Unusual cerebrotendinous xanthomatosis with fronto-temporal dementia phenotype.
ABSTRACT Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP27). We report a 53-year-old man, with an unusual phenotype of CTX. He had xanthomas since adolescence. He had no mental retardation and developed at 44 years a progressive neuropsychiatric phenotype, suggestive of fronto-temporal dementia according to clinical Neary criteria. Cataract and ataxia were absent. Cerebral MRI revealed diffuse hyperintense T2 abnormalities in the supratentorial white matter without cerebellar atrophy or lesions, while Technetium-99m-ECD brain SPECT revealed a severe cerebellar hypoperfusion. Serum cholestanol level was elevated with excessive urinary bile alcohols excretion. Mutation analysis revealed that he was compound heterozygous for two mutations in the CYP27A1 gene: 1016 C > T (exon 5) on one allele and a novel mutation, 1435C > G (exon 8) on the other allele. A follow-up study was conducted to evaluate the effects of chenodeoxycholic acid (CDCA) and simvastatin treatment during 3 years. In spite of this treatment, cognitive functions declined but no other signs of neurological deterioration appeared.
Article: Multi-parametric neuroimaging evaluation of cerebrotendinous xanthomatosis and its correlation with neuropsychological presentations.[show abstract] [hide abstract]
ABSTRACT: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder. Recent studies show that brain damage in CTX patients extends beyond the abnormalities observed on conventional magnetic resonance imaging (MRI). We studied the MRI and 99 mTc-ethyl cysteinate dimer single photon emission computed tomography (SPECT) findings of CTX patients and made a correlation with the neuropsychological presentations. Diffusion tensor imaging (DTI) and 3D T1-weighted images of five CTX patients were compared with 15 age-matched controls. Voxel-based morphometry (VBM) was use to delineate gray matter (GM) and white matter (WM) volume loss. Fractional anisotropy (FA), mean diffusivity (MD), and eigenvalues derived from DTI were used to detect WM changes and correlate with neuropsychological results. SPECT functional studies were used to correlate with GM changes. Cognitive results showed that aside from moderate mental retardation, the patient group performed worse in all cognitive domains. Despite the extensive GM atrophy pattern, the cerebellum, peri-Sylvian regions and parietal-occipital regions were correlated with SPECT results. WM atrophy located in the peri-dentate and left cerebral peduncle areas corresponded with changes in diffusion measures, while axial and radial diffusivity suggested both demyelinating and axonal changes. Changes in FA and MD were preceded by VBM in the corpus callosum and corona radiata. Cognitive results correlated with FA changes. In CTX, GM atrophy affected the perfusion patterns. Changes in WM included atrophy, and axonal changes with demyelination. Disconnection of major fiber tracts among different cortical regions may contribute to cognitive impairment.BMC Neurology 01/2010; 10:59. · 2.17 Impact Factor
Article: A novel mutation in the sterol 27-hydroxylase gene of a woman with autosomal recessive cerebrotendinous xanthomatosis.[show abstract] [hide abstract]
ABSTRACT: Mutations of the gene encoding the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1 gene) cause defects in the cholesterol pathway to bile acids that lead to the storage of cholestanol and cholesterol in tendons, lenses and the central nervous system. This disorder is the cause of a clinical syndrome known as cerebrotendinous xanthomatosis (CTX). Since 1991 several mutations of the CYP27A1 gene have been reported. We diagnosed the clinical features of CTX in a caucasian woman. Serum levels of cholestanol and 7α-hydroxycholesterol were elevated and the concentration of 27-hydroxycholesterol was reduced. Bile alcohols in the urine and faeces were increased. The analysis of the CYP27A1 gene showed that the patient was a compound heterozygote carrying two mutations both located in exon 8. One mutation is a novel four nucleotide deletion (c.1330-1333delTTCC) that results in a frameshift and the occurrence of a premature stop codon leading to the formation of a truncated protein of 448 amino acids. The other mutation, previously reported, is a C - > T transition (c. c.1381C > T) that converts the glutamine codon at position 461 into a termination codon (p.Q461X). These truncated proteins are expected to have no biological function being devoid of the cysteine residue at position 476 of the normal enzyme that is crucial for heme binding and enzyme activity.Orphanet Journal of Rare Diseases 10/2010; 5:27. · 5.83 Impact Factor