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.

Xantomatosis cerebrotendinosa sin xantomas tendíneos: caso clínico / Cerebrotendinous xanthomatosis: report of one case

Cerebrotendinous xanthomatosis (CTX) is an uncommon autosomal recessive disease caused by deficiency of 27-sterol-hydroxylase that results in an accumulation of cholestanol in the central nervous system, eyes, tendons, and blood vessels. We report a 22-year-old woman with a history of cataract surgery at the age of 14, cholecystectomy due to cholelithiasis at the age of 17 and chronic diarrhea, who presented with a six months period of gait instability and frequent falls. Physical examination revealed a bilateral pyramidal and cerebellar syndrome, with no visible tendon xanthomas. Cerebral magnetic resonance imaging showed an increase of the signal intensity on the T2-weighted images in periventricular cerebral white matter, dentate nuclei and spinal cord. With a high suspicion of CXT, a genetic study was conducted identifying a pathogenic variant in the CYP27A1 gene. There is considerable variation in clinical characteristics and age of onset of this disease, including absence of tendon xanthomas, delaying the diagnosis. Early recognition and chronic chenodeoxycholic acid therapy can improve outcome and quality of life.

Analysis of a cerebrotendinous xanthomatosis case with mental retardation as the initial symptom / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To analyze a case of cerebrotendinous xanthomatosis (CTX) with mental retardation as the initial neurological symptom.</p><p><b>METHODS</b>Medical imaging, histopathological assay and genetic testing were carried out to analyze the patient.</p><p><b>RESULTS</b>Neurological manifestations of the 27-year-old male patient were initiated by mental retardation and subsequently memory lapses, ataxia, spastic paraplegia and fuzzy language. Other symptoms included cataract, xanthomatosis in Achilles tendon, kidney stones and high arches. The total bile acid in serum has risen to 14.7 umol/L. There were symmetrical abnormal signals in bilateral cerebellar dentate nuclei, hypointensities on T1WI and DWI and mixed signals on T2WI. Cholesterol crystallization and cholesterol granulomatous inflammation were found upon pathological examination of the Achilles tendon. The patient was found to have carried a compound heterozygous mutation of the CTX gene, which consisted of two novel mutations including c.379C>T (p.Arg127Trp) in exon 2 and c.1174G>A (p.Glu392Lys) in exon 6 of the CYP27A1 gene.</p><p><b>CONCLUSION</b>Clinicians should be alert to cerebrotendinous xanthomatosis when the patient has mental retardation caused by genetic and metabolic factors beginning at a young age, particularly accompanied with tendinous xanthomatosis and cataracts. CTX can be readily diagnosed by histopathological assay and sequencing of the CYP27A1 gene.</p>

Two Siblings with Cerebrotendinous Xanthomatosis / 대한피부과학회지

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease caused by sterol 27-hydroxylase (CYP27) deficiency. We report two CTX siblings that were presented with typical manifestations such as achilles tendon xanthomas, mental retardation, progressive gait ataxia, and upper motor signs. Their parents and other three sisters were healthy. Serum cholesterol level was within normal limits for both siblings. The older brother has been treated conservatively with muscle relaxant and dopamine agonist because the disease was so progressive, but the younger sister has been treated with 250 mg/day chenodeoxycholic acid (CDCA) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (simvastatin 40 mg/day) to prevent the progressive neurologic dysfunction.

A Case of Cerebrotendinous Xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive lipid-storage disease with abnormal deposition of cholesterol and cholestanol in multiple tissues. The disease is caused by mutations in the sterol 27-hydroxylase and characterized by tendon xanthoma, premature cataracts and various neurological manifestations in the central and peripheral nervous systems. A 47-year-old man presented with unsteadiness of gait and weakness on extremities. He had a bilateral cataract extraction at the age of 30 years. Physical examination revealed bilateral elongated mass on Achilles tendons. On neurologic examination, dysarthria, spastic quadriparesis and exaggerated deep tendon reflexes were noted. Surgical excisional biopsy of Achilles tendon revealed a crystalline clefts surrounded by many multinucle-ated giant cells. A moderate degree of cerebral and cerebellar cortical atrophy and focal high signal intensities in sub-cortical white matter were noted on T2-weighted magnetic resonance images. Serum cholestanol was elevated (22 Mg/ml ; normal <2 Mg/ml), while serum cholesterol was normal (186 mg/dl ; normal <250 mg/dl). With clinical, radiologi-cal and biochemical findings, we confirmed a rare case of cerebrotendinous xanthomatosis.