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Cholestanol storage disease(CTX)

MedGen UID:
116041
Concept ID:
C0238052
Disease or Syndrome
Synonyms: Cerebral cholesterinosis; Cerebrotendinous Xanthomatosis; CTX
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
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)
 
Gene (location): CYP27A1 (2q35)
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 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 20s 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, increased concentration of bile alcohols and their glyconjugates, and increased concentrations of cholestanol and apolipoprotein B in cerebrospinal fluid. [from GeneReviews]
Authors:
Antonio Federico  |  Maria Teresa Dotti  |  Gian Nicola Gallus   view full author information

Additional descriptions

From OMIM
Cerebrotendinous xanthomatosis is a rare inherited 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 (143890) and sitosterolemia (210250).  http://www.omim.org/entry/213700
From GHR
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://ghr.nlm.nih.gov/condition/cerebrotendinous-xanthomatosis

Clinical features

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.
Ataxia
MedGen UID:
849
Concept ID:
C0007758
Sign or Symptom
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- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Cholelithiasis
MedGen UID:
3039
Concept ID:
C0008350
Disease or Syndrome
Hard, pebble-like deposits that form within the gallbladder.
Delusions
MedGen UID:
3715
Concept ID:
C0011253
Mental or Behavioral Dysfunction
A belief that is pathological and is held despite evidence to the contrary.
Diarrhea
MedGen UID:
8360
Concept ID:
C0011991
Sign or Symptom
Abnormally increased frequency of loose or watery bowel movements.
Hallucinations
MedGen UID:
6709
Concept ID:
C0018524
Mental or Behavioral Dysfunction
A false sensory perception in the absence of an external stimulus, as distinct from an illusion which is a misperception of an external stimulus.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A form of muscle hypertonia associated with upper MOTOR NEURON DISEASE. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a "free interval") followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. (From Adams et al., Principles of Neurology, 6th ed, p54)
Myocardial infarction
MedGen UID:
10150
Concept ID:
C0027051
Disease or Syndrome
Gross necrosis of the myocardium, as a result of interruption of the blood supply to the area, as in coronary thrombosis.
Generalized osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
A condition of reduced bone mass, with decreased cortical thickness and a decrease in the number and size of the trabeculae of cancellous bone (but normal chemical composition), resulting in increased fracture incidence. Osteoporosis is classified as primary (Type 1, postmenopausal osteoporosis; Type 2, age-associated osteoporosis; and idiopathic, which can affect juveniles, premenopausal women, and middle-aged men) and secondary osteoporosis (which results from an identifiable cause of bone mass loss).
Peripheral neuropathy
MedGen UID:
18386
Concept ID:
C0031117
Disease or Syndrome
A disorder affecting the peripheral nervous system. It manifests with pain, tingling, numbness, and muscle weakness. It may be the result of physical injury, toxic substances, viral diseases, diabetes, renal failure, cancer, and drugs.
Pseudobulbar paralysis
MedGen UID:
10989
Concept ID:
C0033790
Disease or Syndrome
A condition affecting cranial nerves IX-XII resulting from upper motor neuron damage arising from a variety of causes.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Failure to adequately provide oxygen to cells of the body and to remove excess carbon dioxide from them. (Stedman, 25th ed)
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Acquired Abnormality
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Xanthelasma
MedGen UID:
56357
Concept ID:
C0155210
Disease or Syndrome
A condition characterized by the formation of fatty deposits under the skin in the area of the eyelids. These well-demarcated growths, more common in women than men and sometimes hereditary, may indicate elevated cholesterol levels in the blood or the fatty degeneration of the superficial fibers of the orbicularis muscle.
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).
Abnormal pyramidal signs
MedGen UID:
68582
Concept ID:
C0234132
Sign or Symptom
Functional neurological abnormalities related to dysfunction of the pyramidal tract.
Brain 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.
Optic disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
A pale yellow discoloration of the optic disk (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Atrophy (wasting) of the cerebellum.
Abnormality of the periventricular white matter
MedGen UID:
435926
Concept ID:
C2673431
Finding
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as 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).
Abnormality of the dentate nucleus
MedGen UID:
867758
Concept ID:
C4022148
Anatomical Abnormality
An abnormality of the dentate nucleus.
Abnormality of central somatosensory evoked potentials
MedGen UID:
867773
Concept ID:
C4022163
Pathologic Function
Abnormality of cholesterol metabolism
MedGen UID:
871179
Concept ID:
C4025656
Finding
MedGen UID:
500956
Concept ID:
CN003141

Term Hierarchy

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

Recent clinical studies

Etiology

Gong JY, Setchell KDR, Zhao J, Zhang W, Wolfe B, Lu Y, Lackner K, Knisely AS, Wang NL, Hao CZ, Zhang MH, Wang JS
J Pediatr Gastroenterol Nutr 2017 Nov;65(5):561-568. doi: 10.1097/MPG.0000000000001730. PMID: 28937538
Mignarri A, Dotti MT, Federico A, De Stefano N, Battaglini M, Grazzini I, Galluzzi P, Monti L
J Neurol 2017 May;264(5):862-874. Epub 2017 Mar 21 doi: 10.1007/s00415-017-8440-0. PMID: 28324197
Giraldo-Chica M, Acosta-Baena N, Urbano L, Velilla L, Lopera F, Pineda N
Biomedica 2015 Oct-Dec;35(4):563-71. doi: 10.7705/biomedica.v35i4.2690. PMID: 26844446
Khan AO, Aldahmesh MA, Mohamed JY, Alkuraya FS
Ophthalmology 2013 May;120(5):956-60. Epub 2013 Jan 31 doi: 10.1016/j.ophtha.2012.10.032. PMID: 23375591
Berginer VM, Gross B, Morad K, Kfir N, Morkos S, Aaref S, Falik-Zaccai TC
Pediatrics 2009 Jan;123(1):143-7. doi: 10.1542/peds.2008-0192. PMID: 19117873

Diagnosis

Alhariri A, Hamilton K, Oza V, Cordoro K, Sobreira NL, Malloy M, Slavotinek A
Am J Med Genet A 2017 Aug;173(8):2275-2279. Epub 2017 Jun 7 doi: 10.1002/ajmg.a.38314. PMID: 28590052
Abdel-Hamid MS, Issa MY, Otaify GA, Zaki MS
Metab Brain Dis 2017 Apr;32(2):311-315. Epub 2017 Feb 22 doi: 10.1007/s11011-017-9971-x. PMID: 28229379
Rosafio F, Cavallieri F, Guaraldi P, Taroni F, Nichelli PF, Mandrioli J
Clin Neurol Neurosurg 2016 Apr;143:1-3. Epub 2016 Feb 4 doi: 10.1016/j.clineuro.2016.01.032. PMID: 26874936
Abe R, Sekijima Y, Kinoshita T, Yoshinaga T, Koyama S, Kato T, Ikeda SI
J Spinal Cord Med 2016 Nov;39(6):726-729. Epub 2016 Feb 25 doi: 10.1179/1079026815Z.000000000409. PMID: 25941960Free PMC Article
Mignarri A, Gallus GN, Dotti MT, Federico A
J Inherit Metab Dis 2014 May;37(3):421-9. Epub 2014 Jan 18 doi: 10.1007/s10545-013-9674-3. PMID: 24442603

Therapy

Alhariri A, Hamilton K, Oza V, Cordoro K, Sobreira NL, Malloy M, Slavotinek A
Am J Med Genet A 2017 Aug;173(8):2275-2279. Epub 2017 Jun 7 doi: 10.1002/ajmg.a.38314. PMID: 28590052
Abdel-Hamid MS, Issa MY, Otaify GA, Zaki MS
Metab Brain Dis 2017 Apr;32(2):311-315. Epub 2017 Feb 22 doi: 10.1007/s11011-017-9971-x. PMID: 28229379
Rosafio F, Cavallieri F, Guaraldi P, Taroni F, Nichelli PF, Mandrioli J
Clin Neurol Neurosurg 2016 Apr;143:1-3. Epub 2016 Feb 4 doi: 10.1016/j.clineuro.2016.01.032. PMID: 26874936
Huidekoper HH, Vaz FM, Verrips A, Bosch AM
Eur J Pediatr 2016 Jan;175(1):143-6. Epub 2015 Jul 10 doi: 10.1007/s00431-015-2584-7. PMID: 26156051Free PMC Article
Nie S, Chen G, Cao X, Zhang Y
Orphanet J Rare Dis 2014 Nov 26;9:179. doi: 10.1186/s13023-014-0179-4. PMID: 25424010Free PMC Article

Prognosis

Alhariri A, Hamilton K, Oza V, Cordoro K, Sobreira NL, Malloy M, Slavotinek A
Am J Med Genet A 2017 Aug;173(8):2275-2279. Epub 2017 Jun 7 doi: 10.1002/ajmg.a.38314. PMID: 28590052
Mignarri A, Dotti MT, Federico A, De Stefano N, Battaglini M, Grazzini I, Galluzzi P, Monti L
J Neurol 2017 May;264(5):862-874. Epub 2017 Mar 21 doi: 10.1007/s00415-017-8440-0. PMID: 28324197
Giraldo-Chica M, Acosta-Baena N, Urbano L, Velilla L, Lopera F, Pineda N
Biomedica 2015 Oct-Dec;35(4):563-71. doi: 10.7705/biomedica.v35i4.2690. PMID: 26844446
Appadurai V, DeBarber A, Chiang PW, Patel SB, Steiner RD, Tyler C, Bonnen PE
Mol Genet Metab 2015 Dec;116(4):298-304. Epub 2015 Oct 26 doi: 10.1016/j.ymgme.2015.10.010. PMID: 26643207Free PMC Article
Nie S, Chen G, Cao X, Zhang Y
Orphanet J Rare Dis 2014 Nov 26;9:179. doi: 10.1186/s13023-014-0179-4. PMID: 25424010Free PMC Article

Clinical prediction guides

Alhariri A, Hamilton K, Oza V, Cordoro K, Sobreira NL, Malloy M, Slavotinek A
Am J Med Genet A 2017 Aug;173(8):2275-2279. Epub 2017 Jun 7 doi: 10.1002/ajmg.a.38314. PMID: 28590052
Mignarri A, Dotti MT, Federico A, De Stefano N, Battaglini M, Grazzini I, Galluzzi P, Monti L
J Neurol 2017 May;264(5):862-874. Epub 2017 Mar 21 doi: 10.1007/s00415-017-8440-0. PMID: 28324197
Appadurai V, DeBarber A, Chiang PW, Patel SB, Steiner RD, Tyler C, Bonnen PE
Mol Genet Metab 2015 Dec;116(4):298-304. Epub 2015 Oct 26 doi: 10.1016/j.ymgme.2015.10.010. PMID: 26643207Free PMC Article
Yoshinaga T, Sekijima Y, Koyama S, Maruyama K, Yoshida T, Kato T, Ikeda S
Intern Med 2014;53(23):2725-9. Epub 2014 Dec 1 PMID: 25447658
Mignarri A, Gallus GN, Dotti MT, Federico A
J Inherit Metab Dis 2014 May;37(3):421-9. Epub 2014 Jan 18 doi: 10.1007/s10545-013-9674-3. PMID: 24442603

Recent systematic reviews

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
Taboada M, Rodríguez H, Martínez D, Pardo M, Sobrido MJ
Database (Oxford) 2014;2014 Epub 2014 Jun 4 doi: 10.1093/database/bau045. PMID: 24903515Free PMC Article
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
Fraidakis MJ
Transl Psychiatry 2013 Sep 3;3:e302. doi: 10.1038/tp.2013.76. PMID: 24002088Free 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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