Cerebrotendinous xanthomatosis

Summary

Cerebrotendinous xanthomatosis (MONDO:0008948) is a disease caused by CYP27A1 (GenCC Definitive), with 2 cohort genes and 10 clinical trials. Top therapeutic interventions include chenodiol and lovastatin.

At a glance

• Prevalence: 1-9 / 100 000 (Specific population) [Orphanet-validated]
• Causal gene: CYP27A1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1,098
• Phenotypes (HPO): 91
• Clinical trials: 10

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2	Specific population	Validated
Point prevalence	<1 / 1 000 000	0.056	Spain	Validated
Point prevalence	1-9 / 100 000	4	United States	Validated

Signs & symptoms

Clinical features (HPO)

91 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000505	Visual impairment	Very frequent (80-99%)
HP:0001118	Juvenile cataract	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000543	Optic disc pallor	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000649	Abnormality of visual evoked potentials	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000762	Decreased nerve conduction velocity	Frequent (30-79%)
HP:0000939	Osteoporosis	Frequent (30-79%)
HP:0001138	Optic neuropathy	Frequent (30-79%)
HP:0001167	Abnormality of finger	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001317	Abnormal cerebellum morphology	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002028	Chronic diarrhea	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0002310	Orofacial dyskinesia	Frequent (30-79%)
HP:0002385	Paraparesis	Frequent (30-79%)
HP:0002453	Abnormal globus pallidus morphology	Frequent (30-79%)
HP:0002992	Abnormality of tibia morphology	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0005109	Abnormality of the Achilles tendon	Frequent (30-79%)
HP:0006958	Abnormal auditory evoked potentials	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0007272	Progressive psychomotor deterioration	Frequent (30-79%)
HP:0007377	Abnormality of somatosensory evoked potentials	Frequent (30-79%)
HP:0008046	Abnormal retinal vascular morphology	Frequent (30-79%)
HP:0009830	Peripheral neuropathy	Frequent (30-79%)
HP:0010874	Tendon xanthomatosis	Frequent (30-79%)
HP:0011931	Abnormality of the cerebellar peduncle	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0012896	Abnormal motor evoked potentials	Frequent (30-79%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0100872	Abnormality of the plantar skin of foot	Frequent (30-79%)
HP:0000464	Abnormality of the neck	Occasional (5-29%)
HP:0000492	Abnormal eyelid morphology	Occasional (5-29%)
HP:0000520	Proptosis	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000713	Agitation	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebrotendinous xanthomatosis
Mondo ID	MONDO:0008948
MeSH	D019294
OMIM	213700
Orphanet	909
DOID	DOID:4810
ICD-11	1556875179
NCIT	C84628
SNOMED CT	63246000
UMLS	C0238052
MedGen	116041
GARD	0005622
NORD	915
Is cancer (heuristic)	no

Also known as: cerebrotendinous xanthomatosis · cholestanol storage disease · CTX · CTx · sterol 27-hydroxylase deficiency

Data availability: 1,098 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inherited lipid metabolism disorder › lysosomal lipid storage disorder › xanthomatosis › cerebrotendinous xanthomatosis

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

265 likely benign, 228 uncertain significance, 34 likely pathogenic, 31 pathogenic, 19 pathogenic/likely pathogenic, 18 conflicting classifications of pathogenicity, 4 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069502	NM_000784.4(CYP27A1):c.1434_1435delinsAA (p.Arg479Ser)	CYP27A1	Pathogenic	criteria provided, single submitter
1071249	NM_000784.4(CYP27A1):c.813C>G (p.Tyr271Ter)	CYP27A1	Pathogenic	criteria provided, single submitter
1076506	NM_000784.4(CYP27A1):c.46dup (p.Ala16fs)	CYP27A1	Pathogenic	criteria provided, single submitter
1176421	NM_000784.4(CYP27A1):c.1476+2T>C	CYP27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1365147	NM_000784.4(CYP27A1):c.32G>A (p.Trp11Ter)	CYP27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1365358	NM_000784.4(CYP27A1):c.1017+1del	CYP27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1372101	NM_000784.4(CYP27A1):c.1239dup (p.Asp414Ter)	CYP27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1385057	NM_000784.4(CYP27A1):c.1333C>T (p.Gln445Ter)	CYP27A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1385329	NM_000784.4(CYP27A1):c.1087G>T (p.Glu363Ter)	CYP27A1	Pathogenic	criteria provided, single submitter
1393558	NM_000784.4(CYP27A1):c.1191C>A (p.Tyr397Ter)	CYP27A1	Pathogenic	criteria provided, single submitter
1393992	NM_000784.4(CYP27A1):c.253C>T (p.Gln85Ter)	CYP27A1	Pathogenic	criteria provided, single submitter
1418362	NM_000784.4(CYP27A1):c.702del (p.Glu235fs)	CYP27A1	Pathogenic	criteria provided, single submitter
1429007	NM_000784.4(CYP27A1):c.643G>T (p.Glu215Ter)	CYP27A1	Pathogenic	criteria provided, single submitter
1448068	NM_000784.4(CYP27A1):c.426del (p.Thr143fs)	CYP27A1	Pathogenic	criteria provided, single submitter
1455066	NM_000784.4(CYP27A1):c.1339_1342dup (p.Arg448fs)	CYP27A1	Pathogenic	criteria provided, single submitter
1455620	NM_000784.4(CYP27A1):c.753_754del (p.Tyr253fs)	CYP27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456553	NM_000784.4(CYP27A1):c.1184+1G>C	CYP27A1	Pathogenic	criteria provided, single submitter
1456676	NM_000784.4(CYP27A1):c.1519del (p.Glu507fs)	CYP27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457428	NM_000784.4(CYP27A1):c.765_766del (p.Phe256fs)	CYP27A1	Pathogenic	criteria provided, single submitter
1457639	NM_000784.4(CYP27A1):c.45_46del (p.Ala16fs)	CYP27A1	Pathogenic	criteria provided, single submitter
1457667	NC_000002.11:g.(?219646906)(219647180_?)del	CYP27A1	Pathogenic	criteria provided, single submitter
1458431	NC_000002.11:g.(?219674280)(219679753_?)del	CYP27A1	Pathogenic	criteria provided, single submitter
1460072	NM_000784.4(CYP27A1):c.1435C>A (p.Arg479Ser)	CYP27A1	Pathogenic	criteria provided, single submitter
1482764	NM_000784.4(CYP27A1):c.804G>T (p.Trp268Cys)	CYP27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1499459	NM_000784.4(CYP27A1):c.1374del (p.Arg459fs)	CYP27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804131	NM_000784.4(CYP27A1):c.1297dup (p.Arg433fs)	CYP27A1	Pathogenic	criteria provided, single submitter
1804694	NM_000784.4(CYP27A1):c.1126del (p.Gln376fs)	CYP27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1915207	NM_000784.4(CYP27A1):c.1476+2T>A	CYP27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1918228	NM_000784.4(CYP27A1):c.1263+1G>T	CYP27A1	Pathogenic	criteria provided, single submitter
1937463	NM_000784.4(CYP27A1):c.238C>T (p.Gln80Ter)	CYP27A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CYP27A1	Definitive	Autosomal recessive	cerebrotendinous xanthomatosis	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP27A1	Orphanet:909	Cerebrotendinous xanthomatosis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYP27A1	HGNC:2605	ENSG00000135929	Q02318	Sterol 26-hydroxylase, mitochondrial	gencc,clinvar
WNT6	HGNC:12785	ENSG00000115596	Q9Y6F9	Protein Wnt-6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP27A1	Sterol 26-hydroxylase, mitochondrial	Cytochrome P450 monooxygenase that catalyzes regio- and stereospecific hydroxylation of cholesterol and its derivatives.
WNT6	Protein Wnt-6	Ligand for members of the frizzled family of seven transmembrane receptors.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYP27A1	Enzyme (other)	yes	1.14.15.15	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
WNT6	Other/Unknown	no		Wnt, Wnt6, Wnt_CS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
C1 segment of cervical spinal cord	1
liver	1
right lobe of liver	1
Brodmann (1909) area 10	1
endometrium epithelium	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYP27A1	263	ubiquitous	marker	right lobe of liver, liver, C1 segment of cervical spinal cord
WNT6	152	broad	yes	endometrium epithelium, tibial nerve, Brodmann (1909) area 10

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYP27A1	2,351
WNT6	1,263

Structural data

PDB: 0 · AlphaFold-only: 2 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYP27A1	Q02318	89.02
WNT6	Q9Y6F9	83.62

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective CYP27A1 causes CTX	1	5710.0×	0.001	CYP27A1
Synthesis of bile acids and bile salts via 24-hydroxycholesterol	1	439.2×	0.006	CYP27A1
Synthesis of bile acids and bile salts via 27-hydroxycholesterol	1	380.7×	0.006	CYP27A1
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	228.4×	0.006	CYP27A1
WNT ligand biogenesis and trafficking	1	211.5×	0.006	WNT6
Endogenous sterols	1	196.9×	0.006	CYP27A1
Class B/2 (Secretin family receptors)	1	95.2×	0.010	WNT6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
axis specification	1	8426.0×	0.002	WNT6
nephron tubule formation	1	4213.0×	0.002	WNT6
calcitriol biosynthetic process from calciol	1	2808.7×	0.002	CYP27A1
positive regulation of tooth mineralization	1	2808.7×	0.002	WNT6
epithelial-mesenchymal cell signaling	1	2106.5×	0.002	WNT6
cholesterol catabolic process	1	936.2×	0.003	CYP27A1
cornea development in camera-type eye	1	648.1×	0.004	WNT6
sterol metabolic process	1	421.3×	0.005	CYP27A1
bile acid biosynthetic process	1	312.1×	0.006	CYP27A1
branching involved in ureteric bud morphogenesis	1	183.2×	0.010	WNT6
odontogenesis of dentin-containing tooth	1	150.5×	0.010	WNT6
cell fate commitment	1	147.8×	0.010	WNT6
cellular response to retinoic acid	1	117.0×	0.012	WNT6
cholesterol metabolic process	1	98.0×	0.013	CYP27A1
canonical Wnt signaling pathway	1	76.6×	0.016	WNT6
neuron differentiation	1	50.1×	0.022	WNT6
positive regulation of gene expression	1	19.4×	0.054	WNT6
positive regulation of DNA-templated transcription	1	14.0×	0.070	WNT6

Therapeutics

Drugs indicated or in trials for this disease

1 approved drug — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Chenodiol	Approved (phase 4)

1 drug in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Lovastatin	Phase 2

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP27A1	0	0
WNT6	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CYP27A1	5	Binding:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP27A1	1.14.15.15, 1.14.99.38	cholestanetriol 26-monooxygenase, cholesterol 25-monooxygenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CYP27A1
E	Difficult family or no structure, no drug	1	WNT6

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CYP27A1	5	—
WNT6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 10.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	8
PHASE3	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04270682	PHASE3	COMPLETED	Study to Evaluate Patients With Cerebrotendinous Xanthomatosis (RESTORE)
NCT00004346	PHASE2	UNKNOWN	Phase II Study of Cholesterol- and Cholestanol-Free Diet, Lovastatin, and Chenodeoxycholic Acid for Cerebrotendinous Xanthomatosis
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT05368038	Not specified	ENROLLING_BY_INVITATION	ScreenPlus: A Comprehensive, Flexible, Multi-disorder Newborn Screening Program
NCT00018694	Not specified	WITHDRAWN	Cholestanol in Humans
NCT00935389	Not specified	COMPLETED	Prospective Study of TW in the Treatment of LN Type V With Gross Proteinuria
NCT01613898	Not specified	UNKNOWN	Evaluation of Carotid IMT and Atherogenic Risk Factors in Patients With Cerebrotendinous Xanthomatosis
NCT02638220	Not specified	COMPLETED	Cerebrotendinous Xanthomatosis (CTX) Prevalence Study
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT03584893	Not specified	UNKNOWN	The Prevalence of CTX Disorder in Juvenile Cataract Cases in Turkey

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CHENODIOL	4	2
LOVASTATIN	4	1