophysiology:
- name: CYP27A1 sterol 27-hydroxylase deficiency
  description: >
    CYP27A1 pathogenic variants reduce mitochondrial sterol 27-hydroxylase
    activity, disrupting cholesterol side-chain oxidation, a key step in bile
    acid synthesis.
  genes:
  - preferred_term: CYP27A1
    term:
      id: hgnc:2605
      label: CYP27A1
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  cellular_components:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  molecular_functions:
  - preferred_term: steroid hydroxylase activity
    modifier: DECREASED
    term:
      id: GO:0008395
      label: steroid hydroxylase activity
  biological_processes:
  - preferred_term: bile acid biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006699
      label: bile acid biosynthetic process
  - preferred_term: cholesterol catabolic process
    modifier: DECREASED
    term:
      id: GO:0006707
      label: cholesterol catabolic process
  evidence:
  - reference: PMID:20494109
    reference_title: "Cerebrotendinous xanthomatosis: an inborn error in bile acid synthesis with defined mutations but still a challenge."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "accumulation of cholesterol and cholestanol in brain and tendons caused by a mutation in the sterol 27-hydroxylase gene"
    explanation: Review identifies CYP27A1/sterol 27-hydroxylase mutation as the upstream bile-acid synthesis defect.
  - reference: PMID:4031069
    reference_title: "Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To examine the defect in side-chain oxidation during the formation of bile acids"
    explanation: Human biochemical study supports defective sterol side-chain oxidation in bile-acid formation.
  downstream:
  - target: Chenodeoxycholic acid deficiency and disinhibited bile acid precursor synthesis
    description: Loss of sterol 27-hydroxylase reduces chenodeoxycholic acid synthesis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:4031069
      reference_title: "Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "depressed primary bile acid synthesis in cerebrotendinous xanthomatosis with a reduction in chenodeoxycholic acid formation"
      explanation: Human bile-acid synthesis data link CYP27A1 sterol side-chain oxidation failure to reduced CDCA formation.
  - target: Abnormal enzyme/coenzyme activity
    description: CYP27A1 loss causes deficient sterol 27-hydroxylase activity.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:4031069
      reference_title: "Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "To examine the defect in side-chain oxidation during the formation of bile acids"
      explanation: Human biochemical study supports the abnormal sterol side-chain oxidation activity modeled as the enzyme/coenzyme phenotype.
- name: Chenodeoxycholic acid deficiency and disinhibited bile acid precursor synthesis
  description: >
    Reduced chenodeoxycholic acid synthesis weakens bile-acid feedback control
    over cholesterol 7-alpha-hydroxylase, increasing production of upstream bile
    acid precursors.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: bile acid biosynthetic process
    modifier: ABNORMAL
    term:
      id: GO:0006699
      label: bile acid biosynthetic process
  chemical_entities:
  - preferred_term: chenodeoxycholic acid
    modifier: DECREASED
    term:
      id: CHEBI:16755
      label: chenodeoxycholic acid
  evidence:
  - reference: PMID:4031069
    reference_title: "Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "depressed primary bile acid synthesis in cerebrotendinous xanthomatosis with a reduction in chenodeoxycholic acid formation"
    explanation: Biochemical study supports reduced CDCA formation.
  - reference: PMID:20494109
    reference_title: "Cerebrotendinous xanthomatosis: an inborn error in bile acid synthesis with defined mutations but still a challenge."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The gene defect leads to reduced bile acid synthesis with a compensatory increase in the activity of the rate-limiting enzyme in bile acid synthesis"
    explanation: Review supports disinhibition of the rate-limiting bile-acid synthesis step.
  downstream:
  - target: Cholestanol and bile alcohol accumulation
    description: Excess bile-acid precursors are converted into cholestanol and bile alcohols.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20494109
      reference_title: "Cerebrotendinous xanthomatosis: an inborn error in bile acid synthesis with defined mutations but still a challenge."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "This leads to a marked accumulation of 7alpha-hydroxylated bile acid precursors, in particular 7alpha-hydroxy-4-cholesten-3-one."
      explanation: Review explains that disinhibited bile-acid precursor synthesis causes abnormal sterol precursor accumulation.
  - target: Chenodeoxycholic acid
    description: Reduced CYP27A1-dependent bile-acid synthesis lowers chenodeoxycholic acid.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "decreased chenodeoxycholic acid (CDCA)"
      explanation: GeneReviews identifies decreased CDCA as a diagnostic biochemical consequence of CTX bile-acid synthesis failure.
  - target: Prolonged neonatal jaundice
    description: Infantile bile-acid synthetic failure can present as neonatal cholestasis or prolonged jaundice.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Chronic diarrhea from infancy and/or neonatal cholestasis may be the earliest clinical manifestation."
      explanation: GeneReviews links the early bile-acid synthesis disease phase to neonatal cholestasis, corresponding to the jaundice phenotype.
- name: Cholestanol and bile alcohol accumulation
  description: >
    Abnormal sterol precursor flux causes high plasma and tissue cholestanol and
    increased bile alcohols and glyconjugates, the major biochemical signature
    that distinguishes CTX from other xanthoma disorders.
  biological_processes:
  - preferred_term: cholesterol metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0008203
      label: cholesterol metabolic process
  chemical_entities:
  - preferred_term: cholestanol
    modifier: INCREASED
    term:
      id: CHEBI:86570
      label: (5alpha)-cholestan-3beta-ol
  - preferred_term: bile alcohol
    modifier: INCREASED
    term:
      id: CHEBI:50420
      label: bile alcohol
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "high plasma and tissue cholestanol concentration"
    explanation: GeneReviews identifies high plasma and tissue cholestanol as a defining biochemical abnormality.
  - reference: PMID:20494109
    reference_title: "Cerebrotendinous xanthomatosis: an inborn error in bile acid synthesis with defined mutations but still a challenge."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This leads to a marked accumulation of 7alpha-hydroxylated bile acid precursors, in particular 7alpha-hydroxy-4-cholesten-3-one."
    explanation: Review explains conversion of bile-acid precursors into cholestanol.
  downstream:
  - target: Plasma and tissue cholestanol
    description: Abnormal sterol metabolism produces elevated plasma and tissue cholestanol.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "high plasma and tissue cholestanol concentration"
      explanation: GeneReviews identifies elevated plasma and tissue cholestanol as the biochemical readout of sterol accumulation.
  - target: Bile alcohols and glyconjugates
    description: CYP27A1 deficiency increases bile alcohols and their glyconjugates.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "increased concentration of bile alcohols and their glyconjugates"
      explanation: GeneReviews identifies elevated bile alcohols and glyconjugates as a biochemical readout of abnormal bile-acid precursor metabolism.
  - target: Sterol deposition in tendons
    description: Elevated cholestanol and cholesterol deposit in tendon tissue.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23759795
      reference_title: "Cerebrotendinous xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "accumulation of cholesterol and cholestanol in brain and tendons caused by a mutation in the sterol 27-hydroxylase gene (CYP27A1)."
      explanation: Review directly links CYP27A1-related cholestanol/cholesterol accumulation to tendon deposition.
  - target: CNS sterol deposition and white-matter injury
    description: Cholestanol and sterol precursor accumulation injures brain white matter and neural structures.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23759795
      reference_title: "Cerebrotendinous xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CTX patients with white matter lesions and vacuolation are described."
      explanation: Review supports CNS white-matter lesions as a downstream pathology of CTX sterol accumulation.
  - target: Peripheral nerve involvement
    description: >
      Accumulated cholestanol in neuronal membranes is modeled as an upstream
      metabolic driver of the peripheral neuropathy branch observed in CTX.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Cholestanol deposition in neuronal membranes perturbs peripheral neural structures.
    - Axonal injury and demyelinating or axonal neuropathy bridge the metabolic lesion to peripheral nerve manifestations.
    evidence:
    - reference: DOI:10.1186/s13023-025-03889-9
      reference_title: "Cholic acid as a treatment for cerebrotendinous xanthomatosis: a comprehensive review of safety and efficacy"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >
        Deficiencies in CYP27A1 limit the production of both CA and CDCA,
        leading to multisystemic cholestanol deposition in membranes, including
        those of neurons, smooth muscle cells, tendons, and the eye.
      explanation: >
        Review-level CTX pathophysiology links CYP27A1 deficiency and
        accumulated cholestanol to neuronal membrane deposition.
    - reference: PMID:33313117
      reference_title: "Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >
        Pooling our patients and literature review together, peripheral
        neuropathy was predominant sensorimotor demyelinating type in Chinese
        population, with an evident length dependent pattern and increased
        vulnerability in motor nerves.
      explanation: >
        Clinical-neurophysiology data confirm that peripheral neuropathy is a
        recurring CTX neurologic manifestation downstream of the metabolic
        disorder.
  - target: Ocular cholestanol deposition and cataractogenesis
    description: Multisystemic cholestanol deposition includes the eye and contributes to early cataract disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.1186/s13023-025-03889-9
      reference_title: "Cholic acid as a treatment for cerebrotendinous xanthomatosis: a comprehensive review of safety and efficacy"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "leading to multisystemic cholestanol deposition in membranes, including those of neurons, smooth muscle cells, tendons, and the eye."
      explanation: Review-level CTX pathophysiology supports eye involvement within multisystemic cholestanol deposition.
  - target: Skeletal, bone-density, and appendicular involvement
    description: >
      CTX can include bone and appendicular involvement; cached evidence does
      not resolve the intermediate mechanism linking sterol storage to
      osteoporosis and distal morphology findings.
    causal_link_type: UNKNOWN
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Xanthomas have been reported in the lung, bones, and central nervous system."
      explanation: >
        GeneReviews notes that CTX xanthomas can involve bone, supporting a
        skeletal/appendicular involvement branch.
  - target: Chronic diarrhea
    description: Bile-acid synthetic failure and abnormal sterol metabolism contribute to early gastrointestinal disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Chronic diarrhea from infancy and/or neonatal cholestasis may be the earliest clinical manifestation."
      explanation: GeneReviews identifies chronic infantile diarrhea as an early CTX manifestation in the bile-acid synthesis disease phase.
- name: Sterol deposition in tendons
  description: >
    Cholestanol and cholesterol accumulation in tendon tissue causes tendon
    xanthomas and Achilles tendon abnormalities.
  locations:
  - preferred_term: tendon
    term:
      id: UBERON:0000043
      label: tendon
  biological_processes:
  - preferred_term: lipid storage
    modifier: INCREASED
    term:
      id: GO:0019915
      label: lipid storage
  evidence:
  - reference: PMID:23759795
    reference_title: "Cerebrotendinous xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "accumulation of cholesterol and cholestanol in brain and tendons caused by a mutation in the sterol 27-hydroxylase gene (CYP27A1)."
    explanation: Review links CYP27A1 loss to sterol accumulation in tendons and brain.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "adolescent- to young adult-onset tendon xanthomas"
    explanation: GeneReviews identifies tendon xanthomas as a core manifestation.
  downstream:
  - target: Tendon xanthomatosis
    description: Sterol accumulation in tendons causes xanthomatous enlargement.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "tendon xanthomas"
      explanation: GeneReviews identifies tendon xanthomas as the clinical manifestation of tendon sterol deposition.
  - target: Abnormality of the Achilles tendon
    description: Achilles tendon involvement is a characteristic tendon xanthoma location.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0005109 | Abnormality of the Achilles tendon | Frequent"
      explanation: Orphanet reports Achilles tendon abnormality as a frequent CTX phenotype downstream of tendon xanthomatosis.
- name: Skeletal, bone-density, and appendicular involvement
  description: >
    CTX includes bone-density loss and distal appendicular findings in the
    curated phenotype record. These are modeled as a conservative branch from
    systemic sterol accumulation because the cached evidence supports the
    manifestations but not a single resolved mechanism.
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Xanthomas have been reported in the lung, bones, and central nervous system."
    explanation: GeneReviews notes that xanthomas can involve bone in CTX.
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000939 | Osteoporosis | Frequent"
    explanation: Orphanet reports osteoporosis as a frequent CTX phenotype.
  downstream:
  - target: Osteoporosis
    description: Bone involvement and surveillance-relevant bone-density loss are captured as osteoporosis.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000939 | Osteoporosis | Frequent"
      explanation: Orphanet reports osteoporosis as a frequent CTX phenotype.
  - target: Abnormal finger morphology
    description: Orphanet records frequent finger morphology abnormalities, but the intermediate mechanism is unresolved.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001167 | Abnormality of finger | Frequent"
      explanation: Orphanet reports finger morphology abnormality as frequent.
  - target: Abnormal tibia morphology
    description: Orphanet records frequent tibial morphology abnormalities, but the intermediate mechanism is unresolved.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002992 | Abnormality of tibia morphology | Frequent"
      explanation: Orphanet reports tibial morphology abnormality as frequent.
  - target: Abnormality of the plantar skin of foot
    description: Orphanet records frequent plantar skin involvement, but the intermediate mechanism is unresolved.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0100872 | Abnormality of the plantar skin of foot | Frequent"
      explanation: Orphanet reports plantar skin abnormality as frequent.
- name: CNS sterol deposition and white-matter injury
  description: >
    Cholestanol and precursor accumulation in brain tissue is associated with
    white-matter lesions, vacuolation, cerebellar and pyramidal tract disease,
    cognitive decline, psychiatric manifestations, seizures, and extrapyramidal
    signs.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  locations:
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  biological_processes:
  - preferred_term: cholesterol metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0008203
      label: cholesterol metabolic process
  evidence:
  - reference: PMID:23759795
    reference_title: "Cerebrotendinous xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CTX patients with white matter lesions and vacuolation are described."
    explanation: Review supports white-matter injury and vacuolation as brain pathology in CTX.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures)"
    explanation: GeneReviews links CTX to the major progressive neurologic manifestations.
  downstream:
  - target: Cerebellar, corticospinal, and bulbar pathway dysfunction
    description: CNS sterol deposition and white-matter injury involve cerebellar and long-tract pathways.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33313117
      reference_title: "Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cognitive decline, spastic paraplegia, cerebellar ataxia"
      explanation: Human CTX series supports cerebellar and corticospinal pathway manifestations downstream of CNS involvement.
  - target: Extrapyramidal and neuropsychiatric involvement
    description: Progressive CNS disease includes extrapyramidal, cognitive, and psychiatric manifestations.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures)"
      explanation: GeneReviews supports extrapyramidal, cognitive, and psychiatric manifestations as part of progressive CTX neurologic disease.
  - target: CTX neuronal axonopathy
    description: Patient-derived neuronal models show CTX-associated biochemical changes and axonal defects.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.1186/s13023-023-02666-w
      reference_title: "Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "CTX and SPG5 patient iPSC-derived cortical PNs recapitulated several disease-specific biochemical changes and axonal defects of both diseases."
      explanation: Patient-derived neuronal models support CTX-associated axonal defects downstream of the CNS metabolic lesion.
  - target: Cognitive impairment
    description: Progressive CNS injury causes cognitive decline and dementia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "dementia with slow deterioration in intellectual abilities"
      explanation: GeneReviews supports progressive cognitive decline as a manifestation of CNS disease in CTX.
  - target: Ataxia
    description: Cerebellar involvement produces ataxia and gait disturbance.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33313117
      reference_title: "Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cognitive decline, spastic paraplegia, cerebellar ataxia"
      explanation: Human CTX series supports cerebellar ataxia as a downstream CNS manifestation.
  - target: Spasticity
    description: Pyramidal tract involvement produces spasticity and hyperreflexia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Pyramidal signs (i.e., spasticity)"
      explanation: GeneReviews supports spasticity as a pyramidal manifestation of CTX CNS involvement.
  - target: Seizure
    description: Progressive brain involvement can cause seizures.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "peripheral neuropathy, and seizures"
      explanation: GeneReviews includes seizures among manifestations of progressive neurologic dysfunction in CTX.
  - target: Hyperintensity of cerebral white matter on MRI
    description: White-matter injury is visible on MRI.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33313117
      reference_title: "Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "hyperintensity with or without hyposignal is a valuable MRI hallmark."
      explanation: Human neuroimaging series supports cerebral white-matter hyperintensity as a CTX CNS imaging manifestation.
  - target: Abnormal auditory evoked potentials
    description: CNS pathway involvement can be detected as abnormal auditory evoked potentials.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0006958 | Abnormal auditory evoked potentials | Frequent"
      explanation: Orphanet reports abnormal auditory evoked potentials as frequent.
  - target: Abnormality of somatosensory evoked potentials
    description: CNS and sensory pathway involvement can be detected as abnormal somatosensory evoked potentials.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0007377 | Abnormality of somatosensory evoked potentials | Frequent"
      explanation: Orphanet reports abnormal somatosensory evoked potentials as frequent.
- name: Ocular cholestanol deposition and cataractogenesis
  description: >
    Multisystemic cholestanol deposition includes the eye, and CTX commonly
    presents with childhood cataracts and visual impairment.
  locations:
  - preferred_term: eye
    term:
      id: UBERON:0000970
      label: eye
  chemical_entities:
  - preferred_term: cholestanol
    modifier: INCREASED
    term:
      id: CHEBI:86570
      label: (5alpha)-cholestan-3beta-ol
  evidence:
  - reference: DOI:10.1186/s13023-025-03889-9
    reference_title: "Cholic acid as a treatment for cerebrotendinous xanthomatosis: a comprehensive review of safety and efficacy"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "leading to multisystemic cholestanol deposition in membranes, including those of neurons, smooth muscle cells, tendons, and the eye."
    explanation: Review supports eye involvement as part of multisystemic cholestanol deposition.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "cataracts are the first finding, often appearing in the first decade of life."
    explanation: GeneReviews supports early cataract as a major ocular manifestation.
  downstream:
  - target: Juvenile cataract
    description: Ocular sterol deposition is associated with early cataract formation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "cataracts are the first finding, often appearing in the first decade of life."
      explanation: GeneReviews supports early cataract as a common ocular CTX manifestation.
  - target: Visual impairment
    description: Childhood cataracts can reduce vision.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000505 | Visual impairment | Very frequent"
      explanation: Orphanet reports visual impairment as very frequent in CTX, supporting visual impact downstream of ocular involvement.
  - target: Optic neuropathy
    description: Ocular and visual pathway involvement includes optic neuropathy.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001138 | Optic neuropathy | Frequent"
      explanation: Orphanet reports optic neuropathy as frequent.
  - target: Optic disc pallor
    description: Optic disc pallor is modeled as optic pathway involvement.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000543 | Optic disc pallor | Frequent"
      explanation: Orphanet reports optic disc pallor as frequent.
  - target: Abnormality of visual evoked potentials
    description: Visual pathway involvement can be detected as abnormal visual evoked potentials.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000649 | Abnormality of visual evoked potentials | Frequent"
      explanation: Orphanet reports abnormal visual evoked potentials as frequent.
  - target: Abnormal retinal vascular morphology
    description: Retinal vascular abnormalities are modeled under ocular involvement.
    causal_link_type: UNKNOWN
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0008046 | Abnormal retinal vascular morphology | Frequent"
      explanation: Orphanet reports abnormal retinal vascular morphology as frequent.
- name: Cerebellar, corticospinal, and bulbar pathway dysfunction
  description: >
    Progressive CNS involvement affects cerebellar, corticospinal, and bulbar
    motor pathways, producing ataxia, spastic paraparesis, dysarthria, pyramidal
    signs, and characteristic cerebellar/dentate-region MRI abnormalities.
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  - preferred_term: corticospinal tract
    term:
      id: UBERON:0002707
      label: corticospinal tract
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Pyramidal signs (i.e., spasticity)"
    explanation: GeneReviews supports pyramidal and cerebellar pathway involvement.
  - reference: PMID:33313117
    reference_title: "Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cognitive decline, spastic paraplegia, cerebellar ataxia"
    explanation: Clinical series supports corticospinal, cerebellar, and bulbar motor manifestations.
  - reference: PMID:33313117
    reference_title: "Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bulbar palsy"
    explanation: Clinical series supports bulbar motor involvement in CTX.
  - reference: PMID:33313117
    reference_title: "Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperintensity with or without hyposignal is a valuable MRI hallmark."
    explanation: Clinical-neurophysiology study supports dentate-region imaging involvement.
  downstream:
  - target: Ataxia
    description: Cerebellar involvement produces ataxia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33313117
      reference_title: "Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Cognitive decline, spastic paraplegia, cerebellar ataxia"
      explanation: Human CTX series directly supports cerebellar ataxia within this pathway branch.
  - target: Nystagmus
    description: Cerebellar and ocular-motor pathway involvement can produce nystagmus.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000639 | Nystagmus | Frequent"
      explanation: Orphanet reports nystagmus as frequent.
  - target: Gait disturbance
    description: Cerebellar and long-tract involvement impair gait.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001288 | Gait disturbance | Frequent"
      explanation: Orphanet reports gait disturbance as frequent, consistent with cerebellar and corticospinal pathway dysfunction.
  - target: Dysarthria
    description: Cerebellar and bulbar involvement can produce dysarthria.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001260 | Dysarthria | Frequent"
      explanation: Orphanet reports dysarthria as frequent, supporting a bulbar/cerebellar motor manifestation.
  - target: Spasticity
    description: Corticospinal tract involvement produces spasticity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Pyramidal signs (i.e., spasticity)"
      explanation: GeneReviews supports spasticity as a pyramidal tract manifestation in CTX.
  - target: Hyperreflexia
    description: Corticospinal tract involvement produces hyperreflexia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001347 | Hyperreflexia | Frequent"
      explanation: Orphanet reports hyperreflexia as frequent, supporting corticospinal tract involvement.
  - target: Abnormal pyramidal sign
    description: Corticospinal tract dysfunction produces pyramidal signs.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0007256 | Abnormal pyramidal sign | Frequent"
      explanation: Orphanet reports pyramidal signs as frequent, supporting the corticospinal branch.
  - target: Babinski sign
    description: Corticospinal tract dysfunction can cause Babinski signs.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003487 | Babinski sign | Frequent"
      explanation: Orphanet reports Babinski sign as frequent, consistent with corticospinal tract dysfunction.
  - target: Paraparesis
    description: Spastic paraparesis reflects corticospinal pathway involvement.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002385 | Paraparesis | Frequent"
      explanation: Orphanet reports paraparesis as frequent, supporting long-tract motor involvement.
  - target: Abnormal cerebellum morphology
    description: Cerebellar involvement is reflected in cerebellar imaging abnormalities.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001317 | Abnormal cerebellum morphology | Frequent"
      explanation: Orphanet reports cerebellar morphology abnormality as frequent, supporting the cerebellar imaging branch.
  - target: Abnormality of the dentate nucleus
    description: Dentate nucleus involvement is a characteristic MRI abnormality.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0100321 | Abnormality of the dentate nucleus | Occasional"
      explanation: Orphanet reports dentate nucleus abnormality as an occasional CTX neuroimaging manifestation.
  - target: Abnormal cerebellar peduncle morphology
    description: Cerebellar tract disease can involve the cerebellar peduncles.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0011931 | Abnormality of the cerebellar peduncle | Frequent"
      explanation: Orphanet reports cerebellar peduncle abnormality as frequent.
  - target: Abnormal motor evoked potentials
    description: Corticospinal pathway involvement can be detected as abnormal motor evoked potentials.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012896 | Abnormal motor evoked potentials | Frequent"
      explanation: Orphanet reports abnormal motor evoked potentials as frequent.
- name: Extrapyramidal and neuropsychiatric involvement
  description: >
    Progressive CNS disease also involves extrapyramidal and neuropsychiatric
    systems, producing dystonia, atypical parkinsonism, cognitive decline,
    behavioral change, and depression.
  locations:
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures)"
    explanation: GeneReviews supports extrapyramidal, cognitive, and psychiatric manifestations.
  - reference: DOI:10.3389/fneur.2022.1049850
    reference_title: "Cerebrotendinous Xanthomatosis: A practice review of pathophysiology, diagnosis, and treatment"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cerebellar ataxia, peripheral neuropathy, spastic paraparesis, epilepsy, parkinsonism, cognitive decline, intellectual disability, and neuropsychiatric disturbances represent some of the most common neurological signs observed in this condition."
    explanation: Practice review summarizes common neurologic and neuropsychiatric manifestations.
  downstream:
  - target: Dystonia
    description: Extrapyramidal involvement produces dystonia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001332 | Dystonia | Frequent"
      explanation: Orphanet reports dystonia as frequent, supporting extrapyramidal involvement.
  - target: Parkinsonism
    description: Extrapyramidal involvement can produce atypical parkinsonism.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "atypical parkinsonism"
      explanation: GeneReviews includes atypical parkinsonism among CTX neurologic manifestations.
  - target: Abnormality of extrapyramidal motor function
    description: Extrapyramidal system involvement causes abnormal extrapyramidal motor function.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002071 | Abnormality of extrapyramidal motor function | Frequent"
      explanation: Orphanet reports extrapyramidal motor abnormality as frequent.
  - target: Abnormal globus pallidus morphology
    description: Globus pallidus abnormalities are modeled under the extrapyramidal/basal ganglia branch.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002453 | Abnormal globus pallidus morphology | Frequent"
      explanation: Orphanet reports globus pallidus morphology abnormality as frequent.
  - target: Orofacial dyskinesia
    description: Extrapyramidal motor involvement can include orofacial dyskinesia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002310 | Orofacial dyskinesia | Frequent"
      explanation: Orphanet reports orofacial dyskinesia as frequent, supporting extrapyramidal motor involvement.
  - target: Atypical behavior
    description: Neuropsychiatric involvement can cause behavioral change.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000708 | Atypical behavior | Frequent"
      explanation: Orphanet reports atypical behavior as frequent, supporting neuropsychiatric involvement.
  - target: Depression
    description: Neuropsychiatric involvement can include depression.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000716 | Depression | Occasional"
      explanation: Orphanet reports depression as an occasional CTX neuropsychiatric manifestation.
  - target: Cognitive impairment
    description: Progressive CNS involvement causes cognitive decline.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "dementia with slow deterioration in intellectual abilities"
      explanation: GeneReviews supports cognitive decline within the progressive CNS involvement branch.
  - target: Intellectual disability
    description: CTX neurologic involvement can include intellectual disability.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001249 | Intellectual disability | Frequent"
      explanation: Orphanet reports intellectual disability as frequent, supporting neurodevelopmental involvement in CTX.
  - target: Neurodevelopmental delay
    description: Early neurologic involvement can include developmental delay.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0012758 | Neurodevelopmental delay | Frequent"
      explanation: Orphanet reports neurodevelopmental delay as frequent, supporting early neurologic involvement.
  - target: Specific learning disability
    description: Cognitive and neurodevelopmental involvement can include learning disability.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001328 | Specific learning disability | Frequent"
      explanation: Orphanet reports specific learning disability as frequent.
  - target: Progressive psychomotor deterioration
    description: Progressive CNS disease drives psychomotor deterioration.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0007272 | Progressive psychomotor deterioration | Frequent"
      explanation: Orphanet reports progressive psychomotor deterioration as frequent, supporting progressive CNS disease.
- name: CTX neuronal axonopathy
  description: >
    Patient-derived cortical projection neurons recapitulate CTX biochemical
    abnormalities and axonal defects, providing a cellular bridge from bile-acid
    pathway disruption to progressive long-tract and peripheral neurologic disease.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: DOI:10.1186/s13023-023-02666-w
    reference_title: "Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CTX and SPG5 patient iPSC-derived cortical PNs recapitulated several disease-specific biochemical changes and axonal defects of both diseases."
    explanation: Patient-derived cortical projection neuron model supports CTX-associated axonal defects.
- name: Peripheral nerve involvement
  description: >
    CTX can cause a sensorimotor peripheral neuropathy with demyelinating and
    axonal features, contributing to decreased nerve conduction velocity, distal
    amyotrophy, pes cavus, and gait impairment.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: myelinating Schwann cell
    term:
      id: CL:0000218
      label: myelinating Schwann cell
  biological_processes:
  - preferred_term: nerve conduction
    modifier: DECREASED
    term:
      id: GO:0019226
      label: transmission of nerve impulse
  evidence:
  - reference: PMID:33313117
    reference_title: "Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peripheral neuropathy was predominant sensorimotor demyelinating type"
    explanation: Clinical-neurophysiology study supports demyelinating peripheral neuropathy in CTX.
  - reference: PMID:33313117
    reference_title: "Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Demyelinating and axonal degeneration tend to exist in severe neuropathy."
    explanation: Study supports both demyelinating and axonal neuropathy mechanisms.
  - reference: DOI:10.1186/s13023-023-02666-w
    reference_title: "Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CTX and SPG5 patient iPSC-derived cortical PNs recapitulated several disease-specific biochemical changes and axonal defects of both diseases."
    explanation: Patient-derived cortical projection neuron models support CTX-associated neuronal axonal defects.
  downstream:
  - target: Peripheral neuropathy
    description: Peripheral nerve injury causes clinical neuropathy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33313117
      reference_title: "Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Peripheral neuropathy was predominant sensorimotor demyelinating type"
      explanation: Human neurophysiology study supports peripheral neuropathy as the clinical manifestation of CTX peripheral nerve involvement.
  - target: Decreased nerve conduction velocity
    description: Demyelinating neuropathy slows nerve conduction.
    causal_link_type: DIRECT
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0000762 | Decreased nerve conduction velocity | Frequent"
      explanation: Orphanet reports decreased nerve conduction velocity as frequent, consistent with demyelinating peripheral neuropathy.
  - target: Distal amyotrophy
    description: Chronic peripheral nerve injury can cause distal amyotrophy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0003693 | Distal amyotrophy | Frequent"
      explanation: Orphanet reports distal amyotrophy as frequent, supporting motor consequences of chronic peripheral neuropathy.
  - target: Pes cavus
    description: Chronic peripheral neuropathy can contribute to pes cavus.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001761 | Pes cavus | Frequent"
      explanation: Orphanet reports pes cavus as frequent, supporting distal foot morphology changes in the peripheral neuropathy branch.
  - target: Gait disturbance
    description: Peripheral neuropathy contributes to gait impairment.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: ORPHA:909
      reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001288 | Gait disturbance | Frequent"
      explanation: Orphanet reports gait disturbance as frequent, consistent with peripheral neuropathy contributing to gait impairment.
biochemical:
- name: Plasma and tissue cholestanol
  presence: Elevated
  context: Defining biochemical abnormality used diagnostically and for monitoring response.
  biomarker_term:
    preferred_term: cholestanol
    term:
      id: CHEBI:86570
      label: (5alpha)-cholestan-3beta-ol
  readouts:
  - target: Cholestanol and bile alcohol accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated plasma or tissue cholestanol reports the sterol-accumulation branch caused by CYP27A1 deficiency.
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "high plasma and tissue cholestanol concentration"
      explanation: GeneReviews identifies high plasma and tissue cholestanol as a defining CTX biochemical abnormality.
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "high plasma and tissue cholestanol concentration"
    explanation: GeneReviews identifies elevated cholestanol as a distinguishing biochemical abnormality.
- name: Chenodeoxycholic acid
  presence: Decreased
  context: Primary bile acid deficiency caused by impaired CYP27A1-dependent synthesis.
  biomarker_term:
    preferred_term: chenodeoxycholic acid
    term:
      id: CHEBI:16755
      label: chenodeoxycholic acid
  readouts:
  - target: Chenodeoxycholic acid deficiency and disinhibited bile acid precursor synthesis
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Decreased chenodeoxycholic acid reports impaired CYP27A1-dependent primary bile-acid synthesis.
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "decreased chenodeoxycholic acid (CDCA)"
      explanation: GeneReviews identifies decreased CDCA as part of the diagnostic biochemical profile.
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "decreased chenodeoxycholic acid (CDCA)"
    explanation: GeneReviews identifies decreased CDCA as part of the CTX biochemical profile.
- name: Bile alcohols and glyconjugates
  presence: Elevated
  context: Abnormal bile acid pathway intermediates accumulate when CYP27A1 activity is deficient.
  biomarker_term:
    preferred_term: bile alcohol
    term:
      id: CHEBI:50420
      label: bile alcohol
  readouts:
  - target: Cholestanol and bile alcohol accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated bile alcohols and glyconjugates report abnormal bile-acid precursor metabolism in CTX.
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "increased concentration of bile alcohols and their glyconjugates"
      explanation: GeneReviews identifies elevated bile alcohols and glyconjugates as part of the CTX biochemical profile.
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "increased concentration of bile alcohols and their glyconjugates"
    explanation: GeneReviews identifies elevated bile alcohols and glyconjugates.
phenotypes:
- name: Chronic diarrhea
  category: Gastrointestinal
  description: Chronic diarrhea beginning in infancy is a frequent early manifestation.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002028 | Chronic diarrhea | Frequent"
    explanation: Orphanet reports chronic diarrhea as frequent.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "infantile-onset diarrhea"
    explanation: GeneReviews identifies infantile-onset diarrhea as a core clinical characteristic.
- name: Prolonged neonatal jaundice
  category: Hepatic
  description: Neonatal cholestasis or prolonged jaundice may precede later neurologic disease.
  phenotype_term:
    preferred_term: Prolonged neonatal jaundice
    term:
      id: HP:0006579
      label: Prolonged neonatal jaundice
  frequency: Occasional (29-5%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006579 | Prolonged neonatal jaundice | Occasional"
    explanation: Orphanet reports prolonged neonatal jaundice as occasional.
  - reference: PMID:33414089
    reference_title: "Cholestasis as a dominating symptom of patients with CYP27A1 mutations: An analysis of 17 Chinese infants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "consider the possibility of CTX caused by CYP27A1 gene variants for infants with cholestasis."
    explanation: Infant cohort supports cholestasis as an early presentation of CYP27A1-related CTX.
- name: Juvenile cataract
  category: Ophthalmologic
  description: Cataracts often appear in childhood and may be the first recognized sign.
  phenotype_term:
    preferred_term: Juvenile cataract
    term:
      id: HP:0001118
      label: Juvenile cataract
  frequency: Very frequent (99-80%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001118 | Juvenile cataract | Very frequent"
    explanation: Orphanet reports juvenile cataract as very frequent.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "childhood-onset cataract"
    explanation: GeneReviews identifies childhood-onset cataract as a core clinical characteristic.
- name: Visual impairment
  category: Ophthalmologic
  description: Visual impairment reflects cataracts, optic neuropathy, retinal, and visual pathway involvement.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  frequency: Very frequent (99-80%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000505 | Visual impairment | Very frequent"
    explanation: Orphanet reports visual impairment as very frequent.
- name: Optic neuropathy
  category: Ophthalmologic
  description: Optic neuropathy and optic disc pallor are frequent ocular neurologic features.
  phenotype_term:
    preferred_term: Optic neuropathy
    term:
      id: HP:0001138
      label: Optic neuropathy
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001138 | Optic neuropathy | Frequent"
    explanation: Orphanet reports optic neuropathy as frequent.
- name: Nystagmus
  category: Ophthalmologic
  description: Nystagmus is a frequent eye movement abnormality in CTX.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000639 | Nystagmus | Frequent"
    explanation: Orphanet reports nystagmus as frequent.
- name: Tendon xanthomatosis
  category: Musculoskeletal
  description: Tendon xanthomas occur especially in Achilles, patellar, elbow, hand, and neck tendons.
  phenotype_term:
    preferred_term: Tendon xanthomatosis
    term:
      id: HP:0010874
      label: Tendon xanthomatosis
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0010874 | Tendon xanthomatosis | Frequent"
    explanation: Orphanet reports tendon xanthomatosis as frequent.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "tendon xanthomas"
    explanation: GeneReviews identifies tendon xanthomas as a core clinical feature.
- name: Abnormality of the Achilles tendon
  category: Musculoskeletal
  description: Achilles tendon involvement is a characteristic location for tendon xanthomas.
  phenotype_term:
    preferred_term: Abnormality of the Achilles tendon
    term:
      id: HP:0005109
      label: Abnormal Achilles tendon morphology
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005109 | Abnormality of the Achilles tendon | Frequent"
    explanation: Orphanet reports Achilles tendon abnormality as frequent.
- name: Cognitive impairment
  category: Neurodevelopmental
  description: Progressive cognitive impairment and dementia are central adult neurologic manifestations.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100543 | Cognitive impairment | Frequent"
    explanation: Orphanet reports cognitive impairment as frequent.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "dementia with slow deterioration in intellectual abilities"
    explanation: GeneReviews supports progressive cognitive decline.
- name: Intellectual disability
  category: Neurodevelopmental
  description: Intellectual disability or learning disability may be present before adult neurologic decline.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001249 | Intellectual disability | Frequent"
    explanation: Orphanet reports intellectual disability as frequent.
- name: Neurodevelopmental delay
  category: Neurodevelopmental
  description: Some individuals have developmental delay or early cognitive impairment.
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012758 | Neurodevelopmental delay | Frequent"
    explanation: Orphanet reports neurodevelopmental delay as frequent.
- name: Ataxia
  category: Neurologic
  description: Cerebellar dysfunction causes ataxia and contributes to gait disturbance.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001251 | Ataxia | Frequent"
    explanation: Orphanet reports ataxia as frequent.
- name: Gait disturbance
  category: Neurologic
  description: Gait disturbance reflects cerebellar, pyramidal, extrapyramidal, and peripheral nerve involvement.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001288 | Gait disturbance | Frequent"
    explanation: Orphanet reports gait disturbance as frequent.
- name: Spasticity
  category: Neurologic
  description: Pyramidal tract involvement produces spasticity and related long-tract signs.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001257 | Spasticity | Frequent"
    explanation: Orphanet reports spasticity as frequent.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Pyramidal signs (i.e., spasticity)"
    explanation: GeneReviews identifies spasticity as a common pyramidal sign.
- name: Hyperreflexia
  category: Neurologic
  description: Hyperreflexia is a frequent pyramidal sign.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001347 | Hyperreflexia | Frequent"
    explanation: Orphanet reports hyperreflexia as frequent.
- name: Dysarthria
  category: Neurologic
  description: Dysarthria is a frequent bulbar or cerebellar motor manifestation.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001260 | Dysarthria | Frequent"
    explanation: Orphanet reports dysarthria as frequent.
- name: Dystonia
  category: Neurologic
  description: Dystonia is a frequent extrapyramidal manifestation.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001332 | Dystonia | Frequent"
    explanation: Orphanet reports dystonia as frequent.
- name: Parkinsonism
  category: Neurologic
  description: Atypical parkinsonism may occur as part of extrapyramidal dysfunction.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  frequency: Occasional (29-5%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001300 | Parkinsonism | Occasional"
    explanation: Orphanet reports parkinsonism as occasional.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "atypical parkinsonism"
    explanation: GeneReviews includes atypical parkinsonism among neurologic manifestations.
- name: Seizure
  category: Neurologic
  description: Seizures are a frequent neurologic manifestation.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001250 | Seizure | Frequent"
    explanation: Orphanet reports seizures as frequent.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "peripheral neuropathy, and seizures"
    explanation: GeneReviews includes seizures among neurologic manifestations.
- name: Peripheral neuropathy
  category: Neurologic
  description: Peripheral neuropathy may be sensorimotor and demyelinating, sometimes with axonal degeneration.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0009830 | Peripheral neuropathy | Frequent"
    explanation: Orphanet reports peripheral neuropathy as frequent.
  - reference: PMID:33313117
    reference_title: "Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peripheral neuropathy was predominant sensorimotor demyelinating type"
    explanation: Clinical-neurophysiology study supports peripheral neuropathy in CTX.
- name: Decreased nerve conduction velocity
  category: Neurophysiologic
  description: Demyelinating peripheral neuropathy can reduce nerve conduction velocity.
  phenotype_term:
    preferred_term: Decreased nerve conduction velocity
    term:
      id: HP:0000762
      label: Decreased nerve conduction velocity
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000762 | Decreased nerve conduction velocity | Frequent"
    explanation: Orphanet reports decreased nerve conduction velocity as frequent.
- name: Distal amyotrophy
  category: Neurologic
  description: Distal amyotrophy may accompany peripheral neuropathy.
  phenotype_term:
    preferred_term: Distal amyotrophy
    term:
      id: HP:0003693
      label: Distal amyotrophy
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003693 | Distal amyotrophy | Frequent"
    explanation: Orphanet reports distal amyotrophy as frequent.
- name: Pes cavus
  category: Musculoskeletal
  description: Pes cavus may reflect chronic peripheral neuropathy.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001761 | Pes cavus | Frequent"
    explanation: Orphanet reports pes cavus as frequent.
- name: Hyperintensity of cerebral white matter on MRI
  category: Neuroimaging
  description: White matter abnormalities are a frequent brain MRI manifestation.
  phenotype_term:
    preferred_term: Hyperintensity of cerebral white matter on MRI
    term:
      id: HP:0030890
      label: Hyperintensity of cerebral white matter on MRI
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030890 | Hyperintensity of cerebral white matter on MRI | Frequent"
    explanation: Orphanet reports cerebral white matter hyperintensity as frequent.
- name: Abnormal cerebellum morphology
  category: Neuroimaging
  description: Cerebellar abnormalities are frequent and align with ataxia.
  phenotype_term:
    preferred_term: Abnormal cerebellum morphology
    term:
      id: HP:0001317
      label: Abnormal cerebellum morphology
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001317 | Abnormal cerebellum morphology | Frequent"
    explanation: Orphanet reports abnormal cerebellum morphology as frequent.
- name: Abnormality of the dentate nucleus
  category: Neuroimaging
  description: Dentate nucleus abnormalities are a recognized CTX neuroimaging feature.
  phenotype_term:
    preferred_term: Abnormality of the dentate nucleus
    term:
      id: HP:0100321
      label: Abnormal dentate nucleus morphology
  frequency: Occasional (29-5%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100321 | Abnormality of the dentate nucleus | Occasional"
    explanation: Orphanet reports dentate nucleus abnormality as occasional.
- name: Atypical behavior
  category: Psychiatric
  description: Behavioral and psychiatric manifestations can be prominent.
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000708 | Atypical behavior | Frequent"
    explanation: Orphanet reports atypical behavior as frequent.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Neuropsychiatric symptoms such as behavioral changes"
    explanation: GeneReviews supports behavioral and psychiatric manifestations.
- name: Depression
  category: Psychiatric
  description: Depression is one of the recognized neuropsychiatric manifestations.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  frequency: Occasional (29-5%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000716 | Depression | Occasional"
    explanation: Orphanet reports depression as occasional.
- name: Osteoporosis
  category: Skeletal
  description: Bone disease including osteoporosis can occur in CTX.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000939 | Osteoporosis | Frequent"
    explanation: Orphanet reports osteoporosis as frequent.
- name: Abnormal enzyme/coenzyme activity
  category: Biochemical
  description: Sterol 27-hydroxylase activity is deficient due to CYP27A1 pathogenic variants.
  phenotype_term:
    preferred_term: Abnormal enzyme/coenzyme activity
    term:
      id: HP:0012379
      label: Abnormal circulating enzyme concentration or activity
  frequency: Very frequent (99-80%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012379 | Abnormal enzyme/coenzyme activity | Very frequent"
    explanation: Orphanet reports abnormal enzyme/coenzyme activity as very frequent.
- name: Optic disc pallor
  category: Ophthalmologic
  description: Optic disc pallor is a frequent manifestation of optic pathway involvement.
  phenotype_term:
    preferred_term: Optic disc pallor
    term:
      id: HP:0000543
      label: Optic disc pallor
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000543 | Optic disc pallor | Frequent"
    explanation: Orphanet reports optic disc pallor as frequent.
- name: Abnormality of visual evoked potentials
  category: Neurophysiologic
  description: Visual evoked-potential abnormalities are frequent and support visual pathway involvement.
  phenotype_term:
    preferred_term: Abnormality of visual evoked potentials
    term:
      id: HP:0000649
      label: Abnormality of visual evoked potentials
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000649 | Abnormality of visual evoked potentials | Frequent"
    explanation: Orphanet reports abnormal visual evoked potentials as frequent.
- name: Abnormal retinal vascular morphology
  category: Ophthalmologic
  description: Retinal vascular abnormalities are a frequent ocular finding.
  phenotype_term:
    preferred_term: Abnormal retinal vascular morphology
    term:
      id: HP:0008046
      label: Abnormal retinal vascular morphology
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008046 | Abnormal retinal vascular morphology | Frequent"
    explanation: Orphanet reports abnormal retinal vascular morphology as frequent.
- name: Specific learning disability
  category: Neurodevelopmental
  description: Specific learning disability is a frequent neurodevelopmental manifestation.
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001328 | Specific learning disability | Frequent"
    explanation: Orphanet reports specific learning disability as frequent.
- name: Progressive psychomotor deterioration
  category: Neurologic
  description: Progressive psychomotor deterioration captures worsening neurologic and motor function over time.
  phenotype_term:
    preferred_term: Progressive psychomotor deterioration
    term:
      id: HP:0007272
      label: Progressive psychomotor deterioration
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007272 | Progressive psychomotor deterioration | Frequent"
    explanation: Orphanet reports progressive psychomotor deterioration as frequent.
- name: Abnormality of extrapyramidal motor function
  category: Neurologic
  description: Extrapyramidal motor dysfunction includes the dystonia and parkinsonism spectrum seen in CTX.
  phenotype_term:
    preferred_term: Abnormality of extrapyramidal motor function
    term:
      id: HP:0002071
      label: Abnormality of extrapyramidal motor function
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002071 | Abnormality of extrapyramidal motor function | Frequent"
    explanation: Orphanet reports abnormal extrapyramidal motor function as frequent.
- name: Orofacial dyskinesia
  category: Neurologic
  description: Orofacial dyskinesia is a frequent movement disorder manifestation.
  phenotype_term:
    preferred_term: Orofacial dyskinesia
    term:
      id: HP:0002310
      label: Orofacial dyskinesia
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002310 | Orofacial dyskinesia | Frequent"
    explanation: Orphanet reports orofacial dyskinesia as frequent.
- name: Paraparesis
  category: Neurologic
  description: Paraparesis reflects corticospinal tract involvement and contributes to gait impairment.
  phenotype_term:
    preferred_term: Paraparesis
    term:
      id: HP:0002385
      label: Paraparesis
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002385 | Paraparesis | Frequent"
    explanation: Orphanet reports paraparesis as frequent.
- name: Abnormal pyramidal sign
  category: Neurologic
  description: Pyramidal signs are frequent and align with spasticity and hyperreflexia.
  phenotype_term:
    preferred_term: Abnormal pyramidal sign
    term:
      id: HP:0007256
      label: Abnormal pyramidal sign
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007256 | Abnormal pyramidal sign | Frequent"
    explanation: Orphanet reports abnormal pyramidal sign as frequent.
- name: Babinski sign
  category: Neurologic
  description: Babinski sign is a frequent corticospinal tract sign.
  phenotype_term:
    preferred_term: Babinski sign
    term:
      id: HP:0003487
      label: Babinski sign
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003487 | Babinski sign | Frequent"
    explanation: Orphanet reports Babinski sign as frequent.
- name: Abnormal auditory evoked potentials
  category: Neurophysiologic
  description: Auditory evoked-potential abnormalities are a frequent electrophysiologic finding.
  phenotype_term:
    preferred_term: Abnormal auditory evoked potentials
    term:
      id: HP:0006958
      label: Abnormal auditory evoked potentials
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006958 | Abnormal auditory evoked potentials | Frequent"
    explanation: Orphanet reports abnormal auditory evoked potentials as frequent.
- name: Abnormality of somatosensory evoked potentials
  category: Neurophysiologic
  description: Somatosensory evoked-potential abnormalities reflect frequent sensory pathway involvement.
  phenotype_term:
    preferred_term: Abnormality of somatosensory evoked potentials
    term:
      id: HP:0007377
      label: Abnormality of somatosensory evoked potentials
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0007377 | Abnormality of somatosensory evoked potentials | Frequent"
    explanation: Orphanet reports abnormal somatosensory evoked potentials as frequent.
- name: Abnormal motor evoked potentials
  category: Neurophysiologic
  description: Motor evoked-potential abnormalities support frequent corticospinal pathway involvement.
  phenotype_term:
    preferred_term: Abnormal motor evoked potentials
    term:
      id: HP:0012896
      label: Abnormal motor evoked potentials
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012896 | Abnormal motor evoked potentials | Frequent"
    explanation: Orphanet reports abnormal motor evoked potentials as frequent.
- name: Abnormal globus pallidus morphology
  category: Neuroimaging
  description: Globus pallidus abnormalities are frequent basal ganglia imaging findings.
  phenotype_term:
    preferred_term: Abnormal globus pallidus morphology
    term:
      id: HP:0002453
      label: Abnormal globus pallidus morphology
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002453 | Abnormal globus pallidus morphology | Frequent"
    explanation: Orphanet reports abnormal globus pallidus morphology as frequent.
- name: Abnormal cerebellar peduncle morphology
  category: Neuroimaging
  description: Cerebellar peduncle abnormalities are frequent and align with cerebellar tract disease.
  phenotype_term:
    preferred_term: Abnormality of the cerebellar peduncle
    term:
      id: HP:0011931
      label: Abnormal cerebellar peduncle morphology
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011931 | Abnormality of the cerebellar peduncle | Frequent"
    explanation: Orphanet reports abnormal cerebellar peduncle morphology as frequent.
- name: Abnormal finger morphology
  category: Musculoskeletal
  description: Finger morphology abnormalities are frequent in the Orphanet phenotype record.
  phenotype_term:
    preferred_term: Abnormality of finger
    term:
      id: HP:0001167
      label: Abnormal finger morphology
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001167 | Abnormality of finger | Frequent"
    explanation: Orphanet reports abnormality of finger as frequent.
- name: Abnormal tibia morphology
  category: Musculoskeletal
  description: Tibial morphology abnormalities are frequent in the Orphanet phenotype record.
  phenotype_term:
    preferred_term: Abnormality of tibia morphology
    term:
      id: HP:0002992
      label: Abnormal tibia morphology
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002992 | Abnormality of tibia morphology | Frequent"
    explanation: Orphanet reports abnormality of tibia morphology as frequent.
- name: Abnormality of the plantar skin of foot
  category: Dermatologic
  description: Plantar skin abnormalities of the foot are frequent in the Orphanet phenotype record.
  phenotype_term:
    preferred_term: Abnormality of the plantar skin of foot
    term:
      id: HP:0100872
      label: Abnormality of the plantar skin of foot
  frequency: Frequent (79-30%)
  evidence:
  - reference: ORPHA:909
    reference_title: "Cerebrotendinous xanthomatosis (Orphanet structured-database record)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100872 | Abnormality of the plantar skin of foot | Frequent"
    explanation: Orphanet reports abnormality of the plantar skin of foot as frequent.
diagnosis:
- name: Plasma cholestanol testing
  description: Elevated plasma cholestanol supports CTX diagnosis and treatment monitoring.
  results: Elevated plasma cholestanol.
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "high plasma and tissue cholestanol concentration"
    explanation: GeneReviews identifies elevated cholestanol as a key biochemical diagnostic abnormality.
- name: Bile alcohol and bile acid profile
  description: Decreased CDCA with increased bile alcohols and glyconjugates supports a bile-acid synthesis defect.
  results: Decreased CDCA with increased bile alcohols and glyconjugates.
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "decreased chenodeoxycholic acid (CDCA), increased concentration of bile alcohols and their glyconjugates"
    explanation: GeneReviews identifies the diagnostic bile acid and bile alcohol pattern.
- name: CYP27A1 molecular genetic testing
  description: Molecular testing confirms diagnosis by identifying biallelic CYP27A1 pathogenic variants.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  results: Biallelic pathogenic CYP27A1 variants confirm CTX.
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "biallelic pathogenic variants in CYP27A1 identified by molecular genetic testing"
    explanation: GeneReviews establishes molecular confirmation by biallelic CYP27A1 variants.
treatments:
- name: Chenodeoxycholic acid
  description: >
    Long-term chenodeoxycholic acid is targeted replacement/suppression therapy
    that normalizes cholestanol biochemistry and is most neurologically
    protective when started before advanced neurologic damage.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: chenodeoxycholic acid
      term:
        id: CHEBI:16755
        label: chenodeoxycholic acid
  target_mechanisms:
  - target: Chenodeoxycholic acid deficiency and disinhibited bile acid precursor synthesis
    treatment_effect: RESTORES
    description: CDCA restores bile-acid feedback and normalizes excessive precursor synthesis.
    evidence:
    - reference: PMID:20494109
      reference_title: "Cerebrotendinous xanthomatosis: an inborn error in bile acid synthesis with defined mutations but still a challenge."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The activity of cholesterol 7alpha-hydroxylase is normalized by treatment with bile acids."
      explanation: Review supports bile-acid therapy as feedback correction of the upstream metabolic defect.
    - reference: DOI:10.1186/s13023-023-02666-w
      reference_title: "Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the bile acid chenodeoxycholic acid (CDCA) effectively mitigated the biochemical alterations and rescued axonal degeneration in patient iPSC-derived neurons."
      explanation: Patient-derived neuronal model supports CDCA mitigation of CTX-relevant biochemical and axonal abnormalities.
  - target: Cholestanol and bile alcohol accumulation
    treatment_effect: INHIBITS
    description: CDCA suppresses the accumulated cholestanol biochemical signature downstream of CYP27A1 deficiency.
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Long-term treatment with chenodeoxycholic acid (CDCA) normalizes plasma and cerebrospinal fluid concentration of cholestanol"
      explanation: GeneReviews supports CDCA lowering the accumulated cholestanol marker.
  - target: CTX neuronal axonopathy
    treatment_effect: MODULATES
    description: CDCA mitigates CTX-relevant biochemical abnormalities and axonal degeneration in patient-derived neurons.
    evidence:
    - reference: DOI:10.1186/s13023-023-02666-w
      reference_title: "Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients"
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the bile acid chenodeoxycholic acid (CDCA) effectively mitigated the biochemical alterations and rescued axonal degeneration in patient iPSC-derived neurons."
      explanation: Patient-derived neuronal model supports CDCA rescue of axonal degeneration.
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Long-term treatment with chenodeoxycholic acid (CDCA) normalizes plasma and cerebrospinal fluid concentration of cholestanol"
    explanation: GeneReviews supports CDCA as targeted therapy that normalizes cholestanol.
  - reference: PMID:23673909
    reference_title: "Neurological outcome in cerebrotendinous xanthomatosis treated with chenodeoxycholic acid: early versus late diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "preventing neurological damage and deterioration in CTX."
    explanation: Long-term cohort supports early CDCA therapy to prevent neurologic damage.
- name: Cholic acid
  description: Cholic acid is an alternative bile-acid therapy reported to lower cholestanol and improve neurologic symptoms in limited experience.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cholic acid
      term:
        id: CHEBI:16359
        label: cholic acid
  target_mechanisms:
  - target: Chenodeoxycholic acid deficiency and disinhibited bile acid precursor synthesis
    treatment_effect: RESTORES
    description: Cholic acid provides bile-acid feedback when CDCA is not tolerated.
    evidence:
    - reference: DOI:10.1186/s13023-025-03889-9
      reference_title: "Cholic acid as a treatment for cerebrotendinous xanthomatosis: a comprehensive review of safety and efficacy"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CA reduced cholestanol levels in CSF and blood while also reducing bile acid synthesis and excretion of bile alcohols in the urine."
      explanation: Review supports cholic acid reducing bile-acid synthesis output and bile alcohol excretion.
  - target: Cholestanol and bile alcohol accumulation
    treatment_effect: INHIBITS
    description: Cholic acid lowers cholestanol and bile-alcohol biochemical abnormalities.
    evidence:
    - reference: DOI:10.1186/s13023-025-03889-9
      reference_title: "Cholic acid as a treatment for cerebrotendinous xanthomatosis: a comprehensive review of safety and efficacy"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CA reduced cholestanol levels in CSF and blood while also reducing bile acid synthesis and excretion of bile alcohols in the urine."
      explanation: Review supports cholic acid lowering cholestanol and urinary bile alcohol excretion.
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "Cholic acid treatment decreases cholestanol levels and improves neurologic symptoms"
    explanation: GeneReviews supports cholic acid as a limited-experience alternative.
- name: HMG-CoA reductase inhibitor therapy
  description: >
    Statin-class HMG-CoA reductase inhibitors can be used alone or with CDCA to
    decrease cholestanol concentration and improve clinical signs, but require
    caution because GeneReviews notes potential muscle damage.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: HMG-CoA reductase inhibitor
      term:
        id: NCIT:C1655
        label: HMG-CoA Reductase Inhibitor
  target_mechanisms:
  - target: Cholestanol and bile alcohol accumulation
    treatment_effect: INHIBITS
    description: Statin therapy decreases cholestanol concentration but does not correct the primary CYP27A1 defect.
    evidence:
    - reference: PMID:20301583
      reference_title: "Cerebrotendinous Xanthomatosis."
      supports: PARTIAL
      evidence_source: OTHER
      snippet: "Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase alone or in combination with CDCA are also effective in decreasing cholestanol concentration and improving clinical signs; however, they may induce muscle damage."
      explanation: GeneReviews supports statin-class therapy as a cholestanol-lowering adjunct while noting toxicity concerns.
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase alone or in combination with CDCA are also effective in decreasing cholestanol concentration and improving clinical signs; however, they may induce muscle damage."
    explanation: GeneReviews supports statins as adjunct/second-line biochemical therapy while noting myopathy risk.
- name: Multidisciplinary supportive care
  description: >
    Supportive management addresses cataracts, epilepsy, spasticity,
    parkinsonism, neuropsychiatric symptoms, gait impairment, osteoporosis, and
    surveillance of neurologic, cardiac, and bone complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Juvenile cataract
    term:
      id: HP:0001118
      label: Juvenile cataract
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cataract extraction is typically required in at least one eye by age 50 years."
    explanation: GeneReviews supports cataract-directed supportive intervention.
  - reference: PMID:20301583
    reference_title: "Cerebrotendinous Xanthomatosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Epilepsy, spasticity, and parkinsonism are treated symptomatically."
    explanation: GeneReviews supports symptomatic neurologic management.
clinical_trials:
- name: NCT04270682
  phase: PHASE_III
  status: COMPLETED
  description: >
    RESTORE was an interventional phase 3 study of chenodeoxycholic acid in
    adult and pediatric patients with cerebrotendinous xanthomatosis, including
    randomized placebo-withdrawal and pediatric open-label dose-titration
    cohorts.
  evidence:
  - reference: clinicaltrials:NCT04270682
    reference_title: "A Phase 3 Study to Evaluate the Effects of Chenodeoxycholic Acid in Adult and Pediatric Patients With Cerebrotendinous Xanthomatosis"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a randomized double-blind crossover (placebo withdrawal with rescue) study"
    explanation: ClinicalTrials.gov documents a completed phase 3 CDCA study in CTX.
- name: NCT02638220
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >
    Observational multicenter prevalence study that screened children and young
    adults with early-onset idiopathic bilateral cataracts for CTX, reflecting a
    cataract-first disease-detection strategy.
  target_phenotypes:
  - preferred_term: Juvenile cataract
    term:
      id: HP:0001118
      label: Juvenile cataract
  evidence:
  - reference: clinicaltrials:NCT02638220
    reference_title: "An Observational, Multicenter Study of the Prevalence of Cerebrotendinous Xanthomatosis (CTX) in Patient Populations Diagnosed With Early-Onset Idiopathic Bilateral Cataracts"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pediatric cataract evaluation and treatment is a promising avenue for disease detection and prevention."
    explanation: ClinicalTrials.gov documents CTX screening among patients with early-onset idiopathic bilateral cataracts.
notes: >
  This curation uses ORPHA:909 as the direct disease mapping. The mechanism is
  centered on biallelic CYP27A1 pathogenic variants, sterol 27-hydroxylase
  deficiency, impaired bile-acid synthesis and CDCA feedback, cholestanol and
  bile-alcohol accumulation, tissue sterol deposition, and progressive systemic
  and neurologic disease. Falcon deep research was completed and integrated by
  adding recent practice-review, clinical-outcome, cellular-model, bile-acid
  profiling, cholic-acid, and ClinicalTrials.gov references to the curation.
  Chenodeoxycholic acid is modeled as targeted therapy because it normalizes
  cholestanol biochemistry and is most effective when started before
  irreversible neurologic injury.
references:
- reference: ORPHA:909
  title: Cerebrotendinous xanthomatosis
  findings: []
- reference: PMID:20301583
  title: Cerebrotendinous Xanthomatosis.
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20494109
  title: "Cerebrotendinous xanthomatosis: an inborn error in bile acid synthesis with defined mutations but still a challenge."
  findings: []
- reference: PMID:23759795
  title: Cerebrotendinous xanthomatosis.
  findings: []
- reference: PMID:4031069
  title: "Biosynthesis of bile acids in cerebrotendinous xanthomatosis. Relationship of bile acid pool sizes and synthesis rates to hydroxylations at C-12, C-25, and C-26."
  findings: []
- reference: PMID:23673909
  title: "Neurological outcome in cerebrotendinous xanthomatosis treated with chenodeoxycholic acid: early versus late diagnosis."
  findings: []
- reference: PMID:33313117
  title: "Cerebrotendinous xanthomatosis with peripheral neuropathy: a clinical and neurophysiological study in Chinese population."
  findings: []
- reference: PMID:33414089
  title: "Cholestasis as a dominating symptom of patients with CYP27A1 mutations: An analysis of 17 Chinese infants."
  findings: []
- reference: clinicaltrials:NCT04270682
  title: "A Phase 3 Study to Evaluate the Effects of Chenodeoxycholic Acid in Adult and Pediatric Patients With Cerebrotendinous Xanthomatosis"
  found_in:
  - Cerebrotendinous_Xanthomatosis-deep-research-falcon.md
  findings: []
- reference: clinicaltrials:NCT02638220
  title: "An Observational, Multicenter Study of the Prevalence of Cerebrotendinous Xanthomatosis (CTX) in Patient Populations Diagnosed With Early-Onset Idiopathic Bilateral Cataracts"
  found_in:
  - Cerebrotendinous_Xanthomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.3389/fneur.2022.1049850
  title: "Cerebrotendinous Xanthomatosis: A practice review of pathophysiology, diagnosis, and treatment"
  found_in:
  - Cerebrotendinous_Xanthomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.5551/jat.rv17055
  title: "Cerebrotendinous Xanthomatosis: Molecular Pathogenesis, Clinical Spectrum, Diagnosis, and Disease-Modifying Treatments"
  found_in:
  - Cerebrotendinous_Xanthomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.3390/brainsci13070979
  title: "Pathophysiology and Treatment of Lipid Abnormalities in Cerebrotendinous Xanthomatosis: An Integrative Review"
  found_in:
  - Cerebrotendinous_Xanthomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1016/j.jacl.2018.06.008
  title: "Diagnosis, treatment, and clinical outcomes in 43 cases with cerebrotendinous xanthomatosis"
  found_in:
  - Cerebrotendinous_Xanthomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1186/s13023-023-02666-w
  title: "Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients"
  found_in:
  - Cerebrotendinous_Xanthomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.3390/nu15214625
  title: "Characterization of Postprandial Bile Acid Profiles and Glucose Metabolism in Cerebrotendinous Xanthomatosis"
  found_in:
  - Cerebrotendinous_Xanthomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.3389/fneur.2024.1371375
  title: "Frontier and hotspot evolution in cerebrotendinous xanthomatosis: a bibliometric analysis from 1993 to 2023"
  found_in:
  - Cerebrotendinous_Xanthomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.3389/fneur.2024.1409138
  title: "Case report: Cerebrotendinous xanthomatosis treatment follow-up"
  found_in:
  - Cerebrotendinous_Xanthomatosis-deep-research-falcon.md
  findings: []
- reference: DOI:10.1186/s13023-025-03889-9
  title: "Cholic acid as a treatment for cerebrotendinous xanthomatosis: a comprehensive review of safety and efficacy"
  found_in:
  - Cerebrotendinous_Xanthomatosis-deep-research-falcon.md
  findings: []

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