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Journal of Neurology

, Volume 257, Issue 12, pp 1955–1962 | Cite as

The clinical spectrum of late-onset Alexander disease: a systematic literature review

  • Pietro BalbiEmail author
  • Silvana Salvini
  • Cira Fundarò
  • Giuseppe Frazzitta
  • Roberto Maestri
  • Dibo Mosah
  • Carla Uggetti
  • GianPietro Sechi
Review

Abstract

Following the discovery of glial fibrillary acidic protein (GFAP) mutations as the causative factor of Alexander disease (AxD), new case reports have recently increased, prompting a more detailed comprehension of the clinical features of the three disease subtypes (infantile, juvenile and adult). While the clinical pattern of the infantile form has been substantially confirmed, the late-onset subtypes (i.e., juvenile and adult), once considered rare manifestations of AxD, have displayed a wider clinical spectrum. Our aim was to evaluate the clinical phenotype of the adult and juvenile forms by reviewing the previously reported cases. Data were collected from previously published reports on 112 subjects affected by neuropathologically or genetically proven adult and juvenile Alexander disease. Although the late-onset forms of AxD show a wide clinical variability, a common pattern emerges from comparing previously reported cases, characterized by pseudo-bulbar signs, ataxia, and spasticity, associated with atrophy of the medulla and upper cervical cord on neuroimaging. Late-onset AxD cases can no longer be considered as rare manifestations of the disease. The clinical pattern usually reflects the topographic localization of the lesions, with adult cases displaying a predominant infratentorial localization of the lesions. Juvenile cases show clinical and radiological features which are intermediate between adult and infantile forms.

Keywords

Systematic review Alexander disease GFAP Nosology Diagnostic criteria 

Notes

Conflict of interest

None.

Supplementary material

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References

  1. 1.
    Alexander WS (1949) Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. Brain 72:373–381CrossRefPubMedGoogle Scholar
  2. 2.
    Balbi P, Seri M, Ceccherini I, Uggetti C, Casale R, Fundarò C, Caroli F, Santoro L (2008) Adult-onset Alexander disease. Report on a family. J Neurol 255:24–30CrossRefPubMedGoogle Scholar
  3. 3.
    Brenner M, Johnson AB, Boesflug-Tanguy O, Rodriguez D, Goldman JE, Messing A (2001) Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet 27:117–120CrossRefPubMedGoogle Scholar
  4. 4.
    Brenner M, Goldman JE, Quinlan RA, Messing A (2009) Alexander disease: a genetic disorder of astrocytes. In: Parpura V, Haydon P (eds) Astrocytes in (patho)physiology of the nervous system. Springer, New York, pp 591–648Google Scholar
  5. 5.
    Brockmann K, Meins M, Taubert A, Trappe R, Grond M, Hanefeld F (2003) A novel GFAP mutation and disseminated white matter lesions: adult Alexander disease? Eur Neurol 50:100–105CrossRefPubMedGoogle Scholar
  6. 6.
    Brody BA, Kinney HC, Kloman AS, Gilles FH (1987) Sequence of central nervous system myelination in human infancy. 1. An autopsy study of myelination. J Neuropathol Exp Neurol 46:283–301CrossRefPubMedGoogle Scholar
  7. 7.
    Caroli F, Biancheri R, Seri M, Rossi A, Pessagno A, Bugiani M, Corsolini F, Savasta S, Romano S, Antonelli C, Romano A, Pareyson D, Gambero P, Uziel G, Ravazzolo R, Ceccherini I, Filocamo M (2007) GFAP mutations and polymorphisms in 13 unrelated Italian patients affected by Alexander disease. Clin Genet 72:427–433CrossRefPubMedGoogle Scholar
  8. 8.
    Crome L (1953) Megalencephaly associated with hyaline pan-neuropathy. Brain 76:215–228CrossRefPubMedGoogle Scholar
  9. 9.
    Farina L, Pareyson D, Minati L, Ceccherini I, Chiapparini L, Romano S, Gambaro P, Fancellu R, Savoiardo M (2008) Can MR imaging diagnose adult-onset Alexander disease? AJNR Am J Neuroradiol 29:1190–1196CrossRefPubMedGoogle Scholar
  10. 10.
    Friede RL (1964) Alexander’s disease. Arch Neurol 11:414–422PubMedGoogle Scholar
  11. 11.
    Friedman JH, Ambler M (1992) Progressive Parkinsonism associated with Rosenthal fibers: senile-onset Alexander’s disease? Neurology 42:1733–1735PubMedGoogle Scholar
  12. 12.
    Garrett R, Ames RP (1974) Alexander disease: case report with electron microscopical studies and review of the literature. Arch Pathol 98:379–385Google Scholar
  13. 13.
    Gorospe JR, Naidu S, Johnson AB, Puri V, Raymond GV, Jenkins SD, Pedersen RC, Lewis D, Knowles P, Fernandez R, De Vivo D, van der Knaap MS, Messing A, Brenner M, Hoffman EP (2002) Molecular findings in symptomatic and pre-symptomatic Alexander disease patients. Neurology 58:1494–1500PubMedGoogle Scholar
  14. 14.
    Herndon RM, Rubinstein LJ, Freeman JM, Mathieson G (1970) Light and electron microscope observations on Rosenthal fibers in Alexander’s disease and in multiple sclerosis. J Neuropathol Exp Neurol 29:524–551CrossRefPubMedGoogle Scholar
  15. 15.
    Jacob J, Robertson NJ, Hilton DA (2003) The clinicopathological spectrum of Rosenthal fibre encephalopathy and Alexander’s disease: a case report and review of the literature. J Neurol Neurosurg Psychiatry 74:807–810CrossRefPubMedGoogle Scholar
  16. 16.
    Kepes JJ, Ziegler DK (1972) Alexander’s disease in an adult (leukodystrophy with Rosenthal fibers). Missouri Med (Suppl) 69:23–25Google Scholar
  17. 17.
    Kinney HC, Brody BA, Kloman AS, Gilles FH (1988) Sequence of central nervous system myelination in human infancy. 2. Patterns of myelination in autopsied infants. J Neuropathol Exp Neurol 47:217–234CrossRefPubMedGoogle Scholar
  18. 18.
    Kinoshita T, Imaizumi T, Miura Y, Fujimoto H, Ayabe M, Shoji H, Okamoto Y, Takashima H, Osame M, Nakagawa M (2003) A case of adult-onset Alexander disease with Arg416Trp human glial fibrillary acidic protein gene mutation. Neurosci Lett 350:169–172CrossRefPubMedGoogle Scholar
  19. 19.
    Li R, Johnson AB, Salomons G, Goldman JE, Naidu S, Quinlan R, Cree B, Ruyle SZ, Banwell B, D’Hooghe M, Siebert JR, Rolf CM, Cox H, Reddy A, Gutiérrez-Solana LG, Collins A, Weller RO, Messing A, van der Knaap MS, Brenner M (2005) Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease. Ann Neurol 57:310–326CrossRefPubMedGoogle Scholar
  20. 20.
    Mastri AR, Sung JH (1973) Diffuse Rosenthal fiber formation in the adult: report of four cases. J Neuropathol Exp Neurol 32:424–436CrossRefPubMedGoogle Scholar
  21. 21.
    Messing A, Head M, Galles K, Galbreath EJ, Goldman JE, Brenner M (1998) Fatal encephalopathy with astrocyte inclusions in GFAP transgenic mice. Am J Pathol 152:391–398PubMedGoogle Scholar
  22. 22.
    Messing A, Brenner M (2003) Alexander disease: GFAP mutations unify young and old. Lancet Neurol 2:75CrossRefPubMedGoogle Scholar
  23. 23.
    Mignot C, Boespflug-Tanguy O, Gelot A, Dautigny A, Pham-Dinh D, Rodriguez D (2004) Alexander disease: putative mechanisms of an astrocytic encephalopathy. Cell Mol Life Sci 61:369–385CrossRefPubMedGoogle Scholar
  24. 24.
    Namekawa M, Takiyama Y, Aoki Y, Takayashiki N, Sakoe K, Shimazaki H, Taguchi T, Tanaka Y, Nishizawa M, Saito K, Matsubara Y, Nakano I (2002) Identification of GFAP gene mutation in hereditary adult-onset Alexander’s disease. Ann Neurol 52:779–785CrossRefPubMedGoogle Scholar
  25. 25.
    Pareyson D, Fancellu R, Mariotti C, Romano S, Salmaggi A, Carella F, Girotti F, Gattellaro G, Carriero MR, Farina L, Ceccherini I, Savoiardo M (2008) Adult-onset Alexander disease: a series of eleven unrelated cases with review of the literature. Brain 131:2321–2331CrossRefPubMedGoogle Scholar
  26. 26.
    Peiffer J (1968) Alexander’s disease—really a leukodystrophy? Pathol Eur 3:305–312PubMedGoogle Scholar
  27. 27.
    Pridmore CL, Baraitser M, Harding B, Boyd SG, Kendall B, Brett EM (1993) Alexander’s disease: clues to diagnosis. J Child Neurol 8:134–144CrossRefPubMedGoogle Scholar
  28. 28.
    Riggs JE, Schochet SS, Nelson J (1988) Asymptomatic adult Alexander’s disease: entity or nosological misconception? Neurology 38:152–154PubMedGoogle Scholar
  29. 29.
    Romano S, Salvetti M, Ceccherini I, De Simone T, Savoiardo M (2007) Brainstem signs with progressing atrophy of medulla oblongata and upper cervical spinal cord. Lancet Neurol 6:562–570CrossRefPubMedGoogle Scholar
  30. 30.
    Rosenthal W (1898) Über eine eigentümliche, mit Syringomyelie komplizierte Geshwulst des Rückenmarks. Beitr Pathol Anat 23:111Google Scholar
  31. 31.
    Russo LS Jr, Aron A, Anderson PJ (1976) Alexander’s disease: a report and a reappraisal. Neurology 26:607–614PubMedGoogle Scholar
  32. 32.
    Schochet SS, Lampert PW, Earle KM (1968) Alexander’s disease: a case report with electron microscopic observations. Neurology 18:543–549PubMedGoogle Scholar
  33. 33.
    Seil FJ, Schochet SS, Earle KM (1968) Alexander’s disease in an adult: report of a case. Arch Neurol 19:494–502PubMedGoogle Scholar
  34. 34.
    Sherwin RM, Berthrong M (1970) Alexander’s disease with sudanophilic leukodystrophy. Arch Pathol 89:321–328PubMedGoogle Scholar
  35. 35.
    Shiihara T, Sawaishi Y, Adachi M, Kato M, Hayasaka K (2004) Asymptomatic hereditary Alexander’s disease caused by a novel mutation in GFAP. J Neurol Sci 225:125–127CrossRefPubMedGoogle Scholar
  36. 36.
    Soffer D, Horoupian DS (1979) Rosenthal fibers formation in the central nervous system: its relation to Alexander’s disease. Acta Neuropathol 47:81–84CrossRefPubMedGoogle Scholar
  37. 37.
    Stevenson LD, Vogel FS (1952) A case of macrocephaly associated with feeble-mindedness and encephalopathy with peculiar deposit throughout the brain and spinal cord. Ciencia 12:71–74Google Scholar
  38. 38.
    Stumpf E, Masson H, Duquette A, Berthelet F, McNabb J, Lortie A, Lesage J, Montplaisir J, Brais B, Cossette P (2003) Adult Alexander disease with autosomal dominant transmission. Arch Neurol 60:1307–1312CrossRefPubMedGoogle Scholar
  39. 39.
    Thyagarajan D, Chataway T, Li R, Gai WP, Brenner M (2004) Dominantly-inherited adult-onset leukodystrophy with palatal tremor caused by a mutation in the glial fibrillary acidic protein gene. Mov Disord 19:1244–1248CrossRefPubMedGoogle Scholar
  40. 40.
    Tihen WS (1972) Central pontine myelinolysis and Rosenthal fibers of the brainstem: association with emaciation and prolonged intravenous hyperalimentation. Neurology 22:710–716PubMedGoogle Scholar
  41. 41.
    Ule G (1972) Progressive neurogene Muskelatrophie bei neuroaxonaler Distrophie mit Rosenthalschen Fasern. Acta Neuropathol 21:332–339CrossRefPubMedGoogle Scholar
  42. 42.
    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 (2001) Alexander disease: diagnosis with MR imaging. Am J Neuroradiol 22:541–542PubMedGoogle Scholar
  43. 43.
    van der Knaap MS, Gajja SS, Li R, Franzoni E, Gutiérrez-Solana LG, Smit LM, Robinson R, Ferrie CD, Cree B, Reddy A, Thomas N, Banwell B, Barkhof F, Jakobs C, Johnson A, Messing A, Brenner M (2005) Unusual variants of Alexander’s disease. Ann Neurol 57:327–338CrossRefPubMedGoogle Scholar
  44. 44.
    van der Knaap MS, Ramesh V, Schiffmann R, Blaser S, Kyllerman M, Gholkar A, Ellison DW, van der Voorn JP, van Dooren SJ, Jakobs C, Barkhof F, Salomons GS (2006) Alexander disease. Ventricular garlands and abnormalities of the medulla and spinal cord. Neurology 66:494–498CrossRefPubMedGoogle Scholar
  45. 45.
    Vogel FS, Hallervorden J (1962) Leukodystrophy with diffuse Rosenthal fiber formation. Acta Neuropathol 2:126–143CrossRefGoogle Scholar
  46. 46.
    Wilson SP, Al-Sarraj S, Bridges LR (1996) Rosenthal fiber encephalopathy presenting with demyelination and Rosenthal fibers in a solvent abuser: adult Alexander’s disease? Clin Neuropathol 15:13–16PubMedGoogle Scholar
  47. 47.
    Wohlwill FJ, Bernstein J, Yakovlev PI (1959) Dysmyelinogenic leukodystrophy: report of a case of a new, presumably familial type of leukodystrophy with megalobarencephaly. J Neuropathol Exp Neurol 18:359–383CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Pietro Balbi
    • 1
    Email author
  • Silvana Salvini
    • 1
  • Cira Fundarò
    • 1
  • Giuseppe Frazzitta
    • 2
  • Roberto Maestri
    • 3
  • Dibo Mosah
    • 1
  • Carla Uggetti
    • 4
  • GianPietro Sechi
    • 5
  1. 1.Clinical NeurophysiologyScientific Institute of Montescano IRCCS ‘Fondazione S. Maugeri’MontescanoItaly
  2. 2.Department of NeurorehabilitationScientific Institute of Montescano IRCCS ‘Fondazione S. Maugeri’MontescanoItaly
  3. 3.Department of Biomedical EngineeringScientific Institute of Montescano IRCCS ‘Fondazione S. Maugeri’MontescanoItaly
  4. 4.Neuroradiological DepartmentNeurological Institute IRCCS ‘Fondazione C. Mondino’PaviaItaly
  5. 5.Institute of Clinical NeurologyUniversity of SassariSassariItaly

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