Clinical and genetics characteristics of adult-onset cerebrotendinous xanthomatosis: analysis of a Chinese pedigree / 中华内科杂志

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.

Determinación y jerarquización de signos clínicos para diagnóstico temprano de xantomatosis cerebrotendinosa / Determination and hierarchy of clinical signs for early detection of cerebrotendinous xanthomatosis

Background: Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive disease caused by mutations in the CYP27A1 gene resulting in a decreased synthesis of bile acids. An early diagnosis and treatment would reduce the longterm complications observed in this disease. Aim: To identify and hierarchize initial clinical signs of CTX to establish an early diagnostic suspicion index. Material and Methods: Clinical information was collected from 387 patients diagnosed with CTX, published in MEDLINE between 1968 and 2016. Clinical manifestations were identified, determining their prevalence and age of onset. Sensitivity, specificity and the positive Likelihood ratio (LR+) was calculated for each clinical sign evaluated. Results: The average ages for early symptoms' onset and CTX diagnosis were 13.3 ± 10.6 years and 34.6 ± 12.6 years respectively. The early clinical signs and their respective LR+ were: juvenile cataracts (143), epilepsy (81), chronic diarrhea (15.6) and psychomotor development delay (3.4). The presence of consanguinity among parents resulted in a LR+ of 31. The combination of two early signs increased the post-test probability to 30%. If the early diagnostic criteria would have been applied in three Chilean patients with diagnosis of CTX, their disease would have been diagnosed from 12 to 25 years earlier. Conclusions: The use of a hierarchical system of predictive clinical signs allows an early screening of CTX, which may avoid the natural progression of the disease using an appropriate treatment.

Xantomatosis cerebrotendinosa. A Propósito de un Caso / Cerebrotendinous xanthomatosis. A case report

La xantomatosis cerebrotendinosa (XCT) es un raro desorden del almacenamiento de los lípidos, que se transmite en forma autosómica recesiva y se caracteriza por el depósito de colesterol y colestanol en diferentes tejidos, con preferencia por los tendones, los cristalinos y el sistema nervioso central. El diagnóstico de la enfermedad se confirma con la presencia de β–colestanol en sangre y de alcoholes biliares en orina. Obedece a una mutación del gen CYP27A1 (responsable de la síntesis de la enzima esterol 27-hidrolasa) que mapea en el brazo largo del cromosoma 2. Se manifiesta clínicamente por un deterioro neurológico progresivo, además de la presencia de xantomas tendinosos, cataratas juveniles, arterioesclerosis y diarrea crónica. Las alteraciones aparecen en las primeras dos décadas de la vida, pero el diagnóstico definitivo suele hacerse tardíamente (entre la tercera y la cuarta décadas). La terapéutica consiste en la administración de ácido quenodesoxicólico asociado a pravastatina o simvastatina. El tratamiento temprano y prolongado podría detener la progresión de la enfermedad. Se presenta un paciente de 40 años con esta enfermedad y se hace una descripción actualizada de la misma.

Xantomatosis cerebrotendínea: una causa de aumento de volumen bilateral del tendón de Aquiles: caso clínico / Cerebrotendinous xanthomatosis: report of one case

Cerebrotendinous xanthomatosis is an inherited autosomal recessive disease caused by a mutation in the gene for the sterol 27-hydroxylase enzyme, which determines the accumulation of plasmatic cholestanol in various tissues. The natural history of this disease is characterized by chronic diarrhea beginning in childhood, cataract in youth, tendinous xanthomas in adulthood and later progressive neurological dysfunction manifested as dementia, psychiatric disorders, cerebellar, pyramidal or extra pyramidal signs or seizures. We report a 39 year-old male with a history of diarrhea during childhood and bilateral cataracts requiring surgery at 20 years of age, who evolves later with psychiatric disorders and bilateral increased volume in Achules tendons. High levels of plasmatic cholestanol and magnetic resonance imaging confirmed the diagnosis of this disease.

Cerebrotendinous xanthomatosis: neuroimaging findings in two siblings from an Indian family.

Cerebrotendinous xanthomatosis (CTX) is exceptionally rare in the Indian population. We present and discuss the clinical, radiological and histopathologic findings in 2 siblings with CTX. Both the patients had juvenile cataract, mental retardation and marked cerebellar ataxia. The Achilles tendon swelling was present in only 1 patient (Case 2). MR imaging showed typical bilateral and symmetrical involvement of the dentate nuclei, inferior olives, brainstem and cerebellar hemispheric white matter. Although the diagnosis of CTX was made in the 3rd decade in both our cases, early diagnosis is possible if neuroimaging is done in the early course of the disease.