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Table of Contents
Year : 2022  |  Volume : 5  |  Issue : 2  |  Page : 125-130

A novel CYP27A1 frameshift mutation causing cerebrotendinous xanthomatosis in an Indian family

1 Department of Medicine, Shree Krishna Hospital and Pramukhswami Medical College, Bhaikaka University, Gujarat, India
2 Department of Neurology, Shree Krishna Hospital and Pramukhswami Medical College, Bhaikaka University, Gujarat, India
3 CSIR Institute of Genomics and Integrative Biology (CSIR-IGIB), Delhi, India

Date of Submission31-Aug-2021
Date of Decision26-Nov-2021
Date of Acceptance20-Dec-2021
Date of Web Publication24-May-2022

Correspondence Address:
Dr. Soaham Desai
119, Neurology OPD, Privilege Center, Shree Krishna Hospital and Pramukhswami Medical College (PSMC), Bhaikaka University, Gujarat - 388325
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AOMD.AOMD_42_21

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Cerebrotendinous xanthomatosis is a rare and underreported lipid storage disorder caused by various mutations in the CYP27A1 gene. Here, we report a novel homozygous mutation in the CYP27A1 gene in an Indian family. A 30-year-old man presented with childhood cataracts in both eyes; recurrent, intractable watery diarrhea; progressive cognitive impairment; bilateral patellar and Achilles tendon xanthomas; and ataxic speech and gait. Out of five siblings, four had similar symptoms. Three of the patient’s siblings had the same novel mutation in the CYP27A1 gene on the chromosome 2 region with c.301delG (Pro102LeufsTer5 protein change), which was homozygous. To date, the variant status of this mutation has not been reported in the Human Gene Mutation Database, the Exome Aggregation Consortium, and 1000 Genomes Project. Despite the clinical confirmation of the diagnosis and molecular analysis, our patient’s symptoms did not improve with treatment for more than a year, because of delayed presentation with irreversible damage. Treatment with chenodeoxycholic acid and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors can reduce or reverse the progression of the disease; however, early diagnosis is key.

Keywords: c.301delG mutation, cerebrotendinous xanthomatosis, CYP2A1 gene, tendon xanthoma

How to cite this article:
Shukla S, Chovatiya H, Shamim U, Faruq M, Desai S. A novel CYP27A1 frameshift mutation causing cerebrotendinous xanthomatosis in an Indian family. Ann Mov Disord 2022;5:125-30

How to cite this URL:
Shukla S, Chovatiya H, Shamim U, Faruq M, Desai S. A novel CYP27A1 frameshift mutation causing cerebrotendinous xanthomatosis in an Indian family. Ann Mov Disord [serial online] 2022 [cited 2023 May 29];5:125-30. Available from: https://www.aomd.in/text.asp?2022/5/2/0/345849

  Introduction Top

Cerebrotendinous xanthomatosis (CTX) is attributed to biallelic pathogenic mutations in the CYP27A1 gene (a member of cytochrome P450 family) that encodes the mitochondrial enzyme sterol 27-hydroxylase. Sterol 27-hydroxylase is the key enzyme for bile acid synthesis and plays major role in the maintenance of cholesterol in the body.[1] Mutations have been reported in nine exons of the CYP27A1 gene worldwide. Half of the mutations were reported in exons 6 and 8 and some were noted in exons 2, 3, and 4.[2] The prevalence of CTX is three to five per 100,000 individuals among Caucasians.[3] In the family reported in our study, the parents did not have any clinical symptoms, but four out of five siblings were affected. The genetic analysis of all siblings showed homozygous mutations in the CYP27A1 gene, which is novel in context to the known autosomal recessive inheritance of CTX.

  Case Report Top

A 30-year-old unmarried man, born of a non-consanguineous marriage with normal developmental milestones, presented with difficulty in gait for 10 years and speech for 4 years. He had bilateral cataracts at 3 years of age, which required surgery. At 5 years of age, he had recurrent watery diarrhea. Being scholastically poor, he had dropped out of school. He gradually developed cognitive impairment along with psychomotor retardation. By late teenage years, he developed swelling in the major joints, along with mild gait difficulty. In the last 4 years, he had unclear staccato speech, increasing gait difficulty, and frequent falls, necessitating support for ambulation over the last 1 year. The patient eventually become wheel-chair bound after 6 months and required assistance for all daily activities. However, his parents were asymptomatic. Out of five siblings, the proband was the youngest ([Figure 1]a). His brother had similar symptoms, but he was never evaluated and died at the age of 28 years. The patient’s two sisters had similar complaints in childhood with multiple tendon xanthomas ([Figure 2]) and subnormal cognition, while one sister was unaffected.
Figure 1: (a) Pedigree chart of the family. (b) Homozygous mutation c.303delG (NM_000784.4) in CYP27A1(chr2q35) observed using Sanger sequencing

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Figure 2: Timeline of symptom progression in the symptomatic siblings

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Physical examination revealed bilateral Achilles and patellar tendon xanthomas that were firm to hard, non-tender with normal overlying skin, and not attached to the underlying soft tissue ([Figure 3]). Neurological examination revealed cognitive impairment with a Mini-Mental Status Examination score of 13/30 (orientation, attention, recall, and writing being affected) and a Frontal Assessment Battery score of 9/18. In addition, his ability to calculate, draw, and learn new skills were affected. He had slow saccades with saccadic dysmetria and broken pursuits and no nystagmus or gaze limitation. His speech was slow, slurred, and ataxic (staccato). He had spasticity (Modified Ashworth Scale-3) in both lower limbs, with normal power in all limbs. All deep tendon reflexes were exaggerated with ankle clonus and extensor plantar reflexes on normal sensory examination. Cerebellar examination was suggestive of dysmetria, dysdiadochokinesia, and intention tremor in both upper limbs with truncal and gait ataxia.
Figure 3: a and b (patient-II-7): bilateral patellar and Achilles tendon xanthomas, respectively; c and d (elder sister-II-2): bilateral lower limbs with multiple xanthomas; e and f (younger sister-II-5): bilateral hand and bilateral Achilles xanthomas

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Blood investigations revealed a normal hemogram, biochemistry, coagulation profile, and liver and kidney function. Lipid profile was normal. Plain radiograph of the knees revealed soft tissue opacities over the anterior aspect of the patella ([Figure 4]) without calcification. Brain magnetic resonance imaging (MRI) showed symmetrical T2 hyperintensities bilaterally in the dentate nuclei and the deep cerebellar white matter with cerebellar atrophy ([Figure 4]). The serum cholesterol level was assessed done due to financial constraints. Genetic analysis of the patient and his affected siblings was performed using Sanger sequencing of the entire coding region covering the exon–intron boundary of the CYP27A1 gene. The sequencing analysis showed a homozygous single base pair deletion in the CYP27A1 gene (chr2:g.219674345delG;c.301delG;NM_000784.4) that resulted in a frame-shift and premature truncation of the CYP27A1 protein (p.Pro102LeufsTer5). The variant was classified as pathogenic according to the American College of Medical Genetics guidelines, PVS1 [Null variant (frame-shift)], PM2 (absent in the Genome Aggregation Database), and PP3 (pathogenic computational prediction based on the PhyloP100way conservation score of 7.89). His parents and unaffected sister did not provide consent for their genetic evaluation ([Figure 1]b). The patient was treated with 250-mg chenodeoxycholic acid (CDCA) three times a day and atorvastatin 10 mg once a day; however, his symptoms continued to worsen and he defaulted medicine after 1 year and did not follow-up.
Figure 4: Brain magnetic resonance imaging axial view (a–e). a) Diffusion-weighted imaging: no diffusion restriction, left cerebellum hypointense area; b) T1-weighted imaging: hypointense area in the right and left cerebellum hypointense area; c) T2-weighted imaging: hyperintense are in B/L dentate nucleus and left cerebellum hypointense area; d Fluid-attenuated inversion recovery imaging: B/L dentate hyperintensity (small yellow arrow) and B/L cerebellar hypointensities; e) Susceptibility weighted imaging: blooming of hypointense areas in the cerebellum bilaterally; f) Sagittal view of T1-weighted imaging” cerebellar atrophy with prominent folia; g) X-ray of the right knee: patellar tendon xanthoma (yellow arrow)

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  Discussion Top

We report a novel homozygous mutation of the CYP27A1 gene with c.301delG (Pro102LeufsTer5 protein change) in an Indian family. CTX is known to show an autosomal recessive pattern of inheritance; however, in the family reported in our study, four out of five siblings were affected, which is an unusual pattern of inheritance (25% general risk for each offspring in the family to have a homozygous state of the variation as per Mendelian law). To date, only four cases of CTX have been reported in India, with confirmed molecular analysis ([Table 1]).
Table 1: Studies on cerebrotendinous xanthomatosis in India with molecular diagnosis

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CTX is a rare autosomal recessive lipid storage disorder, first described by van Bogaert et al.[7] in 1937. It is characterized by premature cataracts, childhood-onset diarrhea, tendon xanthomas, and intellectual decline. Neurological symptoms usually begin in the second decade of life.[8],[9] Adult-onset progressive neurological dysfunction can manifest as ataxia, dystonia, dementia, epilepsy or even peripheral neuropathy, and myopathy. In addition, psychiatric manifestations such as depression, suicidal thoughts, catatonia, and psychotic symptoms can occur in the early stages of CTX. Biochemical abnormalities include high plasma and tissue cholesterol levels.[10] Tendon xanthomas are an important clinical hallmark of CTX due to increased cholesterol formation, which gets deposited in various tissues. This helps in differentiating it from Marinesco-Sjogren syndrome, which is caused by biallelic pathogenic variants of the SIL1 gene, with typical clinical findings such as cerebellar ataxia, dysarthria, nystagmus, early-onset non congenital cataract, myopathy, psychomotor delay, and hypergonadotropic hypogonadism.[11] Brain MRI shows T2 hyperintensities in dentate nuclei, substantia nigra, and global pallidus, as a result of accumulation of sterols in nervous system and focal demyelination. Other findings include diffused cerebral and cerebellar atrophy. Spine MRI may show T2 hyperintensity.[12]

The first case report on genetic mutation analysis (c.526delG) in India was published in 2012 by Shah K et al.[4] In that case, the patient had cataracts, seizures, cognitive decline, and xanthomas without ataxia. Bajaj et al. reported two cases with different mutations, with presentations similar to those in our case such as cataract, xanthoma, spastic cerebellar ataxia, and cognitive impairment.[5] Dutta et al. reported two families with novel mutations, with diarrhea at 4 years of age, cataract in the second decade of life, and cognitive impairment and ataxia in the third decade. To date, no case with confirmed genetic testing has been reported from western part of India. Four members of the family in our study had a novel homozygous CYP27A1 gene mutation, with manifestations such as early-onset cataracts, diarrhea and malnutrition in early childhood, large xanthomas, and neurologic involvement in the third decade of life. Gallus et al.[13] reviewed 49 different mutations throughout exons 1–8 of the CYP27A1 gene in CTX patients. These mutations were amino-acid substitutions (65%), missense mutations (45%), nonsense mutations (20%), splice site mutations (18%), deletions (14%), and insertions (2%). Based on the literature search, we found a case of CTX in Taiwan that carried another deletion mutation in the vicinity of c.305delC (Human Gene Mutation Database ID: CD063504); however, the changes at the protein level were the same as Pro102LeufsTer5, due to a frameshift mutation. The result of both c.301delG and c.305delC would be the loss of sterol 27-hydroxylase activity.[14]

Early diagnosis of CTX is crucial, since pharmacological treatment with CDCA (750 mg/day) and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors can slow or even reverse the progression of the disease.[15] CDCA normalizes the plasma and cerebrospinal fluid concentrations of cholesterol, which results in improvement of the neurological status and peripheral neuropathy as well as regression of xanthomas.[16] Although CTX is treatable, the time of initiation of the treatment is crucial for favorable therapeutic effect. A study by Pilo-de-la-Fuente et al.[17] of 25 patients in Spain showed that despite treatment, 60% of the patients deteriorated. This poor treatment response was because of delayed diagnosis when the damage was irreversible. The presence of bilateral cataracts and chronic, intractable, and watery diarrhea in children advocates a diagnosis of CTX. Therefore, early diagnosis is crucial to prevent premature aging, cognitive decline, psychomotor retardation, and spinocerebellar dysfunction.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her consent for his/her images, genetic sampling and other clinical information to be reported in the journal. The patient(s) understands that his/her name and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


We acknowledge the assistance by GOMED programme (http:gomed.igib.in), funded by CSIR, MLP1601, MLP1802. We sincerely than Ms. Suman Mudilla for her technical assistance in sequencing experiments.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

Ethical compliance statement

The case study has been approved by the Institutional Ethics Review Board of Shree Krishna Hospital and Pramukhswami Medical College. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

  References Top

Cali JJ, Hsieh CL, Francke U, Russell DW. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem 1991;266:7779-83.  Back to cited text no. 1
Nie S, Chen G, Cao X, Zhang Y. Cerebrotendinous xanthomatosis: A comprehensive review of pathogenesis, clinical manifestations, diagnosis, and management. Orphanet J Rare Dis 2014;9:1-1.  Back to cited text no. 2
Salen G, Steiner RD. Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX). J Inher Metabol Dis 2017;40:771-81.  Back to cited text no. 3
Shah K, Mathew V, Gallus GN, Dotti MT, Federico A, Danda S. Mutation analysis of cerebrotendinous xanthomatosis in an Indian case. Neurol India 2012;60:643-4.  Back to cited text no. 4
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Bajaj BK, Singh A, Anand KS, Garg J. Cerebrotendinous xanthomatosis: Report of two cases and a novel genetic mutation in an Indian patient. J Neurosci Rural Pract 2013;4:S87-90.  Back to cited text no. 5
Dutta AK, Danda S, Muthusamy K, Alexander M, Sudhakar SV, Hansdak S, et al. Cerebrotendinous xanthomatosis: Possibility of founder mutation in CYP27A1 gene (c. 526delG) in Eastern Indian and Surinamese population. Mol Genet Metabol Rep 2015;3:33-5.  Back to cited text no. 6
van Bogaert L, Scherer H, Epstein E. Une Forme Cérébrale De La Cholesterinose Généraliséé. Masson, Paris. 1937.  Back to cited text no. 7
Berginer VM, Gross B, Morad K, Kfir N, Morkos S, Aaref S, et al. Chronic diarrhea and juvenile cataracts: Think cerebrotendinous xanthomatosis and treat. Pediatrics 2009;123:143-7.  Back to cited text no. 8
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Anttonen AK. Marinesco-Sjögren Syndrome. GeneReviews; 2019.  Back to cited text no. 11
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Gallus GN, Dotti MT, Federico A. Clinical and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurol Sci 2006;27:143-9.  Back to cited text no. 13
Wang PW, Chang WN, Lu CH, Chao D, Schrag C, Pan TL. New insights into the pathological mechanisms of cerebrotendinous xanthomatosis in the Taiwanese using genomic and proteomic tools. Proteomics 2006;6:1029-37.  Back to cited text no. 14
Kuriyama M, Tokimura Y, Fujiyama J, Utatsu Y, Osame M. Treatment of cerebrotendinous xanthomatosis: Effects of chenodeoxycholic acid, pravastatin, and combined use. J Neurol Sci 1994;125:22-8.  Back to cited text no. 15
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Pilo-de-la-Fuente B, Jimenez-Escrig A, Lorenzo JR, Pardo J, Arias M, Ares-Luque A, et al. Cerebrotendinous xanthomatosis in Spain: Clinical, prognostic, and genetic survey. Eur J Neurol 2011;18:1203-11.  Back to cited text no. 17


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1]


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