Patients with cerebrotendinous xanthomatosis diagnosed with diverse multisystem involvement.

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease caused by deficiency of sterol 27-hydroxylase enzyme encoded by CYP27A1 gene. This multicenter, cross-sectional descriptive study aimed to document clinical characteristics of CTX patients of different ages, clinical presentations of early-diagnosed patients, and responses to short-term chenodeoxycholic acid (CDCA) treatment. Seven of 11 CTX patients were diagnosed in childhood. Three patients (27%) had neonatal cholestasis, seven (63%) patients had a history of frequent watery defecation started in infantile period, and eight (72.7%) patients had juvenile cataract. Four patients in the adult age group had pyramidal signs and parkinsonism symptoms. The mean Mignarri score at diagnosis was significantly lower in the pediatric patients (267.8 ± 51.4) than in the adult patients (450.0 ± 64.0, p = 0.001). No significant difference was determined between pediatric patients and adult patients regarding plasma cholestanol concentration at diagnosis (p = 0.482). The frequency of defecation decreased with treatment in six children, who had diarrhea at admission. Compared to pretreatment values, patients' body weight and standardized body mass index significantly increased at the 12th month of treatment. In conclusion, Mignarri scores are lower in the pediatric patients than in adult patients since the most determinative signs of the CTX disease are not apparent yet in the childhood. The disease is frequently overlooked in routine practice as the disease presents itself with different clinical combinations both in adults and in children. CTX is potentially a treatable disease; thereby, enhanced awareness is critically important for early diagnosis particularly in children.

Multifocal, hypoechogenic nerve thickening in Cerebrotendinous Xanthomatosis.

OBJECTIVE: To characterize peripheral nerve morphology in cerebrotendinous xanthomatosis (CTX) patients using high-resolution ultrasound (HRUS) in vivo. We hypothesized that nerve enlargements might be present in CTX as a result of accumulation of abnormal lipids with deposition also in peripheral nerves. METHODS: Four CTX patients were examined using HRUS to assess morphological abnormalities of peripheral nerves as well as cervical nerve roots 5 and 6. RESULTS: HRUS revealed mild to moderate, hypoechogenic thickening of sensorimotor nerves (ulnar nerve in 1/4, tibial nerve in 3/4, median nerve 4/4 patients) as well as mild enlargement of pure sensory nerves (sural nerve in 2/3, superficial FN in 2/4 patients). The vagal nerve was moderately enlarged in one patient, cervical roots showed moderate enlargements of C5 in two patients, one of which also showing thickening of C6 as well as in another patient. UPSS score was slightly to moderately abnormal in all patients. The Homogeneity score was not increased suggesting regional to inhomogeneous nerve enlargement. CONCLUSIONS: HRUS shows multifocal, hypoechogenic nerve thickening of peripheral nerves and nerve roots in CTX. SIGNIFICANCE: HRUS might serve as a valuable, additive and non-invasive bedside tool to assess peripheral nerve morphology in future clinical studies on CTX patients.

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.

Prevalence of oropharyngeal dysphagia in hereditary spastic paraplegias / Prevalência de disfagia orofaríngea nas paraparesias espásticas hereditárias

ABSTRACT Hereditary spastic paraplegias (HSP) are a group of genetic diseases characterized by lower limb spasticity with or without additional neurological features. Swallowing dysfunction is poorly studied in HSP and its presence can lead to significant respiratory and nutritional complications. Objectives: The aim of this study was to evaluate the frequency and clinical characteristics of dysphagia in different types of HSP. Methods: A two-center cross-sectional prevalence study was performed. Genetically confirmed HSP patients were evaluated using the Northwestern Dysphagia Patient Check Sheet and the Functional Oral Intake Scale. In addition, self-perception of dysphagia was assessed by the Eat Assessment Tool-10 and the Swallowing Disturbance Questionnaire. Results: Thirty-six patients with spastic paraplegia type 4 (SPG4), five with SPG11, four with SPG5, four with cerebrotendinous xanthomatosis (CTX), three with SPG7, and two with SPG3A were evaluated. Mild to moderate oropharyngeal dysphagia was present in 3/5 (60%) of SPG11 and 2/4 (50%) of CTX patients. A single SPG4 (2%) and a single SPG7 (33%) patient had mild oropharyngeal dysphagia. All other evaluated patients presented with normal or functional swallowing. Conclusions: Clinically significant oropharyngeal dysphagia was only present in complicated forms of HSP Patients with SPG11 and CTX had the highest risks for dysphagia, suggesting that surveillance of swallowing function should be part of the management of patients with these disorders.

RESUMO As paraparesias espásticas hereditárias (PEH) são um grupo de doenças genéticas caracterizado por espasticidade dos membros inferiores com ou sem características neurológicas adicionais. A disfunção da deglutição é pouco estudada nas PEH e sua presença pode levar a complicações respiratórias e nutricionais significativas. Objetivo: O objetivo deste estudo foi avaliar a frequência e a caracterização clínica da disfagia em diferentes tipos de PEH. Métodos: Foi realizado um estudo transversal em dois centros. Os pacientes com PEH confirmados geneticamente foram avaliados pelo Northwestern Dysphagia Patient Check Sheet e pela Escala Funcional de Ingestão Oral. Além disso, a autopercepção da disfagia foi avaliada pelo Eat Assessment Tool-10 e pelo Swallowing Disturbance Questionnaire. Resultados: Trinta e seis pacientes com paraplegia espástica tipo 4 (SPG4), cinco com SPG11, quatro com SPG5, quatro com xantomatose cerebrotendinosa (CTX), três com SPG7 e dois com SPG3A foram avaliados. Disfagia orofaríngea leve a moderada estava presente em 3/5 (60%) dos pacientes com SPG11 e 2/4 (50%) dos pacientes com CTX. Um único SPG4 (2%) e um único SPG7 (33%) apresentaram disfagia orofaríngea leve. Todos os outros pacientes avaliados apresentaram deglutição normal ou funcional. Conclusão: Disfagia orofaríngea clinicamente significativa estava presente apenas nas formas complicadas de PEH. A SPG11 e CTX apresentaram maiores riscos de disfagia, sugerindo que a avaliação da deglutição deve fazer parte do manejo dos pacientes com essas condições.

Early diagnosed cerebrotendinous xanthomatosis patients: clinical, neuroradiological characteristics and therapy results of a single center from Turkey.

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disorder caused by defective sterol 27-hydroxylase activity. In spite of subtle clinical signs beginning from childhood, CTX is generally diagnosed lately. The aim of this study is to evaluate clinical, neuroradiological findings and therapy responses of pediatric CTX patients and raise awareness to early features of disease. Patients who were molecularly diagnosed as CTX before 18 years of age were included in study. Clinical, epidemiological, radiological and genotypic features of patients and chenodeoxycholic acid (CDCA) therapy responses were reviewed retrospectively. Six patients were enrolled in the study. The mean age of diagnosis was 11.1 ± 4.5 years. Apart from previous studies, predominance of cerebellar signs over pyramidal signs, peripheral neuropathy with demyelinating neuropathy in majority of patients and pathological brain imaging findings despite young ages of patients were observed. Intention tremor was the consisting finding of all patients. Optic disc drusen was initially reported in one patient. Skeletal system involvement as coarse extremities, deformities and early osteoporosis was recognized in four patients. CDCA therapy improved or at least stabilized neurological functions in all patients. This study is the first CTX series from Turkey and performed among only in early diagnosed patients with a therapy follow-up contrary to limited data in the literature. We suggest that, awareness of intention tremor and ataxic gait in addition to mental retardation, peripheral neuropathy and early osteoporosis can be suspicious for CTX and lead diagnosis. Early treatment can provide stability and may also ameliorate existing neurological findings.

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.

Prevalence of oropharyngeal dysphagia in hereditary spastic paraplegias.

OBJECTIVES: Hereditary spastic paraplegias (HSP) are a group of genetic diseases characterized by lower limb spasticity with or without additional neurological features. Swallowing dysfunction is poorly studied in HSP and its presence can lead to significant respiratory and nutritional complications. The aim of this study was to evaluate the frequency and clinical characteristics of dysphagia in different types of HSP. METHODS: A two-center cross-sectional prevalence study was performed. Genetically confirmed HSP patients were evaluated using the Northwestern Dysphagia Patient Check Sheet and the Functional Oral Intake Scale. In addition, self-perception of dysphagia was assessed by the Eat Assessment Tool-10 and the Swallowing Disturbance Questionnaire. RESULTS: Thirty-six patients with spastic paraplegia type 4 (SPG4), five with SPG11, four with SPG5, four with cerebrotendinous xanthomatosis (CTX), three with SPG7, and two with SPG3A were evaluated. Mild to moderate oropharyngeal dysphagia was present in 3/5 (60%) of SPG11 and 2/4 (50%) of CTX patients. A single SPG4 (2%) and a single SPG7 (33%) patient had mild oropharyngeal dysphagia. All other evaluated patients presented with normal or functional swallowing. CONCLUSIONS: Clinically significant oropharyngeal dysphagia was only present in complicated forms of HSP Patients with SPG11 and CTX had the highest risks for dysphagia, suggesting that surveillance of swallowing function should be part of the management of patients with these disorders.

Treatment with chenodeoxycholic acid in cerebrotendinous xanthomatosis: clinical, neurophysiological, and quantitative brain structural outcomes.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare neurodegenerative disease related to sterols metabolism. It affects both central and peripheral nervous systems but treatment with chenodeoxycholic acid (CDCA) has been reported to stabilize clinical scores and improve nerve conduction parameters. Few quantitative brain structural studies have been conducted to assess the effect of CDCA in CTX. METHODS AND RESULTS: We collected retrospectively clinical, neurophysiological, and quantitative brain structural data in a cohort of 14 patients with CTX treated by CDCA over a mean period of 5 years. Plasma cholestanol levels normalized under treatment with CDCA within a few months. We observed a significant clinical improvement in patients up to 25 years old, whose treatment was initiated less than 15 years after the onset of neurological symptoms. Conversely, patients whose treatment was initiated more than 25 years after neurological disease onset continued their clinical deterioration. Eleven patients presented with a length-dependent peripheral neuropathy, whose electrophysiological parameters improved significantly under CDCA. Volumetric analyses in a subset of patients showed no overt volume loss under CDCA. Moreover, diffusion weighted imaging showed improved fiber integrity of the ponto-cerebellar and the internal capsule with CDCA. CDCA was well tolerated in all patients with CTX. CONCLUSION: CDCA may reverse the pathophysiological process in patients with CTX, especially if treatment is initiated early in the disease process. Besides tendon xanthoma, this study stresses the need to consider plasma cholestanol measurement in any patient with infantile chronic diarrhea and/or jaundice, juvenile cataract, learning disability and/or autism spectrum disorder, pyramidal signs, cerebellar syndrome or peripheral neuropathy.

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.

Clinical report: A patient with a late diagnosis of cerebrotendinous xanthomatosis and a response to treatment.

Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive, inborn error of bile acid metabolism characterized by diarrhea in infancy, juvenile cataracts in childhood, tendon xanthomas developing in the second to third decades of life, and progressive neurologic dysfunction in adulthood. The condition is caused by mutations in the CYP27A1 gene that result in decreased production of chenodeoxycholic acid (CDCA) and elevated levels of cholestanol and bile alcohols. We present a 36-year-old male of Han ethnicity who developed xanthomas of his Achilles tendons and suffered neurocognitive declines and gait deterioration in his second decade. The diagnosis of CTX was confirmed by marked elevation of the serum cholestanol level. Sequencing of CYP27A1 showed a paternally inherited splice mutation, c.446 + 1G>T, and a maternally inherited nonsense mutation, c.808C>T, predicting p.(Arg270*). Despite the advanced disease in this patient, treatment with CDCA reduced the xanthoma size and improved his cognition and strength, and the patient made significant gains in his ambulation and coordination. We report this case to illustrate the potential benefits of therapy in patients with CTX who have advanced disease at the time of diagnosis.

Cerebellar Disease Mimicking Cerebrotendinous Xanthomatosis: Langerhans Cell Histiocytosis.

BACKGROUND: This report highlights the differential diagnosis of predominant cerebellar white matter abnormalities with dentate nuclei involvement. PATIENT DESCRIPTION: We describe two individuals with Langerhans cell histiocytosis in whom the diagnosis of cerebrotendinous xanthomatosis was initially considered. The clinical picture consisted of a progressive cerebellar syndrome with typical magnetic resonance imaging abnormalities. In both individuals, the cerebellar syndrome preceded the diagnosis of Langerhans cell histiocytosis. CONCLUSIONS: The magnetic resonance imaging abnormalities and neurological features in patients with Langerhans cell histiocytosis can be strikingly similar to those with cerebrotendinous xanthomatosis. In cerebrotendinous xanthomatosis, the cerebellar symptoms and cerebellar white matter abnormalities are usually seen in adult patients. In a pediatric patient with a cerebellar syndrome, showing these cerebellar white matter abnormalities a diagnosis of Langerhans cell histiocytosis is more likely.

The spectrum of magnetic resonance findings in cerebrotendinous xanthomatosis: redefinition and evidence of new markers of disease progression.

Cerebrotendinous xanthomatosis (CTX) is a metabolic disease characterized by systemic signs and neurological impairment, which can be prevented if chenodeoxycholic acid (CDCA) treatment is started early. Despite brain MRI represents an essential diagnostic tool, the spectrum of findings is worth to be reappraised, and follow-up data are needed. We performed clinical evaluation and brain MRI in 38 CTX patients. Sixteen of them who were untreated at baseline examination underwent clinical and MRI follow-up after long-term treatment with CDCA. Brain MRI abnormalities included cortical and cerebellar atrophy, and T2W/FLAIR hyperintensity involving subcortical, periventricular, and cerebellar white matter, the brainstem and the dentate nuclei. Regarding the dentate nuclei, we also observed T1W/FLAIR hypointensity consistent with cerebellar vacuolation and T1W/FLAIR/SW hypointense alterations compatibly with calcification in a subgroup of patients. Long-term follow-up showed that clinical and neuroradiological stability or progression were almost invariably associated. In patients with cerebellar vacuolation at baseline, a worsening over time was observed, while subjects lacking vacuoles were clinically and neuroradiologically stable at follow-up. The brains of CTX patients very often show both supratentorial and infratentorial abnormalities at MRI, the latter being related to clinical disability and including a wide spectrum of dentate nuclei alterations. The presence of cerebellar vacuolation may be regarded as a useful biomarker of disease progression and unsatisfactory response to therapy. On the other hand, the absence of dentate nuclei signal alteration should be considered an indicator of better prognosis.

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

KEY POINTS: 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. ABSTRACT: 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.

Different phenotypes in identical twins with cerebrotendinous xanthomatosis: case series.

Cerebrotendinous xanthomatosis (CTX) is a rare, genetically determined error of metabolism. The characteristic clinical symptoms are diarrhea, juvenile cataracts, tendon xanthomas and neuropsychiatric alterations. The aim of this study is to present a pair of identical adult twins with considerable differences in the severity of phenotype. With regards to neuropsychiatric symptoms, the predominant features were severe Parkinsonism and moderate cognitive dysfunctions in the more-affected individual, whereas these alterations in the less-affected patient were only very mild and mild, respectively. The characteristic increase in the concentrations of serum cholestanol and the lesion volumes in dentate nuclei in the brain assessed with magnetic resonance imaging were quite similar in both cases. The lifestyle conditions, including eating habits of the twin pair, were quite similar as well; therefore, currently unknown genetic modifiers or certain epigenetic factors may be responsible for the differences in severity of phenotype. This case series serves as the first description of an identical twin pair with CTX presenting heterogeneous clinical features.

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.

Late-onset spinal form xanthomatosis without brain lesion: a case report.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive sterol storage disease caused by a mutated sterol 27-hydroxylase (CYP27A1) gene. Patients with typical CTX show neurological dysfunction including bilateral cataracts, paresis, cerebral ataxia, dementia, and psychiatric disorders, and magnetic resonance imaging (MRI) has revealed symmetrical lesions in the cerebellar white matter. CASE PRESENTATION: We report the case of a patient with late-onset spinal form CTX without brain lesion. He showed pyramidal tract signs, and impaired joint position and vibration sensation in the lower limbs. Cervical sagittal MRI demonstrated a longitudinally extensive white matter abnormality in the dorsal column of the C2-C7 spinal cord; however, a brain MRI revealed an absence of lesions, including in the cerebellar white matter. Genetic analysis of CYP27A1 revealed that the patient was compound heterozygous for p.Gln85Arg in exon 1, a novel mutation, and p.Arg405Gln in exon 7, a previously reported mutation. CONCLUSION: This is the first report of late-onset spinal form CTX without typical neurological symptoms, and the first report of p.Gln85Arg in CYP27A1. We speculate that spinal form CTX without brain lesion is a clinically and radiologically rare variation of CTX. Therefore, spinal xanthomatosis should be included in the differential diagnosis of chronic myelopathy even with late-onset and/or no other typical neurological findings.

Clinical and radiological findings of a cerebrotendinous xanthomatosis patient with a novel p.A335V mutation in the CYP27A1 gene.

We herein describe the case of a Japanese cerebrotendinous xanthomatosis (CTX) patient with a novel CYP27A1 gene mutation. The patient had been diagnosed with cataracts at 25 years of age and subsequently developed neurological symptoms in his forties, being referred to our hospital at 47 years of age. Upon admission, Achilles tendon xanthomas, cognitive impairment, dysphagia, dysarthria, dystonia, spasticity, muscle weakness and ataxia were observed. Brain MRI revealed abnormal signals in the dentate nuclei, periventricular white matter and pyramidal tract, and the serum cholestanol level was elevated. A CYP27A1 gene analysis identified compound heterozygosity for p.A335V, a novel mutation, and p.R405Q, a previously reported mutation. Making an early diagnosis of CTX is crucial, as the administration of chenodeoxycholic acid reverses metabolic derangement.

[Cerebrotendinous xanthomatosis: physiopathology, clinical manifestations and genetics]. / Xantomatosis cerebrotendinosa: aspectos fisiopatológicos, clínicos y genéticos.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease, caused by genetic deficiency of the 27-hydroxylase enzyme (encoded by CYP27A1). It plays a key role in cholesterol metabolism, especially in bile acid synthesis and in the 25-hydroxylation of vitamin D3 in the liver. Its deficiency causes reduced bile acid synthesis and tissue accumulation of cholestanol. Clinical manifestations are related to the presence of cholestanol deposits and include tendon xanthomas, premature cataracts, chronic diarrhea, progressive neurologic impairment and less frequently coronary heart disease, early onset osteoporosis and abnormalities in the optic disk and retina. An early diagnosis and treatment with quenodeoxycholic acid may prevent further complications, mainly neurological manifestations. This review summarizes cholesterol metabolism related to bile acid synthesis, physiopathology, biochemistry and treatment of cerebrotendinous xanthomatosis.

[Laboratory diagnosis of a rare congenital neurodegenerative disease: cerebrotendinous xanthomatosis]. / Egy ritka, veleszületett neurodegeneratív betegség: a cerebrotendinosus xanthomatosis laboratóriumi diagnosztikája.

Cerebrotendinous xanthomatosis is a rare neurodegenerative disease characterized by the accumulation of cholesterol and cholestanol in the brain and the tendons caused by mutations of the gene encoding sterol 27-hydroxylase (CYP27A1), which is involved in bile acid synthesis. The diagnosis is often missed and delayed because of the variable clinical presentation of the disease. Blood testing for cerebrotendinous xanthomatosis is routinely performed using gas chromatography-mass spectrometry measurement of elevated cholestanol level, and the diagnosis is confirmed by molecular genetic analysis. Early recognition and initiation of chenodeoxycholic acid therapy with hydoxymethyl­glutaryl­Coenzyme-A reductase inhibitors is critical to prevent irreversible neurological damage and permanent disability. The authors summarize the current knowledge about the pathomechanism, laboratory diagnosis and therapeutic options of cerebrotendinous xanthomatosis.