Alexander disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo M.D.

Synonyms and keywords: Dysmyelogenic leukodystrophy, Dysmyelogenic leukodystrophy-megalobare, Fibrinoid degeneration of astrocytes, Fibrinoid leukodystrophy, Hyaline panneuropathy, Leukodystrophy with Rosenthal fibers, Megalencephaly with hyaline inclusion, Megalencephaly with hyaline panneuropathy

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Alexander disease is a slowly progressing and fatal neurodegenerative disease. It is a very rare disorder that results from a genetic mutation and mostly affects infants and children, causing developmental delay and changes in physical characteristics.

Historical Perspective




  • The most accepted proposed mechanism to explain Alexander disease is as follows:[15]
  1. The accumulation of glial fibrillary acidic protein and the consequent formation of characteristic aggregates, called Rosenthal fibers in various cell types, and especially astrocytes.
  2. The accumulation appears to be due to a gain in function due to the mutation that partially blocks the assembly of the GFAP filaments.[16]
  3. Subsequent sequestration of ubiquitin and the α-B-crystalline chaperone proteins and HSP27 in the Rosenthal fibers.
  4. Activation of both the Jnk protein and the stress response.


Gross Pathology


Differentiating Alexander disease from Other Diseases

Epidemiology and Demographics

  • Alexander disease is a rare condition; since the description of the first affected individual until 2015, only 550 cases have been reported.[20]
  • The incidence of Alexander disease has not been reported.
  • The prevalence world-wide of Alexander disease has not been reported.[20] In a study made by Yoshida et al. in 2012 in Japan, they estimated a prevalence of 1 in 2.7 million population studied.[1][21]
  • Patients of all age groups may develop Alexander disease, but it infantile (type I) form is more common, with presentation appearing usually before 2 years of age.[5]
  • There is no gender predilection to Alexander disease.[1]
  • There is no racial predilection to Alexander disease.[1]
  • There is no geographic predilection to Alexander disease.[1]
  • There is no economic predilection to Alexander disease.[1]

Risk Factors

  • There are no established risk factors for developing Alexander disease.
  • The risk to other family members depends on the genetic status of the proband's parents (if they present with a GFAP pathogenic variant).[20]


  • According to the van der Knaap et al. (2001),genetic testing screening for Alexander disease by searching for GFAP mutations is recommended among patients with classic MRI features.[1][22]
  • Guidelines for GFAP mutations screening in individuals with suspected atypical MRI findings do not exist for Alexander disease type II.[23]
  • It is recommended to screen parents of children with Alexander disease to rule-out familial type of late onset.[1]
  • Testing of asymptomatic siblings is still on debate and will depend on their age and inquiery of the parents. Probability of a second de novo mutation is extremely low.[1]
  • When testing for exonic mutations is negative, you should always consider splice-site mutations.[1]

Natural History, Complications and Prognosis

  • The prognosis of individuals with Alexander disease is generally poor. With early-onset, death usually occurs within 10 years after the onset of symptoms in infantile forms (type I). Usually, the later the disease occurs, the slower its course is.[20]
  • Common complications of Alexander disease are included in the "History and Symptoms" section.


Diagnostic Study of Choice

History and Symptoms


Common symptoms

Less common symptoms

Physical Examination

Laboratory Findings


  • There are no ECG findings associated with Alexander disease.


  • There are no x-ray findings associated with Alexander's disease. However, an x-ray may be helpful in the diagnosis of complications, which include scoliosis and frontal bossing.

Echocardiography or Ultrasound

CT scan


Other Imaging Findings

  • There are no other imaging findings associated with Alexander's disease.

Other Diagnostic Studies

  • Electroencephalogram in Alexander disease may show slow activity, which is much more prominent over the anterior than posterior regions.[19]


Medical Therapy


Primary Prevention

Secondary Prevention

See also

External links


  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 Messing A (2018). "Alexander disease". Handb Clin Neurol. 148: 693–700. doi:10.1016/B978-0-444-64076-5.00044-2. PMID 29478608.
  2. Seil, Fredrick J. (1968). "Alexander's Disease in an Adult". Archives of Neurology. 19 (5): 494. doi:10.1001/archneur.1968.00480050064006. ISSN 0003-9942.
  3. Balbi, Pietro; Salvini, Silvana; Fundarò, Cira; Frazzitta, Giuseppe; Maestri, Roberto; Mosah, Dibo; Uggetti, Carla; Sechi, GianPietro (2010). "The clinical spectrum of late-onset Alexander disease: a systematic literature review". Journal of Neurology. 257 (12): 1955–1962. doi:10.1007/s00415-010-5706-1. ISSN 0340-5354.
  4. Brenner, Michael; Lampel, Keith; Nakatani, Yoshihiro; Mill, John; Banner, Carl; Mearow, Karen; Dohadwala, Mariam; Lipsky, Robert; Freese, Ernst (1990). "Characterization of human cDNA and genomic clones for glial fibrillary acidic protein". Molecular Brain Research. 7 (4): 277–286. doi:10.1016/0169-328X(90)90078-R. ISSN 0169-328X.
  5. 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 Tavasoli A, Armangue T, Ho CY, Whitehead M, Bornhorst M, Rhee J, Hwang EI, Wells EM, Packer R, van der Knaap MS, Bugiani M, Vanderver A (February 2017). "Alexander Disease". J. Child Neurol. 32 (2): 184–187. doi:10.1177/0883073816673263. PMID 28112050.
  6. 6.0 6.1 6.2 6.3 6.4 6.5 Prust M, Wang J, Morizono H, Messing A, Brenner M, Gordon E, Hartka T, Sokohl A, Schiffmann R, Gordish-Dressman H, Albin R, Amartino H, Brockman K, Dinopoulos A, Dotti MT, Fain D, Fernandez R, Ferreira J, Fleming J, Gill D, Griebel M, Heilstedt H, Kaplan P, Lewis D, Nakagawa M, Pedersen R, Reddy A, Sawaishi Y, Schneider M, Sherr E, Takiyama Y, Wakabayashi K, Gorospe JR, Vanderver A (September 2011). "GFAP mutations, age at onset, and clinical subtypes in Alexander disease". Neurology. 77 (13): 1287–94. doi:10.1212/WNL.0b013e3182309f72. PMC 3179649. PMID 21917775.
  7. Springer S, Erlewein R, Naegele T, Becker I, Auer D, Grodd W, Krägeloh-Mann I (April 2000). "Alexander disease--classification revisited and isolation of a neonatal form". Neuropediatrics. 31 (2): 86–92. doi:10.1055/s-2000-7479. PMID 10832583.
  8. 8.0 8.1 "Alexander Disease Information Page | National Institute of Neurological Disorders and Stroke".
  9. Johnson AB (May 2004). "Alexander disease: a leukodystrophy caused by a mutation in GFAP". Neurochem. Res. 29 (5): 961–4. doi:10.1023/b:nere.0000021240.30518.2c. PMID 15139294.
  10. Rodriguez D, Gauthier F, Bertini E, Bugiani M, Brenner M, N'guyen S, Goizet C, Gelot A, Surtees R, Pedespan JM, Hernandorena X, Troncoso M, Uziel G, Messing A, Ponsot G, Pham-Dinh D, Dautigny A, Boespflug-Tanguy O (November 2001). "Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation". Am. J. Hum. Genet. 69 (5): 1134–40. doi:10.1086/323799. PMC 1274357. PMID 11567214.
  11. 11.0 11.1 Vázquez, E.; Macaya, A.; Mayolas, N.; Arévalo, S.; Poca, M.A.; Enríquez, G. (2008). "Neonatal Alexander Disease: MR Imaging Prenatal Diagnosis". American Journal of Neuroradiology. 29 (10): 1973–1975. doi:10.3174/ajnr.A1215. ISSN 0195-6108.
  12. Garcia, Leonardo; Gascon, Generoso; Ozand, Pinar; Yaish, Hassan (2016). "Increased Intracranial Pressure in Alexander Disease: A Rare Presentation of White-Matter Disease". Journal of Child Neurology. 7 (2): 168–171. doi:10.1177/088307389200700206. ISSN 0883-0738.
  13. Lee JM, Kim AS, Lee SJ, Cho SM, Lee DS, Choi SM, Kim DK, Ki CS, Kim JW (October 2006). "A case of infantile Alexander disease accompanied by infantile spasms diagnosed by DNA analysis". J. Korean Med. Sci. 21 (5): 954–7. doi:10.3346/jkms.2006.21.5.954. PMC 2722014. PMID 17043438.
  14. Olabarria M, Putilina M, Riemer EC, Goldman JE (October 2015). "Astrocyte pathology in Alexander disease causes a marked inflammatory environment". Acta Neuropathol. 130 (4): 469–86. doi:10.1007/s00401-015-1469-1. PMID 26296699.
  15. Quinlan RA, Brenner M, Goldman JE, Messing A (June 2007). "GFAP and its role in Alexander disease". Exp. Cell Res. 313 (10): 2077–87. doi:10.1016/j.yexcr.2007.04.004. PMC 2702672. PMID 17498694.
  16. Johnson AB (2002). "Alexander disease: a review and the gene". Int. J. Dev. Neurosci. 20 (3–5): 391–4. doi:10.1016/s0736-5748(02)00045-x. PMID 12175878.
  17. 17.0 17.1 17.2 17.3 17.4 "Alexander Disease - GeneReviews® - NCBI Bookshelf".
  18. Messing A, Brenner M (February 2003). "Alexander disease: GFAP mutations unify young and old". Lancet Neurol. 2 (2): 75. doi:10.1016/s1474-4422(03)00301-6. PMID 12849260.
  19. 19.0 19.1 Pridmore, Clare L.; Baraitser, Michael; Harding, Brian; Boyd, Stewart G.; Kendall, Brian; Brett, Edward M. (2016). "Alexander's Disease: Clues to Diagnosis". Journal of Child Neurology. 8 (2): 134–144. doi:10.1177/088307389300800205. ISSN 0883-0738.
  20. 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean L, Stephens K, Amemiya A, Srivastava S, Naidu S. PMID 20301351. Vancouver style error: initials (help); Missing or empty |title= (help)
  21. Yoshida, Tomokatsu; Nakagawa, Masanori (2012). "Clinical aspects and pathology of Alexander disease, and morphological and functional alteration of astrocytes induced by GFAP mutation". Neuropathology. 32 (4): 440–446. doi:10.1111/j.1440-1789.2011.01268.x. ISSN 0919-6544.
  22. 22.0 22.1 van der Knaap MS, Naidu S, Breiter SN, Blaser S, Stroink H, Springer S, Begeer JC, van Coster R, Barth PG, Thomas NH, Valk J, Powers JM (March 2001). "Alexander disease: diagnosis with MR imaging". AJNR Am J Neuroradiol. 22 (3): 541–52. PMID 11237983.
  23. Farina L, Pareyson D, Minati L, Ceccherini I, Chiapparini L, Romano S, Gambaro P, Fancellu R, Savoiardo M (June 2008). "Can MR imaging diagnose adult-onset Alexander disease?". AJNR Am J Neuroradiol. 29 (6): 1190–6. doi:10.3174/ajnr.A1060. PMID 18388212.
  24. "308 Permanent Redirect".
  25. Salvi F, Aoki Y, Della Nave R, Vella A, Pastorelli F, Scaglione C, Matsubara Y, Mascalchi M (November 2005). "Adult Alexander's disease without leukoencephalopathy". Ann. Neurol. 58 (5): 813–4. doi:10.1002/ana.20634. PMID 16240361.
  26. Johnson AB (2002). "Alexander disease: a review and the gene". Int. J. Dev. Neurosci. 20 (3–5): 391–4. doi:10.1016/s0736-5748(02)00045-x. PMID 12175878.
  27. Balbi P, Seri M, Ceccherini I, Uggetti C, Casale R, Fundarò C, Caroli F, Santoro L (January 2008). "Adult-onset Alexander disease : report on a family". J. Neurol. 255 (1): 24–30. doi:10.1007/s00415-007-0654-0. PMID 18004641.
  28. Kyllerman M, Rosengren L, Wiklund LM, Holmberg E (October 2005). "Increased levels of GFAP in the cerebrospinal fluid in three subtypes of genetically confirmed Alexander disease". Neuropediatrics. 36 (5): 319–23. doi:10.1055/s-2005-872876. PMID 16217707.
  29. Tavasoli A, Armangue T, Ho CY, Whitehead M, Bornhorst M, Rhee J, Hwang EI, Wells EM, Packer R, van der Knaap MS, Bugiani M, Vanderver A (February 2017). "Alexander Disease". J. Child Neurol. 32 (2): 184–187. doi:10.1177/0883073816673263. PMID 28112050.

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