Two new mutations in the sterol 27-hydroxylase gene in two families lead to cerebrotendinous xanthomatosis

Verrips, Aad; Steenbergen-Spanjers, G.C.H.; Luyten, J. A. F. M.; Heuvel, L.P.W.J. van den; Keyser, A.; Gabreëls, F.J.M.; Wevers, Ron A.

doi:10.1007/s004390050294

Cited by 21 publications

(8 citation statements)

References 17 publications

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“…20 In total, we found that 54 patients of the 425 CTX cases published in the medical literature in the period 1937–2012 have had psychiatric manifestations ranging from personality changes and behavioral disorder to frank affective and psychotic disorders 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 (Tables 2 and 3). This amounts to an incidence of 12.7% for psychiatric manifestations in the CTX population.…”

Section: Resultsmentioning

confidence: 99%

Psychiatric manifestations in cerebrotendinous xanthomatosis

Fraidakis

2013

Transl Psychiatry

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Cerebrotendinous xanthomatosis (CTX) is a rare and severe, but treatable, inborn disorder of bile acid biosynthesis and sterol storage with autosomal recessive inheritance and variable clinical presentation. CTX treatment consists of chenodeoxycholic acid and must be started as early as possible to prevent permanent disability. Psychiatric manifestations are rare and non-specific, and often lead to significant diagnostic and treatment delay. Therefore, better recognition of the gamut of psychiatric manifestations in CTX can diminish the risk of misdiagnosis and irreversible neurological deterioration. We hereby describe the psychiatric features in CTX. A complete review of all published cases of CTX in the medical literature was undertaken and the case reports with psychiatric presentation were collected and analyzed. We also describe the psychiatric features in relation to the neurological semeiology in six patients with CTX diagnosed at the La Salpêtrière Hospital. We conclude that psychiatric manifestations in CTX follow a bimodal/bitemporal pattern, appearing early in the disease course in the form of a behavioral/personality disorder associated with learning difficulties or mental retardation, or manifesting in advanced disease in the setting of dementia as rich neuropsychiatric syndromes, such as frontal, orbitofrontal or frontotemporal syndromes of cortico-subcortical dementia encompassing behavioral/personality disturbance, affective/mood disorders or psychotic disorders. Behavioral/personality disturbance in childhood or adolescence, especially when accompanied by learning difficulties, should therefore lead to further investigation to exclude CTX, as early diagnosis and treatment is critical for prognosis.

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Section: Resultsmentioning

confidence: 99%

Psychiatric manifestations in cerebrotendinous xanthomatosis

Fraidakis

2013

Transl Psychiatry

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“…Exons 3-9 with their intron boundaries were subsequently amplified separately, with the two PCR fragments 3-5 and 6-9 as a template (Luyten et al, 1995). The amplimers thus obtained were subjected to single strand conformation polymorphism (SSCP) analysis, followed by sequencing and restriction analysis according to established procedures (Verrips et al, 1996).…”

Section: Molecular Biologymentioning

confidence: 99%

Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis

Verrips

Nijeholt²,

Barkhof³

et al. 1999

Brain

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We describe seven Dutch patients from six families with a slowly progressive, mainly spinal cord syndrome that remained for many years the sole expression of cerebrotendinous xanthomatosis (CTX). MRI demonstrated white matter abnormalities in the lateral and dorsal columns of the spinal cord. Post-mortem examination of one of the patients showed extensive myelin loss in these columns. An array of genotypes was found in these patients. We conclude that 'spinal xanthomatosis' is a clinical and radiological separate entity of CTX that should be included in the differential diagnosis of 'chronic myelopathy'.

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“…The disease is characterized by tendon xanthomatosis, cataracts, diverse neurologic manifestations (1), osteoporosis (2), and premature atherosclerosis (3), due to the deposition of cholesterol and cholestanol in different tissues (4,5). Following the cloning of human sterol 27-hydroxylase cDNA (6) and determination of its genomic structure (7), several types of mutation, including insertion (8), deletion (9,10), and point mutations (11)(12)(13)(14)(15)(16)(17)(18) of the CYP27 gene, have been identified, in CTX patients from different countries.…”

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A Novel Arg³⁶²Ser Mutation in the Sterol 27-Hydroxylase Gene (CYP27): Its Effects on Pre-mRNA Splicing and Enzyme Activity

et al. 1998

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A novel C to A mutation in the sterol 27-hydroxylase gene (CYP27) was identified by sequencing amplified CYP27 gene products from a patient with cerebrotendinous xanthomatosis (CTX). The mutation changed the adrenodoxin cofactor binding residue 362Arg to 362Ser (CGT 362Arg to AGT 362Ser), and was responsible for deficiency in the sterol 27-hydroxylase activity, as confirmed by expression of mutant cDNA into COS-1 cells. Quantitative analysis showed that the expression of CYP27 gene mRNA in the patient represented 52.5% of the normal level. As the mutation occurred at the penultimate nucleotide of exon 6 (-2 position of exon 6-intron 6 splice site) of the gene, we hypothesized that the mutation may partially affect the normal splicing efficiency in exon 6 and cause alternative splicing elsewhere, which resulted in decreased transcript in the patient. Transfection of constructed minigenes, with or without the mutation, into COS-1 cells confirmed that the mutant minigene was responsible for a mRNA species alternatively spliced at an activated cryptic 5' splice site 88 bp upstream from the 3' end of exon 6. Our data suggest that the C to A mutation at the penultimate nucleotide of exon 6 of the CYP27 gene not only causes the deficiency in the sterol 27-hydroxylase activity, but also partially leads to alternative pre-mRNA splicing of the gene. To our knowledge, this is the first report regarding effects on pre-mRNA splicing of a mutation at the -2 position of a 5' splice site.

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Two new mutations in the sterol 27-hydroxylase gene in two families lead to cerebrotendinous xanthomatosis

Cited by 21 publications

References 17 publications

Psychiatric manifestations in cerebrotendinous xanthomatosis

Psychiatric manifestations in cerebrotendinous xanthomatosis

Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis

A Novel Arg³⁶²Ser Mutation in the Sterol 27-Hydroxylase Gene (CYP27): Its Effects on Pre-mRNA Splicing and Enzyme Activity

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Two new mutations in the sterol 27-hydroxylase gene in two families lead to cerebrotendinous xanthomatosis

Cited by 21 publications

References 17 publications

Psychiatric manifestations in cerebrotendinous xanthomatosis

Psychiatric manifestations in cerebrotendinous xanthomatosis

Spinal xanthomatosis: a variant of cerebrotendinous xanthomatosis

A Novel Arg362Ser Mutation in the Sterol 27-Hydroxylase Gene (CYP27): Its Effects on Pre-mRNA Splicing and Enzyme Activity

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A Novel Arg³⁶²Ser Mutation in the Sterol 27-Hydroxylase Gene (CYP27): Its Effects on Pre-mRNA Splicing and Enzyme Activity