TYPE Mini Review

PUBLISHED 17 June 2024

DOI 10.3389/fneur.2024.1409138

Case report: Cerebrotendinous

OPEN ACCESS xanthomatosis treatment
follow-up
EDITED BY
Félix Javier Jiménez-Jiménez,
Hospital Universitario del Sureste, Spain

REVIEWED BY
Svetlana Tomic, Karolina Ejsmont-Sowała 1*, Tomasz Książek 1,
Osijek Clinical Hospital Center, Croatia Katarzyna Maciorowska-Rosłan 1, Joanna Rosłan 1,
*CORRESPONDENCE
Karolina Ejsmont-Sowała
Agata Czarnowska 2, Anna Jakubiuk-Tomaszuk 3,4,
ejsmont.karolina@gmail.com Joanna Tarasiuk 2, Katarzyna Kapica-Topczewska 2 and
RECEIVED 29 March 2024 Alina Kułakowska 2
ACCEPTED 21 May 2024
PUBLISHED 17 June 2024 1
Medical University of Bialystok, Bialystok, Poland, 2 Department of Neurology, Medical University of
Bialystok, Bialystok, Poland, 3 Department of Pediatric Neurology, Medical University of Bialystok,
CITATION
Bialystok, Poland, 4 Medical Genetics Unit, Martermed Medical Center, Bialystok, Poland
Ejsmont-Sowała K, Książek T,
Maciorowska-Rosłan K, Rosłan J,
Czarnowska A, Jakubiuk-Tomaszuk A,
Tarasiuk J, Kapica-Topczewska K and Xanthomatosis is a genetic disease inherited in an autosomal recessive manner.
Kułakowska A (2024) Case report: The specific phenotypic features are associated with patient’s genetic profile. The
Cerebrotendinous xanthomatosis treatment
result of the mutation is disorder of cholesterol synthesis and the accumulation of
follow-up.
Front. Neurol. 15:1409138. its precursors in tissues. The characteristic symptoms are progressive cerebellar
doi: 10.3389/fneur.2024.1409138 ataxia, cataract, diarrhea, and the deposition of cholesterol in the tendons.
COPYRIGHT Our objective is to follow-up information to treatment efficacy of 22-year-
© 2024 Ejsmont-Sowała, Książek, old patient diagnosed with cerebrotendinous xanthomatosis through 1.5 year
Maciorowska-Rosłan, Rosłan, Czarnowska,
Jakubiuk-Tomaszuk, Tarasiuk,
observation. In 2012, an 11-year-old patient with a long history of deformed
Kapica-Topczewska and Kułakowska. This is feet and frequent yellowing of the skin, was admitted to the Department of
an open-access article distributed under the Neurology due to seizures. In 2013, the patient began to suffer from diarrhea,
terms of the Creative Commons Attribution
License (CC BY). The use, distribution or
and its frequency was correlated with the concentration of bilirubin in the
reproduction in other forums is permitted, blood. In the same year cataract was diagnosed. Gradually, the patient starts
provided the original author(s) and the to complain about progressive difficulties in moving. In 2019, genetic tests
copyright owner(s) are credited and that the
original publication in this journal is cited, in
confirmed the diagnosis of cerebrotendinous xanthomatosis. Since July 2021,
accordance with accepted academic the patient has been treated with chenodeoxycholic acid. The deterioration
practice. No use, distribution or reproduction of patient’s mobility has been significantly inhibited, consequently his quality
is permitted which does not comply with
these terms.
of life has improved. The presented case report underscores the efficacy of
CDCA supplementation in halting the progression of CTX, resulting in marked
improvements in the patient’s quality of life.

KEYWORDS

CTX, cerebrotendinous xanthomatosis, CYP27A1, chenodeoxycholic acid, CDCA

1 Introduction
Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive rare neurometabolic
disorder. More than 500 cases have been identified worldwide so far, with a variety of
mutations. The characteristic features of the disease are neurological deficits (seizures, atypical
parkinsonism, peripheral neuropathy, dementia, cognitive impairment, ataxia, dystonia),
juvenile cataract and tendinous xanthoma. According to current reports on the disease,
symptoms and progression can differ among individuals. What is more, considerable
differences in the phenotype severity can be found in identical twins with CTX (1).

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Cerebrotendinous xanthomatosis is a lipid storage disease. Due to deep reflexes and foot shake. In 2019, genetic testing identified a
the lack of the mitochondrial enzyme sterol 27-hydroxylase, which is mutation (c.1184 + 1G > A) present in both alleles of the CYP27A1
involved in bile acid synthesis, the cholesterol synthesis is impaired. gene, thereby confirming the diagnosis of cerebral cholesterosis.
What is more, there is an accumulation of its precursors in different Further diagnostic scrutiny revealed the presence of the
tissues (2). Three symptoms predominate in most patients: cataracts aforementioned mutation in both parental genetic profiles. Since
and xanthomas which are infantile-onset till young adult-onset, and July 2021, the patient has undergone successful treatment with
the progressive spinocerebellar ataxia which usually appears in adult chenodeoxycholic acid, yielding a cessation in the disease’s
life. Other neurological dysfunctions seen in adults are: dementia, progression. This intervention has effectively forestalled the
psychiatric disturbances, atypical parkinsonism, seizures, dystonia (3, deterioration of mobility, prevented further deformities in the lower
4). Even though diarrhea is not included into characteristic triade of limbs, and markedly improved the overall quality of life for
the symptoms, mostly it is the first manifestation of the disease (5). the individual.
Prolonged neonatal jaundice can also be one of the earliest disease
symptom. It is classified as a strong indicator for CTX suspicion
according to suspicion index for CTX published by Mignarri et al. 3 Outcome
Another strong indicator, according to the authors, is intellectual
disability. It is noticed that even 60% of people with cerebrotendinous Prior to commencing treatment, the patient exhibited a bilirubin
xanthomatosis disease may have intellectual disability (6). level of 10.5 mg/dL. Subsequent to one year of therapeutic
The first line treatment is the supplementation of intervention, specifically in March 2023, a substantial reduction in
chenodeoxycholic acid (CDCA) by using the exogenous form of it (7). bilirubin levels was observed, with the metric registering at 2.62.
Chenodeoxycholic acid is known as a medicament for dissolution of Cholestanol concentrations were also observed to decrease by 30%.
gallstones (8). The aim of the treatment is to increase the acids, which Notably, the resolution of diarrhea following the administration of
synthesis is reduced due to the lack of the mitochondrial enzyme medication represents a pivotal indicator of the patient’s enhanced
sterol 27-hydroxylase. Therefore, the delivered CDCA can give health. The inhibition of disease progression, combined with a
negative feedback on cholesterol 7α-hydroxylase which catalyzes the noticeable decrease in bilirubin levels, highlights the encouraging
classical pathway of bile acid synthesis. The products of this reaction results of treatment, despite the remaining neurological deficit.
are cholestanol and bile alcohols (9). Nevertheless, the imperative for ongoing medical care and vigilant
In 2021 the article about first case series of Polish patients with health monitoring persists to ensure the sustained maintenance of
CTX was published. One of those patients was a 20-year-old male who achieved results and the enduring well-being of the patient.
awaited treatment that time. In Novemeber 2021 the patient started
treatment with CDCA (10).
The aim of this study is to evaluate the effect of treatment with 4 Treatment
chenodeoxycholic acid in a 22-year-old patient diagnosed with
Cerebrotendinous xanthomatosis through 1.5 year observation. Patients diagnosed with cerebrotendinous xanthomatosis
necessitate comprehensive care. It is imperative to provide thorough
education to both the patient and their family, fostering informed
2 Case description collaboration for optimal therapeutic outcomes. While acknowledging
the current incurability of this genetic disorder, highlighting the
In 2012, a 11-year-old patient was admitted to the Department potential for well-controlled management becomes essential as it
of Neurology on account of loss of consciousness and a seizure, significantly augments the patient’s quality of life and overall
accompanied by a protracted history of foot deformities and satisfaction. The bedrock of treatment lies in pharmacological
recurrent jaundice. Commencing in 2013, the patient manifested interventions, with the primary goal being the control of symptoms
symptoms of diarrhea, the frequency of which exhibited a and the attenuation of disease progression. Medications encompass
correlation with bilirubin concentration. Within the same year, deoxycholic acid, a naturally occurring substance in the liver, which
diagnoses of cataracts and Gilbert’s syndrome were established. To plays a vital role in fat digestion. By emulsifying and aiding in fat
date, examinations involving the central nervous system and digestion, as well as removing excess cholesterol, it facilitates lipid
abdominal imaging have revealed no anomalies. The patient began metabolism regulation and reduces bilirubin levels (11). Enzyme
expressing concerns about progressive mobility challenges due to inhibitors, such as simvastatin or lovastatin, targeting lipid
deformation of the feet. Subsequent to multiple electromyography accumulation, along with antiepileptic drugs for seizure management,
(EMG) tests, polyneuropathy was conclusively diagnosed, contribute substantially to the therapeutic regimen (12). Nutritional
confirming lengthening the latency, slowing down the conduction therapy is paramount, with a low-fat, carbohydrate-rich diet
velocity and extending the F wave latency in the motor fibers of the recommended to limit lipid intake, particularly saturated fats.
right tibial and peroneal nerves. A discrete decrease in the M Depending on the symptom severity, the incorporation of
amplitude in motor fibers and a slower response in sensory fibers of symptomatic treatment and physical therapy may be introduced to
the right ulnar nerve. Throughout the course of the ailment, the enhance muscle strength and motor function (13). Regular and
patient experienced rest and intention tremors, accompanied by vigilant patient monitoring emerges as a critical aspect, facilitating the
manifestations of flaccid syndrome like muscle atrophy or weakened assessment of disease progression and the early detection of
muscle tension and symptoms indicative of pyramidal syndrome in complications. This monitoring regimen includes MRI for evaluating
the lower extremities - significantly increased tension, excessive cerebral changes and routine ophthalmic examinations (14).

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5 Discussion infant case, which has been already reported (23). Total of 9 serious
adverse events were reported in 7 patients. None of them were related
Cerebrotendinous xanthomathosis constitutes a rare genetic to the study drug (22). In pregnant women, it is recommended to stop
disorder associated with the CYP27A1 mutation. It causes lack of the taking CDCA during pregnancy, however, Duell et al. described two
sterol 27-hydroxylase which takes part in the process of metabolism cases of pregnancies during which CTX treatment was continued.
cholesterol finally to cholic acid and CDCA. However, 27-hydroxylase After two deliveries complicated by pre-eclampsia, two children were
is not the only enzyme involved in cholesterol metabolism. There is born, one was completely healthy, while the other was diagnosed with
also a 7α-hydroxylase due to its activity, 7-α-hydroxycholesterol periventricular leukomalacia. There was no cause-and-effect
appears. In physiological situation, producted CDCA gives negative relationship between the above-mentioned complications and CDCA
feedback to 7-α-hydroxycholesterol. Lack of the CDCA and reduced treatment (24).
amount of cholic acid intensifies convertion of 7-α-hydroxycholesterol Cerebrotendinous xanthomatosis manifests a wide spectrum of
to 7α-hydroxy-4-cholesten-3-one and finally to cholestanol and bile clinical symptoms, stemming from diverse genetic mutations and the
acid. Since the amount of cholestanol and bile acids is produced in the accumulation of lipids in different tissues. Noteworthy neurological
organism in larger quantities, it results in the deposition of these symptoms characteristic of this malady includes psychomotor
substances in lipophilic tissues (10). slowing, tremors, ataxia, epilepsy, and cognitive impairment (4, 25,
On average, the first effects of treatment with CDCA appear after 26). However, the molecular mechanisms dictating the emergence of
4 months of therapy, but the effectiveness of therapy is significantly neurological symptoms remain presently elusive and constitute an
influenced by early diagnosis and early beginning of the treatment (15, area of ongoing investigation. The elucidation of these mechanisms
16). During treatment, inhibition and, in some cases, withdrawal of holds promise for advancing therapeutic strategies in the future (4).
neurological symptoms, improvement of mental condition and It has been shown that there is a relationship between the patient’s
reduction of changes in MRI images are observed. After partial genetic profile and the occurrence of specific phenotypic features (25,
remission of symptoms, the effectiveness of treatment may decrease, 26). Certain genetic variants, namely c.844 + 1 G- > T, p.N403K,
which indicates that neurological changes are irreversible. This p.R395C, p.R405W, p.T339M, p.T343R have been correlated with the
confirms the greatest effectiveness of starting treatment in the early occurrence of epilepsy and dementia (25). Notably, 57% of patients
phase of the disease (17). Starting treatment earlier may even result in bearing the p.R395C genetic variant have presented with ataxia and
resolution of neurological changes, while starting treatment at a later Arnold Chiari Malformation type 1. In this subset of individuals, a
stage does not provide such benefits. This is especially observed in temporal gap of approximately 7 years has been observed from the
CTX-induced parkinsonism, which becomes drug resistant with onset of diarrhea to the manifestation of the initial neurological
age (18). symptoms (25). Patients harboring mutations such as c.255 + 1G > T
Luyckx E. et al. in a scientific work from 2013. recommends the and c.1263 + 1G > A exhibit bilateral cataracts and an elevated
use of CDCA in combination with a strong HMG-CoA reductase incidence of falls, impeding autonomous mobility. The etiology of
inhibitor. There were presented the effects of treatment of two brothers these manifestations is attributed to compromised lower limb
diagnosed with CTX, who after combined therapy showed significant strength. Genetic screening of the parents indicates their status as
improvement in cognitive functioning, complete disappearance of heterozygous carriers. Patients carrying mutations c.1263 + 1G > A,
peripheral neuropathy and inhibition of the progression of intellectual c.1537C > T (p.R513C), c.1263 + 1G > A, and c.1561dupA (p.K520fs)
disorders (19). However, Brlek et al. described case of two brothers exhibit a comparable disease course. These individuals display tendon
whose chenodeoxycholic acid monotherapy was successful. Both xanthomas and pyramidal signs, including exaggerated deep tendon
brothers reported feeling stronger in their extremities. One of them reflexes and a positive Babinski reflex. However, they do not manifest
reported that symptoms associated with diarrhea decreased and the visual disturbances, diarrhea, or limb deformities. In the last
number of stools per day was reduced. The control MRI examination mentioned mutation, c.1263 + 1G > A c.379C > T, present a diverse
proved no progression of lesion growth in both of them (20). The spectrum of symptoms, encompassing diarrhea and challenges in
effectiveness of CDCA monotherapy is also described in an analysis cooperative efforts during assessments of limb muscle strength. These
based on the effects of therapy in 43 cases of CTX, in which the patients encounter difficulties in both balance and muscle strength,
average follow-up time was 8 years (21). Before treatment, the average accompanied by neurological symptoms (26).
plasma cholestanol concentration was 32 mg/L (normal <5.0 mg/L), A table detailing the correlations between specific genetic variants
which decreased to 6.0 mg/L (−81%). Of the respondents, 63% and phenotypic features in CTX has been included in the
achieved cholestanol concentration < 5.0 mg/L. In 20% of patients with Supplementary materials (Table 1).
advanced disease, symptoms continued to worsen. Another data on
the effectiveness of CDCA comes from a single-center cohort study
from the Netherlands (22). In most patients, the signs and symptoms 6 Conclusion
of the disease, such as diarrhea, polyneuropathy, pyramidal or
cerebellar disorders disappeared or improved or stabilized during the The presented case report underscores the efficacy of CDCA
study. It was noticeable that epilepsy resolved in patients who suffered supplementation in halting the progression of CTX, resulting in
with this disease. The CDCA treatment improved the condition of marked improvements in the patient’s quality of life. The observed
patients with psychiatric and cognitive impairment. The same study reduction in bilirubin levels and resolution of diarrhea serve as pivotal
determined the safety of CDCA. There were 76 adverse events indicators of treatment success. The findings contribute valuable
recorded in 26 of patients. The treatment-related adverse effects were insights into the complexities of CTX pathophysiology, highlighting
constipation and toxic hepatitis. However, toxic hepatitis was the the intricate interplay between genetic factors and clinical

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TABLE 1 Correlation between genetic variants and phenotypic features in Cerebrotendinous Xanthomatosis (CTX).

Author Genotype Phenotype

Taboada et al. (10) p.R395C - Ataxia
- Arnold Chiari type 1
- 7 years from the onset of diarrhea to the first neurological symptoms

Taboada et al. (15) p.N403K - Epilepsy

p.R395C - Dementia.
p.R405W
p.T339M
p.T343R

Jiang et al. (16) c.255 + 1G > T - Cataracts

c.1263 + 1G > A - Decreased strength in lower limbs.
- Subnormal intelligence, diminished speech fluency, and compromised memory

Jiang et al. (16) c.1263 + 1G > A and - Tendon xanthomas

c.1537C > T (p.R513C) - Pyramidal signs including deep tendon reflexes
- Positive Babinski reflex

Jiang et al. (16) c.1263 + 1G > A and - Tendon xanthomas

c.1561dupA (p.K520fs) - Pyramidal signs characterized by deep tendon reflexes
- Positive Babinski reflex

Jiang J, et al. (16) c.1263 + 1G > A - Diarrhea

c.379C > T - Gait disturbance
- Slurring dysarthria
- Bilateral cataracts
- Positive pyramidal signs, encompassing hyperactive deep tendon reflexes
- Positive Babinski signs

manifestations. Ultimately, ongoing medical care and continuous Conflict of interest

monitoring remain crucial for sustaining positive treatment outcomes
and ensuring the enduring well-being of CTX patients. The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Author contributions
KE-S: Writing – original draft, Writing – review & editing, Publisher’s note
Conceptualization, Investigation. TK: Writing – original draft, Writing
– review & editing, Conceptualization, Investigation. KM-R: Writing All claims expressed in this article are solely those of the authors
– original draft, Writing – review & editing. JR: Writing – original draft, and do not necessarily represent those of their affiliated
Writing – review & editing. AC: Writing – original draft, Writing – organizations, or those of the publisher, the editors and the
review & editing, Supervision. AJ-T: Writing – original draft, Writing reviewers. Any product that may be evaluated in this article, or claim
– review & editing. JT: Writing – original draft, Writing – review & that may be made by its manufacturer, is not guaranteed or endorsed
editing. KK-T: Writing – original draft, Writing – review & editing. AK: by the publisher.
Supervision, Writing – original draft, Writing – review & editing.

Supplementary material
Funding
The Supplementary material for this article can be found online
The author(s) declare that no financial support was received for at: https://www.frontiersin.org/articles/10.3389/fneur.2024.1409138/
the research, authorship, and/or publication of this article. full#supplementary-material

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