Cerebrotendinous xanthomatosis in Spain: clinical, prognostic, and genetic survey

Pilo‐de‐la‐Fuente, Belén; Jiménez‐Escrig, Adriano; Lorenzo, José Ramón Fernández; Pardo, Julio; Gómez, Manuel; Arés-Luque, Adrián; Duarte, Jacinto; Muñiz-Pérez, S.; Sobrido, María Jesús

doi:10.1111/j.1468-1331.2011.03439.x

Cited by 120 publications

(120 citation statements)

References 24 publications

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“…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). Consistent with this, high CTX gene carrier frequencies have been reported for these populations (Berginer and Abeliovich 1981;Rosner et al 2009;Falik-Zaccai et al 2008) (Table 1).…”

Section: Epidemiologymentioning

confidence: 79%

“…Currently available animal models for CTX (e.g., cyp27a1 knockout mouse models) are suboptimal, as they do not demonstrate clear and consistent accumulation of cholestanol and/or bile alcohols or neurologic signs and symptoms associated with CTX (DeBarber et al 2011;Rosen et al 1998); poor genotype-phenotype correlation in CTX (Verrips et al 2000a;Pilo-de-la-Fuente et al 2011) also limits the ability to extrapolate from animal models. Studies that attempted to duplicate the CTX phenotype by feeding animals cholestanol-enriched diets found increased cholestanol levels in various tissues but not the brain (Berginer et al 2015); such findings suggest that cholestanol does not efficiently pass the intact blood-brain barrier (BBB).…”

Section: Etiologymentioning

confidence: 99%

“…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). In addition, phenotypic variation within families and among individuals with the same mutation has been reported, including a recently reported case of identical twins who presented with considerably different phenotypes (Verrips et al 2000a;Pilo-de-la-Fuente et al 2011;Zadori et al 2017;Leitersdorf et al 1993;Rosafio et al 2016;Giraldo-Chica et al 2015).…”

Section: Etiologymentioning

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%

“…Abnormalities in patients with CTX have been reported for visual evoked potential (VEP), somatosensory evoked potential (SSEP), brainstem auditory evoked potential (BAEP), and nerve conduction velocity (NCV) studies, which may reflect delayed central conduction (Pilo-de-la-Fuente et al 2011;Tokimura et al 1992;Ginanneschi et al 2013). Electromyography (EMG)/NCV findings demonstrating motor or sensorimotor axonal neuropathy, demyelinating neuropathy, and mixed neuropathy have been reported (Pilo-de-laFuente et al 2011;Ginanneschi et al 2013;Verrips et al 2000b).…”

Section: Diagnosis and Testingmentioning

confidence: 99%

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

Salen

Steiner

2017

J of Inher Metab Disea

147

150

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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: 79%

Section: Etiologymentioning

confidence: 99%

Section: Etiologymentioning

confidence: 99%

Section: Clinical Presentationmentioning

confidence: 99%

Section: Diagnosis and Testingmentioning

confidence: 99%

See 3 more Smart Citations

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

Salen

Steiner

2017

J of Inher Metab Disea

147

150

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A Rare Form of Lipid Metabolic Encephalopathy

2020

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A 27-year-old Asian man was found with painless masses of about 5.1 cm in diameter that appeared on both Achilles tendons 10 years ago. Two years prior, he had no obvious inducement and gradually developed indifference, glassy eyes, lethargy, and poor memory. One year prior, the patient's personality changed dramatically, with notably decreased memory formation but intact short-term memory. He was short-tempered, irritable, hyperactive, and exhibited slight balance instability while walking. On admission, physical examination showed unstable balance while walking in a straight line, positive ankle clonus bilaterally, positive Babinski sign bilaterally, positive Chaddock sign bilaterally, positive Romberg sign, and painless lumps of about 8.2 cm in diameter in both Achilles tendons. Routine laboratory test results showed that the patient's triglyceride level was elevated at 342.48 mg/dL (to convert to millimoles per liter, multiply by 0.0013 mg/dL; normal levels are considered to be 30.97-150.44 mg/dL). A brain magnetic resonance imaging (MRI) indicated multiple bilateral, symmetric abnormal signals in the genus of the internal capsules, posterior limbs of internal capsules, cerebral peduncles, pons, and cerebellar dentate nuclei (Figure, A). Genetic testing indicated a known pathogenic mutation c.1214G>A (p.Arg405Gln; Hom) in the CYP27A1 gene. An MRI of the ankle joints revealed an enlargement of the left Achilles tendon with abnormal signal, and the right Achilles tendon was circumscribed by a fusiform enlargement with abnormal signal (Figure, B).

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Clinical report: A patient with a late diagnosis of cerebrotendinous xanthomatosis and a response to treatment

Alhariri

Hamilton

Oza

et al. 2017

American J of Med Genetics Pt A

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Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, inborn error of bile acid metabolism characterized by diarrhea in infancy, juvenile cataracts in childhood, tendon xanthomas developing in the second to third decades of life, and progressive neurologic dysfunction in adulthood. The condition is caused by mutations in the CYP27A1 gene that result in decreased production of chenodeoxycholic acid (CDCA) and elevated levels of cholestanol and bile alcohols. We present a 36-year-old male of Han ethnicity who developed xanthomas of his Achilles tendons and suffered neurocognitive declines and gait deterioration in his second decade. The diagnosis of CTX was confirmed by marked elevation of the serum cholestanol level. Sequencing of CYP27A1 showed a paternally inherited splice mutation, c.446 + 1G>T, and a maternally inherited nonsense mutation, c.808C>T, predicting p.(Arg270*). Despite the advanced disease in this patient, treatment with CDCA reduced the xanthoma size and improved his cognition and strength, and the patient made significant gains in his ambulation and coordination. We report this case to illustrate the potential benefits of therapy in patients with CTX who have advanced disease at the time of diagnosis.

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Cerebrotendinous xanthomatosis in Spain: clinical, prognostic, and genetic survey

Abstract: This is the first nationwide extensive series of CTX reported in Spain. The higher number of cases in some areas suggests a possible founder effect. Spinal forms had a less severe prognosis. A delayed diagnosis could contribute to the lack of significant response to treatment.

Cited by 120 publications

References 24 publications

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

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

A Rare Form of Lipid Metabolic Encephalopathy

Clinical report: A patient with a late diagnosis of cerebrotendinous xanthomatosis and a response to treatment

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