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Vanishing white matter disease

MedGen UID:
347037
Concept ID:
C1858991
Disease or Syndrome
Synonyms: CACH syndrome; CACH/VWM syndrome; Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter; Childhood ataxia with diffuse central nervous system hypomyelination; Cree leukoencehalopathy; EIF2B1-Related Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter; EIF2B2-Related Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter; EIF2B3-Related Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter; EIF2B4-Related Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter; EIF2B5-Related Childhood Ataxia with Central Nervous System Hypomyelination/Vanishing White Matter; Leukoencephalopathy with vanishing white matter; Myelinosis centralis diffusa
SNOMED CT: Vanishing white matter disease (447351004); Myelinosis centralis diffusa (447351004); Childhood ataxia with diffuse central nervous system hypomyelination (447351004); CACH (childhood ataxia with diffuse central nervous system hypomyelination) syndrome (447351004); Leukoencephalopathy with vanishing white matter (447351004)
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).
 
Related genes: AARS2, EIF2B5, EIF2B2, EIF2B3, EIF2B4, EIF2B1
 
Monarch Initiative: MONDO:0800448
OMIM® Phenotypic series: PS603896
Orphanet: ORPHA135

Disease characteristics

Childhood ataxia with central nervous system hypomyelination / vanishing white matter (CACH/VWM) is characterized by ataxia, spasticity, and variable optic atrophy. The phenotypic range includes a prenatal/congenital form, a subacute infantile form (onset age <1 year), an early childhood-onset form (onset age 1 to <4 years), a late childhood-/juvenile-onset form (onset age 4 to <18 years), and an adult-onset form (onset ≥18 years). The prenatal/congenital form is characterized by severe encephalopathy. In the later-onset forms initial motor and intellectual development is normal or mildly delayed, followed by neurologic deterioration with a chronic progressive or subacute course. While in childhood-onset forms motor deterioration dominates, in adult-onset forms cognitive decline and personality changes dominate. Chronic progressive decline can be exacerbated by rapid deterioration during febrile illnesses or following head trauma or major surgical procedures, or by acute and extreme fright. [from GeneReviews]
Authors:
Marjo S van der Knaap  |  Anne Fogli  |  Odile Boespflug-Tanguy, et. al.   view full author information

Additional descriptions

From OMIM
Leukoencephalopathy with vanishing white matter is an autosomal recessive neurologic disorder characterized by variable neurologic features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions on brain imaging. Age at onset ranges from early infancy to adulthood. Rapid neurologic deterioration can occur following minor head trauma. Female mutation carriers may additionally develop ovarian failure, manifest as primary amenorrhea or as secondary amenorrhea lasting more than 6 months, associated with elevated gonadotropin levels at age less than 40 years (summary by Van der Knaap et al., 1998 and Schiffmann et al., 1997). The association of vanishing white matter leukodystrophy with ovarian failure had been referred to as 'ovarioleukodystrophy.' Genetic Heterogeneity of Leukoencephalopathy with Vanishing White Matter Leukoencephalopathy with vanishing white matter may be caused by mutations in any of the 5 genes encoding the subunits of the eukaryotic translation factor initiation factor 2B. VWM2 (620312) is caused by mutation in the EIF2B2 gene (606454) on chromosome 14q24; VWM3 (620313) is caused by mutation in the EIF2B3 gene (606273) on chromosome 1p34; VWM4 (620314) is caused by mutation in the EIF2B4 gene (606687) on chromosome 2p23; and VWM5 (620315) is caused by mutation in the EIF2B5 gene (603945) on chromosome 3q27.  http://www.omim.org/entry/603896
From MedlinePlus Genetics
Leukoencephalopathy with vanishing white matter is a progressive disorder that mainly affects the brain and spinal cord (central nervous system). This disorder causes deterioration of the central nervous system's white matter, which consists of nerve fibers covered by myelin. Myelin is the fatty substance that insulates and protects nerves.

In most cases, people with leukoencephalopathy with vanishing white matter show no signs or symptoms of the disorder at birth. Affected children may have slightly delayed development of motor skills such as crawling or walking. During early childhood, most affected individuals begin to develop motor symptoms, including abnormal muscle stiffness (spasticity) and difficulty with coordinating movements (ataxia). There may also be some deterioration of mental functioning, but this is not usually as pronounced as the motor symptoms. Some affected females may have abnormal development of the ovaries (ovarian dysgenesis). Specific changes in the brain as seen using magnetic resonance imaging (MRI) are characteristic of leukoencephalopathy with vanishing white matter, and may be visible before the onset of symptoms.

While childhood onset is the most common form of leukoencephalopathy with vanishing white matter, some severe forms are apparent at birth. A severe, early-onset form seen among the Cree and Chippewayan populations of Quebec and Manitoba is called Cree leukoencephalopathy. Milder forms may not become evident until adolescence or adulthood, when behavioral or psychiatric problems may be the first signs of the disease. Some females with milder forms of leukoencephalopathy with vanishing white matter who survive to adolescence exhibit ovarian dysfunction. This variant of the disorder is called ovarioleukodystrophy.

Progression of leukoencephalopathy with vanishing white matter is generally uneven, with periods of relative stability interrupted by episodes of rapid decline. People with this disorder are particularly vulnerable to stresses such as infection, mild head trauma or other injury, or even extreme fright. These stresses may trigger the first symptoms of the condition or worsen existing symptoms, and can cause affected individuals to become lethargic or comatose.  https://medlineplus.gov/genetics/condition/leukoencephalopathy-with-vanishing-white-matter

Professional guidelines

PubMed

Mahdieh N, Soveizi M, Tavasoli AR, Rabbani A, Ashrafi MR, Kohlschütter A, Rabbani B
Sci Rep 2021 Feb 5;11(1):3231. doi: 10.1038/s41598-021-82778-0. PMID: 33547378Free PMC Article
van der Lei HD, van Berkel CG, van Wieringen WN, Brenner C, Feigenbaum A, Mercimek-Mahmutoglu S, Philippart M, Tatli B, Wassmer E, Scheper GC, van der Knaap MS
Neurology 2010 Oct 26;75(17):1555-9. doi: 10.1212/WNL.0b013e3181f962ae. PMID: 20975056

Recent clinical studies

Etiology

Wu C, Wang M, Wang X, Li W, Li S, Chen B, Niu S, Tai H, Pan H, Zhang Z
Brain 2023 Jun 1;146(6):2364-2376. doi: 10.1093/brain/awac426. PMID: 36380532Free PMC Article
Güngör G, Güngör O, Çakmaklı S, Maraş Genç H, İnce H, Yeşil G, Dilber C, Aydın K
Childs Nerv Syst 2020 Feb;36(2):353-361. Epub 2019 Aug 5 doi: 10.1007/s00381-019-04334-6. PMID: 31385086
Sassi C, Nalls MA, Ridge PG, Gibbs JR, Lupton MK, Troakes C, Lunnon K, Al-Sarraj S, Brown KS, Medway C, Lord J, Turton J, Bras J; ARUK Consortium, Blumenau S, Thielke M, Josties C, Freyer D, Dietrich A, Hammer M, Baier M, Dirnagl U, Morgan K, Powell JF, Kauwe JS, Cruchaga C, Goate AM, Singleton AB, Guerreiro R, Hodges A, Hardy J
Neurobiol Aging 2018 Jun;66:179.e17-179.e29. Epub 2018 Feb 2 doi: 10.1016/j.neurobiolaging.2018.01.015. PMID: 29544907Free PMC Article
Perlman SJ, Mar S
Adv Exp Med Biol 2012;724:154-71. doi: 10.1007/978-1-4614-0653-2_13. PMID: 22411242
Mathis S, Scheper GC, Baumann N, Petit E, Gil R, van der Knaap MS, Neau JP
Clin Neurol Neurosurg 2008 Dec;110(10):1035-7. Epub 2008 Aug 3 doi: 10.1016/j.clineuro.2008.06.002. PMID: 18678442

Diagnosis

Wu C, Wang M, Wang X, Li W, Li S, Chen B, Niu S, Tai H, Pan H, Zhang Z
Brain 2023 Jun 1;146(6):2364-2376. doi: 10.1093/brain/awac426. PMID: 36380532Free PMC Article
Güngör G, Güngör O, Çakmaklı S, Maraş Genç H, İnce H, Yeşil G, Dilber C, Aydın K
Childs Nerv Syst 2020 Feb;36(2):353-361. Epub 2019 Aug 5 doi: 10.1007/s00381-019-04334-6. PMID: 31385086
Dahmoush HM, Melhem ER, Vossough A
Handb Clin Neurol 2016;136:1221-59. doi: 10.1016/B978-0-444-53486-6.00063-6. PMID: 27430466
Perlman SJ, Mar S
Adv Exp Med Biol 2012;724:154-71. doi: 10.1007/978-1-4614-0653-2_13. PMID: 22411242
van der Knaap MS, Pronk JC, Scheper GC
Lancet Neurol 2006 May;5(5):413-23. doi: 10.1016/S1474-4422(06)70440-9. PMID: 16632312

Therapy

Herstine JA, Chang PK, Chornyy S, Stevenson TJ, Sunshine AC, Nokhrina K, Rediger J, Wentz J, Vetter TA, Scholl E, Holaway C, Pyne NK, Bratasz A, Yeoh S, Flanigan KM, Bonkowsky JL, Bradbury AM
Mol Ther 2024 Jun 5;32(6):1701-1720. Epub 2024 Mar 27 doi: 10.1016/j.ymthe.2024.03.034. PMID: 38549375Free PMC Article
Singh RR, Livingston J, Lim M, Berry IR, Siddiqui A
Eur J Paediatr Neurol 2017 Mar;21(2):410-413. Epub 2016 Sep 6 doi: 10.1016/j.ejpn.2016.08.012. PMID: 27665184
Clayton BLL, Popko B
Brain Res 2016 Oct 1;1648(Pt B):594-602. Epub 2016 Apr 4 doi: 10.1016/j.brainres.2016.03.046. PMID: 27055915Free PMC Article
Eichler F, Van Haren K
Pediatr Neurol 2007 Oct;37(4):235-44. doi: 10.1016/j.pediatrneurol.2007.06.011. PMID: 17903666

Prognosis

Cohen L, Manín A, Medina N, Rodríguez-Quiroga S, González-Morón D, Rosales J, Amartino H, Specola N, Córdoba M, Kauffman M, Vega P
Ann Hum Genet 2020 Jan;84(1):11-28. Epub 2019 Aug 16 doi: 10.1111/ahg.12345. PMID: 31418856
Zhou L, Zhang H, Chen N, Zhang Z, Liu M, Dai L, Wang J, Jiang Y, Wu Y
J Neurol 2018 Jun;265(6):1410-1418. Epub 2018 Apr 16 doi: 10.1007/s00415-018-8851-6. PMID: 29663120
Perlman SJ, Mar S
Adv Exp Med Biol 2012;724:154-71. doi: 10.1007/978-1-4614-0653-2_13. PMID: 22411242
Eichler F, Van Haren K
Pediatr Neurol 2007 Oct;37(4):235-44. doi: 10.1016/j.pediatrneurol.2007.06.011. PMID: 17903666
van der Knaap MS, Pronk JC, Scheper GC
Lancet Neurol 2006 May;5(5):413-23. doi: 10.1016/S1474-4422(06)70440-9. PMID: 16632312

Clinical prediction guides

Nourmohammadi P, Asadollahi M, Karamzade A, Eshaghkhani Y, Babaei M, Golchehre Z, Taheri SR, Hasani S, Taghizadeh M, Keramatipour M
J Genet 2023;102 PMID: 37674283
Zhang J, Ban T, Zhou L, Ji H, Yan H, Shi Z, Cao B, Jiang Y, Wang J, Wu Y
J Neurol 2020 Sep;267(9):2612-2618. Epub 2020 May 9 doi: 10.1007/s00415-020-09889-y. PMID: 32388833
Cohen L, Manín A, Medina N, Rodríguez-Quiroga S, González-Morón D, Rosales J, Amartino H, Specola N, Córdoba M, Kauffman M, Vega P
Ann Hum Genet 2020 Jan;84(1):11-28. Epub 2019 Aug 16 doi: 10.1111/ahg.12345. PMID: 31418856
Mathis S, Scheper GC, Baumann N, Petit E, Gil R, van der Knaap MS, Neau JP
Clin Neurol Neurosurg 2008 Dec;110(10):1035-7. Epub 2008 Aug 3 doi: 10.1016/j.clineuro.2008.06.002. PMID: 18678442
Pronk JC, van Kollenburg B, Scheper GC, van der Knaap MS
Ment Retard Dev Disabil Res Rev 2006;12(2):123-8. doi: 10.1002/mrdd.20104. PMID: 16807905

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