The official journal of the Japan Atherosclerosis Society andthe Asian Pacific Society of Atherosclerosis and Vascular Diseases

Review

J Atheroscler Thromb, 2021; 28: 905-925. http://doi.org/10.5551/jat.RV17055

Cerebrotendinous Xanthomatosis: Molecular Pathogenesis, Clinical
Spectrum, Diagnosis, and Disease-Modifying Treatments
Shingo Koyama 1, Yoshiki Sekijima 2, 3, Masatsune Ogura 4, Mika Hori 5, Kota Matsuki 6, Takashi Miida 7 andMariko Harada-Shiba 8 on behalf of the Committee on Primary Dyslipidemia under the Research Programon Rare and Intractable Disease of the Ministry of Health, Labour and Welfare of Japan†
1

Division of Neurology and Clinical Neuroscience, Department of Internal Medicine III, Yamagata University Faculty of Medicine,
Yamagata, Japan2
Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan
3
Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan
4
Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
5
Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
6
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Aomori, Japan
7
Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
8
Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan†The Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable Disease of the Ministry of
Health, Labour and Welfare of Japan: Mariko Harada-Shiba (Department of Molecular Pathogenesis, National Cerebral andCardiovascular Center Research Institute, Osaka, Japan), Shun Ishibashi (Division of Endocrinology and Metabolism, Department
of Internal Medicine, School of Medicine, Jichi Medical University, Tochigi, Japan), Shinji Yokoyama (Institute for Biological
Functions, Chubu University, Aichi, Japan), Hitoshi Shimano (Department of Internal Medicine (Endocrinology and Metabolism),
Faculty of Medicine University of Tsukuba, Tsukuba, Japan), Koutaro Yokote (Department of Endocrinology, Hematology andGerontology, Chiba University Graduate School of Medicine, Chiba, Japan), Hideaki Bujo (Department of Clinical-Laboratory andExperimental-Research Medicine, Toho University Sakura Medical Center, Chiba, Japan), Shizuya Yamashita (Rinku General
Medical Center, Osaka, Japan), Kazuhisa Tsukamoto (Department of Internal Medicine, Teikyo University, Tokyo, Japan), Toshio
Hayashi (School of Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan), Katsunori Ikewaki (Divisionof Neurology, Anti-Aging, and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Saitama,
Japan), Takanari Gotoda (Department of Metabolic Biochemistry, Faculty of Medicine, Kyorin University, Tokyo, Japan), Kazushige
Dobashi (Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan), Yoshihiro Miyamoto (Open
Innovation Center, National Cerebral and Cardiovascular Center, Osaka, Japan), Misa Takegami (Department of Preventive
Medicine and Epidemiology, National Cerebral and Cardiovascular Center, Osaka, Japan), Yoshiki Sekijima (Department ofMedicine (Neurology & Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan), Yasushi Ishigaki (Division of
Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan), Hiroaki
Okazaki (Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan),Atsushi Nohara (Ishikawa Prefectural Central Hospital, Kanazawa, Japan), Shingo Koyama (Division of Neurology and Clinical
Neuroscience, Department of Internal Medicine III, Yamagata University Faculty of Medicine, Yamagata, Japan), Kyoko Inagaki(Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Nippon Medical School, Tokyo, Japan), Koh
Ono (Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan), Masahiro Koseki(Division of Cardiovascular Medicine, Department of Medicine, Osaka University Graduate School of Medicine, Osaka, Japan),
Hiroyuki Daida (Faculty of Health Science, Juntendo University, Juntendo University Graduate School of Medicine, Tokyo, Japan),
Manabu Takahashi (Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University,
Tochigi, Japan), Kimitoshi Nakamura (Department of Pediatrics, Kumamoto University Graduate School of Medical Sciences,
Kumamoto, Japan), Takashi Miida (Department of Clinical Laboratory Medicine, Juntendo University Graduate School of
Medicine, Tokyo, Japan), Masa-aki Kawashiri (Department of Cardiovascular Medicine, Graduate School of Medical Sciences,
Kanazawa University, Kanazawa, Japan), Tetsuo Minamino (Department of Cardiorenal and Cerebrovascular Medicine, Faculty of
Medicine, Kagawa University, Kagawa, Japan), Sachiko Okazaki (Division for Health Service Promotion, The University of Tokyo,
Tokyo, Japan), Hayato Tada (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences,
Kanazawa, Japan), Jun Wada (Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan), Masatsune Ogura (Division of Lipid
Metabolism, Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute,
Osaka, Japan), Hirotoshi Ohmura (Department of Cardiovascular Medicine, School of Medicine, Juntendo University, Tokyo,
Japan), Mika Hori (Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya,Japan), Kota Matsuki (Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki,

905

Koyama et al .

Japan), Masashi Yamamoto (Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of
Medicine, Chiba, Japan), Yasuo Takeuchi (Division of Nephrology, Kitasato University School of Medicine, Kanagawa, Japan),
Atsuko Nakatsuka (Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate
School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan), Daisaku Masuda (Department of Cardiology,
Health Care Center, Rinku Innovation Center for Wellness Care and Activities (RICWA), Rinku General Medical Center, Osaka,
Japan), Satoshi Hirayama (Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo,
Japan), Masayuki Kuroda (Center for Advanced Medicine, Chiba University Hospital, Chiba University, Chiba, Japan), Takashi
Yamaguchi (Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Chiba, Japan), Takeyoshi
Murano (Clinical Laboratory Program, Faculty of Science, Toho University, Chiba, Japan).

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder caused bymutations in the CYP27A1 gene, which encodes the mitochondrial enzyme sterol 27-hydroxylase. Decreased
sterol 27-hydroxylase activity results in impaired bile acid synthesis, leading to reduced production of bile acids,
especially chenodeoxycholic acid (CDCA), as well as elevated serum cholestanol and urine bile alcohols. The
accumulation of cholestanol and cholesterol mainly in the brain, lenses, and tendons results in the characteristic
clinical manifestations of CTX. Clinical presentation is characterized by systemic symptoms including neonatal
jaundice or cholestasis, refractory diarrhea, juvenile cataracts, tendon xanthomas, osteoporosis, coronary heartdisease, and a broad range of neuropsychiatric manifestations. The combinations of symptoms vary from patientto patient and the presenting symptoms, especially in the early disease phase, may be nonspecific, which leads toa substantial diagnostic delay or underdiagnosis. Replacement of CDCA has been approved as a first-line
treatment for CTX, and can lead to biochemical and clinical improvements. However, the effect of CDCA
treatment is limited once significant neuropsychiatric manifestations are established. The age at diagnosis andinitiation of CDCA treatment correlate with the prognosis of patients with CTX. Therefore, early diagnosis andsubsequent treatment initiation are essential.
Key words: Cerebrotendinous xanthomatosis, CTX, CYP27A1, Cholestanol, Chenodeoxycholic acid

Introduction
Cerebrotendinous xanthomatosis (CTX:OMIM#213700), first described by van Bogaert et al.
in 1937, is a rare autosomal-recessive lipid storage
disease caused by deficiency of the mitochondrial
cytochrome P 450 enzyme, sterol 27-hydroxylase(CYP27A1, EC 1.14.15.15) due to mutations in the
CYP27A1 gene 1). Clinical presentation is characterized
by neonatal jaundice or cholestasis, refractory diarrhea,
juvenile cataracts, tendon xanthomas, osteoporosis,
coronary heart disease, and progressive neuropsychiatricdisturbances including mental retardation ordementia, psychiatric symptoms, pyramidal andcerebellar signs, progressive myelopathy, peripheral
neuropathy, extrapyramidal manifestations, andseizures 2-9). CTX is associated with considerable
variability in clinical manifestations among patientsand even within the same family 2). The broad anddiverse clinical symptoms cause a substantial
diagnostic delay 2-4, 9). Replacement treatment withchenodeoxycholic acid (CDCA) in the early stage ofthe disease has been reported to improve or evenprevent clinical symptoms of CTX 10, 11); however, after
significant neurological pathology is established, theeffect of the treatment is limited and deterioration ofclinical manifestations may continue 3, 8, 12, 13). Therefore,
it is crucial to treat CTX patients at the initial stage ofthe disease. In this article, we provide the current
understanding of the underlying pathomechanisms,
clinical manifestations, diagnosis, and treatment of
CTX.
Pathophysiology
CTX is caused by mutations in the CYP27A1
gene encoding sterol 27-hydroxylase, a key enzyme in
the bile acid synthesis pathway. A schematic

Address for correspondence: Yoshiki Sekijima, Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan
E-mail address: sekijima@shinshu-u.ac.jp
Received: March 17, 2021
Accepted for publication: March 21, 2021
Copyright©2021 Japan Atherosclerosis Society
This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

906

Cerebrotendinous Xanthomatosis

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Fig. 1. Impaired bile acid synthesis in cerebrotendinous xanthomatosis (CTX)
In CTX, mutations in the CYP27A1 gene lead to sterol 27-hydroxylase deficiency, resulting in reduced production of chenodeoxycholic acidand upregulation of the rate-limiting enzyme in the bile acid synthesis pathway, cholesterol 7α-hydroxylase. Increased levels of serum
cholestanol and urinary bile alcohols are biological markers in CTX. HMG-CoA: 3-hydroxy-3-methylglutaryl-CoA.

representation of the bile acid synthesis pathway isshown in Fig. 1. The classical pathway is initiated by
7α-hydroxylation of cholesterol, catalyzed by the ratelimiting enzyme cholesterol 7α-hydroxylase. The
alternative pathway is initiated by 27-hydroxylation ofcholesterol, which is catalyzed by sterol 27-hydroxylase.
Decreased activity of sterol 27-hydroxylase leads toimpaired bile acid synthesis in both the classical andalternative pathways 14), resulting in reduced productionof bile acids, especially CDCA, and to a lesser extent
cholic acid 15). The absence of a negative feedback
effect of CDCA on cholesterol 7α-hydroxylase
accelerates these metabolic abnormalities, leading toincreased levels of the bile acid intermediate 7α-hydroxy-4-cholesten-3-one as a precursor forcholestanol and bile alcohols 16). Elevated serum
cholestanol and urine bile alcohols are the biochemical
diagnostic hallmarks in CTX. Consequently, increasedcholesterol metabolites, such as cholestanol,
accumulate mainly in the brain, lenses, and tendons,leading to the characteristic clinical manifestations of
CTX. Elevated levels of cholestanol have been foundin the serum and tissues, including those of the central
nervous system, tendon xanthomas, and atheromatous
lesions, in CTX patients. Although the cholestanol-tocholesterol ratios of various tissues were higher thanthat of serum, cholesterol was more abundant thancholestanol in both serum and tissues 17). Cholestanol
is widely used as a diagnostic marker but theusefulness of 7α-hydroxy-4-cholesten-3-one
907

Koyama et al .

quantification in both the diagnosis and monitoringof CTX has also been reported 18). It has also beenshown that quantification of a panel of plasma
ketosterol bile acid precursors (7α-hydroxy-4cholesten-3-one, 7α,12α-dihydroxy-4-cholesten-3one, and 7α,12α-dihydroxy-5β-cholestan-3-one)
provides a more sensitive biochemical approach whencompared with measurement of cholestanol 19).
In 1968, Menkes et al. discovered accumulationof cholestanol and cholesterol in the cerebrum andcerebellum of patients with CTX 20). Although themechanism by which cholestanol accumulates in thebrain remains unclear, one possible explanation is thatthe bile acid precursor 7α-hydroxy-4-cholesten-3-one,
which passes through the blood-brain barrier (BBB)
more efficiently than cholestanol, can be converted tocholestanol by neurons, astrocytes, microglia, andhuman monocyte-derived macrophages 21, 22). Anotherpossible explanation is impairment of the BBB.
Increased levels of cholestanol and apolipoprotein B
were observed in the cerebrospinal fluid of patientswith CTX, indicating disrupted function of the
BBB 23). It has also been proposed that large plasma
bile alcohol glucuronides play a role in the abnormal
BBB permeability in CTX, leading to increasedtransport of cholestanol and cholesterol in the brain 24).
Although the major pathway for production ofcholestanol in CTX has been clarified, little is known
about its metabolism. Under normal conditions, the
7α-hydroxy-4-cholesten-3-one-dependent pathway
accounts for only about 30% of cholestanol
biosynthesis in the brain, and cerebral cholestanol ismainly formed from cholesterol 25). Using Cyp27a1
and Cyp46a1 knockout mice, Mast et al. demonstrated
that CYP46A1 plays an important role in cholestanol
removal from the brain and that CYP27A1 deficiency
results in a preferential increase in cholestanol in the
cerebellum 25).
CTX patients develop premature atherosclerosis
and xanthomas despite normal serum cholesterol
concentrations. However, abundant deposits ofcholesterol are detected in addition to cholestanol in
the respective lesions in CTX 17). Although themechanism leading to premature arteriosclerosis andtendon xanthomas in CTX remains unclear, reduced
capacity for reverse cholesterol transport has been
proposed as a possible cause 26-31). Sterol 27-hydroxylase,which is expressed in macrophages, endothelial cells,
and tenocytes as well as in the liver, seems tocontribute to the transport of peripheral cholesterol to
the liver by transforming intracellular cholesterol into
27-hydroxycholesterol, which has a higher capacity forpassing through lipophilic membranes compared withcholesterol 26-28). In addition, 27-hydroxycholesterol is908

an endogenous ligand for liver X receptor (LXR). LXR
activation induces upregulation of ATP-binding
cassette transporter A1 (ABCA1) expression, leading
to increased cholesterol efflux 29-31). Fu et al.
demonstrated that upregulation of ABCA1 in responseto cholesterol loading was impaired in primary
fibroblasts derived from a CTX patient 29). In addition,
since 27-hydroxycholesterol was found to be the major
oxysterol in human atherosclerotic lesions 28) ,extrahepatic sterol 27-hydroxylase is thought to be ananti-atherosclerotic enzyme. Absence of the two above
defense mechanisms may contribute to prematureatherosclerosis and xanthoma formation in CTX.
Epidemiology
CTX patients have been reported worldwide but
prevalence of the disease is considered to beunderestimated 32). Based on the carrier frequency ofthe pathogenic CYP27A1 c.1183C ＞ T (p.R395C)
mutation in 115 control subjects, the prevalence of
CTX in the USA among Caucasians of European
ancestry was estimated to be 3-5:100,000
individuals 32). Pilo-de-la-Fuente et al. estimated aminimum prevalence of 1/1,8000,000 individuals in
Spain 3). Estimates of the incidence of CTX vary
among locations. A recent genetic epidemiologicalstudy based on the Exome Aggregation Consortium(ExAC) cohort, a large cohort of over 60,000
unrelated subjects, evaluated the allele frequency of 57
known and 29 predicted CTX-causing variants andestimated the incidence of CTX to be 1:134,9701:461,358 in Europeans, 1:263,222-1:468,624 in
Africans, 1:71,677-1:148,914 in Americans, 1:64,2471:64,712 in East Asians, and 1:36,072-1:75,601 in
South Asians 33). Prevalence among Jews of Moroccan
origin and the Druze sect in Israel has been reported
to be particularly high 34, 35).
Molecular Genetics
In 1991, human sterol 27-hydroxylase cDNA
was isolated from a liver cDNA library. The CYP27A1
gene consists of nine exons and eight introns andspans 18.6 kb of DNA on chromosome 2q33-qter 36, 37).
Sterol 27-hydroxylase consists of a 33-residue
mitochondrial signal sequence followed by a mature
protein of 498 amino acids containing putative
binding sites for heme and adrenodoxin 1). Cali et al.
first identified two CYP27A1 missense mutations,p.R395C and p.R479C, in patients with CTX anddemonstrated that a loss-of-function mechanism is
responsible for CTX 1).
CYP27A1 is the only gene known to be

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Fig. 2. Representative clinical course of classical form CTX
Figure shows typical ages of onset of CTX-related symptoms.

associated with CTX. Therefore, the diagnostic gold
standard is genetic analysis of the CYP27A1 gene 4, 38).
The diagnosis is confirmed by the presence of biallelicpathogenic CYP27A1 mutations 4, 38). To date, over 99
pathogenic mutations, including missense mutations,nonsense mutations, splice-site mutations, andinsertion/deletion mutations, have been reported
worldwide 6). A relatively high frequency of CYP27A1
mutations in particular ethnic groups has beenreported: c.1016C ＞ T (p.T339M), c.1183C ＞ T (p.
R395C), and c.1263＋1G ＞ A in the Netherlands 13),c.646G ＞ C (p.A216P), c.1183C ＞ T (p.R395C),
c.1184 ＋1G ＞ A, c.1263 ＋1G ＞ A, and a 1.9 kb
deletion including exons 7-9 in Italy 38), c.1183C ＞ T(p.R395C) in northwestern Spain and c.1213C ＞ T(p.R405W) in southern Spain 3), c.1214G ＞ A (p.
R405Q), c.1421G ＞ A (p.R474Q), c.435G ＞ T (p.
G145 = ), and c.1420C ＞ T (p.R474W) in Japan 9),
which seems to be reasonable considering the allele
frequency reported in the ExAC 33). The allele
frequencies of these variants in six global populations
according to the ExAC database (version 0.3) are
shown in Supplementary Table 1. Although no
genotype-phenotype correlation has been reported 2, 3, 13),
our nationwide survey revealed possible associations
between c.1421G ＞ A (p.R474Q) and classical form
CTX, c.1241G ＞ A (p.R405Q) and spinal form CTX,
and c.435G ＞ T (p.G145 = ) and non-neurologicalform CTX despite considerable phenotypic variation
among patients with the same genotype 9).

Clinical Features
Clinical Phenotypes
Clinical presentation of CTX is characterized bydiverse systemic and neuropsychiatric manifestations
and combinations of symptoms vary from patient topatient. Systemic symptoms include neonatal jaundiceor cholestasis, chronic diarrhea, juvenile cataracts,
xanthomas, osteoporosis, and coronary heart disease.
The neurological and psychiatric manifestations of
CTX vary widely. Intellectual disability as well as
pyramidal and cerebellar signs are the most frequent
and are cardinal clinical features 2-4, 7, 9). In addition,
CTX patients can present with extrapyramidal
manifestations, peripheral neuropathy, epilepsy, andpsychiatric disturbances. Autonomic involvement has
also been reported 39).
A representative clinical course of classical form
CTX, the most common form of this condition, isshown in Fig. 2. Patients with classical form CTX
develop neuropsychiatric symptoms attributed to the
cerebrum, cerebellum, and/or brainstem, in
combination with various systemic manifestations.
The concept of spinal form CTX, also called spinal
xanthomatosis, was proposed by Virrips et al. in 1999 40).
Patients exhibit clinical symptoms and signs related to
involvement of the corticospinal tracts and dorsal
columns of the spinal cord, without intellectual
impairment, cerebellar signs, or peripheral neuropathy,
at the time of presentation of the spinal cord
syndrome 40). Although most patients with spinal form
909

Koyama et al .

CTX also exhibit various systemic and neurologicalsymptoms, spinal form CTX without otherneurological manifestations has been reported 41-46).
Spinal form CTX has a relatively mild clinical course
compared with classical form CTX 40).
We have proposed non-neurological form CTX 9)
as another clinical phenotype. Although patients with
the non-neurological form may develop neurologicalsymptoms later in life, two genetically confirmed
CTX patients in their fifties showed no evidence ofneurological manifestations ≥ 20 years after disease
onset. Therefore, we regarded the non-neurologicalform as a distinct clinical phenotype of CTX 9).
All CTX patients exhibit increased serum
cholestanol levels at the time of diagnosis 2-4, 9). While asignificant relationship between serum cholestanol
and clinical phenotype or disability was not detected 3),
Sekijima et al. showed that classical form patients had
significantly higher levels of cholestanol than spinal
form patients 9).
Systemic Manifestations/Neonatal Jaundice or
Cholestasis
Prolonged neonatal jaundice or cholestasis could
be the earliest clinical presentation of CTX 47).
Laboratory findings have revealed conjugatedhyperbilirubinemia with raised transaminases andalkaline phosphatase, whereas levels of γ-glutamyltransferase were normal or minimally elevated 47-50),
which is the characteristic feature of inborn errors ofbile acid synthesis 51). In one study, hepatomegaly or
hepatosplenomegaly was evident 50). Liver biopsy
specimens have revealed nonspecific chronic active
hepatitis with giant cell transformation, piecemeal or
focal bridging necrosis, and fibrosis, in addition to
intralobular cholestasis 47-50). Cirrhosis was detected in
an explanted liver 50). In addition, retrospective cohort
studies have demonstrated that about 8–16% of
patients had a past medical history of neonatalcholestatic jaundice 4, 13, 47). Furthermore, family
histories have revealed fetal deaths or jaundice-related
infantile deaths among siblings of affectedindividuals 47).
Von Bahr et al. described a patient withgenetically confirmed CTX who had fatal cholestatic
liver damage 48). Recently, Gong et al. reported oneight patients who presented with neonatal cholestasis.
Among their cohort, this was fatal in four and one
underwent liver transplantation. Although neonatalcholestasis associated with CTX has been generally
assessed as transient and self-limiting with patient
survival, a substantial proportion of patients could
experience a more severe clinical course thanpreviously recognized 50). The mechanism by which
910

mutations in the CYP27A1 gene lead to cholestasis
may involve nuclear receptors such as farnesoid X
receptor (FXR). CDCA is a potent stimulator of
FXR 52). Marked reduction of CDCA in CTX leads todecreased activation of FXR, which results in reduced
expression of the bile salt export pump, causing adecrease in canalicular bile salt transportation 48, 52).
Systemic Manifestations/Chronic Diarrhea
Chronic unexplained diarrhea begins in infancy
and continues into adulthood 2). It may be the earliest
symptom of CTX and could start within the first yearof life 53). Gastrointestinal tract investigations inpatients with diarrhea did not produce any abnormal
findings 54). Also, rectal biopsy did not demonstrate
any accumulation of cholestenol or cholesterol andfatty acids could not be detected in the feces 54).
Usually, diarrhea ceases immediately after starting
treatment with CDCA 11). Although the pathogenesisof diarrhea is still unclear, presence of bile alcohol in
the lumen of the gut and/or intraluminal deficiency of
CDCA are the most likely causes 54).
Systemic Manifestations/Ocular Manifestations
Juvenile cataracts are one of the earliest clinicalsigns and often precede tendon xanthomas andneurological symptoms, and are usually noted in thesecond decade of life. Lens nuclei from CTX patients
had a greater cholestanol content compared with thesenile lens nuclei used as a control 55). Althoughstabilization of cataracts with CDCA treatment has
been reported 11), complete resolution is unlikely 56) andoperations should be considered. Early onset ofcataracts is uncommon and therefore, juvenile
cataracts are arguably an important cue for early
diagnosis of CTX. A screening for CTX among 170
patients with idiopathic bilateral cataracts diagnosed
between the ages of 2 and 21 years identified 3cases 57).
In addition to cataracts, ophthalmologicalmanifestations include optic neuropathy with optic
disc paleness, premature retinal vessel sclerosis, andcholesterol-like deposits 58). Optic neuropathy withfeatures suggestive of optic neuritis has also beenreported 59).
Systemic Manifestations/Xanthomas
Xanthomas usually appear during the second or
third decade of life. They typically occur on the
Achilles tendon, but may be found on the elbow,
neck, knee, and the bottom of the foot (Fig. 3). The
patellar and finger extensor tendons are also common
sites for development of tendon xanthomas 60-64).
Xanthomas in the lung 65) and choroid plexus have also

Cerebrotendinous Xanthomatosis$%

Fig. 3. Xanthomas in a patient with CTX
Figure shows xanthoma on the knee (A) and one on the Achilles
tendon (B).

been reported 60, 66, 67). It is noteworthy that presence ofxanthomas is a characteristic feature of the disease, but
it is not mandatory for CTX diagnosis 68). Biopsy
specimens of xanthomas show lipid crystal clefts with
infiltration of foamy macrophages 64, 69). In gallium-67
scintigraphy, there can be abnormal uptake in Achilles
tendons 70), even if Achilles tendon xanthomas were
not evident in a physical examination or on MRI 44).
In addition, positron emission tomography (PET)
using 18F-2-deoxy-2-fluoro-glucose (FDG) showedabnormally high radioactivity in the Achilles tendonsand adjacent regions 5). Although CDCA treatment
does not significantly reduce tendon xanthomas 10), a
decrease in size has been reported in some subjects 71, 72).
Systemic Manifestations/Skeletal System Involvement
Osteoporosis and increased bone fractures are
CTX-associated systemic manifestations. However,the underlying pathogenesis of osteoporosis in thiscondition is still unknown. Decreased levels of serum
25-hydroxyvitamin D were detected in CTX
patients 73-75). In contrast, however, Federico et al.
reported that levels of 25-hydroxyvitamin D were
substantially within the normal range 76), indicatingthat a deficiency in vitamin D metabolites may not be
the only factor responsible for the development of
osteoporosis in CTX 74). An alternative hypothesis for
explaining the cause of osteoporosis is impairment ofintestinal calcium absorption due to changes in thequantity and composition of bile acids 76). In general,
osteoporosis has been considered to occur in the laterstages of the disease 4, 9). However, teenage CTX
patients could have early osteoporosis and a history ofbone fracture 77). CDCA treatment has been shown to

improve bone mineral density (BMD) 74, 76).
Skeletal deformities including kyphosis, pectus
excavates, pes equinovarus, and pes cavus were foundin CTX patients 77) and Ginanneschi et al. reported
that pes cavus occurrence was not significantly
different in groups with and without peripheral nerve
abnormalities 78).
Systemic Manifestations/Cardiovascular System
Involvement
Premature atherosclerosis and cardiovasculardisease have been reported as systemic manifestations
in CTX patients even in their thirties 79-82). Myocardial
infarction is a cause of premature death in thiscondition 82). Kuriyama et al. reviewed 144 cases of
CTX and reported that 15 patients (10.4%) had
cardiovascular disease, consisting of coronary arterydisease in ten patients, ischemic changes onelectrocardiogram in four, and mitral valve
insufficiency in one patient 79). Coronary artery disease
was evident in 8 of 40 CTX patients (20%) in anationwide survey on CTX in Japan 9). In this survey,
the mean age at onset of coronary artery disease was
52.5.±5.8 years (mean±standard deviation (SD)) 9).
Duell et al. reported that 3 of 43 CTX patients (7%)
had premature cardiovascular disease, consisting of
myocardial infarction in two patients, and angina
pectoris in one patient in the USA 8). Abdominal aortic
aneurysm, coronary artery dissection, aneurysmal
coronar y ar ter y disease, advanced carotid
atherosclerotic lesions, and thickening of theinteratrial septum compatible with lipomatous
hypertrophy have also been reported in CTX 81, 83-86).
Systemic Manifestations/Pulmonary Involvement
Elevated levels of cholestanol in bronchoalveolar
lavage fluid as well as in serum have been reported in
CTX patients without pulmonary symptoms, orradiological and pulmonary function abnormalities.
Transbronchial lung biopsy specimens have revealed
foamy macrophages and small granulomas in alveolar
septa 87).
Neuropsychiatric Manifestations/Intellectual
disability
Among CTX patients, 48–74% present withintellectual disability 2-4, 9), which is one of the mostfrequent neurological symptoms. It is particularly
important to take developmental delays, mental
retardation, and learning difficulties beginning inchildhood into consideration for early diagnosis of
CTX 2-4, 7, 9, 53). Cognitive decline, presenting inadolescence or early adulthood, is also frequently
observed 2, 3, 9). Although a neuropsychological profile911

Koyama et al .

of patients with CTX remains undetermined, afronto-temporal dementia phenotype exhibiting
behavioral and personality changes 88), extensive
cerebral cortex symptoms including left-rightdisorientation, constructional apraxia, and temporaland spatial disorientation in addition to frontal lobe
dysfunction 89), and a corticobasal syndrome phenotype 90)
have been reported.
Neuropsychiatric Manifestations/Pyramidal andCerebellar Signs
Pyramidal and/or cerebellar signs typicallyemerge in the third or fourth decade and lead to gait
disturbance in CTX patients 2, 4, 9). Pyramidal andcerebellar signs have been detected in 64–92% and
36–83% of patients with CTX, respectively 2-4, 9).
Pyramidal signs such as spasticity, hyperreflexia, andextensor plantar response can be cardinal clinical signs
especially in patients with spinal form CTX 40-46).
Owing to dorsal column involvement, simultaneous
occurrence of impaired position and vibration
sensation in the lower extremities can lead to spasticataxic gait in this form 41, 45). Mignarri et al. havereported the usefulness of transcranial magnetic
stimulation in detecting corticospinal tract damage 91).
Cerebellar signs include nystagmus, ataxic dysarthria,
as well as limb and truncal ataxia 69, 92-94). Pyramidal
signs frequently coexist with cerebellar signs 2, 3).
Neuropsychiatric Manifestations/Extrapyramidal
Manifestations
CTX patients can present with a wide range ofmovement disorders including parkinsonism 90, 95, 96),
dystonia 97-99), myoclonus 98, 100, 101), and postural
tremor 100, 102). When movement disorders are
diagnosed, patients have a tendency to present withother CTX-associated systemic and neuropsychiatricmanifestations 103). Parkinsonism usually occurs laterin life 7, 95, 103) and is the most frequently reported typeof movement disorder in CTX, followed by dystonia,
myoclonus, and postural tremor 103). Parkinsonism
seems to be a treatment-resistant feature in CTX 13),with CDCA treatment seemingly having no effect. In
addition, CTX patients may develop parkinsonism
during treatment with CDCA 103). The effect of
L-dopa is controversial 90, 95, 103-105). In addition to thecharacteristic brain MRI findings of CTX, signal
hyperintensities on T2-weighted images in thesubstantia nigra, globus pallidus, and striatum 90, 95, 96, 103)
have been described and functional dopaminergic
imaging has demonstrated a pre-synaptic dopaminergicd e f i c i t i n C T X p a t i e n t s p re s e n t i n g w i t hparkinsonism 90, 95, 96, 104, 105). Although movement
disorders are considered a late disease manifestation,
912

Zubarioglu et al. reported that all six patients who
were diagnosed before 18 years of age had intention
tremor 77).
Neuropsychiatric Manifestations/Peripheral Nervous
System Involvement
Peripheral neuropathy is an established clinicalfeature of CTX; however, it is still being debatedwhether the underlying pathogenesis of CTX-related
polyneuropathy is demyelinating or axonal in origin.
Based on the presence of onion bulbs, which are
generally considered a hallmark of chronic
demyelination, the pathological process has beeninterpreted as demyelinating 106, 107). On the other
hand, Verrips et al. reported that axonal degeneration
was the predominant process on the basis of nerve
conduction velocity (NCV) studies and sural nerve
biopsy specimens showing features of axonal
degeneration 108). In addition to axonal polyneuropathy
and demyelination polyneuropathy, a mixed type ofneuropathy has been reported, indicating that CTX
could exhibit any type of neuropathy 109). CTX-related
polyneuropathy seems to be predominantly motor
neuropathy 78, 109). Although neurophysiologicallyconfirmed neuropathy frequently occurs in CTX,
signs and symptoms related to polyneuropathy areoften absent or difficult to appreciate because central
nervous system involvement may dominate the clinicalpicture 4, 78, 109). The disease severity of polyneuropathy
varies greatly among patients, ranging from asymptomaticpresentations to severe polyneuropathy 78, 109, 110).
Thickening of the nerve roots and trunks of thelumbosacral plexus or cauda equina has beenreported 90, 111).
Neuropsychiatric Manifestations/Muscle Involvement
Controversy exists regarding whether muscle
involvement is a characteristic feature in CTX.
Federico et al. noted mild myopathic changes 112),
while Verrips et al. reported that muscle biopsies
demonstrated neurogenic changes without any
definite myopathic characteristics 108). The results for
mitochondrial respiratory chain enzymatic activity arealso controversial 108, 113). Abnormal findings fromultrastructural studies of muscles include changes in
the mitochondria and membranous system, and anincreased amount of lipid droplets, lipofuscin, andglycogen; however, the significance of these findings
remains to be determined 39, 108, 112).
Neuropsychiatric Manifestations/Epilepsy
In CTX, 10–33% of patients have epileptic
seizures 2-4, 7, 9). Epilepsy can develop at any stage in life
and is often seen in the early phase of the disease 7).

Cerebrotendinous Xanthomatosis

Epilepsy could be a diagnostic cue in some cases 114-116).
A CTX patient presenting with infantile spasms has
also been reported, but this is a rare case 117).
Electroencephalographic abnormalities are frequently
observed in cases of CTX even without clinical signsof seizures 11, 118). In addition to slow background
activity composed of theta and delta waves, bursts ofhigh voltage slow activity are frequently demonstrated.
Spike and sharp wave complexes can also be
detected 10, 11, 118) . CDCA treatment leads toimprovement or normalization of electroencephalographic
findings 10, 11, 60, 118), and epilepsy in CTX seems to
respond well to anti-epileptic agents 12, 114-116, 119).
CDCA treatment could lead to improved seizure
control 12, 60, 120), even in patients with drug-resistant
epilepsy 121).
Neuropsychiatric Manifestations/Behavioral
manifestations
Psychiatric and behavioral manifestations include
personality changes with irritability and aggressivity,
depression, delusional syndrome, catatonia, psychosis,
attention-deficit hyperactivity disorder, oppositionaldefiant disorder, and autism spectrum disorder 13, 122).
Behavioral disorders and affective/mood disorders
associated with learning difficulties or mental
retardation appearing during childhood or adolescenceshould lead to biochemical investigations to exclude
CTX.

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Radiological, Pathological, andNeurophysiological Examinations
Neuroimaging
The most distinctive neuroradiological findings
are signal hyperintensities on T2-weighted and/or
FLAIR images in the dentate nuclei and adjacentcerebellar white matter 123, 124). Abnormal signal
changes in the dentate nuclei can be more clearly
detected on FLAIR images than on T2-weighted
images 123). It was found that abnormal hyperintensities
on T2-weighted and/or FLAIR images could be
detected in the globus pallidus, internal capsule,
substantia nigra, cerebral peduncles, inferior olive, andperiventricular white matter, with a tendency to spare
the U-fibers and corpus callosum 125). Supratentorial
and/or infratentorial atrophy are also observed 123, 124, 126)
(Fig. 4). Cortical volume, rather than white mattervolume, was correlated with clinical status and cortical
atrophy could be detected in all neocortical regions,with a preference for the fronto-parietal cotrtex 126). In
addition, cerebellar vacuolation, which is detected as
hypointense lesions on both T1-weighted and FLAIR
images, has been recently indicated as a marker of a

Fig. 4. Brain magnetic resonance imaging (MRI)
Axial T2-weighted images of the brain showing abnormal
hyperintensities in the globus pallidus (arrows in B), internal
capsules (arrowheads in B), cerebral peduncles (arrows in C), anddentate nuclei (arrows in D). Diffuse cerebral (A) and cerebellar(D) atrophy are evident. Sagittal T2-weighted image of the spinal
cord exhibiting longitudinally extensive hyperintense lesions(arrows in E). Axial T2-weighted image at the C3 level showing
involvement of lateral corticospinal tracts (arrowheads in F) andgracile tracts (arrow in F).

poor prognosis in CTX 127, 128), while absence ofdentate nuclei signal alteration is considered anindicator of a better prognosis 128). Furthermore,calcifications were detected in the dentate nuclei in a
subgroup of patients 128) and the hot cross bun sign inthe pons, a characteristic finding of multiple system
atrophy, has been reported 69).
In patients with spinal cord involvement, a spinal
cord MRI demonstrated longitudinally extensive
913

Koyama et al .

hyperintense lesions involving lateral corticospinal
tracts and gracile tracts on T2-weighted images 40, 44-46).
It is noteworthy that absence of signal changes on
spinal cord MRI cannot rule out the possibility ofspinal form CTX 42, 43).
On magnetic resonance spectroscopy (MRS),
decreases in N-acetylaspartate (NAA) intensities andincreases in lactate signals point to axonal damage andbrain mitochondrial dysfunction, respectively 123). In
addition to decreased NAA intensities, lipid peaks
were evident on MRS using a short TE 129). Increased
levels of myo-inositol indicate gliosis and astrocytic
proliferation 129, 130).
Cerebellar glucose hypometabolism in 18F-2deoxy-2-fluoro-glucose positron emission tomography(FDG-PET) and cerebellar hypoperfusion in single
photon emission computed tomography (SPECT)
with 99mTc-ethylcysteinate dimer (ECD) have beenreported despite normal cerebellar morphology 88, 131, 132).
In addition to in the cerebellum, SPECT using 99mTcECD and 123I-N-isopropyl-p-iodoamphetamine (123IIMP) revealed cerebral hypoperfusion, predominantlyin the fronto-parietal lobes 88, 89, 132). Gray matter
atrophy patterns were correlated with hypoperfusion
in SPECT using 99mTc- ECD 133).
Diffusion tensor imaging (DTI) revealed thatfractional anisotropy (FA) reduction preceded
structural alterations detected by voxel-based
morphometry and correlated with cognitive
function 133). Widespread reductions of FA anddecreased track-density were demonstrated 120, 134).
Neuropathology
At macroscopic examination, nonspecific brain
and cerebellar atrophy and a yellowish soft tissue inthe cerebellum, cerebrum, choroid plexus, cerebral
peduncles, and globus pallidus were observed 135-138). In
the cerebral peduncles, cystic necrosis of thecorticospinal tracts has been reported 139). Microscopic
examinations have revealed lipid crystal clefts,
neuronal loss, demyelination, reactive astrocytosis, andfoamy macrophages in the affected regions, especiallyin the dentate nucleus and surrounding area, as well as
in the cerebrum, basal ganglia, brainstem, and, spinal
cord 65, 124, 135-139). In patients with spinal cord
involvement, extensive symmetric loss of myelin andaxons was detected particularly in the lateral
corticospinal tracts and gracile tracts of the spinal
cord 40).
Neurophysiological Examinations
In addition to NCV studies andelectroencephalography, abnormalities have beenfound in neurophysiological examinations. The P100
914

peak latency of visual evoked potentials (VEPs) was
delayed 109, 140, 141) and the Ⅰ to Ⅲ , Ⅲ to Ⅴ , and Ⅰ
to Ⅴ interpeak latencies of brain stem evoked potentials(BAEPs) were prolonged 109, 140, 141). Central conduction
time in somatosensory evoked potentials (SSEPs) 109, 142)
and motor evoked potentials (MEPs) 89, 91, 141) wereincreased, with lower extremity predominance.
Diagnosis
Importance of Early Diagnosis and Treatment
CTX is a treatable metabolic disorder; however,once significant neurological symptoms are
established, clinical deterioration can occur despite
normalization of cholestanol levels after treatment
with CDCA 3). Even with therapy, only 28% of thepatients remained stable, whereas 60% continued todeteriorate and 20% died, in a cohort of 25 patientswith CTX in Spain 3). Duell et al. reported that clinicaldeterioration during follow up was observed inpatients who had significant neurological symptoms
when they were diagnosed at the age of 25 years orolder 8). Yahalom et al. and Stelten et al. have shownthat the age of diagnosis and initiation of CDCA
treatment correlates with the prognosis of patientswith CTX 12, 13). Berginer et al. reported two siblings
with CTX who began CDCA treatment from 2 and 7
years of age, respectively, and did not develop any
neurological manifestations during a 14-year follow-up
period 142). These findings strongly suggest that early
diagnosis and treatment are crucial in CTX. However,retrospective cohort studies on CTX have revealed asubstantial diagnostic delay of 15–25 years 2-4, 9).
Juvenile cataracts are usually the earliest clinicalsign that precedes tendon xanthomas and neurologicalsymptoms. Cruysberg et al. emphasized that the
combination of juvenile cataracts and chronic diarrhea
is noteworthy in the early diagnosis of CTX 143). It is
recommended that all patients with cataracts before
the age of 30 years are screened for CTX, especially ifthey also have CTX-related conditions such as chronic
diarrhea, tendon xanthomas, and/or neuropsychiatric
symptoms 8). Verrips et al. emphasized that presence oftendon xanthomas is not obligatory for a diagnosis of
CTX and recommended that presence of two of thefour clinical features of premature cataracts, intractablediarrhea, progressive neurological signs and symptoms,
and tendon xanthomas prompt thorough biochemical
screening for CTX 68). It is also important to consider
intellectual disability, usually presenting at school age,for early diagnosis of CTX 4). In addition, because
affected relatives may be asymptomatic, biochemical
examination of all siblings of a patient with CTX isrecommended 2, 4).

Cerebrotendinous Xanthomatosis

Table 1. Diagnostic criteria for cerebrotendinous xanthomatosis (Sekijima et al.9))
A. Symptoms
1. Tendon xanthoma
2. Progressive neurological dysfunction a or mental retardation
3. Juvenile cataract
4. Juvenile coronary artery disease
5. Chronic unexplained diarrhea
6. Juvenile osteoporosis
7. Prolonged neonatal cholestasis
B. Biochemical finding
Elevated serum cholestanol level
C. Genetic testing
Pathogenic mutation in CYP27A1 gene (homozygosity or compound heterozygosity)
D. Differential diagnosis
Increased serum cholestanol level due to following diseases should be excluded· Familial hypercholesterolemia· Sitosterolemia· Obstructive biliary tract disease· Hypothyroidism
Diagnostic category
Definite: At least one of symptom in A and B+C+D
Probable: At least one of symptom in A and B+D
Possible: At least one of symptom in A and B
a
Representative progressive neurological dysfunction includes cognitive dysfunction, cerebellar symptoms, pyramidal
symptoms, extrapyramidal symptoms, seizure, peripheral neuropathy, and sensory disturbance attributed to spinal cord.

To identify and treat CTX patients at an initialstage of the disease, Mignarri et al. created a suspicion
index and developed a diagnostic algorithm for early
diagnosis of CTX 4). Their suspicion index comprised
weighted scores assigned to indicators such as family
history characteristics and common systemic andneurological symptoms. They suggested that their
proposed algorithm would be useful for early
diagnosis, even in patients before the onset of
disabling neurological symptoms including ataxia,
spasticity, and psychiatric disturbances 4).
Diagnostic Criteria
In the absence of generally accepted diagnostic
criteria for CTX, we recently proposed new diagnostic
criteria with emphasis on early diagnosis (Table 1) 9).
They include clinical symptoms, biochemical findings,
genetic analysis, and differential diagnosis. We
established three diagnostic categories in accordancewith levels of certainty: definite, probable, andpossible CTX. The diagnosis of possible CTX is madewhen there is at least one CTX-related clinicalsymptom and elevated levels of serum cholestanol (≥4.5 µg/mL, mean ±SD: 2.35 ±0.73 µg/mL).
Excluding other conditions with elevated levels ofcholestanol is necessary for diagnosis of probable
CTX. A definite diagnosis of CTX is confirmed by

the presence of biallelic mutations in the CYP27A1
gene.
Differential Diagnosis
Differential diagnosis of CT X differs
substantially according to presenting symptoms.
Inborn errors of bile acid metabolism including CTX
lead to neonatal cholestasis or hepatitis 144, 145), which
can be the first manifestation in this disease. In
patients with juvenile bilateral cataracts and/or
progressive mental deterioration, CTX should beconsidered 2, 57). When xanthomas are evident,
differential diagnosis includes familial hypercholesterolemia(FH) and sitosterolemia. FH is characterized byelevated levels of LDL cholesterol, the presence oftendon xanthomas, and premature coronary arterydisease, and mutations in LDLR, APOB, and PCSK9
have been reported to cause FH 146). Sitosterolemia is
an autosomal recessive sterol storage disordercharacterized by elevated levels of LDL cholesterol andplant sterols such as sitosterol and campesterol,tendinous and tuberous xanthomas, and prematureatherosclerosis. It is caused by biallelic mutations ineither ABCG5 or ABCG8 147). The presence of juvenile
cataracts, chronic unexplained diarrhea, andprogressive neuropsychiatric manifestations candistinguish CTX from these two disorders. Other915

Koyama et al .

conditions with elevated levels of cholestanol include
obstructive biliary tract diseases and hypothyroidism.
In patients with cerebellar ataxia, CTX patients might
be misdiagnosed as spinocerebellar atrophy, multiple
system atrophy, or Marinesco-Sjögren syndrome 68).
CTX should be included in the differential diagnosisof spastic paraplegia 42, 44).
Clinical Management
CDCA has been approved as first-line treatment
for CTX. In a landmark study published in 1984,
Berginer et al. demonstrated the long-term efficacy oforal CDCA treatment 10). In addition to a decrease inserum cholestanol and elimination of abnormal urinary
and biliary excretion of bile alcohols, CDCA treatment
led to an improvement in electroencephalographic
findings and neurological manifestations including
intellectual impairment, pyramidal and cerebellar
signs, and peripheral neuropathy 10, 11). CDCA
treatment is recommended at a dose of 750 mg/day
for adults and 15 mg/kg/day for children in three
divided oral doses 10, 11). It has been shown to result ina gradual decline in serum cholestanol during the first
2 years 148, 149). Assessment of cholestanol levels may be
useful in monitoring patient adherence to treatment.
However, it should be noted that a decreased level ofcholestanol does not necessarily suggest a good
prognosis 3). In Japan, CDCA has been approved for
dissolution of gallstones, but not for the treatment of
CTX.
Although CDCA is a relatively safe drug,
gastrointestinal manifestations and drug-induced liver
damage may occur 44, 60, 150). Huidekoper et al. reported
an infantile patient with CTX who developed jaundicewith hepatomegaly within 6 weeks after initiating
CDCA administration at a dosage of 15mg/kg/day 151).
After treatment with CDCA was stopped, liver sizea n d f u n c t i o n r a p i d l y n o r m a l i ze d . C D C A
supplementation was then restarted and maintained at
5 mg/kg/day with no further evidence of liver
dysfunction and adequate metabolic control. Duell et
al. reported that 9% of patients required dose
adjustment for CDCA owing to moderate druginduced liver damage 8). These findings suggest thatclinical and laboratory monitoring and dosage
adjustment for CDCA are essential in the treatmentof CTX, especially in infants and young children 8, 151).
CDCA was initially preferred to cholic acidbecause it was more effective in reducing cholesterol
7α-hydroxylase and had a stronger negative feedback
effect on it 127, 152). Cholic acid has been shown to beeffective in the treatment of other genetic defects inbile acid synthesis 153). Since CDCA is intrinsically916

hepatotoxic, cholic acid is considered the safer optionin CTX, especially in infancy 49). Mandia et al.
reported potential efficacy for cholic acid in adultpatients with CTX, including individuals whose
CDCA treatment was discontinued due to supply
difficulties 127). Treatment with cholic acid not only
significantly reduced cholestanol levels in all patients
but also led to improvement or stabilization ofsystemic and/or neurological manifestations 127). No
adverse effects were reported in patients undergoingcholic acid treatment, suggesting that cholic acid may
be a suitable alternative treatment, especially inpatients with adverse effects related to CDCA, such as
drug-induced liver damage 60, 127).
Treatment with ursodeoxycholic acid, which does
not inhibit cholesterol 7α-hydroxylase, has beenshown to be ineffective 10, 154). When ursodeoxycholicacid was substituted for CDCA, plasma cholestanol
returned to pretreatment levels 10).
The effectiveness of 3-hydroxy-3-methylglutaryl(HMG)-CoA reductase inhibitors (statins) remains
controversial. Lewis et al. reported that mevinolinnormalized serum cholestanol and reduced the size ofxanthomas 155), whereas Batta et al. found that
lovastatin did not affect abnormal bile acid synthesisor reduce plasma cholestanol levels 154). Althoughsynergistic effects of combination therapy with CDCA
and HMG-CoA reductase inhibitors on serum
cholestanol or urine bile alcohols have been
observed 71, 81, 149), absence of an additive effect has also
been reported 148). After switching from combined
therapy of CDCA and HMG-CoA reductase inhibitors
to HMG-CoA reductase inhibitor monotherapy,
clinical symptoms such as xanthomas and neurologicalmanifestations, and electroencephalographic findings
were re-exacerbated with reappearance of abnormal bilealcohol excretion or elevated plasma cholestanol 71, 156).
Therefore, HMG-CoA reductase inhibitors could be
beneficial when combined with CDCA, but long-termclinical benefits should be proven.
Low-density lipoprotein (LDL) is a major carrierof serum cholestanol. LDL-apheresis, usuallycombined with CDCA and HMG-CoA reductase
inhibitors, has been performed to reduce serum
cholestanol 157-160) Levels of serum cholestanol or 7α-hydroxy-4-cholesten-3-one decreased after each LDLapheresis, but returned to their initial levels within
1–2 weeks 159, 161), suggesting that LDL-apheresis at afrequency of at least once every 2 weeks is necessary.
The effects of LDL-apheresis on clinicalmanifestations are still controversial despite thedecrease in cholestanol. In addition, the invasivenessof this procedure and its necessity for the long-term
management of the disease should be taken into

Cerebrotendinous Xanthomatosis

account 161).
Symptomatic treatments for epilepsy 115, 120),
psychiatric manifestations 122), and movement disorders
such as dystonia 97, 98) and parkinsonism 90, 95) should beconsidered. Cataract extraction is also usuallyrequired 57).
After treatment with CDCA, improvements inneurophysiological examinations including NCV
studies 78), VEP 72, 78), SSEP 72), MEP 72, 91), and EEG 10, 11)have been reported. Besides conventional MRI, DTI
and tractography, MRS, and SPECT imaging might
have potential as neuroimaging modalities formonitoring treatment response 120, 132-134, 162, 163).
Conclusions and Perspectives
CTX is considered a rare inherited metabolic
disorder. However, it may be under- or misdiagnosed,
although effective treatment is available. There is a
crucial “point of no return” in CTX, after which
treatment initiation can no longer prevent the
progression of the disease 12). The earlier the diagnosis
is made and the sooner treatment is started, the more
likely it is that the significant neurologicalmanifestations that diminish the quality of life ofpatients with CTX can be improved or evenprevented. Neonatal jaundice, chronic unexplained
diarrhea, developmental delays, mental retardation,and learning difficulties are non-specific symptoms,
but they could be diagnostic cues for pediatricians.
Ophthalmologists have an opportunity to diagnose
CTX, because bilateral cataracts are one of the earliest
clinical symptoms and juvenile-onset bilateral cataracts
could be useful as a screening marker for CTX 57).
Furthermore, it could be beneficial to screen newborns
for CTX in the future 164).
Acknowledgments andNotice of Grant Support
This work has been supported by Health, Labourand Welfare Sciences Research Grant for Research on
Rare and Intractable Diseases (H30-nanji-ippan-003).
Conflicts of Interest
Atsushi Nohara has nothing to disclose. Hayato
Tada has nothing to disclose. Masatsune Ogura hasreceived honoraria from Amgen Inc., Astellas Pharma
Inc. Sachiko Okazaki has received scholarship grants
from Minophagen Pharmaceutical Co., Ltd., Kowa
Company, Ltd. Koh Ono has nothing to disclose.
Hitoshi Shimano has nothing to disclose. Hiroyuki
Daida has received honoraria from Amgen Inc.,

Daiichi-Sankyo Co., Ltd., Kowa Co., Ltd., and MSD
K.K., Novartis Pharma K.K., Bayer Yakuhin, Ltd. andreceived clinical research funding from Canon Medical
Systems Corporation, Philips Japan, Ltd., Toho
Holdings Co., Ltd., Asahi Kasei Corporation, andInter Reha Co., Ltd. HD has also received scholarshipgrants from Nippon Boehringer Ingelheim Co., Ltd.,
Otsuka Pharmaceutical Co., Ltd., Sanofi K.K., MSD
K.K., Daiichi-Sankyo Co., Ltd., Pfizer Co., Ltd.,
Mitsubishi Tanabe Pharma Corp., Astellas PharmaInc., Takeda Pharmaceutical Co., Ltd., Teijin Pharma,
Ltd., Shionogi & Co., Ltd., Actelion Pharmaceuticals,Ltd., Actelion Ltd., Kowa Co., Ltd., Bayer Yakuhin,Ltd. HD has also courses endowed by companies,
including Philips Japan, Ltd., ResMed, Fukuda
Denshi Co., Ltd., and Paramount Bed Co., Ltd.
Kazushige Dobashi has nothing to disclose. Toshio
Hayashi has nothing to disclose. Mika Hori has
nothing to disclose. Kota Matsuki has nothing todisclose. Tetsuo Minamino has nothing to disclose.
Shinji Yokoyama has nothing to disclose. Mariko
Harada-Shiba has received stock holdings or options
from Liid Pharma, honoraria from Amgen Inc.,
Astellas Pharma Inc., Sanofi, and scholarship grants
from Aegerion Pharmaceuticals, Inc., Recordati Rare
Diseases Japan, and Kaneka Corporation. Katsunori
Ikewaki has nothing to disclose. Yasushi Ishigaki has
nothing to disclose. Shun Ishibashi has received
honoraria from Kowa Co., Ltd., and a scholarshipgrant from Ono Pharmaceutical Co., Ltd. Kyoko
Inagaki has nothing to disclose. Hirotoshi Ohmura
has nothing to disclose. Hiroaki Okazaki has received
scholarship grants from Minophagen PharmaceuticalCo., Ltd., Kowa Company, Ltd. Masa-aki Kawashiri
has nothing to disclose. Masayuki Kuroda has nothing
to disclose. Masahiro Koseki has received clinicalresearch funding from Kowa Company, Ltd., Rohto
Pharmaceutical Co., Ltd. Takanari Gotoda has
nothing to disclose. Shingo Koyama has nothing todisclose. Yoshiki Sekijima has nothing to disclose.
Manabu Takahashi has nothing to disclose. Yasuo
Takeuchi has nothing to disclose. Misa Takegami has
nothing to disclose. Kazuhisa Tsukamoto has received
honoraria from Bayer Yakuhin, Ltd., MSD Ltd.,
Takeda Pharmaceutical Company Ltd., andscholarship grants from Mitsubishi Tanabe Pharma
Corporation., Bayer Yakuhin, Ltd., Sanofi K.K.
Atsuko Nakatsuka has nothing to disclose. Kimitoshi
Nakamura has nothing to disclose. Satoshi Hirayama
has nothing to disclose. Hideaki Bujo has nothing todisclose. Daisaku Masuda has received clinical researchfunding from MSD K.K., Ono Pharmaceutical Co.,
Ltd., Takeda Pharmaceutical Co., Ltd., Kowa Co.,
Ltd. Takashi Miida has nothing to disclose. Yoshihiro
917

Koyama et al .

Miyamoto has nothing to disclose. Takeyoshi Murano
has nothing to disclose. Takashi Yamaguchi has
nothing to disclose. Shizuya Yamashita has received
honoraria from Kowa Company, Ltd., MSD K.K.
Masashi Yamamoto has nothing to disclose. Koutaro
Yokote has received honoraria from Kowa Company,
Ltd., MSD K.K., Astellas Pharma Inc., Mitsubishi
Tanabe Pharma Corp., Amgen K.K., Takeda
Pharmaceutical Company Limited, Sanofi K.K., Ono
Pharmaceutical Co., Ltd., AstraZeneca K.K., DaiichiSankyo Co., Ltd., Novartis Pharma K.K., Sumitomo
Dainippon Pharma Co., Ltd., Kyowa Kirin Co., Ltd.,
Pfizer Japan Inc., Novo Nordisk Pharma Ltd., Nippon
Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K.,
Taisho Pharmaceutical Co., Ltd., Janssen
Pharmaceutical K.K., and received clinical researchfunding from Taisho Pharmaceutical Co., Ltd. KY has
also received scholarship grants from Mitsubishi
Tanabe Pharma Corp., Takeda Pharmaceutical Co.,
Ltd., MSD K.K., Pfizer Japan Inc., Novo Nordisk
Pharma Ltd., Taisho Pharmaceutical Co., Ltd., Kao
Corporation, Ono Pharmaceutical Co., Ltd., Eli Lilly
Japan K.K., Sumitomo Dainippon Pharma Co., Ltd.,
Nippon Boehringer Ingelheim Co., Ltd., DaiichiSankyo Co., Ltd., Teijin Pharma, Ltd., Shionogi Co.,
Ltd., Bayer Yakuhin, Ltd. Jun Wada has nothing todisclose.
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Cerebrotendinous Xanthomatosis

Supplementary Table 1. Allele frequencies of CYP27A1 variants according to Exome Aggregation Consortium database (version 0.3)
variant
p.G145 =p.A216P
p.T339M
p.R395C
p.R405W
p.R405Q
p.R474W
p.R474Q
c.1184+1G ＞ A
c.1263+1G ＞ A

AFR

AMR

EAS

FIN

NFE

SAS

0.00000
0.00000
0.00000
0.000100.00000
0.000100.00000
0.00000
0.00000
0.00000

0.00000
0.00000
0.00000
0.000200.00009
0.00009
0.00000
0.00000
0.00000
0.00009

0.000400.00000
0.000100.00000
0.00000
0.000500.00000
0.000100.00000
0.000100.00000
0.00000
0.00000
0.000300.00000
0.00000
0.00000
0.00000
0.00000
0.00000

0.00000
0.00004
0.000020.000200.00000
0.00004
0.000020.000020.00006
0.000070.00000
0.00000
0.000070.00006
0.00006
0.00000
0.00000
0.00000
0.000700.00000

AFR: African; AMR: Admixed American; EAS: East Asian; FIN: Finnish; NFE: Non-Finnish European; SAS: South Asian.

925