A double CYP27A1 gene mutation in spinal cerebrotendinous xanthomatosis in a patient presenting with spastic gait: a case report.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX, OMIM #213700) is a rare inherited metabolic disease caused by the mutation in the CYP27A1 gene. Spinal CTX is a rare clinical subgroup of CTX which lacks typical symptoms seen in classical CTX. Here we report a spinal CTX case revealed double mutation of CYP27A1 gene. CASE PRESENTATION: A 42-year-old Asian man visited our hospital with spastic gait started at 35. Physical examination showed bilateral masses on his Achilles tendons and were identified as xanthoma on ankle magnetic resonance imaging (MRI). Brain and spinal cord MRI revealed high signal lesions in bilateral cerebellar dentate nuclei and long tract lesions involving lateral corticospinal and gracile tracts. Gene analysis revealed double heterozygous mutation, c.223C > T (p. Gln75Ter) and c.1214G > A (p. Arg405Gln). CONCLUSIONS: We believe that novel mutation detected in our case might have a role in the pathomechanism in CTX. Moreover, spinal CTX should be considered in the patients only presenting with pyramidal symptoms, as CTX shows good prognosis in early treatment with chenodeoxycholic acid.

Clinical, biochemical, and molecular insights into Cerebrotendinous Xanthomatosis: A nationwide study of 100 Turkish individuals.

OBJECTIVE: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder characterized by progressive neurologic and extraneurologic findings. The aim of this retrospective, descriptive study was to explore the time of presentation and diagnosis, and to expand the phenotype and genotype of CTX, based on a nationwide and comprehensive series of patients in Turkey. METHODS: The demographic, clinical, biochemical and genotypic characteristics of the CTX patients were reviewed. Data on molecular analysis, age of onset and diagnosis, diagnostic delay, neurologic and extraneurologic symptomatology, results of plasma cholestanol levels, brain magnetic resonance imaging and electromyography at the time of diagnosis were reviewed. RESULTS: 100 confirmed CTX patients from 72 families were included. The mean age at diagnosis was 28.16 ± 14.28 years, and diagnostic delay was 18.39 ± 13.71 years. 36 patients were diagnosed in childhood. Frequency of intention tremor (p = 0.069), peripheral neuropathy (p = 0.234) and psychiatric manifestations (p = 0.396) did not differ between two groups, demonstrating the high rate in pediatric patients. Three adult patients showed a milder phenotype without neurologic involvement. Seven patients had normal plasma cholestanol levels despite neurological impairment. Sequencing of the CYP27A1 gene revealed 25 different variants, with a novel c.671_672del variant not previously described in literature. CONCLUSION: Based on the observations of this Turkish CTX cohort, it is emphasized that the true prevalence of CTX is probably underestimated and that it has a wide spectrum of clinical phenotypes even without neurological impairment. In children, abnormal cerebellar findings, peripheral neuropathy and psychiatric findings associated with intellectual disability have been suggested as warning signs to avoid diagnostic delay. In cases of clinical suspicion, molecular analysis is recommended despite normal plasma cholestanol levels, as severe neurologic involvement may occur in CTX patients without elevated cholestanol levels.

Cerebrotendinous xanthomatosis with tremor as the main manifestation: A case report.

INTRODUCTION: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid metabolism disorder. It is caused by a defect in the sterol-27-hydroxylase gene, leading to the deposition of cholesteryl and bile alcohol in large amounts, causing a variety of clinical manifestations; however, tremor as the main manifestation of CTX has not been reported. PATIENTS CONCERNS AND CLINICAL FINDINGS: Herein, we report a 27-year-old woman, who developed head and body tremors at the age of 12 years. Many hospitals misdiagnosed her condition as idiopathic tremor and Parkinson disease, with a poor curative effect. PRIMARY DIAGNOSIS AND INTERVENTION: We diagnosed her with CTX and treated with chenodeoxycholic acid and clonazepam. CONCLUSION: The patient's condition considerably improved. This case could help avoid misdiagnosis and mistreatment in clinical practice.

Genetically and clinically confirmed atypical cerebrotendinous xanthomatosis with normal cholestanol and marked elevations of bile acid precursors and bile alcohols.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid disorder. Affected patients often remain undiagnosed until the age of 20-30 years, when they have already developed significant neurologic disease that may not be reversible. An elevated plasma cholestanol concentration has been accepted as a diagnostic criterion for CTX for decades. OBJECTIVE: Full biochemical characterization was performed for three genetically and clinically confirmed atypical CTX cases with normal plasma cholestanol levels. METHODS: Clinical assessment and genetic/biochemical testing for patients with CTX was performed by their physician providing routine standard of care. RESULTS: We report three new atypical CTX cases with large extensor tendon xanthomas but normal plasma cholestanol levels. All three cases had marked elevations of bile acid precursors and bile alcohols in plasma and urine that decreased on treatment with chenodeoxycholic acid. We also review eight published cases of atypical CTX with normal/near normal circulating cholestanol levels. CONCLUSION: The atypical biochemical presentation of these cases provides a diagnostic challenge for CTX, a disorder for which cholestanol has been believed to be a sensitive biomarker. These cases demonstrate measurements of plasma cholestanol alone are insufficient to exclude a diagnosis of CTX. The data presented is consistent with the concept that bile acid precursors and bile alcohols are sensitive biomarkers for atypical CTX with normal cholestanol, and that such testing is indicated, along with CYP27A1 gene analyses, in patients presenting with significant tendon and/or tuberous xanthomas and/or neurologic disease in early adulthood despite normal or near normal cholesterol and cholestanol levels.

Cerebrotendinous Xanthomatosis, a Treatable Disorder Often Missed: Case Series of Three Patients Confirmed by Genetic Testing.

ABSTRACT: Cerebrotendinous xanthomatosis (CTX) is a treatable autosomal recessive disorder with varied clinical manifestations and age of onset and is often diagnosed late. We report three cases of CTX who presented at our center with clinical features of frequent diarrhea, early cataracts, xanthomas, cognitive decline, ataxia, neuropathy, and other manifestations of CTX. Magnetic resonance imaging (MRI) brain in all three patients revealed abnormalities consistent with CTX. Diagnosis was confirmed by next-generation sequencing. Chenodeoxycholic acid (CDCA) is recommended as the drug of choice, as it can halt the disease progression and reverse some of the symptoms. In addition to late diagnosis, nonavailability of CDCA in our part of world adds to the problem of management of such patients; therefore, they are often started on alternative therapies, which are less effective.

Clinical and Imaging Profile of Patients with Cerebrotendinous Xanthomatosis - a Video Case Series from India.

Background: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by bi-allelic pathogenic variants in CYP27A1 gene that results in the deposition of cholestanol in the eyes, tendons, soft tissues and nervous system leading to cataracts, xanthomas, and various neuropsychiatric manifestations. The aim of our study is to describe the clinical, radiological and genetic profile of patients with CTX. Methods: This is a retrospective chart review of patients with CTX diagnosed based on classical clinical and radiological findings. The available clinical details, and investigations, including imaging, electrophysiological, pathological and genetic data, were documented. Results: Five patients (4 males) were recruited in the study. The median age at presentation was 32 years (range: 21-66 years). Walking difficulty was the most common symptom at presentation. All patients had cataracts, tendon xanthomas, eye movement abnormalities, dysarthria, pyramidal signs, ataxia and gait abnormality. Dystonia was noted in three patients. Palatal tremor and parkinsonism were noted in one patient each. In MRI brain, dentate, and corticospinal tract involvement were the most frequent imaging findings. Bilateral hypertrophic olivary degeneration was noted in one patient and hot cross bun sign in two. Three patients underwent genetic testing and all had pathogenic variants confirming the diagnosis. Discussion: CTX is a rare treatable disorder. Apart from the usual neurological presentation with spastic-ataxia, it can present at a later age with parkinsonism. Typical patterns of imaging findings are helpful in early diagnosis which aids in the treatment to prevent the neurological sequelae of the disease.

Malar rash and hand tremor in early symptoms of cerebrotendinous xanthomatosis and the effect of chenodeoxycholic acid on them.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX, OMIM #213700) is a rare but treatable lipid storage disease resulting from mutations in the CYP27A1 gene. PURPOSE: The study aims to evaluate patients diagnosed with CTX and reveal new information, especially about the signs of CTX and patients' response to the treatment. METHODS: The study was conducted retrospectively in 12 definitively diagnosed CTX patients. The patients' clinical, laboratory, imaging, genetic findings, and chenodeoxycholic acid (CDCA) treatment results were analyzed. RESULTS: The median age at diagnosis for the patients was 16.5 years (minimum-maximum: 7-32). Juvenile cataracts, detected in more than 90% (11/12) of the patients, were the most common clinical finding. Malar rash, not previously reported in the literature for CTX, was present in 75% (9/12) of the patients. Hand tremors, the first neurological symptom, occurred in adolescence and were the initial symptom of the disease in five patients. Hand tremors were present in 83.3% (10/12) of the patients. Hand tremors (in 5 patients) and malar rash (in 2 patients) were clinical findings with full recovery due to the CDCA treatment. CONCLUSION: The study defines the malar rash finding, which has not been reported in the literature before, as a possible new clinical finding in CTX disease, attributed to its partial or full recovery with CDCA treatment. Additionally, as a novelty in the literature, our study highlights the full recovery of neurological findings, such as hand tremors, in CTX. Patients presenting with hand tremors and malar rash, especially in adolescence, should undergo CTX investigation for early diagnosis and treatment.

Cerebrotendinous Xanthomatosis patients with late diagnosed in single orthopedic clinic: two novel variants in the CYP27A1 gene.

BACKGROUND: Cerebrotendinous Xanthomatosis (CTX) is a rare autosomal recessive lipid storage disorder caused by loss of function variants in the CYP27A1 gene which encodes sterol 27-hydroxylase, on chromosome 2q35. Although the symptoms begin commonly in infancy, CTX diagnosis is often delayed. The aim of this study is to review the orthopedic findings of the disease by providing an overview of the clinical features of the disease. It is to raise awareness of this condition for which early diagnosis and treatment are important. METHODS: We retrospectively evaluated the clinical, laboratory, radiological, and genetic findings of eight patients from four families who were admitted to our Orthopedics and Traumatology Department between 2017 and 2022 due to bilateral Achilles tendon xanthomas, were found to have high cholestanol and CYP27A1 gene mutations. RESULTS: The mean age of patients was 37, and five of them were male. The mean age at the onset of symptoms was 9.25 years. The mean age of initial diagnosis was 33.75 years. Between symptom onset and clinical diagnosis, an average delay of 24.5 years was observed. All patients had bilateral Achilles tendon xanthoma. Notably, a novel variant (c.670_671delAA) in CYP27A1 gene was identified in three patients who also presented with peripheral neuropathy and bilateral pes cavus. One patient had osteoporosis and four patients had osteopenia. Five patients had a history of bilateral cataracts. Furthermore, three of the patients had early-onset chronic diarrhea and three of the patients had ataxia. Two of the patients had epilepsy and seven of the patients had behavior-personality disorder. All patients had low intelligence, but none of them had cardiac disease. CONCLUSION: We present the diagnostic process and clinical features which the largest CTX case series ever reported from single orthopedic clinic. We suggest that patients with normal cholesterol levels presenting with xanthoma being genetically analyzed by testing at their serum cholestanol level, and that all siblings of patients diagnosed with CTX be examined.

Identification of pathogenic genetic variants in patients with acquired early-onset bilateral cataracts using next-generation sequencing.

BACKGROUND: Acquired early-onset bilateral cataracts can result from systemic etiologies or genetic disorders. METHODS: In this observational study, we analyzed individuals 18 months to 35 years of age with acquired bilateral cataracts via a next-generation sequencing panel of 66 genes to identify disease-causing genetic variants. RESULTS: Of 347 patients enrolled, 313 (90.2%) were <19 years (median, 8 years). We identified 74 pathogenic or likely pathogenic variants in 69 patients. Of the variants, we observed 64 single nucleotide variants (SNV) in 24 genes and 10 copy number variants (CNV) of varying size and genomic location. SNVs in crystallin genes were most common, accounting for 27.0% of all variants (20 of 74). Of those, recurrent variants included known cataract-causing variants CRYBA1 c.215+1G>A, observed in 3 patients, and CRYBA1 c.272_274delGAG, CRYBB2 c.463C>T and c.562C>T, and CRYAA c.62G>A, each observed in 2 patients. In 5 patients, we identified CNV deletions ranging from 1.32-2.41 Mb in size associated with 1q21.1 microdeletion syndrome. Biallelic variants in CYP27A1 were identified in two siblings, one as part of targeted follow-up family testing, who were subsequently diagnosed with cerebrotendinous xanthomatosis, a rare but treatable autosomal recessive disease that often presents with acquired early-onset bilateral cataracts. CONCLUSIONS: This study demonstrates the utility of genetic testing in individuals with acquired early-onset bilateral cataracts to help clarify etiology. Identification of causative genetic variants can inform patient management and facilitate genetic counseling by identifying genetic conditions with risk of recurrence in families.

Chenodeoxycholic acid (CDCA) treatment during pregnancy in women with cerebrotendinous xanthomatosis (CTX): Lessons learned from 19 pregnancies.

PURPOSE: Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder. Biallelic pathogenic variants in CYP27A1, encoding for sterol 27-hydroxylase, impair cholic acid (CA) and chenodeoxycholic acid (CDCA) synthesis and lead to accumulation of cholestanol and C27 bile alcohols. Treatment with CDCA decreases the accumulation of these harmful metabolites and slows disease progression. Currently, CDCA is contraindicated for use during pregnancy based on animal studies that showed that high-dose CDCA may cause fetal harm when administered to pregnant animals. Data regarding the safety of CDCA treatment in humans are lacking. METHODS: We present a case series of 19 pregnancies in 9 women with CTX who either received CDCA treatment throughout pregnancy or did not. RESULTS: In 11 pregnancies where mothers continued CDCA treatment, no complications were reported, and newborns were born at or near full term, with normal birth weight and Apgar scores. In 8 pregnancies where mothers did not receive CDCA, 2 newborns experienced elevated bilirubin soon after birth. One woman who stopped treatment during her pregnancy deteriorated neurologically while off treatment. CONCLUSION: The data we present support the benefit of continued CDCA treatment in pregnant women with CTX for both the affected women and their offspring.

Living with Cerebrotendinous Xanthomatosis: Patient, Caregiver, and Expert Perspectives.

In this article, patients with cerebrotendinous xanthomatosis (CTX) and caregivers detail their experience with lifelong symptoms, diagnosis, treatment and efficacy, and ongoing disease management. One patient and four caregivers describe the challenges associated with pursuing a correct diagnosis for years before testing confirmed a CTX diagnosis. They also detail their ongoing struggles and desire for greater access to physicians with CTX knowledge and to reliable online resources to continue their education about the disease and strategies for symptom management. The expert perspective is a direct response by three CTX researchers, including physicians who are treating patients with CTX in the United States and experts whose laboratories provide genetic and biochemical testing for CTX. They respond to many of the patient and caregiver concerns, including steps that are being taken to identify CTX earlier and provide access to confirmatory diagnostic testing sooner, and suggest the best online resources for CTX-related information and access to webinars and support groups. While the expert perspective is a direct response to the patient and caregiver authors' CTX journeys, it should be beneficial to any patient with CTX or their caregivers.

Resection of bilateral massive Achilles tendon xanthomata with reconstruction using vascularized iliotibial tract: A case report and literature review.

RATIONALE: Cerebrotendinous xanthomatosis is a rare autosomal recessive metabolic disease. Surgical treatment is only indicated when the xanthoma becomes large, painful, and irritable with shoe wear. Reconstruction of the large defect following resection challenging, especially with resection of the entire Achilles tendon. PATIENT CONCERNS: We report a case of bilateral Achilles tendon defects of 16 cm following resection of bilateral Achilles tendon xanthomata, with reconstruction using vascularized iliotibial tract. The patient had a good functional outcome with well-preserved strength and cosmesis. OUTCOMES: Reconstruction of a total Achilles tendon defect using Vascularized iliotibial tract is safe and effective.

Characterization of Postprandial Bile Acid Profiles and Glucose Metabolism in Cerebrotendinous Xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare inherited disease characterized by sterol 27-hydroxylase (CYP27A1) deficiency and, thus, a lack of bile acid synthesis with a marked accumulation of 7α-hydroxylated bile acid precursors. In addition to their renowned lipid-emulgating role, bile acids have been shown to stimulate secretion of the glucose-lowering and satiety-promoting gut hormone glucagon-like peptide 1 (GLP-1). In this paper, we examined postprandial bile acid, glucose, insulin, GLP-1 and fibroblast growth factor 19 (FGF19) plasma profiles in patients with CTX and matched healthy controls. Seven patients and seven age, gender and body mass index matched controls were included and subjected to a 4 h mixed meal test with regular blood sampling. CTX patients withdrew from chenodeoxycholic acid (CDCA) and statin therapy three weeks prior to the test. Postprandial levels of total bile acids were significantly lower in CTX patients and consisted of residual CDCA with low amounts of ursodeoxycholic acid (UDCA). The postprandial plasma glucose peak concentration occurred later in CTX patients compared to controls, and patients' insulin levels remained elevated for a longer time. Postprandial GLP-1 levels were slightly higher in CTX subjects whereas postprandial FGF19 levels were lower in CTX subjects. This novel characterization of CTX patients reveals very low circulating bile acid levels and FGF19 levels, aberrant postprandial glucose and insulin profiles, and elevated postprandial GLP-1 responses.

A case of cerebrotendinous xanthomatosis with massive xanthomas but without a considerable increase in serum cholestanol levels.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder caused by mutations in the sterol 27-hydroxylase gene (CYP27A1). Due to the deficiency of 27-hydroxylase, the synthesis of bile acids from cholesterol is impaired and excessive cholestanol accumulates in various tissues, such as the central nervous system, tendons, and lenses. Patients with CTX typically manifest intellectual decline, pyramidal tract symptoms, cerebellar symptoms, tendon xanthomas, juvenile cataracts, neonatal jaundice, chronic diarrhea, osteoporosis, and premature cardiovascular disease. Here, we report the atypical case of a 35-year-old female with CTX having massive xanthomas but without a considerable increase in serum cholestanol levels (3.9 µg/mL). In the differential diagnosis of xanthoma, CTX should not be ruled out even if the serum levels of cholestanol are not high, and genetic testing is necessary to make the appropriate diagnosis.

Treatment of cerebrotendinous xanthomatosis in pregnancy: Patient and physician perspectives.

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive disorder of bile acid synthesis that presents with varied and progressive symptomology. Early treatment with chenodeoxycholic acid (CDCA) improves symptoms and slows degeneration. Patients with CTX are commonly recommended to discontinue CDCA treatment during pregnancy because of theoretical risks to the fetus, but patient and clinician concerns about the risks of stopping treatment cause uncertainty. Herein, we report the experiences and perspectives of two women with CTX from the time of diagnosis through pregnancy, as well as decisions regarding CDCA treatment during pregnancy. Before becoming pregnant, both women were concerned about potential risks to their newborns if they continued or stopped CDCA treatment during pregnancy. Reassurance from their CTX specialist was the primary factor in their decision to continue treatment during pregnancy. After pregnancies complicated by preeclampsia, one gave birth to a healthy infant and the other gave birth to an infant later diagnosed with periventricular leukomalacia. Neither experienced CDCA-related complications.

Prevalence of cerebrotendinous xanthomatosis among patients diagnosed with early-onset idiopathic bilateral cataracts: final analysis.

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive bile acid synthesis disorder caused by pathologic variants in CYP27A1, a gene involved in bile acid synthesis. Impaired function in this gene leads to accumulation of plasma cholestanol (PC) in various tissues, often in early childhood, resulting in such clinical signs as infantile diarrhea, early-onset bilateral cataracts, and neurological deterioration. The current study aimed to identify cases of CTX in a population of patients with a greater CTX prevalence than the general population, to facilitate early diagnosis. Patients diagnosed with early-onset, apparently idiopathic, bilateral cataracts between the ages of 2 and 21 years were enrolled. Genetic testing of patients with elevated PC and urinary bile alcohol (UBA) levels was used to confirm CTX diagnosis and determine CTX prevalence. Of 426 patients who completed the study, 26 met genetic testing criteria (PC ≥ 0.4 mg/dL and positive UBA test), and 4 were confirmed to have CTX. Prevalence was found to be 0.9% in enrolled patients, and 15.4% in patients who met the criteria for genetic testing.

[Clinical and genetics characteristics of adult-onset cerebrotendinous xanthomatosis: analysis of a Chinese pedigree].

Objective: Clinical manifestations, imaging findings, pathologic features, and genetic mutations of Chinese adult patients with cerebrotendinous xanthomatosis (CTX) were analyzed in order to achieve a greater understanding of CTX that can improve early detection, diagnosis, and treatment. Methods: Clinical data including medical history, neurologic and auxiliary examinations, imaging findings, and genetic profile were collected for an adult patient with CTX admitted to the Sixth Medical Center of Chinese People's Liberation Army General Hospital in August 2020. Additionally, a systematic review of genetically diagnosed Chinese adult CTX cases reported in major databases in China and other countries was performed and age of onset, first symptoms, common signs and symptoms, pathologic findings, imaging changes, and gene mutations were analyzed. Results: The proband was a 39-year-old female with extensive, early-onset nervous system manifestations including cognitive dysfunction and ataxia. Systemic lesions included juvenile cataract and a tendon mass. Cranial magnetic resonance imaging revealed cerebral atrophy, symmetric white matter changes predominantly in the pyramidal tract, and lesions in the cerebellar dentate nucleus. A novel homozygous mutation in the sterol-27-hydroxylase (CYP27A1) gene (c.1477-2A>C) was identified. There were no family members with similar clinical presentation although some were carriers of the c.1477-2A>C mutation. The patient showed a good response to deoxycholic acid treatment. Totally there were 56 cases of adult CTX patients in China, mostly in East China (31/56, 55.4%), at a male-to-female ratio of 1.8 to 1. Multiple organs and tissues including nervous system, tendon, lens, lung, and skeletal muscle were affected in these cases. The most common neurologic manifestations were cognitive dysfunction (44/52, 84.6%) and ataxia (44/51, 86.3%). The cases were characterized by early onset, chronic progressive damage of multiple systems, long disease course, and delayed diagnosis, making the disease difficult to manage clinically and resulting in poor prognosis. The 2 most common genetic mutations in Chinese adult CTX patients were c.1263+1G>A and c.379C>T. Exon 2 of the CYP27A1 gene was identified as a mutation hot spot. Conclusions: Chinese adult patients with CTX have complex clinical characteristics, a long diagnostic cycle, and various CYP27A1 gene mutations. Early diagnosis and intervention can improve the prognosis of these patients.