Cerebrotendinous Xanthomatosis

Inborn error of bile acid synthesis due to deficiency of mitochondrial sterol 27-hydroxylase (CYP27A1), with accumulation of cholestanol and bile alcohols in tissues, presenting with neonatal cholestasis, chronic diarrhoea, juvenile cataract, tendon xanthomas and progressive adult-onset neurological disease, and responding to chenodeoxycholic acid replacement when this is started early.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

Cerebrotendinous xanthomatosis (CTX) is a sterol storage disease caused by deficiency of sterol 27-hydroxylase, a mitochondrial cytochrome P450 enzyme encoded by the CYP27A1 gene, which catalyses the first step of cholesterol side-chain oxidation in the synthesis of the primary bile acids [5, 10]. Interruption of this pathway reduces the production of chenodeoxycholic acid (CDCA), removes the negative feedback on cholesterol 7α-hydroxylase and diverts precursors towards the formation of cholestanol and bile alcohols, which are deposited in the lens, tendons, arterial wall, bone and nervous system [10, 13]. The clinical interest of the entity stems from the combination of three facts: the first manifestations appear in childhood, the diagnosis is usually made in adulthood, and CDCA replacement halts progression and can reverse part of the lesions when started before structural neurological damage is established [9, 11, 17].

1.1 Original description and biochemical characterisation

Ludo van Bogaert, Hans Scherer and Emile Epstein described in 1937 two cousins with symptom onset at 12 or 13 years who, in the fourth decade, showed cerebellopyramidal signs, palatal myoclonus, mental deficiency, cataracts, xanthelasmas and tendon xanthomas; at autopsy they found lipid deposits in the white matter of the cerebellum and in the cerebral peduncles, and called the condition the "cerebral form of generalised cholesterinosis" [2]. Philippart and van Bogaert followed a member of the original family in 1969 and proposed the term "cholestanolosis", which emphasised the nature of the accumulated sterol [3]. In 1968, Menkes, Schimschock and Swanson showed that the lipid deposited in the nervous system was cholestanol, the 5α-saturated derivative of cholesterol, in two brothers aged 60 and 57 years with progressive ataxia, cataracts operated on in youth, enlarged Achilles tendons and normal serum cholesterol [2, 18]. In the same year, Harlan and Still described a "normolipaemic xanthomatosis" with tendon and tuberous xanthomas and pulmonary involvement in two brothers, which Swanson identified as the same entity [2].

The nature of the defect was established in the 1970s. Salen proposed a mechanism for cholestanol deposition in 1971 [19]; Setoguchi, Salen, Tint and Mosbach showed in 1974 that bile acid production was subnormal despite increased cholesterol 7α-hydroxylase activity, with incomplete degradation of the cholesterol side chain [20]; and Oftebro and colleagues showed in 1980 that the hepatic mitochondria of a patient lacked 26-hydroxylation activity (now termed 27-hydroxylation) [2]. In 1987, Salen and colleagues described an approximately 100-fold increase in apolipoprotein B and a 3.5-fold increase in albumin in the cerebrospinal fluid (CSF) of untreated patients, interpreted as a defect of the blood–brain barrier, and its correction by CDCA [21].

1.2 Treatment and molecular discovery

Berginer, Salen and Shefer published in 1984 the first long-term study of CDCA in 17 symptomatic patients treated with 750 mg per day for at least one year: dementia resolved in 10, pyramidal and cerebellar signs disappeared in 5 and improved in 8, and mean plasma cholestanol fell threefold [22]. In 1981, Berginer and Abeliovich had estimated a gene frequency of 1 in 108 in Sephardic Jews of Moroccan origin, demonstrating autosomal recessive transmission [23]. In 1991, Cali and Russell cloned the human sterol 27-hydroxylase cDNA and, with Hsieh and Francke, identified the first point mutations in two unrelated patients, mapped the gene to 2q33-qter and showed that the mutant proteins had greatly reduced activity in transfected cells [5, 24]. Leitersdorf and colleagues described the gene structure (9 exons and 8 introns) in 1993, together with the first frameshift and splicing variants in Jews of Moroccan origin [25]. Cruysberg and colleagues suggested in 1991 that bilateral juvenile cataract associated with chronic diarrhoea was the earliest manifestation; Verrips and colleagues described a predominantly spinal form ("spinal xanthomatosis") in 1999; and Clayton and colleagues reported in 2002 that prolonged neonatal cholestasis is common and may be self-limiting before the classic manifestations appear [2, 26].

1.3 Nomenclature and definition

GeneReviews regards the designations cerebral cholesterinosis, cerebrotendinous cholesterosis and van Bogaert-Scherer-Epstein syndrome as obsolete [1]. The current name is retained even though tendon xanthomas may be absent: in French series only 3 of 13 patients had clinically evident xanthomas, and in the Latin American literature they were present in 61.8% [9, 27]. The operational definition adopted by the 2021 Delphi consensus and by GeneReviews rests on the presence of biallelic pathogenic or likely pathogenic CYP27A1 variants in a patient with suggestive findings, with elevated plasma cholestanol as the biochemical marker of choice [1, 11]. Orphanet defines CTX as a bile acid synthesis anomaly characterised by neonatal cholestasis, childhood-onset cataract, adolescent- or young adult-onset tendon xanthomas and cerebral xanthomas with adult-onset neurological dysfunction [6]. No distinct allelic phenotypes caused by germline CYP27A1 variants are known [1]. The spinal form and the forms without neurological involvement are clinical variants of the same spectrum and not separate entities [1, 28].

CTX belongs to the group of bile acid synthesis defects covered in chapter 38 of Saudubray's Inborn Metabolic Diseases, alongside deficiencies of 3β-hydroxy-Δ5-C27-steroid dehydrogenase, Δ4-3-oxosteroid 5β-reductase, oxysterol 7α-hydroxylase (SPG5), cholesterol 7α-hydroxylase and α-methylacyl-CoA racemase, and the amidation defects; together with AMACR deficiency and SPG5 it belongs to a subgroup of diseases that may present with transient neonatal cholestasis followed, years later, by neurodegenerative disease [10].

2. Molecular Genetics and Pathophysiology

2.1 The CYP27A1 gene and protein

The CYP27A1 gene lies at 2q35, spans about 33 kb (GRCh38, 2:218,781,749–218,815,293) and has 9 exons and 8 introns; the cDNA has 1596 nucleotides and encodes a protein of 532 amino acids (NM_000784.4, MANE Select transcript; NP_000775.1) [1, 4]. Cali and Russell showed that the protein includes a 33-amino-acid mitochondrial signal sequence followed by a mature protein of 498 amino acids [5]. Sterol 27-hydroxylase is a cytochrome P450 monooxygenase of the inner mitochondrial membrane that works with two cofactors, adrenodoxin and adrenodoxin reductase, and hydroxylates several sterols at position C27 in three successive steps (C27 alcohol, aldehyde and acid) [5, 7]. Besides its hepatic role in bile acid synthesis, the enzyme is active in extrahepatic tissues, where it converts cholesterol into 27-hydroxycholesterol, a form that can be metabolised and eliminated from cells: this is a cholesterol removal pathway alternative to reverse transport mediated by high-density lipoproteins (HDL) [10]. The same mitochondrial fraction that hydroxylates C27 sterols catalyses the 25-hydroxylation of vitamin D3 in vitro, although CYP2R1 is the main physiological vitamin D 25-hydroxylase [2, 5].

2.2 Bile acid synthesis pathways and consequences of the deficiency

Bile acids are synthesised from cholesterol by modifications of the steroid nucleus and oxidation of the side chain. In adults the "neutral" or classic pathway predominates, initiated by cholesterol 7α-hydroxylase (CYP7A1), a rate-limiting enzyme regulated by negative feedback from bile acids through direct inhibition, activation of the hepatic farnesoid X receptor (FXR) and activation of intestinal FXR with release of fibroblast growth factor 19 (FGF19), which represses CYP7A1 in the liver [10]. In infants the "acidic" or alternative pathway carries greater weight; it is initiated precisely by the conversion of cholesterol into 27-hydroxycholesterol by CYP27A1, followed by 7α-hydroxylation by oxysterol 7α-hydroxylase (CYP7B1) [10, 29]. This ontogenic difference explains why CTX, AMACR deficiency and CYP7B1 deficiency may present with transient neonatal cholestasis, which regresses as the classic pathway matures, before a symptom-free interval and late neurological disease [10, 30].

In 27-hydroxylase deficiency, 5β-cholestane-3α,7α,12α-triol is not hydroxylated at C27 and accumulates in the liver; it is then metabolised by an alternative microsomal pathway initiated by hydroxylation at C25, followed by hydroxylations at C22 or C23, which produce the characteristic bile alcohols, excreted in urine as glucuronides (mainly 5β-cholestane-3α,7α,12α,23,25-pentol and 3α,7α,12α,22,25-pentol in adults) [2, 10]. Other precursors also accumulate, including 7α-hydroxy-cholest-4-en-3-one (7αC4), partly converted into cholestanol by a pathway involving 7α-dehydroxylation [10]. Because the bile acid pool becomes severely depleted of CDCA, although relatively enriched in cholic acid formed by the microsomal pathway, feedback inhibition of CYP7A1 and HMG-CoA reductase is lost, and the production of bile alcohols and cholestanol increases further [10, 13]. Cholesterol 7α-hydroxylase activity is increased in patients, in some cases up to 20-fold [20, 31].

The clinical manifestations result in part from the accumulation of cholestanol and cholesterol in practically all tissues, particularly the nervous system, atherosclerotic plaques, lens and tendon xanthomas [1, 10]. 7αC4 crosses the blood–brain barrier and is converted into cholestanol in the brain, which contributes to central deposition independently of circulating cholestanol [31]. The blood–brain barrier is altered in untreated patients, with increased apolipoprotein B and albumin in the CSF, changes reversed by CDCA [21]. The lack of 3β,7α-dihydroxy-5-cholestenoic acid, an oxysterol that regulates motor neuron survival through the liver X receptors, may contribute to corticospinal tract injury [10]. Loss of the extrahepatic pathway of cholesterol elimination via 27-hydroxycholesterol explains tissue accumulation of cholesterol in the presence of normal or low plasma cholesterol, and HDL with low cholesterol content have been described [2, 10]. Exogenous CDCA acts by replacement: it restores FXR activation, downregulates CYP7A1 and HMG-CoA reductase and reduces the production of cholestanol, bile alcohols and atypical bile acids; ursodeoxycholic acid, which does not inhibit CYP7A1, is ineffective [10, 13, 14].

2.3 Inheritance pattern

CTX is transmitted in an autosomal recessive manner through biallelic CYP27A1 variants, in homozygosity or compound heterozygosity [1, 10]. No alternative inheritance patterns have been described. Heterozygotes are generally asymptomatic; the GeneReviews authors report, from unpublished personal observation, a higher frequency of cardiovascular disease and gallstones in carriers, a finding that has not been validated in controlled studies [1]. In a case described by Sugama and colleagues, a 44-year-old woman with frontal dementia, spastic paraparesis and elevated cholestanol had only one heterozygous variant identified, which illustrates the need to search for deletions and duplications when only one allele is detected [1, 2].

2.4 Variant spectrum and nomenclature

More than 200 pathogenic variants have been described, distributed across all exons [4]. In 2026, ClinVar listed 151 loss-of-function variants (66 frameshift, 49 nonsense and 36 canonical splice-site) and 25 missense variants classified as pathogenic or likely pathogenic; the literature describes 54 causal missense variants, some of them absent from ClinVar or registered as variants of uncertain significance (VUS) [4]. Many variants affect splice sites, with mRNA instability or products lacking the adrenodoxin- or haem-binding region, and others truncate the protein; the mechanism is loss of function [1]. Frameshift and nonsense variants located in the last ten amino acids are not presumed to cause loss of function [4]. Sequencing detects about 99% and targeted deletion/duplication analysis about 1% of known pathogenic variants, proportions that describe the mutational spectrum and not the clinical sensitivity of the test [1].

Variant numbering has changed with the versions of the reference transcript and with the shift from mature-protein to precursor numbering. The first two variants published in 1991, Arg362Cys and Arg446Cys, now correspond to NM_000784.4:c.1183C>T p.(Arg395Cys) and NM_000784.4:c.1435C>T p.(Arg479Cys) [4, 5]; ClinVar lists "R362C" as a synonym of NM_000784.4:c.1183C>T (p.Arg395Cys), classified as pathogenic or likely pathogenic by several submitters without conflict (assessment of 13/09/2026) [32]. The designation R362C still appears in older prevalence studies, such as that of Lorincz and colleagues [33]. Table 2.1 summarises variants of clinical or population relevance, normalised in VariantValidator.

Table 2.1 — CYP27A1 variants of clinical or population relevance (NM_000784.4 / NP_000775.1, GRCh38)

The variant NM_000784.4:c.1151C>T p.(Pro384Leu), described in three families, has a frequency of 1% or more in Europeans, Latinos and Asians and benign submissions in ClinVar; incidence estimates were calculated with and without it, or assuming that it only causes CTX in trans with a null allele [8, 36]. In a 49-year-old woman of Portuguese and Cape Verdean ancestry, with mild intellectual disability and Achilles xanthomas since adolescence, compound heterozygosity was described for Gly112Glu (historical nomenclature; NM_000784.4:c.434G>A p.(Gly145Glu), registered in ClinVar as pathogenic with the synonym G112E) and for a 5-nucleotide deletion in exon 5 with a premature stop codon [5, 32, 37]. When only one variant is identified, GeneReviews recommends searching for deletions and duplications, and in apparent homozygosity considering an undetected deletion or uniparental isodisomy; a homozygous 1.9 kb deletion with loss of exons 7 to 9 is documented in the clinical case in section 10 [1, 30].

2.5 Genotype–phenotype correlations, penetrance and expressivity

For decades no genotype–phenotype correlations were identified: GeneReviews and the Spanish and Brazilian series found no association between variants and clinical picture or prognosis [1, 28, 38]. The intrafamilial variability described is considerable: a sibling with the same variants may have later neurological onset and a milder picture and not develop xanthomas [1]. Hanson and Bonnen proposed a functional approach: in an information-theory analysis of 218 patients and 12 clinical traits, the phenotype was consistent within families (notable variability in only 4 of 83 families) when traits were compared by decade of age, and patients with two loss-of-function alleles had a greater clinical burden than carriers of two hypomorphic missense variants with residual activity (p = 0.0001) [4]. Ten patients described with normal or upper-limit cholestanol without treatment all had tendon xanthomas and none had a loss-of-function genotype; three were homozygous for hypomorphic alleles [4]. Biochemical penetrance of biallelic genotypes is considered complete in the Delphi consensus, which states that all patients have elevated cholestanol at diagnosis, but atypical cases with normal cholestanol have been published, including a form without neurological manifestations in 2026 [11, 39].

2.6 Allelic disorders and modifiers

No phenotypes distinct from CTX associated with germline CYP27A1 variants are known [1]. The use of drugs that inhibit CYP27A1 or increase HMG-CoA reductase (ciclosporin, sirolimus, phenobarbital) and of oral contraceptives, which reduce the CDCA pool, may worsen the metabolic imbalance during treatment [13]. A patient with coexisting CTX and sitosterolaemia has been described [2].

3. Clinical Spectrum and Manifestations by System

3.1 Temporal sequence and natural history

CTX is a multisystem disease of paediatric onset in which systemic manifestations precede neurological ones by years [1, 9]. In the cohort of 13 patients followed at the Pitié-Salpêtrière and diagnosed in adolescence or adulthood, chronic diarrhoea began in the neonatal period in 10, learning difficulties appeared in 11 at a median age of 10 years (5–15), cataract in 11 with surgery at a median age of 13 years (5–54), psychiatric symptoms in 6 at a median of 15.5 years and walking difficulties in 11 at a median of 20 years (12–50); age at diagnosis had a mean of 30.4 ± 14.9 and a median of 24.5 years (14–55), and disease duration at diagnosis had a mean of 26.2 ± 11.6 years [9]. Saudubray's chapter summarises the same publication as a mean age at diagnosis of 35 years with a delay of 16 years; the values in the original article are those given above [9, 10]. The Delphi consensus reports a diagnostic delay of about 20 to 25 years, the Spanish series 19 years and the Latin American review 31.6 ± 14.8 years [11, 27, 28].

Table 3.1 brings together the frequency of manifestations in series with different methodologies. The GeneReviews frequencies derive from the pooled analysis by Mignarri and colleagues and mainly include untreated adult patients; those of the French, Latin American and Brazilian series depend on age at diagnosis and mode of ascertainment, and are therefore not directly comparable [1, 9, 27, 38].

Table 3.1 — Frequency of manifestations in CTX series

3.2 Neonatal period and digestive system

Neonatal cholestasis may be the first manifestation and usually regresses spontaneously [10, 26]. Clayton and colleagues found prolonged neonatal cholestatic jaundice to be common in the history of patients with CTX, together with fetal and neonatal deaths among siblings, and described an infant with infantile hepatitis who, at 11 years, had a typical cholanoid profile [26]. In a Chinese series, cholestasis was the dominant symptom in 17 infants, and cases of fatal cholestasis and infantile hepatitis have been published [1]. Unlike many infantile cholestases, γ-glutamyltransferase (GGT) is normal, as in 3β-dehydrogenase and 5β-reductase deficiency, whereas in AMACR deficiency it is elevated [10]. Chronic diarrhoea from the neonatal period is common and often does not prompt medical attention because it is not accompanied by growth failure [1, 9]. Wevers and colleagues described four Dutch patients with persistent diarrhoea since early infancy [10]. Excretion of bile alcohol glucuronides has been implicated in the diarrhoea [31]. Gallstones are occasionally described [1].

3.3 Eye

Cataract is the first finding in about 75% of patients, usually in the first decade; in 25% it appears after the age of 40 [1]. It may be visible as early as 5 years and presents as irregular cortical, anterior polar or dense posterior subcapsular opacities; Khan and colleagues described punctate ("fleck") lens opacities with capsular opacities in three siblings, and Ceylan and colleagues cerulean cataracts in two Turkish patients [1, 10, 41]. Other findings include eyelid xanthelasmas, optic atrophy, disc pallor, proptosis, early retinal senescence with vascular sclerosis, cholesterol-like deposits along the vascular arcades and myelinated nerve fibres [1]. Cataract extraction is usually required in at least one eye by the age of 50 [1].

3.4 Tendons, skin and other xanthomas

Tendon xanthomas are detectable in the second decade but usually appear in the third or fourth, preferentially in the Achilles tendon and also over the tibial tuberosities, the extensor tendons of the fingers and elbow, triceps, patellar tendon and cervical tendons [1, 10]. Xanthomas in the lung, bone and central nervous system have been described, including enlarging cerebral xanthomas [1]. The Delphi consensus estimated that fewer than 25% of children have xanthomas before diagnosis, and the absence of xanthomas should not delay investigation [9, 11]. In Latin American patients, enlargement or swelling of the Achilles tendon in 26.5%, brownish dental enamel, hyperlordosis and urinary incontinence have been described [27].

3.5 Nervous system

Intellectual disability may be present from childhood, but most patients have normal or slightly affected intelligence until puberty; dementia due to slow deterioration appears in the third decade in more than half [1]. In the French cohort of 9 children and 18 adults, cognitive impairment was found in 44% and 78%, with executive, attentional, language and visuospatial involvement; 3 adults (16%) developed dementia after the age of 50, all with late treatment and cerebral atrophy, whereas in the others the Mini-Mental State remained stable, suggesting a mainly neurodevelopmental deficit [40]. The Delphi consensus estimated that 25–49% of adults have early dementia before diagnosis [11].

Neuropsychiatric disorders include behavioural changes, hallucinations, agitation, aggressiveness, depression and suicide attempts; some patients have isolated psychiatric symptoms for years, which may mimic schizophrenia, and episodes of acute psychosis occur mainly in adults [1, 42, 43]. Presentations resembling frontotemporal dementia in adults have been described, and autism spectrum disorder and learning difficulties are among the paediatric signs that should prompt cholestanol measurement [2, 44].

Pyramidal and cerebellar signs become almost invariably evident between 20 and 30 years of age, with spasticity, ataxia, dysarthria and pseudobulbar palsy in the advanced stages [1, 10]. Motor dysfunction (spastic paresis, ataxia, expressive dysphasia) develops in about 60% of patients in the second or third decade [10]. In the French series, the motor presentation was cerebellopyramidal in 6 of 13, neuropathic in 3, and isolated cerebellar and pyramidal in 1 each, with saccadic pursuit in 8 and reduced proprioception in the lower limbs in 10 of 11 [9]. In the Brazilian series, the median age at loss of ambulation correlated with the age at onset of neurological symptoms, with a mean interval of 10 years (interquartile range 6.9–11) [38].

The spinal form, characterised by chronic myelopathy with spastic paraparesis and almost always preserved intellect, is easily mistaken for hereditary spastic paraplegia and had a less severe prognosis than the classic form in the Spanish series [1, 28, 45].

Movement disorders are regarded as late manifestations: in a review of 79 patients, the mean age at onset was 40 ± 12 years (13–62), parkinsonism was the most frequent, followed by dystonia, myoclonus and postural tremor, mixed forms occurred in 23% and the movement disorder was the presenting manifestation in 18% [1, 46]. Parkinsonism responds poorly to levodopa and to CDCA [1, 17]. In the French series, 7 of 13 patients had postural myoclonus with dystonia [9], and palatal myoclonus was present in the original family [2]. The Delphi consensus recommends including CTX in the differential diagnosis of early-onset movement disorders, particularly when other neurological or systemic signs are associated [11].

Epilepsy is described in about half of patients in some series and in 33% in the pooled analysis; a Brazilian case presented with early-onset epilepsy as the main neurological manifestation [1, 47]. Peripheral neuropathy, demonstrated electrophysiologically in up to 70%, may be axonal, demyelinating or mixed, and manifests as distal atrophy and pes cavus, with sensory symptoms rarely reported [1, 9, 42].

3.6 Cardiovascular system, bone and other organs

Premature atherosclerosis and coronary disease, which may cause death from myocardial infarction, and lipomatous hypertrophy of the interatrial septum have been described [1, 10]. Bone involvement includes osteoporosis with pathological fractures, granulomatous vertebral and femoral lesions, thoracic kyphosis and reduced radiocalcium absorption, with low 25-hydroxy- and 24,25-dihydroxyvitamin D; bone mineral density improves with CDCA [1, 10, 13]. Respiratory failure has been described [10]. The combination of early cataract, osteopenia with fractures and tooth loss, atherosclerosis and neurological defect has led to CTX being interpreted as a process of premature ageing [1].

3.7 Natural history without and with treatment

Without treatment, patients usually die between 30 and 60 years of age from progressive neurological dysfunction or myocardial infarction [10]. In the Spanish series, 5 of 25 patients died 1 to 4 years after diagnosis despite treatment, in a context of a mean diagnostic delay of 19 years [28]. With early CDCA, the Dutch, French and Turkish series describe resolution or non-appearance of neurological symptoms, whereas late treatment stabilises some patients and does not prevent progression in others; these data are detailed in sections 7 and 11 [17, 44, 48]. Forms without neurological involvement, with tendon xanthomas as the main finding, have been identified in adults, including siblings from a South African family with a mild phenotype and a case published in 2026 with normal cholestanol [1, 8, 39].

4. Clinical Recognition and Warning Signs

4.1 When to suspect, by age

In the neonatal period and in infancy, CTX should be considered in the presence of prolonged cholestasis without an established cause, particularly with normal GGT and serum bile acids and pigmented stools, even when the jaundice regresses spontaneously [10, 11, 30]. The Delphi consensus stresses that prolonged, undiagnosed neonatal jaundice should raise suspicion, because it may cause liver damage [11]. In childhood, the warning signs are chronic diarrhoea from the first months, unexplained bilateral juvenile cataract and learning difficulties or intellectual disability; these were the three pre-diagnostic symptoms that achieved consensus for patients under 18 years (90%, 90% and 100% agreement) [11]. Degos and colleagues recommend that paediatric gastroenterologists investigate CTX in early-onset diarrhoea, particularly with a history of infantile liver dysfunction, and that cataract in a child or adolescent should lead to cholestanol measurement [9]. Autism spectrum disorder and early-onset epilepsy are also among the paediatric presentations [44, 47].

In adolescents and adults, suspicion should arise in the presence of tendon xanthomas with normal or low plasma cholesterol, spastic paraparesis (including presentations suggestive of hereditary spastic paraplegia), cerebellar ataxia, peripheral neuropathy, epilepsy, cognitive decline, psychiatric symptoms beginning in adolescence or young adulthood and early-onset parkinsonism or dystonia, particularly when they coexist with a history of juvenile cataract or chronic diarrhoea [1, 11, 42]. The Oxford Desk Reference includes CTX in the approach to the adult with ataxia (pyramidal or extrapyramidal signs, seizures, dementia, juvenile cataract and tendon xanthomas, usually with onset before 20 years but with possible late forms), to the child with cataract (ask about neonatal jaundice and look for xanthomas and xanthelasmas) and to intracranial calcifications [49–51]. In Saudubray's chapter on adult metabolic diseases, Achilles tendon xanthomas and cataract are listed as signs of high diagnostic value, and a history of prolonged neonatal jaundice is regarded as suggestive of a disorder of sterol metabolism [42].

4.2 High-value combinations and suspicion index

GeneGuidance highlights the triad of juvenile cataract, infantile-onset chronic diarrhoea and Achilles tendon xanthoma, and regards isolated idiopathic bilateral juvenile cataract as sufficient reason to test [7]. Mignarri and colleagues proposed a weighted suspicion index: very strong indicators (100 points) are tendon xanthomas and an affected sibling; strong indicators (50 points) are cataract, chronic diarrhoea, neonatal cholestatic jaundice, intellectual disability, psychiatric disorders, ataxia, spastic paraparesis and dentate nucleus changes on magnetic resonance imaging (MRI); moderate indicators are worth 25 points [52]. A score of 100 or more justifies measurement of serum cholestanol, and an elevated cholestanol or a score of 200 or more (with one very strong or four strong indicators) justifies CYP27A1 analysis; applied retrospectively to the authors' series, the index would have reduced the age at diagnosis from 35.5 ± 11.8 to 10.6 ± 9.8 years [52]. In the Turkish study of 452 patients with juvenile cataract, five of the seven patients with CTX had an index of 100 or more, but the other two scored lower, which shows that the index does not exclude the disease in a child with isolated cataract [53].

4.3 Targeted screening of at-risk populations

Screening studies in patients with idiopathic juvenile cataract found CTX in 1.8% of 170 patients in the USA (cataract diagnosed between 2 and 21 years; cholestanol of 0.4 mg/dL or more or positive urinary bile alcohols as the criterion for genetic testing), in 1.55% of 452 patients in Turkey (cholestanol of 3.75 µg/mL or more) and in 1.5% (95% CI 0.2–5.4) of 128 patients at an Istanbul centre by targeted CYP27A1 sequencing [41, 53, 54]. In the American study, the mean age at cataract diagnosis in patients with CTX was 12 years (8–16) and all three had gait or balance disturbances, two learning difficulties, two cognitive decline, two seizures and two frequent fractures [54]. By contrast, in a tertiary adult ataxia clinic in the USA, none of 50 samples had elevated 7α,12α-dihydroxy-4-cholesten-3-one, indicating a low yield of CTX screening in idiopathic adult ataxia without other signs [55]. In the series of 57 recessive ataxias from Ceará, a region of north-eastern Brazil with high consanguinity, CTX accounted for 10.5% of diagnoses [56].

4.4 Newborn screening

No national newborn screening for CTX has yet been implemented [11]. The methodology has been validated in research studies: Hong and colleagues analysed 32,737 newborn dried blood spots by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS), abandoned 7α,12α-dihydroxy-4-cholesten-3-one because of isobaric interference and defined as positive newborns with elevated 5β-cholestane-3α,7α,12α,25-tetrol glucuronide (GlcA-tetrol) and an elevated GlcA-tetrol/taurochenodeoxycholic acid (t-CDCA) ratio, using the taurotrihydroxycholestanoic acid (t-THCA)/GlcA-tetrol ratio to distinguish Zellweger spectrum disorders; they identified one newborn with a typical profile and two pathogenic variants and obtained a specificity of 100% [57]. Vaz and colleagues applied the same ratios to 20,076 Dutch blood spots with flow injection analysis (FIA-MS/MS) and UPLC-MS/MS, equipment common in screening laboratories, with no overlap with patient values and no false positives [12]. The Delphi consensus regarded the dried blood spot as the optimal screening method and starting treatment at birth, after a positive screen, as the most beneficial strategy [11]. The American expanded newborn screening programmes ScreenPlus (100,000 newborns planned by 2029) and Early Check (30,000) mention CTX in their registrations [58].

4.5 Emergency situations

CTX rarely presents as an emergency. The situations requiring prompt action are severe infantile cholestasis, in which liver transplantation was considered in a Turkish case that recovered fully with CDCA, fatal cholestasis described in isolated cases, and pregnancy in an undiagnosed or untreated woman, with fetal losses described [1, 13, 48, 59].

In neonatal cholestasis, whatever the cause, the French PNDS (National Diagnosis and Care Protocol) for bile acid synthesis defects states that a newborn who remains or becomes jaundiced at or after 14 days of life should have a clinical examination with observation of stool colour, measurement of total and conjugated bilirubin and abdominal ultrasound; biochemical cholestasis is defined by conjugated bilirubin above 17 µmol/L (10 mg/L) or above 20% of total bilirubin [60]. Once cholestasis is confirmed, the child is urgently referred to a specialist centre, because biliary atresia, responsible for about 45% of cases at that age, must be excluded first, and receives a parenteral injection of vitamin K as soon as possible, 10 mg in the text of the PNDS, to prevent bleeding due to coagulopathy [60]. The Portuguese SmPC of Kanakion MM Paediatric (phytomenadione 2 mg/0.2 mL) indicates lower doses: in newborns with risk factors, including obstructive jaundice, 1 mg intramuscularly or intravenously, with further doses guided by coagulation parameters; in preterm infants under 36 weeks and under 2.5 kg, 0.4 mg/kg, a parenteral dose that should not be exceeded; in the treatment of bleeding, 1 mg intravenously as the initial dose. The same SmPC warns that oral prophylaxis is insufficient in cholestatic liver disease with malabsorption [61]. The 2017 joint NASPGHAN/ESPGHAN guideline refers to parenteral vitamin K administration without setting a dose and notes that severe coagulopathy not corrected by it, disproportionate to the liver injury, suggests gestational alloimmune liver disease, metabolic disease or sepsis [62]. CTX enters this evaluation as a rare cause, signposted by normal GGT, and the urinary profile of bile acids and bile alcohols by mass spectrometry is part of the specialised investigations [10, 60].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Diagnostic criteria

There are no formal validated clinical criteria. GeneReviews defines the diagnosis by the presence of suggestive findings and biallelic pathogenic or likely pathogenic CYP27A1 variants; biallelic variants of uncertain significance, or one pathogenic variant with a VUS, neither establish nor exclude the diagnosis [1]. In the Delphi consensus, the presence of pathogenic CYP27A1 variants was the indicator of greatest diagnostic value (80% of panellists), genetic testing was ranked first to confirm the diagnosis (90%) and serum cholestanol second (80%); all panellists agreed that serum cholestanol is the diagnostic marker of choice and that it is elevated in all patients at diagnosis [11]. The same authors acknowledge the existence of atypical cases with normal cholestanol and of cholestanol elevations outside CTX, in primary biliary cirrhosis, Niemann-Pick disease type C and, very rarely, progressive familial intrahepatic cholestasis type 3 [11]. The 2026 genetic review regards biochemical measurement as the reference standard for an inborn error of metabolism and refers to new markers more sensitive than cholestanol, whose use has revealed patients with normal or slightly elevated cholestanol and a milder course [4].

5.2 Biomarkers

Table 5.1 — Biomarkers of CTX

GeneReviews Table 1 gives cholestanol as "up to 5–10 times normal" but presents as the normal value "330 ± 30 µg/dL", a figure incompatible with the reference ranges of other laboratories (2–16 µmol/L, approximately 0.08–0.6 mg/dL); this value should not be used as a reference [1, 10]. Results should be interpreted with the reference range and unit of the laboratory that produced them. In a study published in 2026 with 14 patients, 6 carriers and 24 controls, low 27-hydroxycholesterol (area under the curve 1.000) and elevated 7α-hydroxycholesterol (0.991) outperformed cholestanol (0.903) in distinguishing patients from controls; this is a small series that has not yet been replicated [63]. Urinary excretion of bile alcohols after administration of colestyramine was used historically to identify carriers [2, 10].

5.3 Imaging and neurophysiology

Brain MRI shows bilateral T2 hyperintensity of the dentate nuclei and of the cerebellar and cerebral white matter, diffuse cerebral and cerebellar atrophy and focal cerebellar lesions [1, 10]. In the Siena series of 38 patients, the changes included subcortical, periventricular, cerebellar, brainstem and dentate nucleus T2/FLAIR hyperintensity; T1/FLAIR hypointensity of the dentate nuclei corresponded to cerebellar vacuolation and hypointensity on T1, FLAIR and susceptibility-weighted sequences to calcification [65]. In the French series, dentate nucleus hyperintensity was present in 12 of 13 patients, periventricular hyperintensities in 10 and an increased choline peak on spectroscopy in all [9]. Posterior leukoencephalopathy, spinal cord hyperintensities and intracranial calcifications have been described [27, 51, 66]. The Delphi consensus recommends MRI at diagnosis, to support the diagnosis and exclude other causes (70% agreement) [11]. Electromyography with nerve conduction studies documents axonal, demyelinating or mixed neuropathy, and somatosensory, motor, brainstem auditory and visual evoked potentials may be abnormal [1, 9].

5.4 Molecular tests

GeneReviews proposes two approaches [1]. In a suggestive presentation, CYP27A1 sequencing (exons and exon–intron boundaries) detects missense, nonsense and splice variants and small deletions or insertions; if one or no variant is found, targeted deletion/duplication analysis follows (quantitative PCR, long-range PCR, MLPA or targeted microarray). Alternatively, a multigene panel including CYP27A1 and the genes of the differential diagnosis (spastic paraplegias, ataxias, leukodystrophies, cholestases) may be used. When CTX has not been considered, the diagnosis often emerges from exome or genome sequencing [1, 45]. The limits to bear in mind are: sequencing does not usually detect deletions of one or more exons, which account for about 1% of variants; apparent homozygosity may conceal a hemizygous deletion or uniparental isodisomy; a negative test in a patient with typical cholestanol and bile alcohols does not exclude the diagnosis, as shown by two French siblings with very high cholestanol in whom the second allele was not found; and classification of missense variants is limited, with many VUS and almost no loss-of-function variant of uncertain significance [1, 4, 9]. The variant c.1151C>T p.(Pro384Leu), relatively frequent in the population, requires careful interpretation [8, 36].

The molecular report should state the gene, the versioned reference transcript (NM_000784.4), the HGVS nomenclature of each variant at cDNA and protein level, zygosity, classification according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) criteria and, when applicable, the recommendation for parental testing to confirm the phase of the variants [1]. When there are VUS, correlation with the biochemical profile (cholestanol, bile alcohols, 27-hydroxycholesterol) and family segregation allow the classification to be reassessed [1, 4].

5.5 Diagnostic algorithm

1. Clinical suspicion (section 4) or suspicion index of 100 or more → plasma cholestanol with cholesterol and, if available, urinary or plasma bile alcohols [11, 52].
2. Elevated cholestanol, or index of 200 or more, or a highly suggestive picture with normal cholestanol → CYP27A1 sequencing with deletion/duplication analysis, or panel/exome according to context [1, 52].
3. Biallelic pathogenic variants → diagnosis confirmed; parental testing and cascade testing of siblings [1].
4. One variant or VUS with typical biochemistry → search for deletions, RNA or fibroblast studies, segregation; consider additional markers (27-hydroxycholesterol, 7α-hydroxycholesterol, 7αC4) [1, 63].
5. Normal cholestanol and a suggestive picture with xanthomas → do not exclude: hypomorphic forms with normal cholestanol have been described [4, 39].
6. Assessment of extent after diagnosis (section 11) [1].

5.6 Prenatal and preimplantation diagnosis

Once both pathogenic variants have been identified in the family, prenatal diagnosis on chorionic villi or amniotic fluid and preimplantation genetic testing are possible [1]. The ethical and counselling considerations are described in section 8.

6. Differential Diagnosis

The differential diagnosis depends on the stage of the disease and on the sign prompting presentation: neonatal cholestasis, chronic diarrhoea, juvenile cataract, xanthomas, spastic paraparesis, ataxia, movement disorder, leukoencephalopathy or psychosis [1, 42]. The marker that separates CTX from most alternatives is the combination of elevated cholestanol with normal or low cholesterol and increased bile alcohols [1].

Table 6.1 — Differential diagnosis of cerebrotendinous xanthomatosis

6.1 Main differentials

Tendon xanthomas with normal cholesterol narrow the differential to sitosterolaemia and CTX: in sitosterolaemia the xanthomas appear in childhood, at unusual sites, without cataract or neurological involvement, and plant sterol measurement is diagnostic [1, 67]. In familial hypercholesterolaemia the xanthomas are accompanied by very high LDL-C and score in the Dutch Lipid Clinic Network criteria, and cholestanol is not increased [67]. Autosomal recessive hypercholesterolaemia due to LDLRAP1 variants shares recessive transmission and bulky xanthomas with CTX, but reproduces the phenotype of homozygous familial hypercholesterolaemia, with very high LDL-C; in such a presentation, assessment of first-degree relatives points to a recessive disease, and the diagnosis is made by genetic testing [67]. The xanthomas of CTX may be absent, and their absence does not exclude the diagnosis [9].

In adult spastic paraparesis, the spinal form of CTX is a treatable mimic of the hereditary spastic paraplegias, sometimes identified only by next-generation sequencing [1, 45]. The closest biochemical differential is SPG5A, also a bile acid synthesis defect, in which 27-hydroxycholesterol is elevated, unlike CTX, in which it is low; Saudubray's chapter reports that atorvastatin 40 mg/day for 9 weeks lowered 27-hydroxycholesterol in 14 patients with SPG5, without clinical efficacy data [10, 63]. In infantile cholestasis, normal GGT brings CTX closer to 3β-dehydrogenase and 5β-reductase deficiencies and away from AMACR deficiency and most obstructive cholestases; the profile of urinary bile acids and bile alcohols by mass spectrometry differentiates these entities [10, 30]. Niemann-Pick disease type C shares transient neonatal jaundice, ataxia and psychosis, and may present with increased cholestanol, so interpretation should integrate oxysterols and genetics [11, 43]. In the child with bilateral cataract, the Oxford Desk Reference recommends including sterol analysis in the metabolic work-up, alongside the usual genetic and metabolic causes [50].

The French PNDS for primary bile acid synthesis defects lists ten characterised enzyme deficiencies, distributed across the steps of steroid nucleus modification, side-chain modification and conjugation, and places CTX in the second group, with possible neonatal cholestasis [60]. According to the same document, steroid nucleus defects present mainly with severe and isolated liver disease, whereas side-chain defects (sterol 27-hydroxylase, AMACR and D-bifunctional protein) classically present with neurological disease and malabsorption of fat and fat-soluble vitamins, with secondary liver involvement, because residual synthesis of primary bile acids persists [60]. Overall, synthesis defects account for about 1–2% of childhood cholestases [60]. In 3β-dehydrogenase and 5β-reductase deficiencies, the cholestasis is not accompanied by pruritus, GGT is normal, total serum bile acids are normal or low despite clinical cholestasis and the bile ducts are not dilated on ultrasound; a high serum bile acid concentration rules out these deficiencies and points to the progressive familial intrahepatic cholestases [60]. 5β-reductase deficiency appears earlier (around 3 months), is more severe and progresses faster to liver failure; its urinary profile is not pathognomonic, because enzyme activity decreases in any advanced liver disease (for example, in neonatal haemochromatosis), and confirmation requires AKR1D1 testing [60]. The combined minimum prevalence of these two deficiencies was estimated at 1.13 per 10 million in an international survey and at 4.02 per 10 million in France, a figure influenced by the referral of patients of foreign origin, with probable underdiagnosis [60]. In these deficiencies, which respond to cholic acid, neurological manifestations, when present, result from vitamin E deficiency; in CTX, self-limiting neonatal cholestasis precedes a late neurological and lipid disease, and cholestanol and urinary bile alcohols are the distinguishing markers [1, 10, 60].

7. Treatments and Risk Management Strategies

7.1 Principles and consensus recommendations

Treatment of CTX is lifelong replacement with chenodeoxycholic acid, which restores negative feedback on bile acid synthesis and reduces the production of cholestanol and bile alcohols [11, 13]. In the 2021 Delphi consensus, all panellists agreed that CDCA is a lifelong replacement therapy, which can reverse the pathophysiological process particularly when started early, and that CDCA alone improves or stabilises the prognosis in most patients; CDCA alone was ranked first for biochemical efficacy (80%), the combination of CDCA with an HMG-CoA reductase inhibitor second (71%) and low-density lipoprotein (LDL) apheresis last (71%), and CDCA alone was preferred to the combination as first line (78%) [11]. There was no consensus on cholic acid alone (33% agreement, 50% disagreement) or combined with a statin [11]. Timing of initiation was considered the factor with the greatest impact on outcome (90%), ahead of the extent of neurological deterioration (80%), and cholestanol at diagnosis was considered the factor with the least impact (89%); starting at birth after a positive newborn screen was the preferred option (90%), followed by starting at diagnosis with or without symptoms (80%) [11]. The panel also agreed that support and intensive education improve adherence (90%) and that neurologists and paediatricians or metabolic specialists should take part in diagnosis, prescribing and follow-up [11]. The consensus does not give doses, and it was funded by the holder of a marketing authorisation for CDCA, with panellists not paid for their participation [11].

GeneReviews classifies CDCA as targeted therapy, recommends starting it early because its effect depends on the extent of irreversible axonal injury, and states that early treatment of presymptomatic patients appears to prevent the clinical manifestations [1]. The Oxford Desk Reference states that bile acids and statins may halt, but probably not reverse, the symptoms; this wording diverges from later cohort studies, which document reversal of neurological symptoms in patients treated before 24–28 years of age [17, 48, 50].

7.2 Chenodeoxycholic acid (CDCA)

Name and presentations. Chenodeoxycholic acid (INN used by INFARMED; chenodiol in the USA). In the EU and Portugal: Ácido quenodesoxicólico Leadiant® (Chenodeoxycholic acid Leadiant®, formerly Chenodeoxycholic acid sigma-tau), 250 mg capsules, Leadiant Biosciences Ireland Limited [13, 71]. In the USA: Ctexli® (chenodiol), 250 mg film-coated tablets, Mirum Pharmaceuticals [14]. In Infomed, Ácido quenodesoxicólico Leadiant® is authorised with no marketed presentations; Xebyl® (125 and 250 mg, Laboratórios Basi) is authorised but not marketed, and Chendol® has lapsed [71]. In the open database of the Brazilian Health Regulatory Agency (ANVISA) there is no registration of chenodeoxycholic acid or of cholic acid alone, so there is no Brazilian package leaflet [72].

Mechanism. Exogenous CDCA replaces the missing bile acid in the enterohepatic pool, activates FXR, inhibits CYP7A1 and HMG-CoA reductase and reduces the production of cholesterol, cholestanol, bile alcohols and atypical bile acids [13, 14]. Ursodeoxycholic acid does not inhibit cholesterol 7α-hydroxylase and is ineffective in CTX [10, 11].

Reference dose and comparison with labels. In adults, all sources agree on a dose of 750 mg/day in three doses; GeneReviews and Saudubray's chapter give 750 mg/day, the European SmPC gives 750 mg/day as the starting dose with increases in 250 mg increments up to a maximum of 1000 mg/day if cholestanol or bile alcohols remain elevated, and the FDA label gives 250 mg three times daily [1, 10, 13, 14]. In children, the sources diverge: GeneReviews gives 10–20 mg/kg/day, with no absolute maximum daily dose defined in the source [1]; Saudubray's chapter on medicines gives 5 mg/kg/day and the chapter on bile acid synthesis disorders 5–15 mg/kg/day [10, 73]; the European SmPC, approved from 1 month to 18 years, gives a starting dose of 5 mg/kg/day in three doses, choosing the nearest multiple of 250 mg below the maximum of 15 mg/kg/day, provided it normalises cholestanol or bile alcohols [13]. The reference dose adopted is that of GeneReviews, the clinical guidance source that gives a paediatric dose, and the upper limit of 20 mg/kg/day exceeds the SmPC maximum of 15 mg/kg/day, falling outside the conditions approved in the EU; the FDA label does not include children [1, 13, 14]. In the retrospective studies that supported the European authorisation, children received 5–15 mg/kg/day, all with 15 mg/kg/day as the starting dose, and in the only infant included the dose was reduced to 5 mg/kg/day after a rise in liver tests [13]. In the clinical case in section 10, the dose was 10 mg/kg/day increased to 15 mg/kg/day from 8 months of age [30]. The dose should be adjusted to the lowest dose that normalises serum cholestanol or urinary bile alcohols [13].

Table 7.1 — Dosage of chenodeoxycholic acid in CTX

Monitoring. The European SmPC recommends measurement of serum cholestanol and/or urinary bile alcohols every 3 months during initiation and dose adjustment until metabolic control is achieved, then annually, with at least annual determination of cholestanol, bile alcohols and liver function, and additional checks during periods of rapid growth, intercurrent illness and pregnancy; a concomitant rise in liver enzymes may indicate overdose [13]. The FDA label requires transaminases (ALT, AST) and total bilirubin before initiation and annually, with interruption if ALT or AST exceed 3 times the upper limit of normal or total bilirubin exceeds 2 times, until they return to baseline, and consideration of permanent discontinuation if the abnormalities persist or recur [14]. A missed dose should not be made up with a double dose [13, 14].

Adverse effects. In the European SmPC, adverse reactions are mild to moderate and of unknown frequency: constipation, increased transaminases and jaundice; in the non-interventional studies there were three reactions in 63 patients (two cases of constipation and one hepatic reaction in a two-week-old infant with parechovirus infection, aciclovir, phenobarbital and hyperbilirubinaemia at birth, which normalised on withdrawal and did not recur at 5 mg/kg/day) [13]. In the trial that supported the American label (14 patients aged 16 to 55 years, mean exposure 139 days), the most frequent reactions were diarrhoea (36%), headache (21%), abdominal pain, constipation, hypertension, muscle weakness and upper respiratory tract infection (14% each); one patient (7%) had ALT above 3 times normal with treatment interruption; after marketing, hepatotoxicity and hypersensitivity reactions (facial oedema, pruritus, rash, urticaria) were reported [14]. The FDA notes a higher risk of hepatotoxicity in patients with pre-existing liver disease or bile duct abnormalities and in poor sulphators of lithocholic acid, a bacterial metabolite of CDCA [14]. In a series of 43 patients cited in a review, 9% had a moderate rise in liver enzymes requiring dose reduction or discontinuation [31]. In the Dutch cohort treated with compounded capsules, 45% of the 55 patients reported some adverse event, mainly diarrhoea (16%), constipation (7%) and fatigue (7%), the diarrhoea being difficult to distinguish from a symptom of the disease [29]. Overdose has a potential for harm considered very low in the SmPC; intentional doses of 3–4.5 g and 30 g caused nausea, dizziness and diarrhoea [13, 14].

Interactions. Bile acid sequestrants and aluminium-containing antacids reduce absorption: the European SmPC recommends taking colestipol or antacids containing aluminium hydroxide or smectite 2 hours before or after CDCA, and CDCA 1 hour before or 4–6 hours after colestyramine; the FDA label recommends avoiding the combination [13, 14]. Ciclosporin and sirolimus inhibit CYP27A1 and increase HMG-CoA reductase, and phenobarbital increases HMG-CoA reductase; the combination is not recommended and, if it is necessary, bile alcohols should be monitored and the dose adjusted [13]. Oral contraceptives reduce the CDCA pool and are not recommended; another effective contraceptive method should be used [13]. With coumarins, the FDA recommends monitoring the prothrombin time [14].

Expected clinical response. The documented effects include normalisation of plasma and CSF cholestanol within a few months, suppression of urinary bile alcohols, normalisation of nerve conduction velocities and slow improvement of evoked potentials, improvement of bone mineral density and resolution of diarrhoea; parkinsonism and myoclonus respond poorly and psychosis is the most refractory psychiatric manifestation [1, 13, 44, 48]. The biochemical response does not always correlate with the clinical course [48].

7.3 Cholic acid

Cholic acid reduces bile acid synthesis by feedback and was proposed as treatment by Koopman and colleagues in 1985 [2]. Saudubray's chapter describes a study of 12 adults (Mandia and colleagues, 2019) in which cholic acid reduced cholestanol in untreated patients and kept it low in those switched from CDCA, with 10 patients stable or better and 2 deteriorating, and concludes that CDCA remains the bile acid of choice for the neurological manifestations [10]. GeneReviews regards it as useful in patients with adverse effects from CDCA, and the Delphi consensus did not reach consensus on its efficacy [1, 11]. A 2025 review, funded by a company with rights to the cholic acid marketed in the USA, argues for results equivalent to those of CDCA with fewer adverse effects, relying on an open-label trial of 54 children with single enzyme defects (5 with CTX) in which urinary bile alcohols fell from 72.1% to 14% (p < 0.0001); neurological efficacy in CTX cannot be calculated from the available literature [31]. Cholic acid has a smaller theoretical advantage than CDCA because cholic acid is not deficient in CTX and because CDCA also inhibits HMG-CoA reductase [13, 30].

In infantile cholestasis that does not resolve spontaneously, Saudubray's chapter regards cholic acid as probably preferable to CDCA, although the Turkish series describes a cholestatic child for whom liver transplantation was being considered and who recovered fully with CDCA [10, 48]. The French PNDS for 3β-dehydrogenase and 5β-reductase deficiencies bases the preference for cholic acid in these liver diseases on arguments that help weigh the risk of CDCA in the cholestatic infant: cholic acid accounts for two thirds of physiological primary bile acid production; CDCA is more detergent and its metabolite, lithocholic acid, is hepatotoxic in overdose, so CDCA may be hepatotoxic at high doses and in severe liver failure; lithocholic acid has been suggested as a possible colon carcinogen; and CDCA has no marketing authorisation for these indications in any country [60]. In CTX, in which the deficient bile acid is CDCA, these arguments do not alter the first line defined by the consensus, but they reinforce the hepatic monitoring provided for in the European SmPC and the FDA label, particularly in infantile cholestasis [11, 13, 14].

Regulatory status: in the USA, Cholbam® (Mirum; initial approval 17/03/2015) is indicated for bile acid synthesis disorders due to single enzyme defects, at a dose of 10–15 mg/kg/day once daily or in two divided doses, in children from 3 weeks of age and adults, with monthly monitoring of liver function in the first 3 months, every 3 months for the next 9 months, every 6 months for 3 years and annually thereafter; the label limits demonstrated efficacy to the hepatic manifestations, and the Delphi consensus considers that this indication covers CTX [11, 74]. This dose corresponds to the approved indication for single enzyme defects, and its application to the neurological manifestations of CTX is an extrapolation. In the EU, Kolbam® had an indication that included sterol 27-hydroxylase deficiency and was withdrawn in 2020; Orphacol® is indicated only for 3β-hydroxy-Δ5-C27-steroid oxidoreductase and Δ4-3-oxosteroid 5β-reductase deficiencies, so the use of cholic acid in CTX is, in the EU, off-label [75]. In England, according to the Delphi consensus, cholic acid is recommended as second line when CDCA is not tolerated or is ineffective [11]. Saudubray's chapter gives 6–8 mg/kg/day in 3β-dehydrogenase and 5β-reductase deficiencies, a dose for an analogous condition [73]. The Orphacol® dosage described in the French PNDS for these two deficiencies, approved in France and the EU since 2013, is 5–15 mg/kg/day orally in infants (from 1 month), children, adolescents and adults, with a minimum dose of 50 mg and adjustments in 50 mg steps, not exceeding 500 mg/day in adults (an amount close to physiological synthesis in adults), divided into two doses when it includes more than one capsule; the dose chosen is the lowest that reduces atypical metabolites to values as close to zero as possible, with measurement of urinary and/or serum bile acids by chromatography coupled with mass spectrometry at least every 3 months in the first year and every 6 months in the second [60]. Overdose is suspected in the presence of pruritus, diarrhoea or a simultaneous rise in GGT and transaminases, and is confirmed by elevated total serum bile acids [60]. In CTX, these doses are an extrapolation from an analogous condition, off-label in the EU, and the PNDS dose differs from that of the American label (10–15 mg/kg/day) and from that of Saudubray's chapter (6–8 mg/kg/day) [60, 73, 74].

7.4 HMG-CoA reductase inhibitors, apheresis and other measures

Statins (simvastatin, pravastatin, lovastatin) reduce cholestanol alone or combined with CDCA, but GeneReviews recommends caution because of the risk of muscle injury and rhabdomyolysis, and one study found lovastatin ineffective [1, 10]. The Delphi consensus accepts the combination of CDCA with a statin as effective, but prefers CDCA alone as first line [11]. LDL apheresis has been used in isolated cases and was considered by the consensus the least effective option, without prognostic benefit [10, 11]. Fat-soluble vitamin supplementation is part of the management of infantile cholestasis [30]. The French PNDS for synthesis defects provides, in the diagnostic phase, for oral or, if necessary, parenteral supplementation of vitamins A, D, E and K, to be stopped when serum levels normalise on bile acid therapy, to avoid overdose [60].

7.5 Symptomatic and surgical treatment

Cataract requires surgical extraction, usually in at least one eye by the age of 50 [1]. Epilepsy, spasticity and psychiatric disorders are treated with the usual symptomatic therapies; parkinsonism responds poorly to levodopa [1]. Osteoporosis improves with CDCA, which increases lumbar and hip bone mineral density [1, 13]. The Delphi consensus recommends that follow-up include a neurologist, a paediatrician or metabolic specialist and an ophthalmologist, with neuropsychological assessment when needed; the cognitive deficit of most patients has a neurodevelopmental profile and involves executive functions, attention, language and visuospatial abilities [11, 40].

7.6 Regulatory status

Table 7.2 — Regulatory status of bile acids in CTX

The European authorisation of CDCA as an orphan medicinal product in 2017 was followed, according to the Dutch authors, by a sharp price increase; insurers in the Netherlands stopped reimbursing it and the hospital pharmacy of Amsterdam UMC began producing compounded capsules (35–250 mg) with raw material compliant with the European Pharmacopoeia [29]. In a retrospective study of 55 patients (6 to 73 years, mean 40.2) followed for a mean of 1460 days between 2020 and 2024, cholestanol and bile alcohols remained suppressed after switching from the authorised to the compounded formulation (n = 25) and normalised in four patients who started treatment with the compounded capsules [29]. These are observational single-centre data, without a comparison group.

7.7 Evidence from trials and cohorts

Table 7.3 — Studies of CDCA treatment in CTX

The available studies have limitations that constrain their interpretation. The only randomised trial, RESTORE, is a withdrawal trial in adults already on treatment, with short-term biochemical outcomes (4 weeks per period) and no clinical outcome; clinical response and neurological benefit still rest on open series and retrospective cohorts without a control group, in which age at the start of treatment is confounded with severity and disease duration [7, 14, 64]. The age thresholds of 24, 25 and 28 years come from different cohorts and from exploratory analyses, and should not be read as efficacy boundaries, particularly because the Turkish cohort also documented benefit in patients diagnosed late [17, 44, 48]. A review points out that, in one of the retrospective studies, mean Rankin and EDSS scores worsened significantly in patients with advanced disease, which shows that stabilisation in some patients does not exclude mean progression of the group [13, 31]. There are no head-to-head comparisons between CDCA and cholic acid. A phase 3 trial by the European holder in newly diagnosed patients (NCT06260748, diarrhoea outcome) was withdrawn for lack of feasibility before enrolling patients, and the open-label paediatric cohort of RESTORE has no published results in the sources consulted [58].

7.8 Developments in the last 12 months (November 2025 to October 2026)

GeneReviews refers to gene therapy by CYP27A1 supplementation under study in a mouse model, still at the preclinical stage [1]. The ClinicalTrials.gov search did not identify ongoing trials of gene therapy or new drugs in patients with CTX, which does not demonstrate that none exist [58].

7.9 Pregnancy, lactation and contraception

The sources diverge. GeneReviews recommends not interrupting CDCA during pregnancy [1]. The European SmPC describes adverse outcomes in pregnant women with CTX and elevated cholestanol (two intrauterine deaths in one mother and two preterm infants with growth restriction), considers data on CDCA in pregnancy to be non-existent or limited, refers to reproductive toxicity in animals and does not recommend the drug during pregnancy or in women not using effective contraception, advising against oral contraceptives [13]. The FDA label states that decades of published reports have not identified an increase in major malformations, miscarriages or other adverse outcomes, and that the hepatic, renal and adrenal lesions observed in Rhesus monkey fetuses (at 1 to 2 times the human dose) and in neonatal baboons have not been demonstrated in humans, possibly because non-human primates sulphate lithocholic acid less [14]. In the Delphi consensus, the statement that CDCA in pregnancy protects against fetal injury and miscarriage did not reach consensus (67% agreement, no disagreement) [11]. The French PNDS for bile acid synthesis defects regards CDCA as contraindicated in pregnancy because of a teratogenic effect, without presenting supporting data, as one of the arguments for preferring cholic acid in 3β-dehydrogenase and 5β-reductase deficiencies; this position is more restrictive than that of the European SmPC (not recommended) and contradicts that of GeneReviews and the FDA's reading of the human data [1, 13, 14, 60]. The same document describes nine pregnancies in four patients treated with cholic acid, all with a favourable course and healthy newborns, data from an analogous condition to be considered when cholic acid is the alternative weighed in a pregnant woman with CTX [60]. The 2026 Turkish multicentre study included 19 pregnancies in 12 women: 16 ended in live births and the 3 losses occurred in a patient not yet diagnosed; in the 4 pregnancies treated with CDCA there was no maternal neurological deterioration and no malformations, whereas maternal neurological decline, one case of spina bifida and cognitive impairment in the offspring occurred in untreated pregnancies [59]. In practice, the decision should be individualised and shared, with information on the risk of untreated disease and on the position of the European SmPC; the available human data, observational and few in number, have not identified teratogenicity [13, 14, 59]. There are no data on the passage of CDCA into human milk; the decision to breastfeed weighs the benefit to the child against the mother's need for treatment [13, 14].

7.10 Special populations and transition

In infants with cholestasis, bile acid treatment was effective when the cholestasis did not resolve spontaneously, and the European SmPC does not establish safety before 1 month of age [10, 13]. In renal or hepatic impairment there are no data and the SmPC recommends monitoring and individual titration; no adjustment is needed in the elderly [13]. Transition from paediatric to adult care should maintain follow-up at a specialist centre (one visit a year) and locally (two visits a year), as recommended by the Delphi consensus for children and adults [11]. The sources consulted do not describe specific perioperative recommendations; the interaction with ciclosporin and sirolimus is relevant in transplant recipients [13].

7.11 Agents to avoid

GeneReviews advises caution with statins because of the muscle risk [1]. The European SmPC advises against co-administration with ciclosporin, sirolimus, phenobarbital and oral contraceptives and recommends separating in time the intake of bile acid sequestrants and of antacids containing aluminium or smectite [13]. Ursodeoxycholic acid does not replace CDCA [10]. The French PNDS accepts ursodeoxycholic acid only as a temporary measure in infantile cholestasis while awaiting confirmation of a synthesis defect, and not as monotherapy, because it exerts no feedback on cholesterol 7α-hydroxylase and does not reduce atypical metabolites [60].

8. Reproductive Options and Family Counselling

8.1 Recurrence risks

CTX is transmitted in an autosomal recessive manner [1]. The parents of a patient are presumed to be heterozygous, and GeneReviews recommends testing both to confirm the phase of the variants and allow a reliable estimate of recurrence risk; if only one parent is a carrier and paternity and maternity are confirmed, one of the variants may have arisen de novo in the patient or in a mosaic parent, and in apparent homozygosity an undetected deletion or uniparental isodisomy should be considered [1]. When both parents are heterozygous, each sibling of the patient has, at conception, a 25% chance of being affected, a 50% chance of being an asymptomatic carrier and a 25% chance of inheriting neither of the familial variants [1]. The children of a patient are obligate heterozygotes; their risk of having CTX depends on the partner's status, and is higher when the partner belongs to a population with founder variants, such as the Druze or Jews of Moroccan origin [1]. Each sibling of the patient's parents has a 50% chance of being a carrier [1].

Table 8.1 — Recurrence risks by scenario

8.2 Cascade testing and asymptomatic relatives

GeneReviews recommends clarifying the genetic status of apparently asymptomatic older and younger siblings, in order to start CDCA as early as possible and organise surveillance: molecular testing if the familial variants are known, or plasma cholestanol if they are not [1]. This recommendation is clinical and not merely reproductive in nature, because presymptomatic treatment appears to prevent the manifestations and because an affected sibling may be milder, have later onset and lack xanthomas [1]. In the French series, the diagnosis of an index case led to the diagnosis of a sibling in three of ten families [9]. Testing asymptomatic minors with a 25% risk of being affected is justified in this context by the direct therapeutic benefit [1, 11]. Carrier testing in relatives requires prior identification of the familial variants [1].

8.3 High-risk populations and carrier screening

The Delphi consensus recommends premarital genetic counselling in high-risk populations, such as people of Israeli or Moroccan origin (75% agreement), and the authors mention Moroccan Jews and the Druze community of the Middle East, noting that feasibility should be weighed against the high frequency of other recessive diseases in these populations [11]. In a screening programme in a Druze village in northern Israel, 1425 residents accepted testing between 2003 and 2007, the CTX carrier frequency was 1:11 and 10 couples at risk for four diseases were identified and offered prenatal diagnosis [77]. Hanson and Bonnen concluded that the carrier frequency in Ashkenazi Jews is comparable to that of diseases included in carrier screening panels for that population and that Sephardic and Ashkenazi Jews could benefit from newborn and carrier screening [35].

8.4 Prenatal and preimplantation diagnosis

With both pathogenic variants identified, prenatal diagnosis and preimplantation genetic testing are possible [1]. The discussion should ideally take place before pregnancy, and GeneReviews recommends offering genetic counselling to young adults who are affected, carriers or at risk of being carriers [1]. The decision is personal and should take into account that CTX has effective treatment when started early, which weighs in the assessment made by families and professionals [1, 11]. Testing of the at-risk newborn, by cholestanol or bile alcohols and for the familial variants, allows treatment to begin in the first months, a strategy considered the most beneficial in the Delphi consensus [1, 11]. In probands without a molecular diagnosis, GeneReviews suggests considering DNA banking [1].

8.5 Women with CTX who wish to become pregnant

Preconception counselling should address the risk to the offspring, the choice of non-oral contraception during treatment (recommendation of the European SmPC) and the divergent positions on CDCA in pregnancy described in section 7.9, including the adverse outcomes described in untreated pregnant women with elevated cholestanol [1, 13, 59].

9. Special Considerations: Population Diversity and Epidemiology

9.1 What the estimates measure

Frequency estimates for CTX are of three types and should not be confused: the number of patients described in the literature (more than 400 worldwide in 2021, about 70 in Latin America in 2026), prevalences calculated from carriers in a small sample (1/50,000 in white people, from one carrier of the R362C variant among 115 controls) and genetic prevalences calculated by the Hardy-Weinberg principle from the frequency of pathogenic variants in population databases [8, 11, 27, 33]. The latter depend on the pathogenicity criteria (for example, inclusion of missense variants predicted as pathogenic by algorithms or of frequent variants such as NM_000784.4:c.1151C>T p.(Pro384Leu) or c.1148T>A p.(Met383Lys), the latter classified in ClinVar as of uncertain significance), assume complete penetrance and measure the expected frequency of genotypes, not the prevalence of diagnosed disease [4, 8, 32]. The gap between the two quantities is interpreted by the authors as evidence of underdiagnosis [8, 36].

Table 9.1 — Frequency estimates for CTX

9.2 Geographical distribution and founder populations

The largest groups of patients have been described in Italy, the Netherlands, Germany, Japan, China, Turkey, Israel and Spain [1]. In Israel, the high frequency of the disease was recognised before the gene was cloned; the variants c.819del and c.845-1G>A were identified in Moroccan Sephardic Jews, c.1016C>T in Algerian, Moroccan and Tunisian Jews, and c.355del in a Druze village with consanguinity estimated at 47% [4, 35]. In Ashkenazi Jews, gnomAD analysis identified c.845-1G>A (26 in 29,606 alleles, against 12 in 1,180,032 in Europeans), c.1184G>A and c.1321C>T [35]. In Spain, the variant p.Arg395Cys predominates in the north-west and p.Arg405Trp in the south, suggesting regional founder effects [28]. In Sardinia, the variant p.Arg479Cys was found in two consanguineous families, without data allowing conclusions on its frequency on the island [4]. The variant p.Arg395Cys is the most frequent in Europeans and Latin Americans, p.Gly472Ala and c.1184+1G>A in Asians and p.Arg127Trp in Africans/African Americans, among whom there are no published patients with this variant, which suggests underdiagnosis [4, 8].

9.3 United States and Europe

In the USA, with about 336 million inhabitants in 2024 and an estimate of 1/72,000 to 1/150,000, 2000 to 4000 patients would be expected, a number far higher than that of described cases [55]. The American multicentre prevalence study in juvenile cataracts (26 centres, 2015–2017, 442 participants in the final registry, 4 with a positive genetic test) and the research expanded newborn screening programmes are the main early detection initiatives [54, 58]. In Europe, the largest treatment cohorts come from the Netherlands (56 to 79 patients followed for decades), Italy, France and Turkey (86 patients in a national study) [17, 48, 66, 76]. The Dutch newborn screening study of 20,076 blood spots demonstrated technical feasibility with standard equipment [12].

9.4 Portugal and Brazil

In the sources consulted, no prevalence data or patient series from Portugal were found; a 49-year-old woman of Portuguese and Cape Verdean ancestry, followed in the USA, has been described with compound heterozygosity for Gly112Glu, now NM_000784.4:c.434G>A p.(Gly145Glu), and a 5-nucleotide deletion [5, 32, 37]. In Portugal, Ácido quenodesoxicólico Leadiant® is authorised but with no marketed presentations in Infomed [71]. In Brazil, the multicentre cohort from six reference centres (2020–2023) included 38 patients from 26 families from four regions, with 13 CYP27A1 variants (3 novel); the most frequent initial symptoms were cataract (27%), xanthomas (24%), chronic diarrhoea (13.5%) and developmental delay (13.5%), and walking was lost on average 10 years after neurological onset [38]. Eleven Brazilian patients with published individual data are included in the Latin American review, and in Ceará CTX accounted for 10.5% of recessive ataxias in a region of high consanguinity [27, 56]. Brazilian centres in Fortaleza, São Paulo and Porto Alegre took part in the RESTORE trial [64]. ANVISA has no registration of CDCA, and access to treatment in Brazil is not documented in the sources consulted [72]. The absence of data in these sources does not demonstrate an absence of publications on Portuguese or Brazilian patients.

9.5 Latin America

The 2026 review brought together 34 Latin American patients (6 unpublished Mexican patients and 28 published from Brazil, Argentina, Chile, Colombia, Peru and Ecuador), with symptom onset at 9.2 ± 8.1 years, diagnosis at 41.7 ± 16.2 years and a mean delay of 31.6 years, earlier in onset and later in diagnosis than in other regions; the variant c.1183_1184insT was the most frequent and CDCA, used in 13 patients, was associated with clinical improvement in 9 [27].

9.6 Special populations

Children diagnosed by family screening or because of cataract, pregnant women and patients with liver disease or transplant recipients form groups with specific needs, described in sections 7.9 and 7.10 [13, 59].

9.7 European reference networks and patient associations

The relevant European reference network is MetabERN (inherited metabolic diseases), whose centres include departments with declared experience in CTX, such as that at the Pitié-Salpêtrière in Paris [15]. The neurological manifestations (ataxia, paraparesis, leukoencephalopathy) also fall within the scope of ERN-RND (rare neurological diseases), although a search of its website did not return a CTX-specific page [78]. Patient associations include the CTX Alliance, dedicated to education, support, advocacy and research, which organised a patient-focused drug development meeting, the United Leukodystrophy Foundation, Metabolic Support UK and the National Organization for Rare Disorders (NORD); the Myelin Disorders Bioregistry Project and the registry of the STAIR (Sterol and Isoprenoid Research) consortium of the Rare Diseases Clinical Research Network collect patient data [1, 16]. In France, infantile cholestases, including the neonatal presentations of bile acid synthesis defects, are managed by the coordinating reference centre for biliary atresia and genetic cholestases (Hôpital Bicêtre, AP-HP, Le Kremlin-Bicêtre), part of the FILFOIE health network (rare liver diseases of children and adults), with regional competence centres and the patient association Association maladies foie enfants (AMFE); the PNDS serves as the basis for the care protocol for exemption from co-payment as an off-list condition [60].

10. Illustrative Clinical Case

Degrassi and colleagues published in 2020 the case of a Caucasian girl with CTX diagnosed from neonatal cholestasis and treated from 8 months of age, with 13 years of follow-up [30]. Pregnancy and delivery were uneventful, birth weight was 3.100 kg and the non-consanguineous parents had no ophthalmological, neurological, cardiac or liver disease. The child, breastfed and with normal growth, was referred at 2 months for jaundice; examination showed marked jaundice and a slightly firm liver, palpable 2 cm below the costal margin, without dysmorphic features, steatorrhoea, choluria or acholia. On laboratory testing, total bilirubin was 13.56 mg/dL, conjugated bilirubin 8.79 mg/dL, AST 473 IU/L and ALT 530 IU/L, with normal GGT, alkaline phosphatase, serum bile acids and INR; ophthalmoscopic examination and abdominal ultrasound were normal. Supplementation with vitamins A, D, E and K was started at 2 months. After the main causes of neonatal cholestasis had been excluded, percutaneous liver biopsy showed non-specific hepatocellular cholestasis, with marked lobular disarray, giant cells and bile pigment in hepatocytes, without ductular proliferation.

At 3 months ursodeoxycholic acid (15 mg/kg) was started; the jaundice slowly disappeared, with normal bilirubin at 6 months and normal transaminases at 8 months [30]. At 7 months, the combination of intrahepatic cholestasis with pigmented stools, absence of pruritus and normal GGT and serum bile acids led to suspicion of a bile acid synthesis defect: the urinary profile showed cholestanepentol glucuronide of 38.4 (ratio per mM of creatinine; normal 0.86) and serum cholestanol was 3140 ± 55, against a control value of 470, in the unit published by the authors (µg/dL) [30]. CYP27A1 analysis revealed homozygosity for a 1.9 kb deletion with loss of exons 7, 8 and 9; the authors do not give the HGVS nomenclature of the deletion [30].

Ursodeoxycholic acid was stopped and CDCA started at 8 months at a dose of 10 mg/kg/day, increased up to 15 mg/kg/day; plasma cholestanol fell steadily, from 3140 to 600 after 14 months of treatment [30]. Figure 2 of the article shows the course of cholestanol and urinary cholestanepentols over follow-up (https://pmc.ncbi.nlm.nih.gov/articles/PMC7381104/figure/F2/). Over 13 years, values remained normal with dose adjustments guided by plasma cholestanol and urinary cholestanepentols; liver tests were always normal, abdominal ultrasounds normal and transient elastography at 11 years showed normal liver stiffness (4.1 kPa). Annual electroencephalograms, neurological examinations and ophthalmoscopy and a brain MRI at 8 years showed no abnormalities, no xanthomas appeared and the child had normal growth, cognitive development, school results and physical performance, with no adverse effects of treatment [30].

The case illustrates the hepatic phase of CTX, normal GGT as a diagnostic clue and the spontaneous regression of cholestasis that may delay diagnosis [10, 30]. It also illustrates the aim of early treatment, consistent with the Delphi consensus, which regards starting at birth or at presymptomatic diagnosis as the most beneficial option [11]. Some aspects should not be taken as routine: the ursodeoxycholic acid used initially has no efficacy in CTX; the CDCA dose (10 to 15 mg/kg/day from 8 months) is within the GeneReviews range but above the starting dose of 5 mg/kg/day in the European SmPC, which recommends titrating up to a maximum of 15 mg/kg/day; and cholestanol of 600 at 22 months still exceeded the control value given by the authors [1, 10, 13, 30]. The absence of manifestations at 13 years is an individual result and does not establish preventive efficacy, which rests on the cohorts described in section 7 [17, 48].

11. Prognosis and Long-Term Follow-up

11.1 Prognosis

Without treatment, CTX progresses to increasing neurological disability, and death usually occurs between 30 and 60 years of age from neurological dysfunction or myocardial infarction [10]. In the Brazilian series, loss of walking occurred on average 10 years after the onset of neurological symptoms [38]. The prognosis with treatment depends mainly on age and on the extent of neurological injury when CDCA is started, factors ranked first and second in the Delphi consensus [11]. In the Dutch cohort of 56 patients, all patients with good adherence treated before 24 years became free of neurological symptoms or did not develop them, whereas 61% of those treated after that age deteriorated [17]. In the French cohort, there was improvement in patients up to 25 years of age treated less than 15 years after neurological onset and deterioration when treatment began more than 25 years after onset [44]. In the Turkish study of 86 patients, all those diagnosed before 28 years stabilised or improved, and treatment was also beneficial in patients diagnosed later; longer diagnostic delay, anxiety and pyramidal and cerebellar signs were associated with a worse course [48]. In the Spanish series, the spinal form had a less severe prognosis and five patients died 1 to 4 years after diagnosis despite treatment [28].

MRI provides prognostic markers: cerebellar vacuolation was associated with worsening and poorer response, absence of dentate nucleus changes with a better prognosis, and increasing atrophy or signal changes accompany clinical deterioration [11, 65]. In the 7- to 27-year follow-up of 12 Dutch patients, changes progressed in the 7 diagnosed at 24 years or older and in only 1 of 5 diagnosed earlier; in the others, an MRI that was normal at diagnosis remained normal for more than 25 years [66]. In the French cognitive impairment cohort, dementia after 50 years occurred only in patients with late treatment and marked cerebral atrophy [40]. Cholestanol at diagnosis does not predict outcome, and the biochemical response is not always accompanied by clinical improvement [11, 28, 48].

11.2 Initial assessment

After diagnosis, GeneReviews recommends: lipid profile with plasma cholestanol; baseline electromyography and nerve conduction studies; cardiological assessment with electrocardiogram and echocardiogram; bone densitometry; ophthalmological examination; baseline neurological and neuropsychiatric assessment; genetic counselling; and assessment of family and social support needs [1]. The Delphi consensus adds brain MRI at diagnosis and includes liver function tests in surveillance, and the FDA label requires transaminases and bilirubin before starting CDCA [11, 14].

11.3 Surveillance

Surveillance recommendations differ between sources. The Delphi consensus, the only source with formal consensus, recommends for children plasma cholestanol and liver tests 1 to 2 times a year and neurological (and neuropsychological if needed) assessment twice a year, and for adults cholestanol, liver tests and neurological assessment once a year; in the early phases of treatment, it recommends assessing, in children, the nervous, ocular and enterohepatic systems and cognitive performance 1 to 2 times a year, and in adults, once a year, also the cardiovascular and skeletal systems; annual MRI and annual urinary bile alcohols did not reach consensus [11]. GeneReviews proposes annual surveillance with cholestanol, neurological and neuropsychological assessment, brain MRI, echocardiogram and densitometry [1]. The European SmPC requires cholestanol and/or bile alcohols every 3 months until metabolic control and, thereafter, cholestanol, bile alcohols and liver function at least once a year, with more frequent checks during rapid growth, intercurrent illness and pregnancy [13]. The FDA label requires annual transaminases and bilirubin [14]. In patients treated with cholic acid, the Cholbam® label provides for monthly liver tests in the first 3 months, every 3 months for the next 9 months, every 6 months for 3 years and annually thereafter [74]. The consensus also recommends one visit a year to a specialist centre and two visits a year to a local centre [11].

Table 11.1 — Surveillance in CTX

12. Summary and Final Considerations

Cerebrotendinous xanthomatosis is an autosomal recessive inborn error of bile acid synthesis caused by biallelic CYP27A1 variants that abolish or reduce the activity of mitochondrial sterol 27-hydroxylase. The lack of chenodeoxycholic acid removes the feedback on cholesterol 7α-hydroxylase and diverts precursors towards the formation of cholestanol and bile alcohols, which are deposited in the lens, tendons, arteries, bone and nervous system. The disease begins in childhood, with transient neonatal cholestasis, chronic diarrhoea, bilateral juvenile cataract and learning difficulties, and progresses, in the absence of treatment, to tendon xanthomas, spastic paraparesis, ataxia, neuropathy, epilepsy, cognitive decline, psychiatric disorders and late parkinsonism, with death between 30 and 60 years of age. Diagnosis is made on average two to three decades after the first symptoms, and the xanthomas that give the disease its name are absent in many patients.

Elevated plasma cholestanol with normal or low cholesterol and increased urinary bile alcohols point to the diagnosis, which is confirmed by CYP27A1 sequencing with deletion analysis; hypomorphic forms with normal cholestanol exist, and oxysterols are emerging as complementary markers. Idiopathic juvenile cataract reveals CTX in about 1.5% to 1.8% of cases studied, and newborn screening by cholestanetetrol glucuronide in dried blood spots has shown feasibility in research studies in the USA and the Netherlands, with no national programme implemented.

Chenodeoxycholic acid, 750 mg per day in adults and 5 to 15 mg/kg/day in children according to the European SmPC (10 to 20 mg/kg/day according to GeneReviews), is the first-line treatment and should be maintained for life. The Dutch, French and Turkish cohorts show that treatment started before neurological damage is established, usually before 24 to 28 years of age, stabilises or reverses symptoms and prevents new ones from appearing, whereas late treatment stabilises only some patients; the only randomised trial demonstrated the biochemical dependence on CDCA in adults. The drug has been authorised in the EU since 2017 for all ages from 1 month and in the USA since 2025 for adults; in Portugal it is authorised but not marketed and in Brazil it has no registration, and its price led to hospital production of compounded capsules in the Netherlands. Cholic acid and statins are alternatives with limited evidence, and pregnancy is a point of divergence between the European SmPC and the other sources, with recent observational data favouring continuation of treatment.

Surveillance rests on plasma cholestanol, liver tests and neurological assessment, at six-monthly to annual intervals, and on follow-up by teams with neurology, metabolic medicine and ophthalmology. Testing of asymptomatic siblings and counselling of populations with founder variants allow patients to be identified at the stage when treatment has the greatest effect.

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