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2 Novel deletions of the sterol 27-hydroxylase gene in a Chinese Family with Cerebrotendinous Xanthomatosis
© Tian and Zhang; licensee BioMed Central Ltd. 2011
Received: 9 February 2011
Accepted: 21 October 2011
Published: 21 October 2011
Cerebrotendinous xanthomatosis (CTX) is a rare lipid-storage disease. We investigated the clinic manifestation, histopathology and sterol 27-hydroxylase gene (CYP27A1) in a Chinese family with Cerebrotendinous Xanthomatosis (CTX).
A 36-year-old female with typical CTX clinical manifestation had Spindle-shaped lipid crystal clefts in xanthomas and "onion-like demyelination" in sural nerve. The patient was compound heterozygote carrying two deletions in exon 1 (c.73delG) and exon 2 (c.369_375delGTACCCA). The family memebers were carriers.
A Chinese family with Cerebrotendinous Xanthomatosis had typical clinical manifestation. CYP27A1 mutations were found in the proband and all other family members.
Cerebrotendinous Xanthomatosis (CTX) is a rare autosomal recessive sterol storage disease caused by a mutated sterol 27-hydroxylase gene (CYP27A1) . The CYP27A1 gene is located on chromosome 2q33-qter and consists of 9 exons. Sterol 27-hydroxylase is a mitochondrial cytochrome P 450 enzyme that catalyzes the initial steps in the oxidation of side chain of sterol intermediates in the pathway leading to the formation of bile acids in the liver . As the normal pathway is impaired, cholesterol and cholestanol accumulate at central nervous system, tendon, lenses, lung and bones . Many cases were reported all around the world, and more than 50 mutations of CYP27A1 were reported in the literature [4–8]. Here we describe clinical findings, neuro-imaging, pathology and two novel mutations of the CYP27A1 gene in a Chinese family.
A 36 year-old Chinese female had a disturbance of gait, recurrent diarrhea and bilateral cataracts when she was 7 years old. Because of the poor eyesight she dropped out of school. When she was 13 years old, she had cognitive impairments, and developed digestive symptom of diarrhea initially and constipation later. At the age of 27 years, she spoke unclearly, had weakness of bilateral lower limbs and found swelling of Achilles tendon. She could still walk unassisted. As she was 32 years old, her head swayed left-to-right involuntarily, which was prominent while sleeping. When 34 years old, dry cough at night and dysphagia appeared. She could not walk at the age of 35 years and her right knee joint luxated three times when she tried to stand. There was no known consanguinity in previous generations.
Cholesterol was 3.67 mmol/L (3.2-5.17 mmol/L), HDL 1.09 mmol/L(1.0-1.8 mmol/L), and LDL 2.03 mmol/L (1.5-3.1 mmol/L). The chest X-ray showed left lung hyperdense with clear round boundary. T2-weighted MRI of brain showed hyperintensive signals on both sides of the internal capsule, cerebral peduncle, pons and cerebellar hemisphere (Figure 1B). Biopsy of xanthomas and sural nerve was done to confirmed the diagnosis, H-E staining (Figure 1C) and electron microscope (Figure 1D) showed the typical lesion of spindle-shaped lipid crystal clefts.
Treatment with chenodeoxycholic acid, atorvastatin and aspirin was initiated. Two weeks later, the patient could stand holding on to the bed, and her cough abated. The dorsi and plantar flexion of ankle improved to grade 5-/5.
Written informed consent was obtained from all the family members. The Ethics committee of our hospital approved the study protocol. Blood samples were collected from the patient and her family. Genomic DNA was isolated from peripheral blood leukocytes according to standard procedures and was used as a template for PCR. The sequence information was obtained from Ensembl Genome Browser. 9 exons of the CYP27A1 were amplified by PCR. The primers were designed with Primer3 at internet. For the sequence of exon 1, we used following oligonucletides:5'CCG ATT TCG AAA GAA TCT CG 3', 5'GCA GCC TTC ACT TTC TGT CC3'. For exon 2 we used:5' CTC TGG AAC AAC AGG CCA TC 3', 5'AGA CCA TCA GGC TCA GAG GA 3'. The PCR products were sequenced directly (Invitrogen, Shanghai, China).
A Chinese family with Cerebrotendinous Xanthomatosis had typical clinical manifestation. CYP27A1 mutations were found in the proband and all other family members. Genetic analyses should be needed by asymptomatic patients in the family.
We are grateful to Dr Bin Chen and Jin-xi Lin for their help in DNA extraction and PCR. The authors also want to express their gratitude to the patients and her families for participating in this study. Written consent was obtained from the patient or their relative for publication of study.
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