Brain, Vol. 123, No. 5, 908-919,
May 2000
© 2000 Oxford University Press
Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis
1 Department of Neurology, 2 Department of Human Genetics and 3 Laboratory of Pediatrics and Neurology, University Hospital Nijmegen, Nijmegen, The Netherlands
Correspondence to:
L. P. W. J. van den Heuvel, Laboratory of Pediatrics and Neurology, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands E-mail: B.vandeHeuvel{at}ckslkn.azn.nl
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Abstract |
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Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP 27), due to mutations in its gene. In this study we report on mutations in 58 patients with CTX out of 32 unrelated families. Eight of these were novel mutations, two of which were found together with two already known pathogenic mutations. Twelve mutations found in this patient group have been described in the literature. In the patients from 31 families, mutations were found in both alleles. In the literature, 28 mutations in 67 patients with CTX out of 44 families have been described. Pooling our patient group and the patients from the literature together, 37 different mutations in 125 patients out of 74 families were obtained. Identical mutations have been found in families from different ethnic backgrounds. In 41% of all the patients, CYP 27 gene mutations are found in the region of exons 6–8. This region encodes for adrenodoxin and haem binding sites of the protein. Of these 125 patients, a genotype–phenotype analysis was done for 79 homozygous patients harbouring 23 different mutations, out of 45 families. The patients with compound heterozygous mutations were left out of the genotype–phenotype analysis. The genotype–phenotype analysis did not reveal any correlation.
cerebrotendinous xanthomatosis; mutations; genotype–phenotype correlation; pathogenesis
CTX = cerebrotendinous xanthomatosis; CYP 27 = sterol 27-hydroxylase
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Introduction |
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Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP 27). Because of this deficiency, large amounts of cholestanol and cholesterol are produced. These metabolites accumulate in many tissues, especially eye lenses, the CNS and muscle tendons. Besides the cholestanol and cholesterol production, large amounts of bile alcohols are produced in CTX, which are excreted in urine. Clinical characteristics of CTX are premature bilateral cataracts, formation of tendon xanthomas (most often in the Achilles tendons), neurological and neuropsychiatric abnormalities such as pyramidal and cerebellar signs, peripheral neuropathy and dementia (Björkhem and Boberg, 1995
). Most patients have cerebellar signs and dementia from the age of 20 years onwards. In childhood, the combination of bilateral cataracts and diarrhoea is almost pathognomonic for the disease (Cruysberg et al., 1991; van Heijst et al., 1996). The biochemical diagnosis is made by determination of the serum cholestanol level and by the determination of bile alcohol excretion in urine (Wolthers et al., 1983, 1991).
In 1989, Andersson and colleagues characterized the cDNA encoding rabbit mitochondrial CYP 27 starting with rabbit enzyme protein, which is a member of the mitochondrial cytochrome P-450 enzyme family (Andersson et al., 1989). In 1991, the cDNA for human CYP 27 was isolated by hybridizing rabbit cDNA to a liver cDNA library and its gene was localized on the long arm of chromosome 2 (Cali and Russell, 1991). The genomic structure of the CYP 27 gene was elucidated in 1993; the gene contains nine exons and eight introns and spans 18.6 kb of DNA (Leitersdorf et al., 1993). The mature enzyme consists of 498 amino acids and contains putative binding sites for adrenodoxin and haem; these sites are encoded by the region between exons 6 and 8 (Leitersdorf et al., 1993). The enzyme is expressed in the CNS, liver, lung, duodenum and endothelial cells (Reiss et al., 1997). In 1991, the first mutations in the CYP 27 gene were described (Cali et al., 1991).
In this paper we present the phenotypes and genotypes (including eight novel mutations) of 58 patients with CTX out of 32 families, of which 21 were Dutch families; this is the largest series ever reported. We have reviewed the literature and identified 67 additional CTX patients out of 44 families in whom the genotype had been established. Finally, we have performed a genotype–phenotype analysis for 79 homozygous patients harbouring 23 different mutations, out of 45 families.
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Patients
Between 1983 and 1998 the clinical and biochemical information of 42 Dutch CTX patients, of which seven were children, out of 21 families in the Netherlands were collected. DNA from these 42 patients and from 16 CTX patients out of 11 families from the UK, Belgium, Spain, Tunisia, Germany and China was also analysed. All patients had elevated serum cholestanol levels and an excessive urinary excretion of bile alcohols, measured according to Wolthers and colleagues using capillary gas chromatography (Wolthers et al., 1983
, 1991). Informed consent was obtained from each participating subject or the parents of younger children. The study was approved by the Ethics Committee of the University Hospital Nijmegen, The Netherlands.
Mutation analysis
The CYP 27 gene was amplified in four fragments (exons 1, 2, 3–5 and 6–9), by PCR (polymerase chain reaction) from genomic DNA of leucocytes. Exons 3–9 with their intron boundaries were subsequently amplified separately, with the two PCR fragments 3–5 and 6–9 as templates (Luyten et al., 1995). The oligonucleotides used as primers for PCR amplification and for sequence analysis are those described by Leitersdorf and colleagues (Leitersdorf et al., 1993). Human genomic DNA from patients from these 32 families was screened for mutations in the CYP 27 gene by single strand conformation polymorphism analysis using the Pharmacia Phast System (Amersham Pharmacia Biotech. Ruusendaal, The Netherlands), or were directly sequenced. Cycle sequencing of the coding and the non-coding strands was carried out by the Taq Dye Deoxy Terminator method (Applied Biosystems Inc., Forster City, Calif., USA) using an ABI 377 DNA sequencer.
To analyse the effects of the splice site mutations, RNA from cultured fibroblasts was reverse transcribed to cDNA according to established procedures (Ploos van Amstel et al., 1996; Verrips et al., 1997). The CTX cDNA, amplified by PCR, was used for agarose gel electrophoresis and for DNA sequence analysis, as described above. The segregation of novel mutations has been studied in members of families 6, 14, 16, 21, 28, 31 and 32 (Table 1). In families 24 and 30 no family members could be evaluated.
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Results |
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Patients
The clinical characteristics of 54 patients are listed in Table 1
. In 10 of the 32 families, three patients were present and in six families two patients. Sixteen patients were sporadic cases and accurate clinical information could not be obtained in two families (19 and 29). The phenotypes of families 2–8, 10, 12–16, 24 and 31 have been described in previous publications. In two families (16 and 18) consanguinity was present: in both families the parents are first cousins. Among the general signs, bilateral premature cataracts were present in 90% of the patients, tendon xanthomas in 45% and intractable diarrhoea in 33%. Among the most frequent neurological signs were pyramidal (67%) and cerebellar signs (60%) and low intelligence (57%). Epilepsy and peripheral neuropathy were both present in 24% of the patients. The high prevalence of diarrhoea in our patient group in contrast to reports in the literature may be due to the fact that it is generally not known that diarrhoea is an important phenomenon in this mainly neurological disease. In all patients, excessive amounts of bile alcohols were found in the urine. In the patients in whom serum cholestanol levels were determined, elevated levels were found. Cranial MRI findings were available in 34 patients. In two-thirds of the patients global atrophy and parenchymal lesions were seen. In the majority of the patients in whom an EMG was performed, axonal neuropathy could be established. Evoked potentials studies (visual evoked potential, brainstem auditory evoked potential and somatosensory evoked potential) revealed delayed central conduction times. A diffuse slowing with paroxysmal discharges were the main EEG findings.
Mutations
Mutations found in the 32 families, together with their distribution among these families and the mutations described in the literature are listed in Table 2. The distribution of the mutations over the CYP 27 gene is depicted in Fig. 1. In the 32 families presented, 20 different mutations were found of which 12 were discovered in the Dutch CTX patients.
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Eight novel mutations were found in the 32 families presented. A 1151C
T transition in exon 6, resulting in the substitution of proline by leucine in codon 384 (families 5, 14, 16 and 26), and a 1213CT transition in exon 7, resulting in replacement of arginine by tryptophan in codon 405 (family 6), were observed. A missense mutation in exon 6 was found in the same allele as a C insertion in exon 1 on position 5–6, an already known mutation (Segev et al., 1995) (Table 2). We found these two mutations on the same allele in families 5, 14, 16 and 26. In one allele from the patients of family 16 and in both alleles in their mother, no mutation in the CYP 27 gene was found, indicating a co-segregation of these two mutations. In families 24 and 32, a 776AG transition in exon 4, resulting in substitution of lysine by arginine in codon 259, was found. On the other allele in family 24, a novel nonsense mutation was present: a 779GA transition in exon 4, changing codon 260 into an opal termination codon. Another novel nonsense mutation was found in family 31: a 745CT transition in exon 4 changing codon 249 into an amber termination codon, together with a splice site mutation on the other allele were present. In family 21, patients were compound heterozygotes for a novel splice site mutation: a 446+1ga transition in the splice donor site in intron 2. On the other allele a missense mutation in exon 2 was found (already known) (Watts et al., 1996). In family 30, a 1061AG transition leading to a replacement of asparagine by glycine in codon 354 was found, together with an already known splice site mutation on the other allele (Garuti et al., 1997). A 1415GA homozygous transition in exon 8, resulting in the substitution of glycine by alanine in codon 472 was found in family 29, together with the known 1016CT transition in exon 5 (Reshef et al., 1994). None of the novel mutations mentioned above were found in any of the 50 controls (100 alleles).
Overview of mutations in the Dutch CTX patients and in the world literature
In the Dutch CTX patients, three mutations were most frequent, being found in almost two-thirds of the alleles. These were the 1016CT transition in exon 5 (Reshef et al., 1994), a 1263+1g a transition in intron 7, leading to exon skipping and a frameshift (Garuti et al., 1996b), and finally the 5–6 C insertion in exon 1 (Segev et al., 1995), together with the exon 6 1151CT missense mutation. Since these recurrent mutations were identified in patients from different geographical origins, it is likely that they are ancient variants occurring frequently in CTX. An additional 42 families (67 patients) in whom genotyping has been done were identified from the literature. These, taken together with our 32 families, gave a total of 45 families which were homozygous for one mutation, and 29 families which were compound heterozygous.
Mutations 2, 5, 6, 9, 16, 18, 24, 25, 34, 35 and 37 were only found in homozygous patients. Mutations 1, 4, 6, 10, 15, 17, 19, 20, 23, 26, 27, 30, 31 and 36 were found in both homozygous and compound heterozygous families. Mutations 3, 7, 8, 11–14, 21, 22, 28–30, 32 and 33 were only found in compound heterozygous patients.
Overall, five mutations were found in eight or more alleles (Fig. 2). These are mutations 2 (in Israeli Druze patients only), 20 (in Sephardic Jews, Chinese and Dutch patients), 23 (USA, Belgium, The Netherlands, Germany), 31 (Italy, UK, the Netherlands), and 30, 34 and 36 (only in the Japanese patients).
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Of all point mutations identified in the CYP 27 gene, eight were transversions and 26 were transitions. There were 13 point mutations in CpG dinucleotides; eight C
T transitions together with four GA transitions were found in the same codon. These mutations led to a substitution of arginine by another amino acid. Codon 395 was affected in three patients by a point mutation. Several non-CpG point mutations were found within 10 bp up- or downstream of mutation sites harbouring tetra- and trinucleotide motifs. These gene structures are hypothesized to be hotspots for point mutations or deletions (Cooper et al., 1995). Two CTTT tetranucleotide motifs were present in exon 4 in the vicinity of mutations 17 and 18. A TTTG motif was present in exon 3 (mutation 10) and in exon 8 in the neighbourhood of mutation 35. Trinucleotide motifs were CTT (mutations 10) and TGA (mutation 21). Tetra- and trinucleotide motifs within a 10 bp region of deletions were AAGT (mutation 2), CTTT (mutation 9), TTGG and GAA (mutation 16).
Genotype–phenotype correlations
Genotypical and phenotypical characteristics of 125 patients out of 74 families identified in the literature, together with the presented cohort were determined. Forty-six patients out of 29 families were compound heterozygous, 79 patients (45 families) were homozygous for 23 different mutations. In these homozygous patients we examined possible differences in sex, age of onset, diagnosis, biochemical characteristics and the presence of signs and symptoms with respect to mutation site (exon 1–5 versus exon 6–9) and mutation type (missense versus other types of mutations, frameshift or mutations resulting in a premature termination codon versus other types of mutations). No specific genotype–phenotype correlation could be established.
Apart from the different phenotypes displayed between patients from different families, there is also a striking intrafamilial phenotypic variability in CTX (Dotti et al., 1996; Nagai et al., 1996) (Table 1).
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Discussion |
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The diagnosis of all the CTX patients was made on clinical grounds. The biochemical diagnosis was made by the determination of the bile alcohols in urine and of the cholestanol in serum, rather than by measurement of the CYP 27 enzyme activity. As mutations in the CYP 27 gene were found in 63 of the 64 alleles in all of these patients, it is highly unlikely that another gene is involved in the pathogenesis of CTX.
Including the novel mutations presented in the current patient cohort, 37 different mutations have been described in the CYP 27 gene in CTX patients. They consist of 16 missense mutations (resulting in amino acid replacements), three mutations in the last nucleotides of exons (resulting in both amino acid replacements and affecting pre-mRNA splicing), three deletions, one insertion, eight splice site and six nonsense mutations (Cali et al., 1991; Leitersdorf et al., 1993, 1994; Kim et al., 1994; Meiner et al., 1994; Nakashima et al., 1994; Reshef et al., 1994; Segev et al., 1995; Garuti et al., 1996a, b, 1997; Okuyama et al., 1996; Watts et al., 1996; Verrips et al., 1996, 1997, 1999a; Ahmed et al., 1997; Chen et al., 1996, 1997, 1998a, b, c).
In 19 of the 32 families in this study, mutations were located in the region of exons 6–8 of the CYP 27 gene. Although the mutations were distributed throughout the whole gene, 15 of the 37 mutations (41%) were found in this region that comprises 28.4% of the nucleotides of the CYP 27 gene. This finding may indicate that this conserved part of the gene, coding for adrenodoxin and haem binding sites, plays a pivotal role in the function of the enzyme. The pathogenicity of individual CTX mutations is based on their predicted effect on the CYP 27 protein and on segregation in families. None of the novel mutations were found during the analysis of 50 control chromosomes. Among the CYP 27 gene mutations identified in our CTX cohort are variants which are likely to have deleterious effects on the function of the CYP 27 protein. Thus, the deletion/insertion (mutations 1 and 9), and nonsense mutations (mutations 8, 12, 14) will cause premature termination of translation and result in truncated CYP 27 proteins. The different splice site mutations (mutations 7, 17, 26, 31) will lead to incorrect splicing and exon skipping, resulting in incorrect CYP 27 proteins. However, the majority of the mutations detected in the CTX cohort are amino acid substitutions. Our data, together with the results of previous studies, indicate that 16 out of 37 are missense mutations of which five are novel to the described patient cohort. These mutations are inferred to be pathogenic when they substitute amino acids, which, in view of their conservation through evolution, are presumed to be of functional importance. Except for the 1061AG transition, which leads to a replacement of asparagine by glycine in codon 354, all novel missense mutations detected in our CTX cohort are substitutions of strongly conserved amino acids by non-conservative ones (Table 3). Three novel missense mutations (mutations 3, 13, 22) were found in unrelated CTX families. Except for the presence of two mutations together on the same allele in families 5, 14, 16 and 26, screening of the remaining exons of the CYP 27 gene in patients with missense mutations did not reveal other mutations. Therefore, it is likely that these missense mutations are indeed pathogenic mutations and not innocuous polymorphisms. However, the ultimate proof that these amino acid substitutions can indeed result in impairment of CYP 27 function are expression studies which are currently being conducted in our laboratory. In one allele of the patients from family 16, no mutations were found. In the mother of these patients the absence of mutations in the CYP 27 gene indicated co-segregation of mutations 1 and 22. It is possible that in this family, a mutation is present in the promoter region of the CYP 27 gene or at a branch point within one of the introns.
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It is remarkable that the amino acid arginine is frequently involved in missense mutations. In 12 missense mutations, there is involvement of CpG dinucleotides leading to the replacement of arginine by another amino acid. Arginine can form two hydrogen bonds which may be of major importance for the conservation of tertiary structure or may play a role in substrate binding. Both of these aspects could influence the catalytic activity of the enzyme.
Mutations 1, 3, 4, 10, 15, 19, 20, 22, 23, 26 and 31 were found in CTX patients from different ethnic backgrounds (Table 2). The mutations may be ancient variants frequently occurring in CTX. In order to determine whether these mutations are introduced into the population by a single founder, it is necessary to study the chromosome 2 haplotypes of the patients carrying these identical mutations.
In a large series of 58 CTX patients out of 32 unrelated families, we found 21 different mutations and a striking phenotypic heterogeneity, even within families. No genotype–phenotype correlation could be established with these patients taken together with all CTX patients reported in the literature. Several authors have stressed the marked phenotypic heterogeneity between CTX patients, even between patients with the same mutation (Dotti et al., 1996; Nagai et al., 1996). Since the phenotype varies between patients independent of their biochemical characteristics, other features must be responsible for these clinical differences and it has been suggested that environmental factors are responsible (Chen et al., 1996; Nagai et al., 1996; Garuti et al., 1997). In CTX the same mutation may result in different phenotypes, or mutations at different sites of the CYP 27 gene may result in the same or in different phenotypes. Recently, we described a spinal variant of CTX, spinal xanthomatosis, that has a relatively mild clinical course compared with the classic form of CTX, which shows cerebellar involvement, dementia, tendon xanthoma formation and peripheral neuropathy early in the disease process. Mutation analysis in these patients revealed missense mutations, predominantly in exons 5 and 6 of the gene, that were also found in the classical form of CTX (Verrips et al., 1999a). This polyphenotypy in CTX is the result of a complex pathophysiology. The CYP 27 deficiency, caused by mutations in the CYP 27 gene, leads to several, different cascades of metabolic derangement, such as excessive production of cholestanol and bile alcohols (Batta et al., 1987; Björkhem and Boberg, 1995). The contribution of each of these pathological metabolic processes to the phenotype is poorly understood at the present time. The excessive cholestanol production and its accumulation within many tissues, particularly the CNS, play a major role in the disease process. Recently it was shown that in rats fed a cholestanol enriched diet, cholestanol accumulated in Purkinje cells, resulting in apoptosis (Inoue et al., 1999). However, in patients with sitosterolaemia, a rare lipid storage disorder, serum hypercholestanolaemia is also found. These patients do not develop neurological disease (Björkhem and Boberg, 1995).
In 1987 it was reported that a defect of the blood–brain barrier was present in CTX, which was reflected by an elevation of the CSF/serum albumin quotient (Salen et al., 1987). In the CSF, high amounts of apolipoprotein B, the protein component of low-density lipoproteins and a carrier of cholestanol, were present. This finding suggested an increased influx of sterols from the blood into the CNS. The defect in the blood–brain barrier disappears after several months of chenodeoxycholic acid therapy, so the deficiency of CYP 27 itself cannot be responsible for this dysfunction. It can be hypothesized that the phenotype in CTX is the result of a primary membrane dysfunction, followed by an increased influx of sterols into the eye lens (blood–lens barrier), the CNS (blood–brain barrier), peripheral nerves (blood–nerve barrier), and vessel wall (endothelial cell membrane) leading to accelerated arteriosclerosis.
It is unlikely that use of an animal model will clarify the complex genotype–phenotype relationship. Mice with a disrupted CYP 27 gene, which resulted in a markedly reduced synthesis of bile acids, had normal plasma levels of cholesterol and cholestanol. In bile and in faeces of these CYP 27 –/– mice, only traces of bile alcohols were found. There was no cholestanol accumulation or CTX-related pathological abnormalities (Rosen et al., 1998).
Since 1975, chenodeoxycholic acid has been commonly used as a therapy for CTX (Salen et al., 1975) and has proven to be effective (Berginer et al., 1984). With this therapy there is a considerable decrease in the serum cholestanol level and a sharp decline in the excretion of bile alcohols in the urine (Wolthers et al., 1983; Batta et al., 1985). Perhaps the most effective inhibitor of cholestanol production is a combination of chenodeoxycholic acid with a ß-HMG-CoA reductase inhibitor, resulting in a further lowering of an already normal serum cholestanol level (Verrips et al., 1999b) and facilitating the long-term washout of cholestanol from the CNS. Finally, as therapy is available, the early recognition of CTX is important. Because of the phenotypic heterogeneity, in all siblings of novel CTX patients determination of the genotype must be done to exclude or confirm the diagnosis.
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Acknowledgments |
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The authors wish to thank F. Barkhof, Department of Diagnostic Radiology, Free University Hospital, Amsterdam, The Netherlands, for the evaluation of the MRIs, and R. P. Kleyweg (family 25), Department of Neurology, Hospital Dordrecht; M. de Visser (family 18), B. M. van Geel (family 23) and J. J. P. Kastelein (family 2), Academic Medical Centre, Amsterdam; J. W. B. Moll (family 10), University Hospital Rotterdam; J. H. J. Wokke (family 3), Department of Neurology, University Hospital Utrecht, Utrecht, The Netherlands; S. Tam (family 29), Department of Clinical Biochemistry, Queen Mary Hospital, Hong Kong, China; R. Denays (family 26), Department of Neurology, New Paul Brien Centre, Brussels, Belgium; P. Hart (family 27), Neurology Department, Atkinson Morley's Hospital, London, UK; R. Pérez Moyano (family 21), Almeria, Spain; T. J. Walls (family 31), Regional Neurosciences Centre, Newcastle upon Tyne, UK; J. Mebis (family 28), Algemeen Ziekenhuis Middelheim, Department of Internal Medicine, Antwerpen, Belgium; N. Miladi (family 20), Institut National de Neurologie, Tunis, Tunisia; L. van Malderghem (family 19), Institute de Pathologie et de Génétique, Gerpinnes (Loverval), Belgium; R. Kimmelre (families 30 and 32), Heinrich Heine Universität Düsseldorf, Klinik für Stoffwechselkrankheiten und Ernährung, Düsseldorf, Germany; and S. Berndt (family 24), Department of Neurology, Paderborn, Germany for referring the patients.
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Received July 15, 1999. Revised October 12, 1999. Accepted November 11, 1999.
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