CerebroTendinous Xanthomatosis (CTX) via the CYP27A1 Gene

Cerebrotendinous xanthomatosis (CTX) is rare lipid storage disease with accumulation of cholestenol and cholesterol in most tissues such as bile and brain. Elevated levels of cholestenol in these tissues leads to a variable clinical presentation that often includes chronic diarrhea, cataracts, pyramidal signs, neurological dysfunction marked by dementia, spinal cord paresis, progressive cerebellar ataxia, and multiple xanthomas of tendons and other tissues (Cali et al. 1991. PubMed ID: 2019602; Berginer et al. 2009. PubMed ID: 19117873; Cruysberg et al. 1995. PubMed ID: 7485361; Di Taranto et al. 2016. PubMed ID: 27225395). Variability in phenotype is a significant barrier to diagnosis. For example, identical adult twins have presented with considerable differences in the severity of phenotype (Zádori et al. 2017. PubMed ID: 27888347).

Infantile-onset chronic diarrhea may be the earliest clinical manifestation of CTX and followed by childhood-onset cataract, adolescent to young adult-onset tendon xanthomas, and adult-onset progressive neurologic dysfunctions (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures) (Federico et al. 1993. PubMed ID: 20301583). A study of the clinical course, genotypes and metabolic background in 175 patients with CTX observed that the incidence of tendon xanthomas was 71%, cataracts was 92%, low intelligence was 81%, and other neurologic symptoms 100% (Moghadasian. 2004. PubMed ID: 15061585). Less commonly, seizures, osteoporosis, coronary artery disease, premature atherosclerosis and Parkinsonism have been reported (Berginer et al. 2009. PubMed ID: 19117873; Gallus et al. 2010. PubMed ID: 20402754

Early diagnosis of CTX is essential as many of the clinical manifestations of this disease may be prevented by administration of chenodeoxycholic acid (CDCA) (Keren and Falik-Zaccai. 2009. PubMed ID: 19696711; Berginer et al. 2009. PubMed ID: 19117873). CDCA treatment after disease progression appears to be less effective.

The prevalence of CTX is estimated at 3 to 5 per 100,000 (Lorincz et al. 2005. PubMed ID: 16157755).

CTX is a rare autosomal recessive inborn error of bile acid synthesis due to markedly diminished activity of the mitochondrial enzyme sterol 27-hydroxylase (CYP27). The CYP27 enzyme is encoded by CYP27A1 located on the long arm of chromosome 2. CYP27 is responsible for the conversion of cholesterol to cholic and chenodeoxycholic acid. Almost all the causative variants in CYP27A1 lead to the absence of or the inactive form of CYP27 enzyme and altered urinary bile acid composition (Moghadasian. 2004. PubMed ID: 15061585; Gallus et al. 2006. PubMed ID: 16816916).

Although CTX is rare disorder worldwide, high frequency genetic islands have been reported (Keren and Falik-Zaccai. 2009. PubMed ID: 19696711). Some pathogenic variants have relatively high frequency in some ethnic groups such as p.Thr339Met (alternatively defined as p.Thr306Met) in Dutch patients, different substitutions for Arg479 amino acid (alternatively defined as Arg446) in Japanese and Sardinia patients and p.Ala216Pro (alternatively defined as p.Ala183Pro) in Italian cases (Gallus et al. 2006. PubMed ID: 16816916).

Knock-out mice model studies suggest that disruption of the CYP27 (Sterol 27-Hydroxylase) gene results in markedly reduced bile acid synthesis, but maintained levels of cholesterol and vitamin D metabolites (Rosen et al. 1998. PubMed ID: 9614081). CYP27A1 has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info). CYP27A1 is relatively tolerant to loss of function variants (Genome Aggregation Database).

So far, over 100 CTX causative variants (missense/nonsense, splicing, small and gross insertions/duplications) have been reported in CYP27A1 (Human Gene Mutation Database). Copy number variants are less frequently reported in this gene.

In one study, ~41% of all the patients with CTX had causative variants in the region of exons 6 to 8 This region encodes for adrenodoxin and haem binding sites of the protein (Verrips et al. 2000. PubMed ID: 10775536). No de novo variants in this gene have been reported to date.

CYP27A1 causative variant screening in patients identified pathogenic variants in 63 out of 64 alleles, which indicates that it is unlikely that another gene is involved in the pathogenesis of CTX (Verrips et al. 2000. PubMed ID: 10775536).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the CYP27A1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.