We searched CTX literature at Web of Science Core Collection (WoSCC) on December 31, 2023. The following search strategies were used: TS = (cerebrotendinous xanthomatosis) AND DT = (Article OR Review) AND language = (English) AND PY = (1993.01.01–2023.12.31).

A total of 561 publications met the retrieval requirements, and the fully recorded and cited references of the literature are derived in plain text format. The flowchart of the literature search is depicted in Figure 1.

Key information such as title, author, country, institution, keyword, and the year of publication were extracted from articles that met the criteria. Microsoft Excel 2019, CiteSpace 6.2.R4, VOSviewer 1.6.18 and online bibliometrics website¹ were used to process the above data.

Figure 2 depicts the annual number of CTX-related publications. Over the past 30 years, the cumulative yearly total shown an overall upward trend, despite significant fluctuations in the annual number of papers published each year. In order to understand the trend of CTX research, the polynomial function Y = 0.2176X² + 10.411X + 18.889 (R² = 0.9962, X is the year, Y is the annual cumulative number of articles) was constructed. And 2021 is the peak year for publication, with 35 articles.

A total of 49 countries and 221 institutions have participated in CTX research in the past 30 years. Table 1 displays the top 10 countries ranked by both publications and centrality. Betweenness centrality assesses a node’s significance in a network, where higher values indicate the node acts more frequently as a bridge in facilitating communication between other nodes (18). Nodes with centrality value >0.1 are deemed significant. Among the papers published in this research field, the United States made the greatest contribution, with 172 papers, far more than other countries. Japan, Italy, the Netherlands and Sweden ranked from 2 to 5. Figure 3 represents the CTX national collaboration network analysis. Figure 3A illustrates the geographical distribution of CTX publications, with a primary focus in North America and Western Europe. Figure 3B examines the international collaborations between clusters, where the size of the nodes reflects the number of publications and the lines denote the intensity of collaboration. As shown in Table 1 and Figure 3B, the United States is the core of the CTX collaboration network.

Table 2 lists the top 5 most publication and top five most centrality institutions. 2 of the top 5 institutions are from the United States, and Karolinska Institute has the largest number of publications, with a total of 35 related papers. Figure 4 shows the institutional collaboration network, with purple circles highlighting entities with centrality values greater than 0.1, denoting their significance within the network. Oregon Health & Science University is the most centrality institution, which has some influence in the field of CTX.

Table 3 lists the top 5 authors with the most CTX publications and the most cited in CTX literature over the past three decades, primarily from Europe and the United States. The “co-citation analysis” feature identifies instances where two authors are cited together by other publications. CiteSpace software limits this analysis to the co-citations of the first author and counts multiple citations within the same publication once. The resulting co-citation network map reveals the academic collaborations within a research domain. Björkhem I. is the most prolific and cited author, with 23 publications and 254 citations. Figure 5 generated by VOSviewer, illustrates the author collaboration network. Figures 5A,B display the collaboration between authors and cited authors, with various colors indicating different clusters of collaborative relationships. These authors are at the central of distinct clusters, and collaborate closely. The burst detection analysis reflects hotspots emerging in field research, and when combined with timelines, it can clearly show the change trend of keyword, which effectively help the researchers in understanding shifts of the research focus. Among the top 25 cited authors in CTX publications from 1993 to 2023, Nie S. K. emerged as the author with the strongest burst of citations, while Oftebro H. had the longest duration of citation burst (Figure 6).

The top 5 publications and the top 5 cited journals are shown in Table 4. Table 4 shows that the top three prolific journals are Journal of Lipid Research, Journal of Inherited Metabolic Disease and Journal of the Neurological Sciences. In addition, Journal of Lipid Research is also the most frequently cited journal, followed by Journal of Biological Chemistry and Neurology. Journal of Lipid Research is the largest node in Figure 7. Combined with Table 4, it can be seen that its academic authority in the field of CTX research is better than that of other journals.

Keywords can reflect the hot spots and cutting-edge trends in the research field. Table 5 lists the top 10 high-frequency keywords, cerebrotendinous xanthomatosis (411), chenodeoxycholic acid (152), cholesterol (91), mutation (82), bile acid (71) in the top five, and all of them had a centrality > 0.1.

The analysis of keyword co-occurrence by VOSviewer showed that the keywords formed three clusters as shown in Figure 8A. The first cluster (red) mainly includes the diagnosis and treatment of CTX such as diagnosis disease follow-up therapy. The second cluster (green) mainly explores the pathogenesis of CTX such as cholesterol sterol 27-hydroxylase bile acid biosynthesis oxysterol. The third cluster (blue) mainly focused on the prognosis of CTX such as metabolism primary biliary-cirrhosis neonatal cholestasis liver-disease.

Keywords were detected and analyzed for bursts using CiteSpace, Figure 8B shows the keywords in the top 25 of burst intensity. Diagnosis ranked first in burst intensity, followed by sterol 27 hydroxylase gene (7.88) and acid biosynthetic enzyme (7.25). 26 hydroxylation is a keyword that burst lasts for a long time. In recent years, the research hotspots for bursts have been diagnosis, disease, CYP27A1 gene, inborn error metabolism and spectrum.

Over the past three decades research has greatly enhanced our understanding of CTX which can be outlined as follows: (1) Insight into the genetic landscape with the identification of several new and rare CYP27A1 gene mutations contributing to the recognition of genetic variability in CTX (19). (2) Detailed exploration of clinical symptoms where early detection and intervention have been shown to notably improve patient prognoses (20, 21). (3) Advancements in diagnostic approaches with the rise in levels of 7alpha-hydroxy-4-cholesten-3-one and cholesterol precursors confirmed as significant biomarkers for CTX (22). The broad use of imaging techniques such as MRI to detect the deposition of cholesterol and lipids in the brain (23).

From the curve fitting results in Figure 1, it can be seen that although the annual number of papers published fluctuates greatly, the cumulative number of papers shows a rapid growth trend as a whole. From each viewpoint of time, the number of published articles was unstable from 1999 to 2005, and dropped sharply to 8 in 2005, which indicated that the study of CTX was still in its infancy and did not attract the attention of scholars at that time. However, the curve has shown an overall upward trend since 2005 and reached a peak in 2021.

From the perspective of countries and institutions, the United States is the main contributor, and it is the country with the largest number of publications and the highest centrality. Although the number of German publications ranks 7, its centrality was 2nd, which indicated that its academic status and influence in the field of CTX are better than others. As for China, although it has 44 publications, its centrality was 0, which showed that China has little cooperation with other countries and needs to strengthen effective academic exchanges. Most of the top 5 institutions were located in North America and Europe, and Oregon Health & Science University and Helmholtz Association were the top 2 centrality institutions, which showed that they are playing an important role in the field of CTX research and their international academic influence has been further strengthen.

Regarding author productivity, Björkhem I. has published the most works in the last three decades, with Salen G. and Federico A. ranking second and third, respectively. In addition, Björkhem I. stands as the author with the highest number of citations in publications, achieving considerable progress in the biochemistry of CTX. He found that sterol 27-hydroxylase is a key enzyme in the conversion of cholesterol to 27-oxygenated steroids, and that loss of sterol 27-hydroxylase induces CTX and is associated with an early risk of atherosclerosis (24–26). Salen G. and Berginer V. M. have made groundbreaking contributions to the identification and treatment of CTX. Salen and his team had confirmed that CDCA is the most effective treatment. There is a significant increase in the risk of osteoporosis and fracture in patients with CTX (27, 28). Berginer and his team contributed to the accurate diagnosis of CTX by investigating the genetic architecture and traits of prevalent CTX mutation alleles among Moroccan Jews (29). Among the top 25 cited authors, Nie S. K. and his team indicate that increased cholesterol levels in CTX patients may lead to degeneration in the nigrostriatal dopaminergic pathway, potentially exacerbating the progression of Parkinson’s syndrome (30). Oftebro H. found that the metabolic defect in CTX is due to a complete absence of mitochondrial C27-steroid 26-hydroxylase (6).

With regard to journals, it can be seen from Table 4 that Journal of Lipid Research is the journal with the most output and citations, which shows that the journal has made great contributions in the field of CTX research. The journals listed in Table 4 belong to the Q1 or Q2, which indicated that these journals have a high academic status in CTX research and are supported by the majority of scholars.

Based on keyword co-occurrence, clustering, burst detection analysis and burst detection analysis of references, we have established the research hotspots of CTX: pathogenesis, diagnosis and treatment.

There are some limitations to our study. To begin with, we exclusively utilized the WoSCC database for our search. Moreover, we only included publications that were in English-language publications and categorized them as articles or reviews. Lastly, the basic functionalities of CiteSpace and VOSviewer were constrained, enabling us to analyze citation data for a maximum duration of 30 years.