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Cholestanol storage disease(CTX)

MedGen UID:
116041
Concept ID:
C0238052
Disease or Syndrome
Synonyms: Cerebral cholesterinosis; Cerebrotendinous Xanthomatosis; CTX; CTX: Cerebrotendinous xanthomatosis
SNOMED CT: Cholestanol storage disease (63246000); Cerebrotendinous xanthomatosis (63246000); Cerebral cholesterinosis (63246000); van Bogaert-Scherer-Epstein syndrome (63246000); CTX - Cerebrotendinous xanthomatosis (63246000); Cerebrotendinous cholesterinosis (63246000); Cholestanolosis (63246000); Van Bogaert-Scherer-Epstein disease (63246000)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): CYP27A1 (2q35)
 
Monarch Initiative: MONDO:0008948
OMIM®: 213700
Orphanet: ORPHA909

Disease characteristics

Excerpted from the GeneReview: Cerebrotendinous Xanthomatosis
Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease characterized by infantile-onset diarrhea, childhood-onset cataract, adolescent- to young adult-onset tendon xanthomas, and adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures). Chronic diarrhea from infancy and/or neonatal cholestasis may be the earliest clinical manifestation. In approximately 75% of affected individuals, cataracts are the first finding, often appearing in the first decade of life. Xanthomas appear in the second or third decade; they occur on the Achilles tendon, the extensor tendons of the elbow and hand, the patellar tendon, and the neck tendons. Xanthomas have been reported in the lung, bones, and central nervous system. Some individuals show cognitive impairment from early infancy, whereas the majority have normal or only slightly impaired intellectual function until puberty; dementia with slow deterioration in intellectual abilities occurs in the third decade in more than 50% of individuals. Neuropsychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicide attempts may be prominent. Pyramidal signs (i.e., spasticity) and/or cerebellar signs almost invariably become evident between ages 20 and 30 years. The biochemical abnormalities that distinguish CTX from other conditions with xanthomas include high plasma and tissue cholestanol concentration, normal-to-low plasma cholesterol concentration, decreased chenodeoxycholic acid (CDCA), increased concentration of bile alcohols and their glyconjugates, and increased concentrations of cholestanol and apolipoprotein B in cerebrospinal fluid. [from GeneReviews]
Authors:
Antonio Federico  |  Gian Nicola Gallus   view full author information

Additional descriptions

From OMIM
Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid-storage disease characterized clinically by progressive neurologic dysfunction (cerebellar ataxia beginning after puberty, systemic spinal cord involvement and a pseudobulbar phase leading to death), premature atherosclerosis, and cataracts. Large deposits of cholesterol and cholestanol are found in virtually every tissue, particularly the Achilles tendons, brain, and lungs. Cholestanol, the 5-alpha-dihydro derivative of cholesterol, is enriched relative to cholesterol in all tissues. The diagnosis can be made by demonstrating cholestanol in abnormal amounts in the serum and tendon of persons suspected of being affected. Plasma cholesterol concentrations are low normal in CTX patients. Dotti et al. (2001) examined the ophthalmologic findings of 13 CTX patients. In addition to cataracts, which were found in all cases, optic disc pallor was identified in 6 of the patients. Premature retinal senescence was also observed. In a tabular presentation, Moghadasian et al. (2002) compared and contrasted CTX with 2 other lipid disorders with certain similarities and clinical course: familial hypercholesterolemia (see 143890) and sitosterolemia (see 210250).  http://www.omim.org/entry/213700
From MedlinePlus Genetics
Cerebrotendinous xanthomatosis is a disorder characterized by abnormal storage of fats (lipids) in many areas of the body. People with this disorder cannot break down certain lipids effectively, specifically different forms of cholesterol, so these fats accumulate in the body in the form of fatty yellow nodules called xanthomas. These xanthomas are most commonly found in the brain and in connective tissue called tendons that attach muscle to bone, which is reflected in the condition name (cerebro- meaning brain and -tendinous referring to tendons).

People with cerebrotendinous xanthomatosis often develop neurological problems in early adulthood that are thought to be caused by an abnormal accumulation of fats and an increasing number of xanthomas in the brain. These neurological problems include recurrent seizures (epilepsy), movement disorders, impaired speech (dysarthria), loss of sensation in the arms and legs (peripheral neuropathy), decline in intellectual function (dementia), hallucinations, and depression. Xanthomas can accumulate in the fatty substance that insulates and protects nerves (myelin), causing the destruction of myelin and disrupting nerve signaling in the brain. Degeneration (atrophy) of brain tissue caused by excess lipid deposits also contributes to the neurological problems.

Xanthomas in the tendons begin to form in early adulthood. The most common areas for xanthomas to develop are tendons in the hands, elbows, knees, neck, and in the Achilles tendon, which connects the heel of the foot to the calf muscles in the leg. Tendon xanthomas may cause discomfort and interfere with tendon flexibility. While many affected people develop tendon xanthomas, these nodules may not be easily visible underneath the skin.

Other features of cerebrotendinous xanthomatosis include clouding of the lenses of the eyes (cataracts) and chronic diarrhea in childhood; a reduced ability to produce and release a digestive fluid called bile (cholestasis), which can lead to a yellowing of the skin or whites of the eyes (jaundice); and progressively brittle bones that are prone to fracture (osteoporosis). People with cerebrotendinous xanthomatosis are also at an increased risk of developing cardiovascular disease or respiratory failure because of lipid accumulation in the heart or lungs, respectively. If untreated, the signs and symptoms related to cerebrotendinous xanthomatosis worsen over time; however, this condition varies greatly among those who are affected.  https://medlineplus.gov/genetics/condition/cerebrotendinous-xanthomatosis

Clinical features

From HPO
Ankle clonus
MedGen UID:
68672
Concept ID:
C0238651
Finding
Clonus is an involuntary tendon reflex that causes repeated flexion and extension of the foot. Ankle clonus is tested by rapidly flexing the foot upward.
Lower limb muscle weakness
MedGen UID:
324478
Concept ID:
C1836296
Finding
Weakness of the muscles of the legs.
Angina pectoris
MedGen UID:
1929
Concept ID:
C0002962
Sign or Symptom
Paroxysmal chest pain that occurs with exertion or stress and is related to myocardial ischemia.
Myocardial infarction
MedGen UID:
10150
Concept ID:
C0027051
Disease or Syndrome
Necrosis of the myocardium caused by an obstruction of the blood supply to the heart and often associated with chest pain, shortness of breath, palpitations, and anxiety as well as characteristic EKG findings and elevation of serum markers including creatine kinase-MB fraction and troponin.
Cholelithiasis
MedGen UID:
3039
Concept ID:
C0008350
Disease or Syndrome
Hard, pebble-like deposits that form within the gallbladder.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency (usually defined as three or more) loose or watery bowel movements a day.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Delusion
MedGen UID:
3715
Concept ID:
C0011253
Mental or Behavioral Dysfunction
A delusion is a fixed false belief held despite evidence to the contrary. The term delusion broadly encompasses all false judgments that possess the following external characteristics to a significant, albeit unspecified, extent
Hallucinations
MedGen UID:
6709
Concept ID:
C0018524
Mental or Behavioral Dysfunction
Perceptions in a conscious and awake state that, in the absence of external stimuli, have qualities of real perception. These perceptions are vivid, substantial, and located in external objective space.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Peripheral neuropathy
MedGen UID:
18386
Concept ID:
C0031117
Disease or Syndrome
Peripheral neuropathy is a general term for any disorder of the peripheral nervous system. The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course.
Pseudobulbar paralysis
MedGen UID:
10989
Concept ID:
C0033790
Disease or Syndrome
Bilateral impairment of the function of the cranial nerves 9-12, which control musculature involved in eating, swallowing, and speech. Pseudobulbar paralysis is characterized clinically by dysarthria, dysphonia, and dysphagia with bifacial paralysis, and may be accompanied by Pseudobulbar behavioral symptoms such as enforced crying and laughing.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Abnormal pyramidal sign
MedGen UID:
68582
Concept ID:
C0234132
Sign or Symptom
Functional neurological abnormalities related to dysfunction of the pyramidal tract.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Abnormal periventricular white matter morphology
MedGen UID:
435926
Concept ID:
C2673431
Finding
A structural abnormality of the myelinated axons (white matter) located near the cerebral ventricles.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
EEG with generalized slow activity
MedGen UID:
866862
Concept ID:
C4021217
Finding
Diffuse slowing of cerebral electrical activity recorded along the scalp by electroencephalography (EEG).
Abnormal dentate nucleus morphology
MedGen UID:
867758
Concept ID:
C4022148
Anatomical Abnormality
An abnormality of the dentate nucleus.
Delayed somatosensory central conduction time
MedGen UID:
867773
Concept ID:
C4022163
Pathologic Function
An abnormal increase (delay) in the somatosensory central conduction time (CCT), which can be measured from the peak of N13 to the peak of N20 (peak CCT) or from the onset of N11 to the onset of N20 (onset CCT).
Elevated CSF cholestanol concentration
MedGen UID:
1052708
Concept ID:
CN376716
Finding
The concentration of cholestanol in the cerebrospinal fluid (CSF) is above the upper limit of normal. Cholestanol is the 5-alpha-dihydro derivative of cholesterol.
Osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).
Tendon xanthomatosis
MedGen UID:
450999
Concept ID:
C0221253
Disease or Syndrome
The presence of xanthomas (intra-and extra-cellular accumulations of cholesterol) extensor tendons (typically over knuckles, Achilles tendon, knee, and elbows).
Difficulty walking
MedGen UID:
86319
Concept ID:
C0311394
Finding
Reduced ability to walk (ambulate).
EMG: axonal abnormality
MedGen UID:
871138
Concept ID:
C4025609
Pathologic Function
Electromyographic (EMG) findings characteristic of axonal neuropathy, with normal or slightly decreased nerve conduction velocities, normal or slightly prolonged distal latencies, but significantly reduced motor potentials and sensory amplitudes. There may be spontaneous activity upon needle EMG studies, such as increased insertional activity, positive sharp waves, and fibrillation potentials.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Abnormal circulating cholesterol concentration
MedGen UID:
871179
Concept ID:
C4025656
Finding
Any deviation from the normal concentration of cholesterol in the blood circulation.
Xanthomatosis
MedGen UID:
21939
Concept ID:
C0043325
Disease or Syndrome
The presence of multiple xanthomas (xanthomata) in the skin. Xanthomas are yellowish, firm, lipid-laden nodules in the skin.
Xanthelasma
MedGen UID:
56357
Concept ID:
C0155210
Disease or Syndrome
The presence of xanthomata in the skin of the eyelid.
Tuberous xanthoma
MedGen UID:
86213
Concept ID:
C0302164
Disease or Syndrome
A type of xanthoma characterized by a nodular form. Tuberous xanthomas are firm subcutaneous nodules,whereby the overlying skin can have red or red-yellow color changes.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Optic disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
A pale yellow discoloration of the optic disc (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCholestanol storage disease
Follow this link to review classifications for Cholestanol storage disease in Orphanet.

Professional guidelines

PubMed

Amine R, Traboulsi EI
J Binocul Vis Ocul Motil 2023 Oct 2;73(4):104-108. Epub 2023 Nov 6 PMID: 37931120
Vaz FM, Jamal Y, Barto R, Gelb MH, DeBarber AE, Wevers RA, Nelen MR, Verrips A, Bootsma AH, Bouva MJ, Kleise N, van der Zee W, He T, Salomons GS, Huidekoper HH
Clin Chim Acta 2023 Jan 15;539:170-174. Epub 2022 Dec 16 doi: 10.1016/j.cca.2022.12.011. PMID: 36529270Free PMC Article
Salen G, Steiner RD
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Recent clinical studies

Etiology

DeBarber AE, Duell PB
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Ashrafi MR, Amanat M, Garshasbi M, Kameli R, Nilipour Y, Heidari M, Rezaei Z, Tavasoli AR
Expert Rev Neurother 2020 Jan;20(1):65-84. Epub 2019 Dec 12 doi: 10.1080/14737175.2020.1699060. PMID: 31829048
Köhler W, Curiel J, Vanderver A
Nat Rev Neurol 2018 Feb;14(2):94-105. Epub 2018 Jan 5 doi: 10.1038/nrneurol.2017.175. PMID: 29302065
Jayadev S, Bird TD
Genet Med 2013 Sep;15(9):673-83. Epub 2013 Mar 28 doi: 10.1038/gim.2013.28. PMID: 23538602
Vecka M, Zak A, Tvrzická E
Acta Univ Carol Med Monogr 2008;154:5-101. PMID: 19283968

Diagnosis

DeBarber AE, Duell PB
Curr Opin Lipidol 2021 Apr 1;32(2):123-131. doi: 10.1097/MOL.0000000000000740. PMID: 33630770
Ashrafi MR, Amanat M, Garshasbi M, Kameli R, Nilipour Y, Heidari M, Rezaei Z, Tavasoli AR
Expert Rev Neurother 2020 Jan;20(1):65-84. Epub 2019 Dec 12 doi: 10.1080/14737175.2020.1699060. PMID: 31829048
Boltshauser E, Weber KP
Handb Clin Neurol 2018;154:287-298. doi: 10.1016/B978-0-444-63956-1.00017-5. PMID: 29903445
Köhler W, Curiel J, Vanderver A
Nat Rev Neurol 2018 Feb;14(2):94-105. Epub 2018 Jan 5 doi: 10.1038/nrneurol.2017.175. PMID: 29302065
Leitersdorf E, Meiner V
Curr Opin Lipidol 1994 Apr;5(2):138-42. doi: 10.1097/00041433-199404000-00010. PMID: 8044416

Therapy

DeBarber AE, Duell PB
Curr Opin Lipidol 2021 Apr 1;32(2):123-131. doi: 10.1097/MOL.0000000000000740. PMID: 33630770
Faoucher M, Demily C
Handb Clin Neurol 2019;165:191-205. doi: 10.1016/B978-0-444-64012-3.00011-3. PMID: 31727212
Heubi JE, Setchell KDR, Bove KE
Clin Liver Dis 2018 Nov;22(4):671-687. Epub 2018 Aug 22 doi: 10.1016/j.cld.2018.06.006. PMID: 30266156
Salen G, Steiner RD
J Inherit Metab Dis 2017 Nov;40(6):771-781. Epub 2017 Oct 4 doi: 10.1007/s10545-017-0093-8. PMID: 28980151
Brautbar A, Leary E, Rasmussen K, Wilson DP, Steiner RD, Virani S
Curr Atheroscler Rep 2015 Apr;17(4):491. doi: 10.1007/s11883-015-0491-z. PMID: 25712136

Prognosis

DeBarber AE, Duell PB
Curr Opin Lipidol 2021 Apr 1;32(2):123-131. doi: 10.1097/MOL.0000000000000740. PMID: 33630770
Köhler W, Curiel J, Vanderver A
Nat Rev Neurol 2018 Feb;14(2):94-105. Epub 2018 Jan 5 doi: 10.1038/nrneurol.2017.175. PMID: 29302065
Salen G, Steiner RD
J Inherit Metab Dis 2017 Nov;40(6):771-781. Epub 2017 Oct 4 doi: 10.1007/s10545-017-0093-8. PMID: 28980151
Fraidakis MJ
Transl Psychiatry 2013 Sep 3;3(9):e302. doi: 10.1038/tp.2013.76. PMID: 24002088Free PMC Article
Palau F, Espinós C
Orphanet J Rare Dis 2006 Nov 17;1:47. doi: 10.1186/1750-1172-1-47. PMID: 17112370Free PMC Article

Clinical prediction guides

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Metab Brain Dis 2021 Aug;36(6):1201-1211. Epub 2021 Mar 11 doi: 10.1007/s11011-021-00714-7. PMID: 33704661
Gelzo M, Di Taranto MD, Sica C, Boscia A, Papagni F, Fortunato G, Corso G, Dello Russo A
Lipids Health Dis 2019 Dec 30;18(1):235. doi: 10.1186/s12944-019-1176-3. PMID: 31888647Free PMC Article
Lee CW, Lee JJ, Lee YF, Wang PW, Pan TL, Chang WN, Tsai MH
J Clin Lipidol 2019 Nov-Dec;13(6):954-959.e1. Epub 2019 Oct 10 doi: 10.1016/j.jacl.2019.10.001. PMID: 31706903
Abate M, Salini V, Andia I
Adv Exp Med Biol 2016;920:117-22. doi: 10.1007/978-3-319-33943-6_10. PMID: 27535253

Recent systematic reviews

Badura-Stronka M, Hirschfeld AS, Winczewska-Wiktor A, Budzyńska E, Jakubiuk-Tomaszuk A, Piontek A, Steinborn B, Kozubski W
Clin Genet 2022 Feb;101(2):190-207. Epub 2021 Nov 24 doi: 10.1111/cge.14079. PMID: 34689324
Bonnot O, Klünemann HH, Sedel F, Tordjman S, Cohen D, Walterfang M
Orphanet J Rare Dis 2014 Apr 28;9:65. doi: 10.1186/1750-1172-9-65. PMID: 24775716Free PMC Article
Lagarde J, Roze E, Apartis E, Pothalil D, Sedel F, Couvert P, Vidailhet M, Degos B
Mov Disord 2012 Dec;27(14):1805-10. Epub 2012 Oct 31 doi: 10.1002/mds.25206. PMID: 23115103

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