Diagnosis, treatment, and clinical outcomes in 43 cases with cerebrotendinous xanthomatosis

Duell, P. Barton; Salen, Gerald; Eichler, Florian; DeBarber, Andrea E.; Connor, Sonja L.; Casaday, Lise; Jayadev, Suman; Kisanuki, Yasushi; Lekprasert, Patamaporn; Malloy, Mary J.; Ramdhani, Ritesh A.; Ziajka, Paul; Quinn, Joseph F.; Su, Kimmy; Geller, Andrew M.; Diffenderfer, Margaret R.; Schaefer, Ernst J.

doi:10.1016/j.jacl.2018.06.008

Cited by 87 publications

(74 citation statements)

References 36 publications

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“…In this study, cerebellar signs were also more prevalent than pyramidal signs in pediatric cases [21]. In our cohort, all patients were diagnosed with CTX after neurological symptoms developed, and the mean age at diagnosis was 38.7 ± 9.6 years despite a mean onset age of 12.4 ± 10.6 years, which is consistent with the results of previous studies [7,17,18]. The most common, initial clinical abnormalities in our cohort were unexplained chronic diarrhea, febrile convulsion, juvenile cataract, childhood depression, autism, parkinsonism, and intellectual disability.…”

Section: Discussionsupporting

confidence: 91%

“…Mignarri et al [20] reviewed the diagnosis, treatment, and clinical course of 19 previously untreated CTX patients. Their mean age was 33 years at CTX diagnosis, with prevalence of the following clinical features: cataracts (84%), cognitive dysfunction (74%), tendon xanthomas (79%), and neurological disease (68%) [7]. Wong et al [18] carried out a retrospective review of 194 CTX cases (ranging in age between 1 and 67 years) in 2018.…”

Section: Discussionmentioning

confidence: 99%

“…Systemic abnormalities include juvenile cataracts, tendon xanthomas, and chronic diarrhea [1,[3][4][5]. Chronic diarrhea may begin in infancy [5][6][7][8]. Although the most common finding in childhood and adolescence is premature bilateral cataracts, cognitive impairment and psychiatric disturbances are also frequently encountered in this age group [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…Neuroimaging of the brain reveals cerebellar atrophy and hyperintense lesions of the dentate nucleus and cerebellar white matter [9,14,15]. Since the diagnosis is often delayed due to heterogeneous manifestations and early-stage replacement therapy, chenodeoxycholic acid (CDCA) might suppress clinical deterioration, including neurological manifestations, and a diagnostic tool called "Mignarri suspicion index" has been developed [7,[16][17][18], which facilitates early diagnosis and helps with long-term treatment. In this study, we report the clinical, laboratory, neuroimaging, and genetic findings of the aforementioned 7 patients (2 siblings and 5 patients from unrelated families) with CTX.…”

Section: Introductionmentioning

confidence: 99%

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Patients with Lately Diagnosed Cerebrotendinous Xanthomatosis

et al. 2019

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Objectives: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive inborn lipid storage disorder due to various pathogenic mutations in the CYP27A1 gene. Although the symptoms begin commonly in infancy, CTX diagnosis is often delayed. In this study, we report 7 Turkish CTX patients who had a delayed diagnosis despite early clinical signs and belonged to 6 unrelated families. Methods:We have retrospectively evaluated clinical, laboratory, imaging, and genetic findings of CTX patients, which were collected from 2 centers specialized in movement disorders:

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Patients with Lately Diagnosed Cerebrotendinous Xanthomatosis

et al. 2019

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“…CDCA remains the treatment of choice in CTX as it down-regulates CYP27A1, restores the imbalance between CDCA and cholic acid, and is the only drug that has shown beneficial effects on neurological symptoms so far (Nie et al, 2014;Salen and Steiner, 2017). Several studies have emphasized that the response to treatment strongly depends on when CDCA is initiated (Amador et al, 2018;Duell et al, 2018;Stelten et al, 2019). In a cohort of 56 Dutch CTX patients treated by CDCA with a median follow-up time of 8 years, neurological symptoms, assessed by the modified Rankin Scale and Expanded Disability Status Scale (EDSS) scores, disappeared in all patients who were diagnosed before the age of 24 and treated since (Stelten et al, 2019).…”

Section: Cholesterol Hydroxylationmentioning

confidence: 99%

Lipids in the Physiopathology of Hereditary Spastic Paraplegias

2020

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Hereditary spastic paraplegias (HSP) are a group of neurodegenerative diseases sharing spasticity in lower limbs as common symptom. There is a large clinical variability in the presentation of patients, partly underlined by the large genetic heterogeneity, with more than 60 genes responsible for HSP. Despite this large heterogeneity, the proteins with known function are supposed to be involved in a limited number of cellular compartments such as shaping of the endoplasmic reticulum or endolysosomal function. Yet, it is difficult to understand why alteration of such different cellular compartments can lead to degeneration of the axons of cortical motor neurons. A common feature that has emerged over the last decade is the alteration of lipid metabolism in this group of pathologies. This was first revealed by the identification of mutations in genes encoding proteins that have or are supposed to have enzymatic activities on lipid substrates. However, it also appears that mutations in genes affecting endoplasmic reticulum, mitochondria, or endolysosome function can lead to changes in lipid distribution or metabolism. The aim of this review is to discuss the role of lipid metabolism alterations in the physiopathology of HSP, to evaluate how such alterations contribute to neurodegenerative phenotypes, and to understand how this knowledge can help develop therapeutic strategy for HSP.

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Prevalence of Cerebrotendinous Xanthomatosis Among Patients Diagnosed With Acquired Juvenile-Onset Idiopathic Bilateral Cataracts

Freedman

Brennand²,

Chiang

et al. 2019

JAMA Ophthalmol

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IMPORTANCE Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive bile acid synthesis disorder caused by mutations in CYP27A1, the gene encoding sterol 27-hydroxylase, which results in elevated levels of plasma cholestanol and urinary bile alcohols. Clinical symptoms and signs may include early-onset chronic diarrhea, juvenile-onset bilateral cataracts, cholestatic jaundice, tendon xanthomas, and progressive neurological deterioration. Although initiation of treatment at a young age can prevent disease complications, diagnosis often occurs after the onset of permanent neurologic damage. Strategies are needed to facilitate early diagnosis. OBJECTIVE To evaluate the prevalence of CTX in a patient population diagnosed with early-onset idiopathic bilateral cataracts. DESIGN, SETTING, AND PARTICIPANTS This interim analysis of the Cerebrotendinous Xanthomatosis Prevalence Study was conducted in 26 active US sites from November 2015 to June 2017. The study included patients diagnosed as having idiopathic bilateral cataracts from ages 2 to 21 years. Potentially eligible study participants were identified through retrospective medical record review or on receiving care for cataracts at an active site. Data were analyzed from July 2017 to October 2018. MAIN OUTCOMES AND MEASURES Measurement of plasma cholestanol levels and optional urine bile alcohol screening were performed. A plasma cholestanol concentration of 0.4 mg/dL or greater or a positive urine bile alcohol result prompted CYP27A1 genetic testing to confirm the diagnosis of CTX. RESULTS Of 170 tested patients, 88 (51.8%) were male, and the median (range) age was 10 (2-49) years. A total of 3 patients (1.8%) had biochemical and genetic confirmation of newly diagnosed CTX (plasma cholestanol level greater than 1.0 mg/dL, positive urine bile alcohol result, and disease-causative mutations in CYP27A1). The mean (range) age at cataract diagnosis for patients with CTX was 12 (8-16) years. Reported symptoms included abnormal gait or balance (n = 3), learning disability (n = 2), cognitive decline (n = 2), seizures (n = 2), frequent bone fractures (n = 2), and chronic diarrhea (n = 1). CONCLUSIONS AND RELEVANCE To date, 1.8% of patients in this study were diagnosed as having CTX, which is approximately 500-fold the currently estimated prevalence of CTX in the general population (3 to 5 per 100 000). These data suggest that juvenile-onset idiopathic bilateral cataracts may be useful as a screening marker for CTX and that ophthalmologists can play an important role in facilitating early identification of this condition.

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Diagnosis, treatment, and clinical outcomes in 43 cases with cerebrotendinous xanthomatosis

Cited by 87 publications

References 36 publications

Patients with Lately Diagnosed Cerebrotendinous Xanthomatosis

Patients with Lately Diagnosed Cerebrotendinous Xanthomatosis

Lipids in the Physiopathology of Hereditary Spastic Paraplegias

Prevalence of Cerebrotendinous Xanthomatosis Among Patients Diagnosed With Acquired Juvenile-Onset Idiopathic Bilateral Cataracts

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