Yanagihashi et al. BMC Neurology (2016) 16:21
DOI 10.1186/s12883-016-0542-2

CASE REPORT

Open Access

Late-onset spinal form xanthomatosis
without brain lesion: a case report
Masaru Yanagihashi1†, Osamu Kano1*†, Tomoya Terashima2†, Yuji Kawase1, Sayori Hanashiro1, Masahiro Sawada1,
Yuichi Ishikawa1, Nobuyuki Shiraga3, Ken Ikeda1 and Yasuo Iwasaki1

Abstract
Background: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive sterol storage disease caused by
a mutated sterol 27-hydroxylase (CYP27A1) gene. Patients with typical CTX show neurological dysfunction including
bilateral cataracts, paresis, cerebral ataxia, dementia, and psychiatric disorders, and magnetic resonance imaging
(MRI) has revealed symmetrical lesions in the cerebellar white matter.
Case presentation: We report the case of a patient with late-onset spinal form CTX without brain lesion. He showed
pyramidal tract signs, and impaired joint position and vibration sensation in the lower limbs. Cervical sagittal MRI
demonstrated a longitudinally extensive white matter abnormality in the dorsal column of the C2-C7 spinal cord;
however, a brain MRI revealed an absence of lesions, including in the cerebellar white matter. Genetic analysis of
CYP27A1 revealed that the patient was compound heterozygous for p.Gln85Arg in exon 1, a novel mutation, and
p.Arg405Gln in exon 7, a previously reported mutation.
Conclusion: This is the first report of late-onset spinal form CTX without typical neurological symptoms, and the
first report of p.Gln85Arg in CYP27A1. We speculate that spinal form CTX without brain lesion is a clinically and
radiologically rare variation of CTX. Therefore, spinal xanthomatosis should be included in the differential
diagnosis of chronic myelopathy even with late-onset and/or no other typical neurological findings.
Keywords: Cerebrotendinous xanthomatosis (CTX), Chenodeoxycholic acid (CDCA), Cholestanol, Cholic acid,
Spinal form CTX, Sterol 27-hydroxylase (CYP27A1)

Background
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease caused by a deficiency in sterol
27-hydroxylase (CYP27A1), a key enzyme in the synthesis of chenodeoxycholic acid (CDCA), a primary bile
acid. Deficiency of CYP27A1 and a lack of CDCA leads
to the accumulation of cholesterol and cholestanol [1].
Typical clinical manifestations of CTX include bilateral
cataracts and diarrhea in childhood [2] and progressive
neurologic dysfunction (cerebral ataxia, paresis, dementia, low intelligence, and psychiatric disorder), tendon
xanthoma, and atherosclerosis in adolescence and early
adulthood [3]. Brain magnetic resonance imaging (MRI)
typically reveals symmetrical lesions in the cerebellar
* Correspondence: osamukano@aol.com
†
Equal contributors
1
Division of Neurology, Department of Internal Medicine, Toho University
School of Medicine, 6-11-1 Omorinishi, Ota-ku, Tokyo 143-8541, Japan
Full list of author information is available at the end of the article

white matter; however, white matter lesion restricted to
the spinal cord are rare [4, 5].
In this paper, we report the case of a patient with predominantly spinal form of CTX, who had a clinical
course, radiological pattern, and genetic background distinct from that of typical CTX.

Case presentation
A 77-year-old Japanese man with no particular medical
history had observed thickening of the Achilles tendon
bilaterally and patellar tendon enlargement (Fig. 1) from
the age of 40. He reported paresthesia that began in the
legs and later spread to the arms. He was admitted to
Toho University Omori Medical Center for diagnosis a
progressively unsteady gait from the age of 65 years,
which was considered due to spinal ataxia. His father
had died of lung cancer and his mother of renal failure.
There was no family history (parents, siblings, or children) of CTX and his parents’ marriage was not

© 2016 Yanagihashi et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
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(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Yanagihashi et al. BMC Neurology (2016) 16:21

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Fig. 1 Thickening of bilateral Achilles tendon and patellar tendon enlargement

consanguineous. He was born in Japan and worked as a
public employee after graduating high school.

the lower extremities. After diagnosing spinal form
CTX, the patient was treated with 750 mg/day CDCA.

Clinical and laboratory examination

Genetic diagnosis

The deep tendon reflex in the lower limbs was hyperactive, and the Babinski reflex was present bilaterally.
Pain and temperature sensation was normal; however,
joint positioning and vibration sensation were impaired
in the lower extremities, and the Romberg sign was
present. General physical examination revealed no abnormalities, and he did not show signs of either dementia (his mini-mental state examination [6] score was 29)
or any psychiatric disorder. Cataracts were not observed
upon ophthalmologic examination.
Serum cholesterol and triglyceride levels were normal,
while cholestanol levels were elevated (10.4 μg/ml; normal,
3.3–5.6 μg/ml). Serum antinuclear antibody, anti-SSA antibody, vitamins B12 and E, folate, copper, lactic acid were
normal, syphilis and anti-aquaporin 4 antibody were negative and cerebrospinal fluid examinations were normal.
Brain MRI, including the images of the cerebellar
white matter, was normal; however, cervical sagittal T2weighted MRI revealed a high intensity area in the dorsal columns of the C2–C7 cervical cord (Fig. 2). Knee
axial and sagittal gadolinium-enhanced T1-weighted
MRI showed a low intensity area in the fringes and an
unbalance enhanced area in the center (Fig. 3). A nerve
conduction study and visual evoked potential were normal, but somatosensory evoked potential was absent in

Genomic DNA was isolated from the peripheral blood
leukocytes using a DNeasy blood and tissue kit (Qiagen,
Hilden, Germany), following the manufacturer’s instructions, and was used as a template for polymerase chain
reaction (PCR). All 9 exons of CYP27A1 were separately
amplified by PCR and their nucleotide sequences were
ascertained by direct nucleotide sequence analysis.
CYP27A1 analysis revealed two point mutations. One
was an A-to-G mutation in exon 1, resulting in an
amino acid substitution of Gln (CAG) to Arg (CGG) at
codon 254 (Q85R) (Fig. 4a), and the other was a G-to-A
mutation in exon 7, resulting in an amino acid substitution of Arg (CGG) to Gln (CAG) at codon 1214
(R405Q) (Fig. 4b). p.R405Q in CYP27A1 had previously
been reported in three siblings with CTX [7], and in
several Japanese CTX patients [5, 8]. p.Q85R had previously been reported as the first mutation identified in all
variations of CTX.

Conclusions
This spinal variant of CTX has a relatively mild course
as compared with the classic form of CTX, which shows
cerebellar involvement, dementia, tendon xanthoma formation, and peripheral neuropathy early in the disease
process. Although neurological symptoms in CTX are

Fig. 2 Magnetic resonance imaging of the patient. Brain axial MRI was normal, including images of the cerebellar white matter. However, cervical
sagittal (arrows) and axial (arrow head) T2-weighted MRI revealed a high intensity area in dorsal columns of the C2-C7 spinal cord

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Fig. 3 Gadolinium-enhanced T1-weighted magnetic resonance imaging Knee gadolinium-enhanced T1-weighted MRI showed a low-intensity area in
the outer regions (arrows) and a heterogeneously enhanced area in the central region (arrow heads)

often highly variable, most patients demonstrate cerebellar signs and mental retardation from a young age, as
well as familial history, dementia, juvenile cataracts, and
pyramidal tract lesion. However, in this case, it was important to exclude other diseases (Table 1) causing only

a

b

Fig. 4 CYP27A1 contained two point mutations. a. A-to-G mutation in
exon 1, resulting in an amino acid substitution of Gln (CAG) to Arg (CGG)
at codon 254 (Q85R). b. G-to-A mutation in exon 7, resulting in an amino
acid substitution of Arg (CGG) to Gln (CAG) at codon 1214 (R405Q)

myelopathy as no cerebral involvement was observed.
The spinal cord pathology was different from that seen
in multiple sclerosis, where a patchy, irregularly distributed involvement of the white matter is found, rather
than a symmetrical distribution as seen in this case.
Neuromyelitis optica is one of the differential diagnoses
in this case; however, the anti-aquaporin 4 antibody tests
were negative and optic neuritis was not observed. Hereditary spastic paraparesis is another differential diagnosis, and genetic testing would be needed if our case did
not show any abnormal spine lesions [9].
The spinal form CTX without cerebral involvement is
quite rare. Verrips et al. [4] reported seven Dutch patients from six families with a slowly progressing clinical
course. Post-mortem examination of one of the patients
showed extensive loss in the lateral and dorsal columns.
The onset in these patients was between the ages of 20
and 35 years. Abe et al. [5] also reported a Japanese
young-onset spinal form CTX. However, our patient
showed late-onset, and did not show any cerebral involvement in brain MRI findings even at the age of
77 years old.
Early diagnosis of xanthomatosis is crucial as treatment
with chenodeoxycholic acid can reduce plasma cholestanol level and may prevent disease progression [10], or
even reverse some of the neurological disabilities [11]. A
relatively high prevalence of CTX has been noticed in
Japan, compared to that in other countries [12].
When we performed mutational analysis of all 9
exons of CYP27A1 in our Japanese patient with lateonset xanthomatosis with longitudinally extensive
spinal cord lesion, we found one novel (Q85R) and
one previously reported CTX-associated missense mutation (R405Q). None of the patient’s immediate family members showed similar symptoms, and his
parents were not consanguineous. As they had not
demonstrated a similar condition prior to their
deaths, and as the patient’s siblings were not affected,

Yanagihashi et al. BMC Neurology (2016) 16:21

Table 1 Differential diagnosis of chronic myelopathy
(Intramedullary) based on MRI
Immune-mediated Behcet’s disease
Mixed connective tissue disease
Multiple sclerosis
Neuro-sarcoidosis
Paraneoplastic
Sjogren disease
Solitary sclerosis
Systemic lupus erythematosus
Infectious

Cysticercosis
Echinococcosis
Fungal
HTLV
HIV/AIDS
Schistosomiasis
Syphilis
Tuberculosis
Whipple’s disease

Vascular

Cavernous malformation
Spinal arteriovenous malformation

Congenital

Arachnoid cyst
Epidermoid cyst
Hypomyelination with brain stem and spinal cord
involvement and leg spasticity
Spinal xanthomatosis

Toxic/metabolic

Copper deficiency
Folic acid
Heroin
Konzo (cassava)
Neurolathyrism
Nitrous oxide toxicity
Radiation-induced
Vitamin B12 deficiency

Page 4 of 5

we assume that the patient’s parents were each heterozygous for one of the two mutations.
Residue Q85 in CYP27A1 is a well-conserved amino
acid, similar to R405, according to multiple sequence
alignments analysis (Consurf Server http://consurf.tau.ac.il/). The effect of the novel p.Q85R mutation
on the function of CYP27A1 was predicted to be
damaging as assessed a missence prediction tool,
Polymorphism Phenotyping v2 (PolyPhen-2 http://
genetics.bwh.harvard.edu/pph2/). Indeed, Q85 in
CYP27A1 plays an important role in protein folding
and binding with substrates, such as vitamin D3 [13].
Considering the impact of p.Q85R and p.R405Q on
clinical features, the compound heterozygosity of these
two mutations may have resulted in a mild pathological
change and late-onset of CTX, as compared to other
missense mutations in CYP27A1. Moreover, p.R405Q
may be associated with spinal form CTX, as a patient
with homozygous mutations of p.R405Q presented with
spinal form CTX [5].
Genetic testing in not readily available for diagnosing
spinal form CTX; therefore, the presence of xanthoma in
tendons and serum cholestenol levels should be assessed
when the patient presents with chronic myelopathy.
CTX is treated with CDCA and/or competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase to reverse the metabolic defect and prevent
neurological dysfunction. Previous reports have shown
that this treatment results in reduction of the serum
cholestenol level to less than 50 % of the pretreatment
levels [5]. Lewis et al. [14] reported that mevinolin normalizes serum cholestenol level within 4 days and reduces the size of the xanthoma. However, whether these
therapies will be effective for long-term prevention remains to be established.
Our results suggest that spinal form CTX should be
considered in the differential diagnosis of chronic myelopathy, and clinicians should check for the presence of
xanthomatosis in the tendons in such cases.

Vitamin E deficiency toxicity
Degenerative

Post-traumatic
Spondylotic myelopathy

Tumor/neoplasm

Astrocytoma
Ependymoma

Consent
We obtained written informed consent from the patient
for publication of this case report and any accompanying
images. A copy of the written consent is available for
review by the Editor-in-Chief of this journal.

Hemangioblastoma
Intravascular lymphoma
Metastases
Schwannoma
Spinal lymphoma
Other

Syringomyelia

Abbreviations
CDCA: Chenodeoxycholic acid; CTX: Cerebrotendinous xanthomatosis;
CYP27A1: Sterol 27-hydroxylase; MRI: Magnetic resonance imaging;
PCR: Polymerase chain reaction.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
Study concept and design: MY, OK. Acquisition of data: TT, MY, OK. Analysis
and interpretation of data: OK, TT, YK, SH, SM, YI, KI, YI. Drafting of the

Yanagihashi et al. BMC Neurology (2016) 16:21

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manuscript: MY, OK, TT. Critical revision of the manuscript for important
intellectual content: All authors. All authors read and approved the final
manuscript.
Acknowledgments
None.
Author details
1
Division of Neurology, Department of Internal Medicine, Toho University
School of Medicine, 6-11-1 Omorinishi, Ota-ku, Tokyo 143-8541, Japan.
2
Department of Stem Cell Biology and Regenerative Medicine, Shiga
University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192,
Japan. 3Department of Radiology, Toho University School of Medicine, 6-11-1
Omorinishi, Ota-ku, Tokyo 143-8541, Japan.
Received: 26 August 2015 Accepted: 2 February 2016

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