Apparent underdiagnosis of Cerebrotendinous Xanthomatosis revealed by analysis of ~60,000 human exomes

Appadurai, Vivek; DeBarber, Andrea E.; Chiang, Pei Wen; Patel, Shailendra B.; Steiner, Robert D.; Tyler, Charles R.; Bonnen, Penelope E.

doi:10.1016/j.ymgme.2015.10.010

Cited by 85 publications

(97 citation statements)

References 15 publications

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“…Although epidemiologic data are limited and methodology differs among studies, available data suggest that CTX may be substantially underdiagnosed. For example, the prevalence of CTX in the USA among whites of European ancestry is estimated to be 3-5:100,000 individuals (Lorincz et al 2005) and the incidence among Americans~1:72,000 to 1:150,000 (Appadurai et al 2015). Considering the population of >320 million (United States Census Bureau 2017), the number of cases from the USA alone should exceed the several hundred that have been reported worldwide to date.…”

Section: Epidemiologymentioning

confidence: 99%

“…Over 99 different mutations implicated in CTX have been identified, including missense mutations, deletions, insertions, splice site mutations, and nonsense mutations (Verrips et al 2000a;Appadurai et al 2015; The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff 2017). No correlation has been established between specific mutations and specific clinical features or disease severity (i.e., no genotype-phenotype correlation) (Verrips et al 2000a;Pilo-de-la-Fuente et al 2011).…”

Section: Etiologymentioning

confidence: 99%

“…Estimates of the incidence of CTX vary by location. A genetic epidemiology study using the Exome Aggregation Consortium (ExAC) cohort of~60,000 unrelated adults from global populations evaluated the allele frequency of 57 known and 29 predicted CTXcausing variants and found that estimated incidence of CTX was highest in South Asians and East Asians, followed by North Americans, Europeans, and Africans (Appadurai et al 2015) (Table 1). Prevalence estimates vary considerably among different populations, with a particularly high prevalence reported for Jews of Moroccan origin and Druze in Israel (Table 1) (Berginer and Abeliovich 1981;Lorincz et al 2005;Pilo-de-la-Fuente et al 2011).…”

Section: Epidemiologymentioning

confidence: 99%

“…Neurologic symptoms are an important clinical hallmark of CTX, are present in many cases at diagnosis, and distinguish CTX from other lipid disorders (e.g., familial hypercholesterolemia; sitosterolemia) (Moghadasian 2004). A broad range of neurologic findings have been reported in patients with CTX, with low intelligence, pyramidal signs (e.g., spasticity, hyperreflexia, extensor plantar responses), cerebellar signs (e.g., ataxia, dysarthria, (Berginer et al 1993); d (Berginer and Abeliovich 1981); e (Verrips et al 1999a); f (Waterreus et al 1987); g (Verrips et al 2000a); h (Berginer et al 1994) (Appadurai et al 2015) nystagmus), and peripheral neuropathy among the most common (Verrips et al 2000c;Pilo-de-la-Fuente et al 2011;Ly et al 2014); others include dementia, psychiatric symptoms, autism, epileptic seizures, and parkinsonism (e.g., spasticity, resting tremors) (Kuriyama et al 1991b;Verrips et al 2000c;Degos et al 2016;Berginer et al 2015;Stelten et al 2017). Symptoms reflecting neurologic dysfunction, such as intellectual disability and gait disturbances, are common presenting symptoms (Pilo-de-la-Fuente et al 2011).…”

Section: Clinical Presentationmentioning

confidence: 99%

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Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Salen

Steiner

2017

J of Inher Metab Disea

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Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis caused by mutations in the cytochrome P450 CYP27A1 gene that result in production of a defective sterol 27‐hydroxylase enzyme. CTX is associated with abnormally high levels of cholestanol in the blood and accumulation of cholestanol and cholesterol in the brain, tendon xanthomas, and bile. Hallmark clinical manifestations of CTX include chronic diarrhea, bilateral cataracts, tendon xanthomas, and neurologic dysfunction. Although CTX is a rare disorder, it is thought to be underdiagnosed, as presenting signs and symptoms may be nonspecific with significant overlap with other more common conditions. There is marked variability in signs and symptoms, severity, and age of onset between patients. The disease course is progressive and potentially debilitating or fatal, particularly with respect to neurologic presentations that can include intellectual disability, autism, behavioral and psychiatric problems, and dementia, among others. Treatment with chenodeoxycholic acid (CDCA; chenodiol) is the current standard of care. CDCA can help restore normal sterol, bile acid, bile alcohol, and cholestanol levels. CDCA also appears to be generally effective in preventing adverse clinical manifestations of the disease from occurring or progressing if administered early enough. Improved screening and awareness of the condition may help facilitate early diagnosis and treatment.

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Section: Epidemiologymentioning

confidence: 99%

Section: Etiologymentioning

confidence: 99%

Section: Epidemiologymentioning

confidence: 99%

Section: Clinical Presentationmentioning

confidence: 99%

See 2 more Smart Citations

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Salen

Steiner

2017

J of Inher Metab Disea

Self Cite

139

150

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“…The mean age at diagnosis was 35 years with mean age of onset of symptoms at 9 years, implying that delays to diagnosis are significant and that opportunities for early treatment initiation have historically been missed. The incidence of CTX is not known, but recent estimates range from 1:134,970 to 1:461,358 in Europeans and even higher in Asians (~1:70,000), also supporting the notion that some cases may go undiagnosed (Appadurai et al 2015). Noninvasive testing of cholesterol metabolites and bile acid intermediates facilitates diagnosis of CTX.…”

Section: Introductionmentioning

confidence: 99%

Cerebrotendinous Xanthomatosis Presenting with Infantile Spasms and Intellectual Disability

et al. 2016

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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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Apparent underdiagnosis of Cerebrotendinous Xanthomatosis revealed by analysis of ~60,000 human exomes

Cited by 85 publications

References 15 publications

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Cerebrotendinous Xanthomatosis Presenting with Infantile Spasms and Intellectual Disability

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

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