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.

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.

Early diagnosis for cerebrotendinous xanthomatosis with juvenile cataract and family history.

PURPOSE: Cerebrotendinous xanthomatosis is characterized by excessive accumulation of cholestanol and cholesterol in multiple tissues including the brain, tendons, and the crystalline lens. Since juvenile cataract is the most common and early pathognomonic feature of this disease, it is critical to analyze some factors such as family history, systemic findings, and cataract morphology in children with cataracts. This study aims to report the early diagnosis of cerebrotendinous xanthomatosis in four siblings presenting with unique juvenile cataracts from a family with consanguineous marriage. METHODS: This is a retrospective noncomparative case series. Four symptomatic siblings and their asymptomatic parents were examined. Detailed eye examination, medical history analysis, evaluation of systemic findings, biochemical tests, and mutation analysis were performed. RESULTS: While one sister presented with bilateral fleck-like opacities and posterior subcapsular cataract, two twin sisters had anterior star-shaped sutural cataract and posterior subcapsular cataract besides bilateral fleck-like opacities. The 20-year-old brother who had previously died in a traffic accident had bilateral juvenile cataract of unknown morphology. When asked specifically, none of the cases described a history of childhood diarrhea. Two sisters and one brother had neurological findings such as trouble walking and slowed speech. No significant ocular or systemic finding was found in both asymptomatic parents. Homozygous c.1263 + 1 G>A (intron 7) mutation was detected in the CYP27A1 gene in all symptomatic cases. CONCLUSION: In the absence of chronic diarrhea, the presence of juvenile cataract (especially bilateral fleck-like opacities), neurological symptoms in the family history, and consanguinity of the parents might be considerably helpful for the early diagnosis of cerebrotendinous xanthomatosis.

A Rare Case of Cerebrotendinous Xanthomatosis Associated With a Mutation on COG8 Gene.

Cerebrotendinous xanthomatosis (CTX) is a rare hereditary disease described by a mutation in the CYP27A1 gene, which encodes the sterol 27-hydroxylase enzyme involved in the synthesis of bile acid. Accumulation of cholesterol and its metabolite, cholestanol, in multiple body organs causes the symptoms of this disease. In addition, a mutation in the COG8 gene, which encodes a subunit of conserved oligomeric Golgi (COG) complex, causes another rare disorder attributed to type IIh of congenital disorder of glycosylation (CDG). We described a rare case of CTX disorder associated with a mutation on COG8 gene, which presented by unusual symptoms.

Liver transplantation in an infant with cerebrotendinous xanthomatosis, cholestasis, and rapid evolution of liver failure.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a disorder of bile acid (BA) metabolism due to biallelic mutations in CYP27A1. The deposition of cholesterol and cholestanol in multiple tissues results, manifesting as neurologic disease in adults or older children. Neonatal cholestasis (NC) as a presentation of CTX is rare; it may self-resolve or persist, evolving to require liver transplantation (LT). METHODS: We present in the context of similar reports an instance of CTX manifest as NC and requiring LT. RESULTS: A girl aged 4mo was evaluated for NC with normal serum gamma-glutamyl transpeptidase activity. An extensive diagnostic work-up, including liver biopsy, identified no etiology. Rapid progression to end-stage liver disease required LT aged 5mo. The explanted liver showed hepatocyte loss and micronodular cirrhosis. Bile salt export pump (BSEP), encoded by ABCB11, was not demonstrable immunohistochemically. Both severe ABCB11 disease and NR1H4 disease-NR1H4 encodes farsenoid-X receptor, necessary for ABCB11 transcription-were considered. However, selected liver disorder panel sequencing and mass-spectrometry urinary BA profiling identified CTX, with homozygosity for the predictedly pathogenic CYP27A1 variant c.646G > C p.(Ala216Pro). Variation in other genes associated with intrahepatic cholestasis was not detected. Immunohistochemical study of the liver-biopsy specimen found marked deficiency of CYP27A1 expression; BSEP expression was unremarkable. Aged 2y, the girl is free from neurologic disease. CONCLUSIONS: Bile acid synthesis disorders should be routinely included in the NC/"neonatal hepatitis" work-up. The mutually supportive triple approach of BA profiling, immunohistochemical study, and genetic analysis may optimally address diagnosis in CTX, a treatable disease with widely varying presentation.

Differing clinical features between Japanese siblings with cerebrotendinous xanthomatosis with a novel compound heterozygous CYP27A1 mutation: a case report.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal-recessive lipid storage disorder caused by mutations in the CYP27A1 gene encoding the key enzyme in the bile acid synthesis, sterol 27-hydroxylase. Here, we report two Japanese CTX siblings with a novel compound heterozygous CYP27A1 mutation, showing different clinical phenotypes and responses to chenodeoxycholic acid (CDCA) therapy. CASE PRESENTATION: The proband, a 32-year-old man, who had chronic diarrhea, bilateral cataracts, and xanthomas, demonstrated progressive neurological manifestations including ataxia, and spastic paraplegia during a 5-year follow-up period despite normalization of serum cholestanol after initiation of CDCA treatment. He also exhibited cognitive decline although improvement had been observed at the beginning of treatment. Follow-up brain magnetic resonance imaging (MRI) revealed pronounced progressive atrophy in the cerebellum, in addition to expanding hyperintense lesions in the dentate nuclei, posterior limb of the internal capsule, cerebral peduncles, and inferior olives on T2-weighted images. In contrast, the two-year-younger sister of the proband presented with chronic diarrhea, cataracts, xanthomas, and intellectual disability but no other neurological symptoms at the time of diagnosis. CDCA treatment lead to improvement of cognitive function and there were no characteristic CTX-related MRI features during the follow-up period. The siblings shared a paternally inherited c.1420C > T mutation (p.Arg474Trp) and a maternally inherited novel c.1176_1177delGA mutation, predicting p.(Glu392Asp*20). CONCLUSIONS: Our cases suggest that early diagnosis and subsequent initiation of CDCA treatment are crucial before the appearance of characteristic MRI findings and severe neurological manifestations related to CTX. Further studies are required to elucidate mechanisms responsible for the clinical diversity of CTX and prognostic factors for long-term outcomes following initiation of CDCA treatment.

A case of cerebrotendinous xanthomatosis with brain and spinal involvement without tendon xanthomas: Identification of a novel mutation of the CYP27A1 gene.

Cerebrotendinous xanthomatosis (CTX) is a rare inherited disorder of the alternative pathway of bile acid biosynthesis, due to mutation(s) of the gene CYP27A1, leading to sterol 27-hydroxylase deficiency. The latter results in a systematic deposition of cholestanol and cholesterol to the central nervous system and tendons, premature cataract, as well as the manifestation of systematic symptoms, such as chronic diarrhea, osteoporosis, and premature atherosclerosis. Due to its marked clinical heterogeneity, prompt diagnosis of this disorder is challenging. We present a case of a 38-year-old male with gait difficulty, a progressive deterioration in ambulation, several episodes of vertigo and episodic diarrhea. Clinical history revealed neonatal jaundice, juvenile bilateral cataracts, borderline intellectual capacity, hypothyroidism, testicular cancer. Magnetic resonance imaging demonstrated increased T2-weighted signal in internal capsules, midbrain, cerebellum, and spinal cord. Electrodiagnostic study showed mixed polyneuropathy. Genetic analysis revealed a novel, biallelic, most likely pathogenic mutation, in gene CYP2A1 (c.1410_1411del). Plasma sterol profiling confirmed the diagnosis of CTX. Our patient was treated with chenodeoxycholic acid and one year later, he shows a progressive improvement of gait, normalization of plasma sterol biochemistry and electrophysiological parameters. This case highlights the importance of maintaining a high index of suspicion as the key to an early diagnosis of CTX, taking into consideration its clinical variability and, if promptly identified, the good response to treatment.

Endoscopic resection of tendon xanthoma in the elbow of a patient with cerebrotendinous xanthomatosis.

We describe the case of a 44-year-old woman with cerebrotendinous xanthomatosis (CTX) who had a tendon xanthoma on the right olecranon. The patient successfully underwent endoscopic resection. There were no signs of recurrence on MRI 2 years postoperatively. There were no complications related to the surgery, and the patient is completely satisfied with the treatment outcomes. CTX, a genetic metabolic disorder, is associated with the development of tendon xanthomas. Endoscopic resection of tendon xanthoma in the elbow of patients with CTX is a less invasive method than open resection.

Cerebrotendinous xanthomatosis revisited.

Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid storage syndrome defined clinically by the triad of progressive neurodegeneration, juvenile cataracts and tendon xanthomas in adults. It is treatable, and a prompt diagnosis can improve outcomes. We describe a patient with this condition who presented with progressive ataxia.

Clinical Note: Bipolar disorder in Cerebrotendinous Xanthomatosis: a case report.

Cerebrotendinous X anthomatosis (CTX) is a rare autosomal recessive disorder presenting with possible psychiatric manifestations that, once established, are difficult to control. We present the case of a 29-year-old woman diagnosed with CTX who developed bipolar disorder. Owing to difficulties in pharmacological management, the patient underwent electroconvulsive therapy (ECT), which lead to a favorable outcome. Little is known about the treatment of psychiatric symptoms of CTX, un uncommon disorder, though ECT may be an effective and safe approach.

Patients with cerebrotendinous xanthomatosis diagnosed with diverse multisystem involvement.

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease caused by deficiency of sterol 27-hydroxylase enzyme encoded by CYP27A1 gene. This multicenter, cross-sectional descriptive study aimed to document clinical characteristics of CTX patients of different ages, clinical presentations of early-diagnosed patients, and responses to short-term chenodeoxycholic acid (CDCA) treatment. Seven of 11 CTX patients were diagnosed in childhood. Three patients (27%) had neonatal cholestasis, seven (63%) patients had a history of frequent watery defecation started in infantile period, and eight (72.7%) patients had juvenile cataract. Four patients in the adult age group had pyramidal signs and parkinsonism symptoms. The mean Mignarri score at diagnosis was significantly lower in the pediatric patients (267.8 ± 51.4) than in the adult patients (450.0 ± 64.0, p = 0.001). No significant difference was determined between pediatric patients and adult patients regarding plasma cholestanol concentration at diagnosis (p = 0.482). The frequency of defecation decreased with treatment in six children, who had diarrhea at admission. Compared to pretreatment values, patients' body weight and standardized body mass index significantly increased at the 12th month of treatment. In conclusion, Mignarri scores are lower in the pediatric patients than in adult patients since the most determinative signs of the CTX disease are not apparent yet in the childhood. The disease is frequently overlooked in routine practice as the disease presents itself with different clinical combinations both in adults and in children. CTX is potentially a treatable disease; thereby, enhanced awareness is critically important for early diagnosis particularly in children.

The clinical and imaging features of cerebrotendinous xanthomatosis: A case report and review of the literature.

RATIONALE: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid deposition disorder characterized by systemic signs and neurological dysfunction. The radiological features of CTX are infrequently summarized in the literature. PATIENT CONCERNS: We described a 40-year-old male patient who repeatedly engaged in wrestling matches and presented with progressive difficulty in walking and reduced balance with egg-sized, hard, smooth, and painless masses in both ankles. DIAGNOSIS: Neuroimaging examination showed abnormalities both supra- and infratentorially. Bilateral ankle joint magnetic resonance imaging showed bilateral xanthomata of the Achilles tendon. The diagnosis was confirmed by the detection of a sterol 27-hydroxylase gene mutation. INTERVENTIONS: The patient was treated with chenodeoxycholic acid (250 mg 3 times per day). OUTCOMES: To date, the patient's bilateral xanthomas of the Achilles tendon have begun to diminish, and his neurological impairment has not deteriorated further but has not yet improved. LESSONS: We report a rare case of CTX and summarize the clinical and imaging features of this disease. Our findings suggest that the abnormal signals in the dentate nucleus or a long spinal cord lesion involving the central and posterior cord, combined with tendon xanthoma, are important clues for the diagnosis of CTX.

Nota Clínica: Trastorno bipolar en xantomatosis cerebrotendinosa: a propósito de un caso / Clinical Note: Bipolar disorder in Cerebrotendinous Xanthomatosis: a case report

La xantomatosis cerebrotendinosa (XCT) es una rara enfermedad autosómica recesiva que puede cursar con manifestaciones psiquiátricas cuyo tratamiento puede resultarcomplejo. Presentamos el caso de una mujer de 29 años, diagnosticada de XCT, que desarrolló un trastorno bipolar queno respondió a tratamiento farmacológico, precisando terapia electroconvulsiva (TEC), cuyo resultado fue positivo. Alser la XCT una enfermedad rara, existe poca evidencia sobreel abordaje farmacológico de la sintomatología psiquiátricaque puede aparecer en el curso de la enfermedad. En estesentido, planteamos que la TEC pueda ser una opción de tratamiento segura y eficaz. (AU)

Cerebrotendinous X anthomatosis (CTX) is a rare autosomal recessive disorder presenting with possible psychiatricmanifestations that, once established, are difficult to control. We present the case of a 29-year-old woman diagnosedwith CTX who developed bipolar disorder. Owing to difficulties in pharmacological management, the patient underwentelectroconvulsive therapy (ECT), which lead to a favorableoutcome. Little is known about the treatment of psychiatricsymptoms of CTX, un uncommon disorder, though ECT maybe an effective and safe approach. (AU)

A case of Cerebrotendinous Xanthomatosis with spinal cord involvement and without tendon xanthomas: identification of a new mutation of the CYP27A1 gene.

Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive defect of the alternative pathway of bile acid biosynthesis, due to the deficiency of mitochondrial cytochrome P450 sterol 27-hydroxylase enzyme encoded by CYP27A1. The deficit of sterol 27-hydroxylase raises cholestanol in plasma and tissues of affected patients. Although there is a marked variability of signs, symptoms, severity and age of onset, the main clinical manifestations of CTX include chronic diarrhea, bilateral cataract, tendon xanthomas and neurological dysfunction. Herein, we report the clinical, biochemical and molecular characterization of a Caucasian female affected by CTX diagnosed at 28 years. The patient's clinical history revealed neurological and behavioral manifestations already at fifth year of life, following by bilateral cataract and chronic diarrhea without xanthomas. At diagnosis, an involvement of the cervical spinal cord was also observed on MRI. Sterols profile analysis in plasma and red blood cell membranes showed very high cholestanol levels. CYP27A1 sequencing revealed a new variant (e.g., c.850_854delinsCTC) at homozygous status. The follow-up after 5 months of chenodeoxycholic acid treatment showed a decrease of plasma cholestanol of 64%. After 1 year, the patient showed normalization of bowel function, reduction of risk of falls, improvement of cognitive function although brain and spine MRI and other instrumental examinations remained unchanged. This case highlights the variability of the CTX phenotype that makes it difficult to reach an early diagnosis. Biochemical and/or molecular screening of CTX should be taken into account to early start the pharmacological treatment limiting neurological damages.

Double trouble: a case of an ataxic young man with coeliac disease and cerebrotendinous xanthomatosis.

We present the case of a 29-year-old south Asian man born of consanguineous marriage, presenting with ataxia, peripheral neuropathy and cognitive impairment. An initial diagnosis of coeliac disease was thought to explain the pertinent clinical features; however, further investigation led to an additional diagnosis of the rare yet treatable autosomal recessive condition, cerebrotendinous xanthomatosis. With both conditions employing highly diverse and overlapping clinical phenotypes, this contributed to a delay in diagnosis. Our report highlights the importance of paying close attention to both the clinical phenotype and family history.