CYP27A1 Mutations Research Articles

A Rare Symptomatic Case of Heterozygous Cerebro-Tendinous Xanthomatosis (CTX) Treated with Urso-Deoxycholic Acid (UDCA): With Mini Review

Cerebrotendinous Xanthamatosis (CTX) is a rare autosomal recessive disorder caused by a mutation in the CYP27A1 gene leading to impaired metabolism of cholesterol and accumulation of cholestenol and the cholesterol in various tissues such as the brain, eyes, lungs and bones and reduced formation of cheno-deoxycholic acid (CDCA). The clinical presentation is diverse, starting in the early neonatal period and progressing till adulthood unless treated early. A common neurological manifestation is a spino-cerebellar ataxia followed by spastic paraparesis. Tendon xanthoma is a classical finding that usually helps in clinching the diagnosis but may not be present in all cases. Brain MRI also reveals characteristic abnormalities with cerebellar atrophy and hyper-intensities in the dentate nucleus and surrounding cerebellar white matter on T1weighted images. It is a rare cause of treatable ataxia in young individuals. Treatment is by replacement by CDCA or Urso-deoxycholic acid (UDCA). Supplemented with statins these individuals also have premature atherosclerosis causing death due to athero-sclerotic coronary artery disease. Here a rare case of symptomatic heterologous CYP27A1 mutation is reported with syndrome of spino-cerebellar ataxia treated with UDCA.

Rare genetic cerebrotendinous xanthomatosis (CTX) cases without cholestanol elevation but with prominent cholesterol-rich tendon xanthomas

Cerebrotendinous xanthomatosis (CTX) is a rare inherited metabolic disease attributed to the mutation of the gene CYP27A1, resulting in sterol 27-hydroxylase deficiency characterized by deposition of cholestanol and cholesterol in several tissues, like the central nervous system and tendons. Furthermore, cataracts, gallstones, diarrhea and premature atherosclerosis have been reported. Nonetheless, clinical development is extremely heterogeneous in CTX. We report here two cases of CTX genetic alteration in the absence of cholestanol elevation in plasma and tendons but with prominent xanthomas. We propose that CTX may not be characteized by increased plasma cholestanol concentration due to alteration in the sterol 27-hydroxylase gene, but is a more complex pathology where there is significant genetic heterogeneity caused by various CYP27A1 mutations.

Cerebrotendinous xanthomatosis presenting with schizophrenia-like disorder: A case report

BACKGROUND Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid-storage disorder caused by mutations in CYP27A1 . Psychiatric manifestations in CTX are rare and nonspecific, and they often lead to considerable diagnostic and treatment delay. CASE SUMMARY A 33-year-old female patient admitted to the psychiatric ward for presentation of delusions, hallucinations, and behavioral disturbance is reported. The patient presented with cholestasis, cataract, Achilles tendon xanthoma, and cerebellar signs in adulthood and with intellectual disability and learning difficulties in childhood. After the characteristic CTX findings on imaging were obtained, a pathological examination of the Achilles tendon xanthoma was refined. Re-placement therapy was then initiated after the diagnosis was clarified by genetic analysis. During hospitalization in the psychiatric ward, the nonspecific psychiatric manifestations of the patient posed difficulty in diagnosis. After the patient’s history of CTX was identified, the patient was diagnosed with organic schizophrenia-like disorder, and psychotic symptoms were controlled by replacement therapy combined with antipsychotic medication. CONCLUSION Psychiatrists should be aware of CTX, its psychiatric manifestations, and clinical features and avoid misdiagnosis of CTX for timely intervention.

Chenodeoxycholic acid rescues axonal degeneration in induced pluripotent stem cell-derived neurons from spastic paraplegia type 5 and cerebrotendinous xanthomatosis patients

BackgroundBiallelic mutations in CYP27A1 and CYP7B1, two critical genes regulating cholesterol and bile acid metabolism, cause cerebrotendinous xanthomatosis (CTX) and hereditary spastic paraplegia type 5 (SPG5), respectively. These rare diseases are characterized by progressive degeneration of corticospinal motor neuron axons, yet the underlying pathogenic mechanisms and strategies to mitigate axonal degeneration remain elusive.MethodsTo generate induced pluripotent stem cell (iPSC)-based models for CTX and SPG5, we reprogrammed patient skin fibroblasts into iPSCs by transducing fibroblast cells with episomal vectors containing pluripotency factors. These patient-specific iPSCs, as well as control iPSCs, were differentiated into cortical projection neurons (PNs) and examined for biochemical alterations and disease-related phenotypes.ResultsCTX and SPG5 patient iPSC-derived cortical PNs recapitulated several disease-specific biochemical changes and axonal defects of both diseases. Notably, the bile acid chenodeoxycholic acid (CDCA) effectively mitigated the biochemical alterations and rescued axonal degeneration in patient iPSC-derived neurons. To further examine underlying disease mechanisms, we developed CYP7B1 knockout human embryonic stem cell (hESC) lines using CRISPR-cas9-mediated gene editing and, following differentiation, examined hESC-derived cortical PNs. Knockout of CYP7B1 resulted in similar axonal vesiculation and degeneration in human cortical PN axons, confirming a cause-effect relationship between gene deficiency and axonal degeneration. Interestingly, CYP7B1 deficiency led to impaired neurofilament expression and organization as well as axonal degeneration, which could be rescued with CDCA, establishing a new disease mechanism and therapeutic target to mitigate axonal degeneration.ConclusionsOur data demonstrate disease-specific lipid disturbances and axonopathy mechanisms in human pluripotent stem cell-based neuronal models of CTX and SPG5 and identify CDCA, an established treatment of CTX, as a potential pharmacotherapy for SPG5. We propose this novel treatment strategy to rescue axonal degeneration in SPG5, a currently incurable condition.

Prospective cholestanol screening of cerebrotendinous xanthomatosis among patients with juvenile-onset unexplained bilateral cataracts

BackgroundCerebrotendinous xanthomatosis (CTX) is a rare genetic disorder related to CYP27A1 biallelic mutations, leading to decreased synthesis of bile acids and increased cholestanol. Juvenile bilateral cataracts are one of the most common findings in the disease, frequently occurring before the onset of neurological manifestations. While early treatment with chenodeoxycholic acid can prevent the onset of neurological impairment, poor awareness of CTX accounts for a markedly delayed diagnosis. The objective of this study was to evaluate the utility of plasma cholestanol analysis at the moment of cataract diagnosis and before the onset of neurological impairment in CTX.MethodsMulticenter prospective cohort study of patients with juvenile-onset unexplained bilateral cataracts recruited from seven French ophthalmology departments. Plasma cholestanol analysis was performed at diagnosis from January 2018 to January 2020. CYP27A1 genetic testing was performed at the ophthalmologist’s discretion. Cholestanol levels were compared with those of a similar population of patients without cataracts (control cohort).Results30 patients were finally recruited, with a mean age at cataract diagnosis of 7.1 years (± 4.8 SD, range 1–19 years). One patient had a very high cholestanol level (68 μmol/L, reference < 10) and carried two pathogenic heterozygous mutations in CYP27A1 confirming CTX. This patient was a 19-year-old female, reporting chronic diarrhea only in childhood, and diagnosed with bilateral posterior cataracts with cortical fleck-like opacities. Therefore, the incidence of CTX in our cohort of patients was 3.3%. Five further patients (5/29; 17.2%) had moderate elevations of cholestanol level (between 10.3 and 16.5 μmol/L), compared to 12/286 (4.2%) in the control cohort (p = 0.014) after adjustment for age.ConclusionOur study argue for the relevance of plasma cholestanol CTX screening in all patients with juvenile-onset unexplained cataracts, even without other CTX identified manifestations. Whether moderate elevations of plasma cholestanol unrelated to CTX may be a risk factor for bilateral cataracts occurrence needs further examination.

Differing clinical features between Japanese siblings with cerebrotendinous xanthomatosis with a novel compound heterozygous CYP27A1 mutation: a case report

BackgroundCerebrotendinous xanthomatosis (CTX) is an autosomal-recessive lipid storage disorder caused by mutations in the CYP27A1 gene encoding the key enzyme in the bile acid synthesis, sterol 27-hydroxylase. Here, we report two Japanese CTX siblings with a novel compound heterozygous CYP27A1 mutation, showing different clinical phenotypes and responses to chenodeoxycholic acid (CDCA) therapy.Case presentationThe proband, a 32-year-old man, who had chronic diarrhea, bilateral cataracts, and xanthomas, demonstrated progressive neurological manifestations including ataxia, and spastic paraplegia during a 5-year follow-up period despite normalization of serum cholestanol after initiation of CDCA treatment. He also exhibited cognitive decline although improvement had been observed at the beginning of treatment. Follow-up brain magnetic resonance imaging (MRI) revealed pronounced progressive atrophy in the cerebellum, in addition to expanding hyperintense lesions in the dentate nuclei, posterior limb of the internal capsule, cerebral peduncles, and inferior olives on T2-weighted images. In contrast, the two-year-younger sister of the proband presented with chronic diarrhea, cataracts, xanthomas, and intellectual disability but no other neurological symptoms at the time of diagnosis. CDCA treatment lead to improvement of cognitive function and there were no characteristic CTX-related MRI features during the follow-up period. The siblings shared a paternally inherited c.1420C > T mutation (p.Arg474Trp) and a maternally inherited novel c.1176_1177delGA mutation, predicting p.(Glu392Asp*20).ConclusionsOur cases suggest that early diagnosis and subsequent initiation of CDCA treatment are crucial before the appearance of characteristic MRI findings and severe neurological manifestations related to CTX. Further studies are required to elucidate mechanisms responsible for the clinical diversity of CTX and prognostic factors for long-term outcomes following initiation of CDCA treatment.

Analysis of CYP27A1 mutations in Han Chinese women with intrahepatic cholestasis of pregnancy

Objective To explore the cytochrome P450 family 27 subfamily A member 1 (CYP27A1) gene mutations in Chinese women with intrahepatic cholestasis of pregnancy (ICP) and the correlation between CYP27A gene mutations and BA (bile acid) level changes. Methods In this study, the entire coding region of the CYP27A1 gene was sequenced in 151 Han Chinese women with ICP and 1029 matched samples, and the pathogenicity of identified CYP27A1 gene mutations was judged through evolutionary conservation analysis, computational analysis and protein structure modeling. Finally, we verified the relationship between gene mutations and total serum bile acid (TBA) and cholesterol (CHOL) levels through experiments in cell culture. Results We identified five heterozygous CYP27A1 missense mutations in five ICP samples. Three online tools, Polyphen-2, MutationTaster and SIFT, predicted that the five CYP27A1 mutations were pathogenic. Furthermore, all five mutations caused marked protein structural changes. Experiments in cells showed that the intracellular and medium levels of TBA in the mutant groups were lower than those in the wild-type group, while the CHOL levels were higher in all mutants except for the R158H mutant. Conclusions CYP27A1 mutations are associated with the levels of TBA and CHOL, suggesting that CYP27A1 mutations contribute to abnormal total cholesterol and BA levels, which leads to ICP.

Metabolic profiling in serum, cerebrospinal fluid, and brain of patients with cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is caused by autosomal recessive loss-of-function mutations in CYP27A1, a gene encoding cytochrome p450 oxidase essential for bile acid synthesis, resulting in altered bile acid and lipid metabolism. Here, we aimed to identify metabolic aberrations that drive ongoing neurodegeneration in some patients with CTX despite chenodeoxycholic acid (CDCA) supplementation, the standard treatment in CTX. Using chromatographic separation techniques coupled to mass spectrometry, we analyzed 26 sterol metabolites in serum and cerebrospinal fluid (CSF) of patients with CTX and in one CTX brain. Comparing samples of drug naive patients to patients treated with CDCA and healthy controls, we identified 7α,12α-dihydroxycholest-4-en-3-one as the most prominently elevated metabolite in serum and CSF of drug naive patients. CDCA treatment substantially reduced or even normalized levels of all metabolites increased in untreated patients with CTX. Independent of CDCA treatment, metabolites of the 27-hydroxylation pathway were nearly absent in all patients with CTX. 27-hydroxylated metabolites accounted for ∼45% of total free sterol content in CSF of healthy controls but <2% in patients with CTX. Metabolic changes in brain tissue corresponded well with findings in CSF. Interestingly, 7α,12α-dihydroxycholest-4-en-3-one and 5α-cholestanol did not exert toxicity in neuronal cell culture. In conclusion, we propose that increased 7α,12α-dihydroxycholest-4-en-3-one and lack of 27-hydroxycholesterol may be highly sensitive metabolic biomarkers of CTX. As CDCA cannot reliably prevent disease progression despite reduction of most accumulated metabolites, supplementation of 27-hydroxylated bile acid intermediates or replacement of CYP27A1 might be required to counter neurodegeneration in patients with progressive disease despite CDCA treatment.

Cholestasis as a dominating symptom of patients with CYP27A1 mutations: An analysis of 17 Chinese infants

BackgroundCYP27A1 is the disease-causing gene of cerebrotendinous xanthomatosis (CTX). As a treatable lipid storage disease, early treatment can improve the prognosis. However, CTX patients reported in the literature are mostly adult patients; the phenotype spectrum of CTX in the infantile population remains elusive. ObjectiveWe aimed to investigate the phenotype spectrum of infants who carried pathogenic or likely pathogenic variants in the CYP27A1 gene and were suspected of having CTX. MethodsFrom June 2014 to May 2020, infants with pathogenic or likely pathogenic variants in CYP27A1 gene were enrolled, who underwent next-generation sequencing or Sanger sequencing in Children's Hospital of Fudan University. Patient characteristics, clinical treatments and outcomes were extracted from electronic medical records. ResultsA total of 17 patients with an average onset age of 8 (1–42) days were found. The average diagnosis age was ten months. Cholestasis was the dominant symptom of these infants. Thirteen variants were detected, of which c.379C > T was a hotspot variant (26.5% alleles, 9/34). Cholestatic CTX is usually underestimated, but it could be severe or even fatal in infancy. For outcomes, 5 suffered from liver failure (36%, 5/14), 1 still showed cholestasis (7%, 1/14), 7 were asymptomatic (50%, 7/14), and 1 presented seizure and developmental delay in later childhood (7%, 1/14). ConclusionBased on this infantile cohort, we concluded that it is necessary to consider the possibility of CTX caused by CYP27A1 gene variants for infants with cholestasis.

C.1263+1G>A Is a Latent Hotspot for CYP27A1 Mutations in Chinese Patients With Cerebrotendinous Xanthomatosis.

BackgroundCerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder of bile acid synthesis caused by mutations in the CYP27A1 gene. CTX is an underdiagnosed and potentially treatable disease, thus a detailed appreciation of the phenotypic spectrum and genetic characteristics are crucial for early diagnosis and treatment.Objectives and MethodsFour CTX families with mutations in the CYP27A1 gene were enrolled in our study. We investigated the clinical characteristics and molecular genetic features of the probands with CTX. Genetic analysis was performed for detecting gene variants. Sanger sequencing and segregation analysis were conducted for haplotype analysis.ResultsAll the four probands were compound heterozygote for two CYP27A1 variants, including one mutation in c.1263+1G>A (intron 7) splice site, two novel likely pathogenic mutations (c.255+1G>T and c.1561dupA) and three pathogenic mutations including c.379C>T, c.1263+1G>A and c.1537C>T previously reported. All of the subjects presented with spastic paraparesis. The other common clinical features included ataxia, childhood-onset diarrhea, cataracts, intellectual disability, tendinous xanthomas and dentate nuclei signal alterations at MRI.ConclusionTwo novel likely pathogenic mutations (c.255+1G>T and c.1561dupA) were reported in our study. The 1263+1G>A mutation was commonly seen in Chinese reported case series (7/25, 28%) and could be a latent hotspot for Chinese CTX mutations. Our study expanded the mutation spectrum of CYP27A1 gene and provide an insightful view of the phenotypic spectrum and genetic characteristics to help early diagnosis and treatment with to improve neurologic dysfunction.

Clinical and genetic characteristics of Chinese patients with cerebrotendinous xanthomatosis

BackgroundCerebrotendinous xanthomatosis (CTX) is a rare inborn lipid-storage disease caused by mutations in the sterol 27-hydroxylase (CYP27A1) gene with an autosomal recessive pattern of inheritance. To date, only 19 CTX patients from 16 families have been reported in the Chinese population.ResultsThree novel likely pathogenic mutations (c.368_374delCCAGTAC, c.389 T > A and c.571C > T) and 7 previously reported pathogenic mutations (c.379C > T, c.435G > T, c.1016C > T, c.1214G > A, c.1263 + 1G > A, c.1420C > T and c.1435C > T) were identified. In addition, we summarized the genotypes and phenotypes of reported Chinese CTX patients. The most predominant mutations in CYP27A1 were c.410G > A and c.379C > T, and the most common clinical manifestations were pyramidal signs, xanthomatosis, cerebellar ataxia, and cognitive impairment.ConclusionOur study broadens the genetic and clinical spectrum of CTX and provides insightful information to help better diagnose and understand the disease.

Clinical and molecular genetic features of cerebrotendinous xanthomatosis in Taiwan: Report of a novel CYP27A1 mutation and literature review

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder associated with mutations in the CYP27A1 gene, and the genetic features of CTX in Taiwanese have not been examined before. We report a new CTX family with a novel mutation in the CYP27A1 gene and analyze the clinical and molecular genetic features of CTX in Taiwan. The clinical and molecular genetic features of the two siblings from the new CTX family and the other 7 reported Taiwanese CTX patients were included for analysis. The clinical features of the enrolled CTX patients were recorded using the indicators that make up the suspicion index (SI). The age at CTX diagnosis of the two siblings in the new CTX family were in late 30s, and predominantly psychiatric features. Both siblings had compound heterozygous splicing mutations in the CYP27A1 gene, including one mutation in exon 2 (c.435G>T, cryptic splice site) and one mutation in intron 7 (c.1264A>G, canonical splice site). None of the CTX patients in Taiwan were diagnosed during childhood or adolescence, and the most common clinical features of the 9 Taiwanese CTX patients were tendinous xanthomas, followed by ataxia and/or spastic paraparesis, dentate nuclei signal alternation at magnetic resonance imaging, intellectual disability and/or psychiatric disturbance, and polyneuropathy. Mutations in the CYP27A1 gene in the Taiwanese population were most commonly observed in exon 2, followed by exon 8 and intron 7. Except for one CTX patient who had an SI score of 100, the SI scores ranged from 300 to 400 before the study of the CYP27A1 gene and diagnosis. We reported two Taiwanese CTX siblings who had compound heterozygous mutations in CYP27A1. Exons 2 and 8 and intron 7 are the hotspots for Taiwanese CTX mutations. The diagnosis of CTX in Taiwan is usually delayed and is probably under-recognized based on statistical estimations. Early identification and genetic diagnosis may be helpful to CTX patients because early treatment can reduce the accumulation of cholestanol and slow disease progression.

Severe Neonatal Cholestasis in Cerebrotendinous Xanthomatosis: Genetics, Immunostaining, Mass Spectrometry.

Cerebrotendinous xanthomatosis (CTX) is caused by defects in sterol 27-hydroxylase (CYP27A1, encoded by CYP27A1), a key enzyme in the bile acid synthesis pathway. CTX usually presents as neurologic disease in adults or older children. The rare reports of CTX manifest as neonatal cholestasis assess the cholestasis as transient, with patient survival. Our experience differs. Homozygous or compound heterozygous CYP27A1 mutations were detected in 8 neonatal cholestasis patients by whole exome sequencing, panel sequencing, or Sanger sequencing. Their clinical and biochemical data were retrospectively reviewed. Immunostaining for CYP27A1 was conducted in liver of 4 patients. Mass spectrometry was used to analyze patients' urine samples. All 8 infants had severe cholestasis. Five died from, or were transplanted for, liver failure; 3 cleared their jaundice eventually. Marking for CYP27A1 was weak or absent in 3 of the 4 patient specimens. Mass spectrometry of urine revealed a predominance of sulfated and doubly conjugated (sulfated-glucuronidated) bile alcohols. No patient harbored a putatively pathogenic mutation in genes other than CYP27A1 that have been implicated in cholestatic liver disease. CTX manifest as neonatal cholestasis has a bile acid profile different from CTX manifest in later life, and thus may be overlooked. Immunostaining, mass spectrometry of urine, and genetic studies can support one another in making the diagnosis. A substantial proportion of CTX patients with severe neonatal cholestasis may die or need liver transplantation. CTX manifest in infancy as severe cholestasis warrants further investigation of biochemical diagnostic criteria and best management.

Clinical and molecular genetic features of cerebrotendinous xanthomatosis patients in Chinese families

Cerebrotendinous xanthomatosis (CTX) is a lipid-storage disease caused by mutations in CYP27A1. Current publications of Chinese CTX were mainly based on case reports. Here we investigated the clinical manifestations, genetic features in Chinese CTX patients. The clinical materials of 4 Chinese CTX pedigrees were collected. The genetic testing was done by polymerase chain reaction plus Sanger sequencing. The features of Chinese CTX patients reported previously were also reviewed. Three novel mutations of p.Arg513Cys, c.1477-2A>C in family 1 and p.Arg188Stop in family 4 (NM 000784.3) in CYP27A1 were found. The probands in our study manifested cerebellar ataxia, tendon xanthoma and spastic paresis in family 1 and 4, tendon xanthoma plus spastic paraparesis in family 2, asymptomatic tendon xanthoma in family 3. Three known mutations of p.Arg137Gln, p.Arg127Trp and p.Arg405Gln were found respectively in Family 2, 3 and 4. For the Chinese patients reviewed, the most common findings were xanthomatosis (100%), pyramidal signs (100%), cerebellar ataxia (66.7%), cognitive impairment (66.7%), cataracts (50.0%), and peripheral neuropathy (33.3%). Chronic diarrhea was infrequently seen (5.6%). No mutation was found associated with any given clinical features. We identified 3 novel mutations in CYP27A1. In Chinese CTX patients, xanthomatosis was the most common symptom while cataracts and chronic diarrhea were less frequent. The special features in Chinese CTX patients might caused by the lack of serum cholestanol test and should be confirmed in larger number of patients in the future.

The role of dentate nuclei in human oculomotor control: insights from cerebrotendinous xanthomatosis.

A cerebellar dentate nuclei (DN) contribution to volitional oculomotor control has recently been hypothesized but not fully understood. Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disease typically characterized by DN damage. In this study, we compared the ocular movement characteristics of two sets of CTX patients, with and without brain MRI evidence of DN involvement, with a set of healthy subjects. Our results suggest that DN participate in voluntary behaviour, such as the execution of antisaccades, and moreover are involved in controlling the precision of the ocular movement. The saccadic abnormalities related to DN involvement were independent of global and regional brain atrophy. Our study confirms the relevant role of DN in voluntary aspects of oculomotion and delineates specific saccadic abnormalities that could be used to detect the involvement of DN in other cerebellar disorders. It is well known that the medial cerebellum controls saccadic speed and accuracy. In contrast, the role of the lateral cerebellum (cerebellar hemispheres and dentate nuclei, DN) is less well understood. Cerebrotendinous xanthomatosis (CTX) is a lipid storage disorder due to mutations in CYP27A1, typically characterized by DN damage. CTX thus provides a unique opportunity to study DN in human oculomotor control. We analysed horizontal and vertical visually guided saccades and horizontal antisaccades of 19 CTX patients. Results were related to the presence/absence of DN involvement and compared with those of healthy subjects. To evaluate the contribution of other areas, abnormal saccadic parameters were compared with global and regional brain volumes. CTX patients executed normally accurate saccades with normal main sequence relationships, indicating that the brainstem and medial cerebellar structures were functionally spared. Patients with CTX executed more frequent multistep saccades and directional errors during the antisaccade task than controls. CTX patients with DN damage showed less precise saccades with longer latencies, and more frequent directional errors, usually not followed by corrections, than either controls or patients without DN involvement. These saccadic abnormalities related to DN involvement but were independent of global and regional brain atrophy. We hypothesize that two different cerebellar networks contribute to the metrics of a movement: the medial cerebellar structures determine accuracy, whereas the lateral cerebellar structures control precision. The lateral cerebellum (hemispheres and DN) also participates in modulating goal directed gaze behaviour, by prioritizing volitional over reflexive movements.

Pathophysiology of cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal-recessive lipid storage disease caused by mutations in the CYP27A1 gene, which lead to deficiency of the mitochondrial enzyme, sterol 27-hydroxylase, resulting in the accumulation of cholestanol in the serum and many affected lesions. To date, more than 50 different CYP27A1 mutations, including missense mutations, frameshifts, and splice site mutations, have been reported worldwide in patients with CTX. Clinical presentation is characterized by neonatal jaundice or cholestasis, refractory diarrhea, juvenile cataracts, tendon xanthomas, osteoporosis, coronary heart disease, and progressive neuropsychiatric disturbances; however, combinations of symptoms vary from patient to patient. Neuropsychiatric abnormalities include mental retardation or dementia, psychiatric symptoms, cerebellar signs, pyramidal signs, progressive myelopathy, peripheral neuropathy, extrapyramidal manifestations, and seizures. Replacement treatment with chenodeoxycholic acid in the early stage of the disease has been reported to improve or even prevent clinical symptoms of CTX. After significant neurological pathology is established, the effect of the treatment is limited and the deterioration of clinical manifestations may continue; therefore, early diagnosis of CTX is crucial.

Cerebrotendinous xanthomatosis: a comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management.

Cerebrotendinous xanthomatosis (CTX) OMIM#213700 is a rare autosomal-recessive lipid storage disease caused by mutations in the CYP27A1 gene; this gene codes for the mitochondrial enzyme sterol 27-hydroxylase, which is involved in bile acid synthesis. The CYP27A1 gene is located on chromosome 2q33-qter and contains nine exons. A CYP27A1 mutation leads to decreased synthesis of bile acid, excess production of cholestanol, and consequent accumulation of cholestanol in tissues. Currently there is no consensus on the prevalence of CTX, one estimate being <5/100,000 worldwide. The prevalence of CTX due to the CYP27A1 mutation R362C alone is approximately 1/50,000 in Caucasians. Patients with CTX have an average age of 35 years at the time of diagnosis and a diagnostic delay of 16 years. Clinical signs and symptoms include adult-onset progressive neurological dysfunction (i.e., ataxia, dystonia, dementia, epilepsy, psychiatric disorders,peripheral neuropathy, and myopathy) and premature non-neurologic manifestations (i.e., tendon xanthomas, childhood-onset cataracts, infantile-onset diarrhea, premature atherosclerosis, osteoporosis, and respiratory insufficiency). Juvenile cataracts, progressive neurologic dysfunction, and mild pulmonary insufficiency are unique symptoms that distinguish CTX from other lipid storage disorders including familial dysbetalipoproteinemia, homozygous familial hypercholesterolemia, and sitosterolemia, all of which might also present with xanthomas and cardiovascular diseases. Brain magnetic resonance imaging (MRI) shows bilateral lesions in the dentate nucleus of the cerebellum and mild white matter lesions. The classical symptoms and signs, namely elevated levels of cholestanol and bile alcohols in serum and urine, brain MRI, and the mutation in the CYP27A1 gene confirm the diagnosis of CTX. Early diagnosis and long-term treatment with chenodeoxycholic acid (750 mg/d) improve neurological symptoms and contribute to a better prognosis.

Cerebrotendinous xanthomatosis: recurrence of the CYP27A1 mutation p.Arg479Cys in Sardinia

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder, due to mutations of the CYP27A1 gene, leading to cholestanol accumulation because of the sterol27-hydroxylase enzyme deficiency [1]. Treatment with chenodeoxycholic acid (CDCA) normalizes cholestanol and improves neurophysiological findings. Several mutations of the CYP27A1 gene are described in different ethnic groups [1], without genotype–phenotype correlations. We describe two unrelated Sardinian families sharing the same CYP27A1 mutation.

Juvenile Cataract Morphology in 3 Siblings Not Yet Diagnosed with Cerebrotendinous Xanthomatosis

Cerebrotendinous xanthomatosis is a progressive neurodegenerative storage disease caused by recessive CYP27A1 mutations and is characterized by abnormal deposition of cholestanol and cholesterol in multiple tissues, including the lens and brain. Oral chenodeoxycholic acid is preventive and can be therapeutic, but is not used optimally because the condition typically is diagnosed late or not at all. When affected children demonstrate lens opacities, ophthalmologists have the unique potential to facilitate earlier diagnosis and treatment by recognizing the juvenile cataract phenotype. This study highlights the morphology of lens opacities in a family with genetically confirmed disease. Prospective case series. Four siblings and their 2 parents, who are first cousins. Ophthalmic examination, general physical examination, and exome sequencing guided by homozygosity analysis. Ophthalmic findings, general clinical findings, and results of CYP27A1 candidate gene testing. Two sisters, each visually symptomatic before 10 years of age, had a unique pattern of bilateral fleck deposits throughout the lens with significant posterior capsular cataract. When initially examined at 8 years of age, their then-asymptomatic younger brother had the same bilateral fleck deposits with minimal posterior capsular opacity; 1 year later, he demonstrated anterior capsular opacity and became symptomatic. Both asymptomatic parents had few but distinct similar flecks localized at or near the anterior Y-suture, whereas an asymptomatic sister did not. Genetic analysis revealed homozygosity for a known CYP27A1 mutation (c.1263+1G → A) in the 3 symptomatic siblings, heterozygosity for the mutation in the 2 parents, and no mutation in the asymptomatic sister. When specifically questioned, the 3 affected children had experienced recurrent bouts of diarrhea in early childhood, which is a common feature of the disease. An unusual pattern of fleck lenticular deposits was seen in affected children. With time, capsular opacities (posterior only or posterior and anterior) developed and caused visual symptoms. Such juvenile lenticular findings should raise suspicion for this treatable metabolic disorder, especially when in the context of recurrent diarrhea during early childhood. Asymptomatic fleck-like opacities at or near the anterior Y-suture may be a carrier sign. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Mapping of Gene Expression Reveals CYP27A1 as a Susceptibility Gene for Sporadic ALS

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27×10−51) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS.