Diagnosis Of Cerebrotendinous Xanthomatosis Research Articles

Living with Cerebrotendinous Xanthomatosis: Patient, Caregiver, and Expert Perspectives.

In this article, patients with cerebrotendinous xanthomatosis (CTX) and caregivers detail their experience with lifelong symptoms, diagnosis, treatment and efficacy, and ongoing disease management. One patient and four caregivers describe the challenges associated with pursuing a correct diagnosis for years before testing confirmed a CTX diagnosis. They also detail their ongoing struggles and desire for greater access to physicians with CTX knowledge and to reliable online resources to continue their education about the disease and strategies for symptom management. The expert perspective is a direct response by three CTX researchers, including physicians who are treating patients with CTX in the United States and experts whose laboratories provide genetic and biochemical testing for CTX. They respond to many of the patient and caregiver concerns, including steps that are being taken to identify CTX earlier and provide access to confirmatory diagnostic testing sooner, and suggest the best online resources for CTX-related information and access to webinars and support groups. While the expert perspective is a direct response to the patient and caregiver authors' CTX journeys, it should be beneficial to any patient with CTX or their caregivers.

A case of cerebrotendinous xanthomatosis with brain and spinal involvement without tendon xanthomas: Identification of a novel mutation of the CYP27A1 gene

Cerebrotendinous xanthomatosis (CTX) is a rare inherited disorder of the alternative pathway of bile acid biosynthesis, due to mutation(s) of the gene CYP27A1, leading to sterol 27-hydroxylase deficiency. The latter results in a systematic deposition of cholestanol and cholesterol to the central nervous system and tendons, premature cataract, as well as the manifestation of systematic symptoms, such as chronic diarrhea, osteoporosis, and premature atherosclerosis. Due to its marked clinical heterogeneity, prompt diagnosis of this disorder is challenging. We present a case of a 38-year-old male with gait difficulty, a progressive deterioration in ambulation, several episodes of vertigo and episodic diarrhea. Clinical history revealed neonatal jaundice, juvenile bilateral cataracts, borderline intellectual capacity, hypothyroidism, testicular cancer. Magnetic resonance imaging demonstrated increased T2-weighted signal in internal capsules, midbrain, cerebellum, and spinal cord. Electrodiagnostic study showed mixed polyneuropathy. Genetic analysis revealed a novel, biallelic, most likely pathogenic mutation, in gene CYP2A1 (c.1410_1411del). Plasma sterol profiling confirmed the diagnosis of CTX. Our patient was treated with chenodeoxycholic acid and one year later, he shows a progressive improvement of gait, normalization of plasma sterol biochemistry and electrophysiological parameters. This case highlights the importance of maintaining a high index of suspicion as the key to an early diagnosis of CTX, taking into consideration its clinical variability and, if promptly identified, the good response to treatment.

Cerebrotendinous xanthomatosis: A multidisciplinary approach for early diagnosis

Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of bile acid metabolism which manifests in the form of variable neurological and non-neurological symptoms. Early recognition of the disease leads to a timely implementation of treatment and hence better prognosis. The early diagnosis of CTX depends on a multidisciplinary approach in which radiological imaging plays a pivotal role.

The Importance of Ophthalmic Examination in Initial Diagnostic Process of Xanthoma: Two Case Reports and Literature Review of Cerebrotendinous Xanthomatosis

Background: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease where deficiency of sterol 27-hydroxylase leads to reduced production of CDCA. In such cases, life expectancy is only 4–6 decades, with progressive neurologic dysfunction such as dementia and spinal cord paresis, unless the condition is diagnosed early and treated appropriately. Herein, we aim to raise awareness regarding the importance of ophthalmic examination in evaluating of xanthoma. Clinical Cases: Case 1: In a 58-year-old man with no neurological symptoms; bilateral cataracts were detected during the initial diagnostic process. This patient had two siblings with xanthoma; one died from cerebral infarction and the other from biliary tract cancer. Another sibling had premature acute cardiovascular disease without xanthomas. Baseline lipid profiles were nearly within the normal range, while lipoprotein A was approximately 2.5 times higher than the normal. CTX was confirmed by the detection of a homozygous mutation in the CYP27A1 gene and high plasma cholestanol level (8.5 mg/L; reference range 0.0–5.0 mg/L). He has been taking oral CDCA (250 mg, three times daily). Case 2: In a 24-year-old man with no neurological symptoms or intellectual disability, premature bilateral cataracts were detected 1 year prior to diagnosis of CTX. None of his family members had xanthoma or premature cardiovascular disease. Lipid profile showed a similar pattern to that of Case 1; CTX was confirmed by the detection of a homozygous mutation in the CYP27A1 gene and high plasma cholestanol level (21.33 mg/L). One year after starting CDCA (250 mg, three times daily), cholestanol levels dropped to 7.34 mg/L. They were measured annually and identified as 5.08 mg/L, 4.2 mg/L, 4.7 mg/L, and 3.8 mg/L at 24, 38, 61, and 72 months, respectively. It took approximately 2 years for the normalization of his cholestanol level. There were no recurrences of xanthoma or progression of complications in target organs after 6 years of treatment. Conclusion: Early diagnosis improves the outcomes of CTX, allowing proper treatment. Bilateral cataracts caused by cholestanol buildup on the crystalline lens due to CTX usually occur within the first three decades of life. This manifestation does not occur in patients with xanthoma, familial hypercholesterolemia, or sitosterolemia. Taken together, this report suggests that premature bilateral cataracts are a specific marker that can accelerate early diagnosis of CTX.

Update on cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a rare genetic lipid storage disorder with highly pleomorphic clinical phenotype. Complications of this disease can be devastating and may include severe cognitive impairment and dementia in later stages. Disease progression can be prevented or stabilized by bile acid replacement therapy, although a subset of patients with advanced disease continue to deteriorate despite therapy. Delayed diagnosis of CTX continues to impede effective treatment. A clinical diagnostic algorithm for CTX was developed that can decrease the age of diagnosis of CTX. The strategy of screening children with bilateral juvenile cataracts for CTX also improved diagnosis, as this group had a 500-fold higher-rate of CTX than the general population. Improved diagnosis of CTX is critical, as patients treated early in the course of the disease have significantly better outcomes compared with those treated later. More sensitive and specific biochemical testing for CTX has been developed that is potentially more informative than blood cholestanol to assess treatment efficacy and medication compliance in CTX. Because we are recognizing more severe presentations of CTX in infants and children, and delayed diagnosis and treatment worsens the prognosis, CTX is an excellent candidate disorder for newborn screening using recently reported methods for newborn dried bloodspot analysis.

Patients with Lately Diagnosed Cerebrotendinous Xanthomatosis

Objectives: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive inborn lipid storage disorder due to various pathogenic mutations in the CYP27A1 gene. Although the symptoms begin commonly in infancy, CTX diagnosis is often delayed. In this study, we report 7 Turkish CTX patients who had a delayed diagnosis despite early clinical signs and belonged to 6 unrelated families. Methods: We have retrospectively evaluated clinical, laboratory, imaging, and genetic findings of CTX patients, which were collected from 2 centers specialized in movement disorders: the Department of Neurology, Faculty of Medicine, Istanbul University, and the Department of Neurology, Faculty of Medicine, Mersin University. Results: All patients were diagnosed with CTX after neurological symptom development, and their mean age at diagnosis was 38.7 ± 9.6 years, despite a mean onset age of 12.4 ± 10.6 years. The mean follow-up period was 28 months (range: 3–60 months). The most common initial clinical abnormalities in our cohort were unexplained chronic diarrhea (42%), febrile convulsion (42%), juvenile cataract (85%), childhood depression and autism (14%), parkinsonism (14%), and intellectual disability (100%). The most prominent neurological findings were the pyramidal-cerebellar syndrome (85%) and extrapyramidal signs (42%). All patients were genetically confirmed. Serum cholestanol levels were elevated in all patients and decreased after chenodeoxycholic acid (CDCA) treatment in 6 patients. Conclusion: This cohort is the largest CTX case series in Turkey. All cases showed improvement in gastrointestinal symptoms as a response to CDCA treatment and stabilization on neurological symptoms, i.e., no further progression of neurological abnormalities were noted during this treatment. Therefore, early diagnosis and treatment is crucial in preventing clinical deterioration.

Misdiagnosis of CTX due to propofol: The interference of total intravenous propofol anaesthesia with bile acid profiling.

BackgroundCerebrotendinous xanthomatosis (CTX) is a rare genetic disorder, characterised by chronic diarrhoea, xanthomas, cataracts, and neurological deterioration. CTX is caused by CYP27A1 deficiency, which leads to abnormal cholesterol and bile acid metabolism. Urinary bile acid profiling (increased m/z 627: glucuronide‐5β‐cholestane‐pentol) serves as diagnostic screening for CTX. However, this led to a false positive CTX diagnosis in two patients, who had received total intravenous anaesthesia (TIVA) with propofol.MethodsTo determine the influence of propofol on bile acid profiling, 10 urinary samples and 2 blood samples were collected after TIVA with propofol Fresenius 7 to 10 mg/kg/h from 12 subjects undergoing scoliosis correction. Urinary bile acids were analysed using flow injection negative electrospray mass spectrometry. Propofol binding to recombinant CYP27A1, the effects of propofol on recombinant CYP27A1 activity, and CYP27A1 expression in liver organoids were investigated using spectral binding, enzyme activity assays, and qPCR, respectively. Accurate masses were determined with high‐resolution mass spectrometry.ResultsAbnormal urinary profiles were identified in all subjects after TIVA, with a trend correlating propofol dose per kilogramme and m/z 627 peak intensity. Propofol only induced a weak CYP27A1 response in the spectral binding assay, minimally affected CYP27A1 activity and did not affect CYP27A1 expression. The accurate mass of m/z 627 induced by propofol differed >10 PPM from m/z 627 observed in CTX.ConclusionsTIVA with propofol invariably led to a urinary profile misleadingly suggestive of CTX, but not through CYP27A1 inhibition. To avoid further misdiagnoses, propofol administration should be considered when interpreting urinary bile acid profiles.

A novel mutation in the CYP27A1 gene in a family with cerebrotendinous xanthomatosis

Purpose of the study Cerebrotendinous xanthomatosis (CTX) is an inherited disorder associated with abnormal deposition of cholestenol in the brain and other tissues. Here we report a Chinese family with two affected members of CTX. Materials and Methods Clinical data were collected. Gene analysis, MRI, neuropsychological assessments, and the biopsy of right Achilles tendon xanthoma were carried out. Results The two cases had similar symptoms for cataracts, chronic diarrhea, progressive cognitive impairment and a disturbance of gait, and were identified with the same compound heterozygous mutations, c.435G>T in exon 2 and c.562C>T in exon 3. Conclusions Cerebrotendinous xanthomatosis (CTX) is an inherited disorder associated with abnormal deposition of cholestenol in the brain and other tissues. Although CTX is a treatable disease, the time of beginning treatment is crucial for therapeutic effect. Unfortunately, it usually takes years even decades from initial symptoms to the diagnosis of CTX. The screening for 27-hydroxylase (CYP27A1) gene even before the occurrence of tendon xanthoma is important for early diagnosis.

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.

A preventable ataxia: Cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis is an autosomal recessive inborn error of metabolism that is an often missed but treatable cause of hereditary ataxia. We report a case of cerebrotendinous xanthomatosis (CTX) that was diagnosed only after the development of cognitive decline and adult onset ataxia in a 35-year-old man. He had poor scholastic performance in childhood followed by gradually progressive cognitive decline. He presented to us with severe cerebellar ataxia and oculomotor apraxia. The key features that led to the diagnosis of CTX were the history of cataracts in childhood and Achilles tendon xanthoma. His brain magnetic resonance imaging showed characteristic features of CTX, and the diagnosis was confirmed by demonstrating the mutation in exon 2 of the CYP27A1 gene. The recognition of CTX earlier could have prevented his significant disabilities. The definitive treatment is oral chenodeoxycholic acid, which will prevent the accumulation of the cholestanol, which is thought to be responsible for the neurotoxicity.

Usefulness of brain magnetic resonance in the diagnosis of cerebrotendinous xanthomatosis

Usefulness of brain magnetic resonance in the diagnosis of cerebrotendinous xanthomatosis

Diagnosis, treatment, and clinical outcomes in 43 cases with cerebrotendinous xanthomatosis

Cerebrotendinous xanthomatosis (CTX) is a rare disorder due to defective sterol 27-hydroxylase causing a lack of chenodeoxycholic acid (CDCA) production and high plasma cholestanol levels. Our objective was to review the diagnosis and treatment results in 43 CTX cases. We conducted a careful review of the diagnosis, laboratory values, treatment, and clinical course in 43 CTX cases. The mean age at diagnosis was 32years; the average follow-up was 8years. Cases had the following conditions: 53% chronic diarrhea, 74% cognitive impairment, 70% premature cataracts, 77% tendon xanthomas, 81% neurologic disease, and 7% premature cardiovascular disease. The mean serum cholesterol concentration was 190mg/dL; the mean plasma cholestanol level was 32mg/L (normal <5.0mg/L), which decreased to 6.0mg/L (-81%) with CDCA therapy generally given as 250mg orally 3 times daily. Of those tested on treatment, 63% achieved cholestanol levels of <5.0mg/L; 91% had normal liver enzyme levels; none had significant liver problems after dose adjustment. Treatment improved symptoms in 57% at follow-up, but 20% with advanced disease continued to deteriorate. In the United States, CDCA has been approved for gallstone dissolution, but not for CTX despite long-term efficacy and safety data. Health care providers seeing young patients with tendon xanthomas and relatively normal cholesterol levels, especially those with cataracts and learning problems, should consider the diagnosis of CTX so they can receive treatment. CDCA should receive regulatory approval to facilitate therapy for the prevention of the complications of the disease.

Determination and hierarchy of clinical signs for early detection of cerebrotendinous xanthomatosis

Cerebrotendinous Xanthomatosis (CTX) is an autosomal recessive disease caused by mutations in the CYP27A1 gene resulting in a decreased synthesis of bile acids. An early diagnosis and treatment would reduce the longterm complications observed in this disease. To identify and hierarchize initial clinical signs of CTX to establish an early diagnostic suspicion index. Clinical information was collected from 387 patients diagnosed with CTX, published in MEDLINE between 1968 and 2016. Clinical manifestations were identified, determining their prevalence and age of onset. Sensitivity, specificity and the positive Likelihood ratio (LR+) was calculated for each clinical sign evaluated. The average ages for early symptoms' onset and CTX diagnosis were 13.3 ± 10.6 years and 34.6 ± 12.6 years respectively. The early clinical signs and their respective LR+ were: juvenile cataracts (143), epilepsy (81), chronic diarrhea (15.6) and psychomotor development delay (3.4). The presence of consanguinity among parents resulted in a LR+ of 31. The combination of two early signs increased the post-test probability to 30%. If the early diagnostic criteria would have been applied in three Chilean patients with diagnosis of CTX, their disease would have been diagnosed from 12 to 25 years earlier. The use of a hierarchical system of predictive clinical signs allows an early screening of CTX, which may avoid the natural progression of the disease using an appropriate treatment.

Cerebrotendinous xanthomatosis-a case report with novel compound heterozygous mutation of CYP27A1 gene

Abstract Cerebrotendinous xanthomatosis (CTX), a rare autosomal recessive lipid storage disorder which is caused by mutations in gene CYP27A1 leads to deficiency of enzyme sterol 27-hydroxylase. Clinically, CTX is characterized by tendon xanthomas, premature atherosclerosis, juvenile cataracts and progressive neurological deficits. In this study, we report one 34 year-old Taiwanese man who developed bilateral xanthomas on Achilles tendon and progressive neuropsychiatric disorder. DNA sequencing revealed novel compound heterozygous mutation of CYP27A1 gene, 1072C > T (Gln358X) in exon 6 and c.496–497, 503–514 deletion in exon 1. Early diagnosis of CTX is crucial because treatment with chenodeoxycholic acid in time may prevent or improve neurological dysfunction.

Cerebrotendinous xanthomatosis: early diagnosis on the basis of juvenile cataracts

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease characterized by a broad spectrum of clinical manifestations, including bilateral juvenile cataracts. Untreated CTX leads to progressive permanent neurologic decline and early death. Although symptoms begin in early childhood, diagnosis and replacement therapy with chenodeoxycholic acid is often delayed until adulthood. Frequently bilateral juvenile cataracts present in early childhood which provides ophthalmologists an opportunity to aid in early diagnosis and initiate treatment. We report the case of a child presenting with juvenile bilateral cataracts leading to the diagnosis of CTX. The morphology of cataracts and the effect of systemic treatment on its progression are described.

Sonographic Findings of Polyneuropathy Associated With Cerebrotendinous Xanthomatosis: A Case Report.

Cerebrotendinous xanthomatosis is a rare autosomal recessive disease that involves multiple organs, including the peripheral nervous system. The present study is the first to report the ultrasonographic findings of peripheral nerves in a patient with cerebrotendinous xanthomatosis. The patient presented with bilateral Achilles tendon enlargement and foot hypesthesia. Sonographic examination revealed hypoechoic, swollen peripheral nerves with enlarged bilateral Achilles tendons. Since the ultrasonographic findings revealed peripheral involvement, the diagnosis of cerebrotendinous xanthomatosis was established after laboratory and genetic studies along with clinical findings.

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.

Evaluation of cholesterol metabolism in cerebrotendinous xanthomatosis.

Cerebrotendinous xanthomatosis (CTX) is a treatable bile acid disorder caused by mutations of CYP27A1. The pathogenesis of neurological damage has not been completely explained. Oral chenodeoxycholic acid (CDCA) can lead to clinical stabilization, but in a subgroup of patients the disease progresses despite treatment. In the present study, we aimed at clarifying cholesterol metabolism abnormalities and their response to CDCA treatment, in order to identify reliable diagnostic and prognostic markers and understand if differences exist between stable patients and those with neurological progression. We enrolled 19 untreated CTX patients and assessed serum profile of bile acids intermediates, oxysterols, cholesterol, lathosterol, and plant sterols. Then we performed a long-term follow up during CDCA therapy, and compared biochemical data with neurological outcome. We observed increase of cholestanol, 7α-hydroxy-4-cholesten-3-one (7αC4), lathosterol, and plant sterols, whereas 27-hydroxycholesterol (27-OHC) was extremely low or absent. CDCA treatment at a daily dose of 750mg normalized all biochemical parameters except for 7αC4 which persisted slightly higher than normal in most patients, and 27-OHC which was not modified by therapy. Biochemical evaluation did not reveal significant differences between stable and worsening patients. Cholestanol and 7αC4 represent important markers for CTX diagnosis and monitoring of therapy. Treatment with CDCA should aim at normalizing serum 7αC4 as well as cholestanol, since 7αC4 better mirrors 7α-hydroxylation rate and is thought to be correlated with cholestanol accumulation in the brain. Assessment of serum 27-OHC is a very good tool for biochemical diagnosis at any stage of disease. Lathosterol and plant sterols should be considered as additional markers for diagnosis and monitoring of therapy. Further studies including long-term assessment of bile acid intermediates in cerebrospinal fluid are needed in patients who show clinical progression despite treatment.

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: An Early Diagnosis by Biochemical Tests

To the Editor:A 17-y-old girl born to non-consanguineously married couple presented with bilateral, painless achillestendon swellings for 6 mo. She had normal birth and developmental history. She was operated for developmental cataract at 8 y of age. She did not have chronic diarrhea as a young child and had no history suggestive of nervous system involvement. Examination revealed a thinly built girl with firm, non-tender, fusiform swellings of both Achilles tendons, measuring 5 cm × 3 cm. She had pseudophakia (implanted intraocular lens) of both eyes. There was no evidence of pyramidal tract or cerebellar involvement. Based on her clinical presentation, the diagnosis of cerebrotendinous xanthomatosis (CTX) was suspected. Fine needle aspiration cytology of tendo-achilles swellings (Fig. 1a) showed giant cells with lipoid deposits within consistent with xanthomas. Differential diagnoses considered were hypercholesterolemia and sitosterolemia. Serum cholesterol was normal (144 mg%) which excluded hypercholesterolemia. Sitosterolemia is an inherited sterol storage disease characterized by tendon xanthomas but cataract is characteristically not a feature. Her serum cholestanol was elevated at 29.4 microgram/mL (normal 4.2±1.2 microgram/mL). Other cholesterol metabolites, 7-dehydro cholesterol, 8-dehydro cholesterol and 8(9)cholestenol were mildly elevated which confirmed the diagnosis. MRI brain was unremarkable except for altered Welchers angle – the angle between a line extending across the anterior cranial fossa to the tip to the dorsum sellae and another line along the posterior margin of the clivus. It was 120° (normal 113 to 115) (Fig. 1b). This has not been described as a feature of CTX in the literature. However, the classical MRI findings of the disease were demonstrated in two cases reported from the same region [1]. Plain X-ray of long bones, thyroid function tests, nerve conduction studies, ECG and echocardiogram were normal. Diagnosis was made before the onset of neurological manifestations. Van-Bogaert et al. first described the CTX phenotype in 1937 [2]. The varied manifestations of the disease are described in Table 1. CTX is a lipid storage disease. CYP27A1 is the only causative gene. The gene codes for the mitochondrial sterol 21-hydroxylase enzyme, which catalyzes oxidation of sterol intermediates during bile acid synthesis [3]. Loss of enzyme causes accumulation of cholestanol in many tissues. Deficiency of cholic acid and chenodeoxycholic acid also occurs; this alters permeability of blood–brain barrier and accumulation of excess cholestenol in brain causing neuronal cells apoptosis [4]. Treatment of choice is chenodeoxy-cholicacid. Early treatment prevents neurological abnormalities [5]. HMG-CoA-reductase-inhibitors alone or along with chenodeoxy-cholic-acid are also useful [6]. M. L. Kulkarni (*) Department of Pediatrics, JJM Medical College, Davanagere, Karnataka 577004, India e-mail: kulkarniml@yahoo.com