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{{SI}}
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{{CMG}}; {{AE}}
{{CMG}}; {{AE}}[[User:MoisesRomo|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]]
'''''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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==Overview==
==Overview==
'''Alexander disease''' is a slowly progressing and fatal [[neurodegenerative disease]]. It is a very rare disorder which results from a genetic mutation and mostly affects infants and children, causing developmental delay and changes in physical characteristics.
'''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==
==Historical Perspective==
* Alexander disease was first described in 1949 by the New Zealand [[pathologist]] William Alexander in London, England under his paper "Progressive fibrinoid degeneration of [[fibrillary astrocytes]] associated with [[mental retardation]] in a [[Hydrocephalus|hydrocephalic]] infant", where he reported a case of a 16-month old child who died after presenting a history of increasing [[macrocephaly]] and [[developmental delay]].<ref name="pmid29478608">{{cite journal |vauthors=Messing A |title=Alexander disease |journal=Handb Clin Neurol |volume=148 |issue= |pages=693–700 |date=2018 |pmid=29478608 |doi=10.1016/B978-0-444-64076-5.00044-2 |url=}}</ref>
*In 1959, Wohwill et al. reported the case of siblings with Alexander disease [[phenotype]] and suggested the possibility of an [[autosomal recessive]] transmission.
* By the decade of 1960´s, the presence of [[Rosenthal fiber|Rosenthal fibers]] accompanied by the destruction of [[white matter]] and progressive [[neurologic imapairment]] was recognized as the hallmark of patients with Alexander disease.<ref name="Seil1968">{{cite journal|last1=Seil|first1=Fredrick J.|title=Alexander's Disease in an Adult|journal=Archives of Neurology|volume=19|issue=5|year=1968|pages=494|issn=0003-9942|doi=10.1001/archneur.1968.00480050064006}}</ref><ref name="pmid29478608" /><ref name="BalbiSalvini2010">{{cite journal|last1=Balbi|first1=Pietro|last2=Salvini|first2=Silvana|last3=Fundarò|first3=Cira|last4=Frazzitta|first4=Giuseppe|last5=Maestri|first5=Roberto|last6=Mosah|first6=Dibo|last7=Uggetti|first7=Carla|last8=Sechi|first8=GianPietro|title=The clinical spectrum of late-onset Alexander disease: a systematic literature review|journal=Journal of Neurology|volume=257|issue=12|year=2010|pages=1955–1962|issn=0340-5354|doi=10.1007/s00415-010-5706-1}}</ref>
* In 2001, Brenner et. al discovered that [[mutations]] in [[GFAP]] encoding for [[glial fibrillary acidic protein]], could be the causant of most of the cases of Alexander disease.<ref name="BrennerLampel1990">{{cite journal|last1=Brenner|first1=Michael|last2=Lampel|first2=Keith|last3=Nakatani|first3=Yoshihiro|last4=Mill|first4=John|last5=Banner|first5=Carl|last6=Mearow|first6=Karen|last7=Dohadwala|first7=Mariam|last8=Lipsky|first8=Robert|last9=Freese|first9=Ernst|title=Characterization of human cDNA and genomic clones for glial fibrillary acidic protein|journal=Molecular Brain Research|volume=7|issue=4|year=1990|pages=277–286|issn=0169328X|doi=10.1016/0169-328X(90)90078-R}}</ref><ref name="pmid29478608" />


==Classification==
==Classification==
* Alexander disease is classified according to the age of onset and [[clinical]] course as:
** Type I (infantile). The most common type of Alexander disease, usually caused by ''[[de novo]]'' [[mutations]], with an age of onset before 4 years of age. It presents with [[Seizure|seizures]], [[macrocephaly]], [[developmental delay]], [[failure to thrive]], intractable [[vomiting]], [[encephalopathy]], and classic [[imaging]] findings.<ref name="pmid281120502" /><ref name="pmid21917775" />
** Type II (juvenile and adult). Often [[familial]], with an age of onset after 4 years of age. It presents with [[bulbar dysfunction]], [[palatal myoclonus]], [[autonomic dysfunction]], less significant [[encephalopathy]], and atypical [[imaging]] findings.<ref name="pmid281120502">{{cite journal |vauthors=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 |title=Alexander Disease |journal=J. Child Neurol. |volume=32 |issue=2 |pages=184–187 |date=February 2017 |pmid=28112050 |doi=10.1177/0883073816673263 |url=}}</ref><ref name="pmid21917775">{{cite journal |vauthors=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 |title=GFAP mutations, age at onset, and clinical subtypes in Alexander disease |journal=Neurology |volume=77 |issue=13 |pages=1287–94 |date=September 2011 |pmid=21917775 |pmc=3179649 |doi=10.1212/WNL.0b013e3182309f72 |url=}}</ref>
*Some authors propose the inclusion of a [[neonatal]] form in the [[classification]] of Alexander disease to describe patients with the onset of [[symptoms]] within the first month of life.<ref name="pmid10832583">{{cite journal |vauthors=Springer S, Erlewein R, Naegele T, Becker I, Auer D, Grodd W, Krägeloh-Mann I |title=Alexander disease--classification revisited and isolation of a neonatal form |journal=Neuropediatrics |volume=31 |issue=2 |pages=86–92 |date=April 2000 |pmid=10832583 |doi=10.1055/s-2000-7479 |url=}}</ref>


==Pathophysiology==
==Pathophysiology==
[[Image:autodominant2.jpg|thumb|left|Alexander disease is inherited in an [[autosomal dominant]] pattern.]] The cause of Alexander disease is a mutation in the gene encoding glial fibrillary acidic protein.


Alexander disease belongs to [[leukodystrophies]], a group of diseases which affect growth or development of the [[myelin sheath]]. The destruction of [[white matter]] in the [[brain]] is accompanied by the formation of fibrous, eosinophilic deposits known as [[Rosenthal fibers]].
* Alexander disease is an [[Astrocyte|astrocytopathy]] that belongs to the group of disorders called [[leukodystrophies]], which affect growth or development of the [[myelin sheath]].<ref name="urlAlexander Disease Information Page | National Institute of Neurological Disorders and Stroke">{{cite web |url=https://www.ninds.nih.gov/disorders/all-disorders/alexander-disease-information-page |title=Alexander Disease Information Page &#124; National Institute of Neurological Disorders and Stroke |format= |work= |accessdate=}}</ref>
* Alexander disease is characterized by a [[white matter]] destruction in the [[midbrain]] and [[cerebellum]].<ref name="pmid281120502" /><ref name="pmid15139294">{{cite journal |vauthors=Johnson AB |title=Alexander disease: a leukodystrophy caused by a mutation in GFAP |journal=Neurochem. Res. |volume=29 |issue=5 |pages=961–4 |date=May 2004 |pmid=15139294 |doi=10.1023/b:nere.0000021240.30518.2c |url=}}</ref>
* The destruction of [[white matter]] destruction in the [[Central nervous system|central nervous system (CNS)]] is accompanied by the formation of [[fibrous]], [[eosinophilic]] deposits known as [[Rosenthal fibers]].<ref name="urlAlexander Disease Information Page | National Institute of Neurological Disorders and Stroke" />
*[[Mutation|Mutated]] [[glial fibrillary acidic protein]] accumulates which in turn aggregates [[astrocytes]] to form the so called [[Rosenthal fibers]].<ref name="pmid11567214">{{cite journal |vauthors=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 |title=Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation |journal=Am. J. Hum. Genet. |volume=69 |issue=5 |pages=1134–40 |date=November 2001 |pmid=11567214 |pmc=1274357 |doi=10.1086/323799 |url=}}</ref>
*[[Rosenthal fibers]] are known to be the major contributer in the [[pathogenesis]] of Alexander disease and its accumulation in especific sites may cause obstructive [[hydrocephalus]].<ref name="VázquezMacaya2008">{{cite journal|last1=Vázquez|first1=E.|last2=Macaya|first2=A.|last3=Mayolas|first3=N.|last4=Arévalo|first4=S.|last5=Poca|first5=M.A.|last6=Enríquez|first6=G.|title=Neonatal Alexander Disease: MR Imaging Prenatal Diagnosis|journal=American Journal of Neuroradiology|volume=29|issue=10|year=2008|pages=1973–1975|issn=0195-6108|doi=10.3174/ajnr.A1215}}</ref><ref name="GarciaGascon2016">{{cite journal|last1=Garcia|first1=Leonardo|last2=Gascon|first2=Generoso|last3=Ozand|first3=Pinar|last4=Yaish|first4=Hassan|title=Increased Intracranial Pressure in Alexander Disease: A Rare Presentation of White-Matter Disease|journal=Journal of Child Neurology|volume=7|issue=2|year=2016|pages=168–171|issn=0883-0738|doi=10.1177/088307389200700206}}</ref><ref name="pmid17043438">{{cite journal |vauthors=Lee JM, Kim AS, Lee SJ, Cho SM, Lee DS, Choi SM, Kim DK, Ki CS, Kim JW |title=A case of infantile Alexander disease accompanied by infantile spasms diagnosed by DNA analysis |journal=J. Korean Med. Sci. |volume=21 |issue=5 |pages=954–7 |date=October 2006 |pmid=17043438 |pmc=2722014 |doi=10.3346/jkms.2006.21.5.954 |url=}}</ref>
*[[Glial fibrillary acidic protein]] accumulation causes an overload of long-chain [[fatty acids]] in the [[brain]], which induces [[T-cells]] infiltrates that destroy the [[myelin sheath]].<ref name="pmid26296699">{{cite journal |vauthors=Olabarria M, Putilina M, Riemer EC, Goldman JE |title=Astrocyte pathology in Alexander disease causes a marked inflammatory environment |journal=Acta Neuropathol. |volume=130 |issue=4 |pages=469–86 |date=October 2015 |pmid=26296699 |doi=10.1007/s00401-015-1469-1 |url=}}</ref><ref name="pmid281120502" />
 
=== Pathogenesis ===
 
* The most accepted proposed mechanism to explain Alexander disease is as follows:<ref name="pmid17498694">{{cite journal |vauthors=Quinlan RA, Brenner M, Goldman JE, Messing A |title=GFAP and its role in Alexander disease |journal=Exp. Cell Res. |volume=313 |issue=10 |pages=2077–87 |date=June 2007 |pmid=17498694 |pmc=2702672 |doi=10.1016/j.yexcr.2007.04.004 |url=}}</ref>
 
# The accumulation of [[glial fibrillary acidic protein]] and the consequent formation of characteristic aggregates, called [[Rosenthal fibers]] in various cell types, and especially [[astrocytes]].
# The accumulation appears to be due to a gain in function due to the [[mutation]] that partially blocks the assembly of the [[GFAP]] filaments.<ref name="pmid121758782">{{cite journal |vauthors=Johnson AB |title=Alexander disease: a review and the gene |journal=Int. J. Dev. Neurosci. |volume=20 |issue=3-5 |pages=391–4 |date=2002 |pmid=12175878 |doi=10.1016/s0736-5748(02)00045-x |url=}}</ref>
# Subsequent sequestration of [[ubiquitin]] and the α-B-crystalline chaperone proteins and [[HSP27]] in the [[Rosenthal fibers]].
# Activation of both the Jnk protein and the [[stress]] response.
 
===Genetics===
===Genetics===
Alexander disease is a genetic disorder affecting the central nervous system ([[midbrain]] and [[cerebellum]]). It is caused by mutations in the [[gene]] for glial fibrillary acidic protein ([[GFAP]]) that maps to [[Chromosome 17 (human)|chromosome 17]]q21. It is inherited in an [[autosomal dominant]] manner.
 
* Individuals with Alexander disease present a mutation in the [[gene]] [[GFAP]] that maps to [[Chromosome 17 (human)|chromosome 17]]q21.<ref name="pmid29478608" /><ref name="pmid281120502" /><ref name="pmid21917775" />
*[[GFAP]] [[gene]] comprises nine exons distributed over 9.8 kb, transcribed into a 3-kb mRNA.<ref name="urlAlexander Disease - GeneReviews® - NCBI Bookshelf" />
* When inherited, Alexander disease is transmitted in an [[autosomal dominant]] manner.<ref name="urlAlexander Disease - GeneReviews® - NCBI Bookshelf">{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK1172/ |title=Alexander Disease - GeneReviews® - NCBI Bookshelf |format= |work= |accessdate=}}</ref>
*[[Penetrance]] appears to be close to 100% in patients with Alexander disease type I.<ref name="pmid12849260">{{cite journal |vauthors=Messing A, Brenner M |title=Alexander disease: GFAP mutations unify young and old |journal=Lancet Neurol |volume=2 |issue=2 |pages=75 |date=February 2003 |pmid=12849260 |doi=10.1016/s1474-4422(03)00301-6 |url=}}</ref>
 
=== Gross Pathology ===
 
* The main features in brain biopsies of patients with Alexander disease are [[Rosenthal fibers]] accumulation (mostly in the superficial [[cortex]]) and loss of [[myelin]] from the [[white matter]].<ref name="PridmoreBaraitser2016">{{cite journal|last1=Pridmore|first1=Clare L.|last2=Baraitser|first2=Michael|last3=Harding|first3=Brian|last4=Boyd|first4=Stewart G.|last5=Kendall|first5=Brian|last6=Brett|first6=Edward M.|title=Alexander's Disease: Clues to Diagnosis|journal=Journal of Child Neurology|volume=8|issue=2|year=2016|pages=134–144|issn=0883-0738|doi=10.1177/088307389300800205}}</ref>
* It may be challenging to differentiate mass-like lesions in Alexander disease from low-grade [[astrocytomas]] due to the proliferative nature of the [[astrocytic]] lesions; one finding that may separate Alexander disease is the presence of [[biphasic]] [[morphology]] and eosinophylic [[Granular cell|granular]] bodies.<ref name="pmid281120502" />


==Causes==
==Causes==
* The cause of Alexander disease is a [[mutation]] in one or more exons of the gene [[GFAP]], encoding for [[glial fibrillary acidic protein]]:<ref name="pmid29478608" /><ref name="pmid281120502" /><ref name="pmid21917775" />
**[[Exon|''E''xon]] 1 (45.5% of cases)
**[[Exon|''E''xon]] 3 (3.3% of cases)
**[[Exon|''E''xon]] 4 (27.2% of cases)
**[[Exon|''E''xon]] 5 (1.8% of cases)
**[[Exon|''E''xon]] 6 (16.0% of cases)
**[[Exon|''E''xon]] 7 (<1% of cases)
**[[Exon|''E''xon]] 8 (7.5% of cases).


==Differentiating {{PAGENAME}} from Other Diseases==
==Differentiating {{PAGENAME}} from Other Diseases==
* Alexander disease must be differentiated from other disorders that affect the [[white matter]] such as:
**[[X-linked adrenoleukodystrophy]]
**[[Krabbe disease]]
**[[Canavan disease]]
**[[Arylsulfatase A deficiency]]
** Megalencephalic leukoencephalopathy


==Epidemiology and Demographics==
==Epidemiology and Demographics==
This is a very rare with no more than 300 cases reported. The infantile form (80% of all cases) starts usually at the age of six months or within the first two years. The average duration of the infantile form of the illness is usually about 3 years. Onset of the juvenile form (14% of all cases) presents usually between four to ten years of age. Duration of this form is in most cases about 8 years. In younger patients, seizures, megalencephaly, developmental delay, and spasticity are usually present. Neonatal onset is also reported. Onset in adults is least frequent. In older patients, bulbar or pseudobulbar symptoms and spasticity predominate. Symptoms of the adult form may also resemble [[multiple sclerosis]].
 
* Alexander disease is a rare condition; since the description of the first affected individual until 2015, only 550 cases have been reported.<ref name="pmid20301351">{{cite journal |vauthors=Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, Srivastava S, Naidu S |title= |journal= |volume= |issue= |pages= |date= |pmid=20301351 |doi= |url=}}</ref>
* The [[incidence]] of Alexander disease has not been reported.
* The [[prevalence]] world-wide of Alexander disease has not been reported.<ref name="pmid20301351" /> In a study made by Yoshida et al. in 2012 in Japan, they estimated a [[prevalence]] of 1 in 2.7 million population studied.<ref name="pmid29478608" /><ref name="YoshidaNakagawa2012">{{cite journal|last1=Yoshida|first1=Tomokatsu|last2=Nakagawa|first2=Masanori|title=Clinical aspects and pathology of Alexander disease, and morphological and functional alteration of astrocytes induced by GFAP mutation|journal=Neuropathology|volume=32|issue=4|year=2012|pages=440–446|issn=09196544|doi=10.1111/j.1440-1789.2011.01268.x}}</ref>
* 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.<ref name="pmid281120502" />
* There is no gender predilection to Alexander disease.<ref name="pmid29478608" />
* There is no [[racial]] predilection to Alexander disease.<ref name="pmid29478608" />
* There is no geographic predilection to Alexander disease.<ref name="pmid29478608" />
* There is no economic predilection to Alexander disease.<ref name="pmid29478608" />


==Risk Factors==
==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).<ref name="pmid20301351" />


==Screening==
==Screening==
* 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.<ref name="pmid29478608" /><ref name="pmid11237983">{{cite journal |vauthors=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 |title=Alexander disease: diagnosis with MR imaging |journal=AJNR Am J Neuroradiol |volume=22 |issue=3 |pages=541–52 |date=March 2001 |pmid=11237983 |doi= |url=}}</ref>
* Guidelines for [[GFAP]] [[mutations]] screening in individuals with suspected atypical [[MRI]] findings do not exist for Alexander disease type II.<ref name="pmid18388212">{{cite journal |vauthors=Farina L, Pareyson D, Minati L, Ceccherini I, Chiapparini L, Romano S, Gambaro P, Fancellu R, Savoiardo M |title=Can MR imaging diagnose adult-onset Alexander disease? |journal=AJNR Am J Neuroradiol |volume=29 |issue=6 |pages=1190–6 |date=June 2008 |pmid=18388212 |doi=10.3174/ajnr.A1060 |url=}}</ref>
* It is recommended to [[Screening|screen]] parents of children with Alexander disease to rule-out familial type of late onset.<ref name="pmid29478608" />
* 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.<ref name="pmid29478608" />
* When testing for [[Exon|exonic]] [[mutations]] is negative, you should always consider [[splice-site]] [[mutations]].<ref name="pmid29478608" />


==Natural History, Complications and Prognosis==
==Natural History, Complications and Prognosis==
The prognosis is generally poor. With early onset, death usually occurs within 10 years after the onset of symptoms. Usually, the later the disease occurs, the slower its course is.
 
*[[Life expectancy]] in individuals with Alexander disease is variable.<ref name="pmid20301351" />
*In some cases of the adult form, patients present no [[symptoms]].<ref name="url308 Permanent Redirect">{{cite web |url=http://www.ninds.nih.gov/disorders/alexander_disease/alexander_disease.htm |title=308 Permanent Redirect |format= |work= |accessdate=}}</ref>
* Individuals with type I of Alexander disease typically do not [[Reproduction|reproduce]].<ref name="pmid20301351" />
 
* 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.<ref name="pmid20301351" />
* Common complications of Alexander disease are included in the "''History and Symptoms''" section.


==Diagnosis==
==Diagnosis==
===Diagnostic Criteria===
=== Diagnostic Study of Choice ===
 
* The diagnosis of Alexander disease is made when [[genetic testing]] confirms a [[heterozygous]] [[pathogenic]] variant of [[GFAP]] [[gene]] in a [[proband]], although, first step is to suspect the [[disorder]] by clinical presentation and back it up with [[CNS]] [[imaging]] (signal abnormalities or [[atrophy]] of the [[medulla]] or [[spinal cord]] have sufficient weight to warrant a [[genetic study]]).<ref name="urlAlexander Disease - GeneReviews® - NCBI Bookshelf" /><ref name="pmid16240361">{{cite journal |vauthors=Salvi F, Aoki Y, Della Nave R, Vella A, Pastorelli F, Scaglione C, Matsubara Y, Mascalchi M |title=Adult Alexander's disease without leukoencephalopathy |journal=Ann. Neurol. |volume=58 |issue=5 |pages=813–4 |date=November 2005 |pmid=16240361 |doi=10.1002/ana.20634 |url=}}</ref>


===History and Symptoms===
=== History and Symptoms ===
* Delays in development of some physical, psychological and behavioral skills
* Progressive enlargement of the head ([[macrocephaly]])
* [[Seizures]]
* [[Spasticity]] 
* [[Hydrocephalus]]
* [[Dementia]]
* Clumsy movements.


===Physical Examination===
==== History ====


===Laboratory Findings===
* There is not a single specific [[clinical presentation]] of Alexander disease, since it varies among the [[age of onset]].<ref name="urlAlexander Disease - GeneReviews® - NCBI Bookshelf" />


===CT Findings===
==== Common symptoms ====
* Decreased density of white matter
* Frontal lobe predominance
* +/- Dilated lateral ventricles


===Imaging Findings===
* Common [[symptoms]] of Alexander disease include:<ref name="pmid21917775" /><ref name="VázquezMacaya2008" /><ref name="pmid12175878">{{cite journal |vauthors=Johnson AB |title=Alexander disease: a review and the gene |journal=Int. J. Dev. Neurosci. |volume=20 |issue=3-5 |pages=391–4 |date=2002 |pmid=12175878 |doi=10.1016/s0736-5748(02)00045-x |url=}}</ref>
** Type I:
***[[Seizures]]
***[[Encephalopathy]]
*** Paroxysmal deterioration
***[[Failure to thrive]]
***[[Developemental delay]]
*** Focal mass-like symptoms
** Type II:
***[[Autonomic dysfunction]]
***[[Bulbar]] symptoms
***[[Ocular]] movement abnormalities
***[[Palatal myoclonus]]


===Other Diagnostic Studies===
==== Less common symptoms ====
 
* Less common symptoms of Alexander disease include:<ref name="pmid21917775" />
*[[Dysarthria]]
*[[Sleep]] disturbance
*[[Dysphonia]]
*[[Gait]] disturbance
* Frequent [[emesis]]
*[[Hiccups]]
* Frequent [[vomiting]]
*[[Dementia]]
 
=== Physical Examination ===
 
*[[Physical examination]] will also vary depending on the age of presentation; the most typical findings that make Alexander disease more suspicious are:
** Infantile: progressive [[psychomotor retardation]], [[developmental]] regression, [[megalencephaly]] with [[frontal bossing]], [[Seizure|seizures]], [[Pyramidal system|pyramidal signs]], [[ataxia]], and occasional [[hydrocephalus]] secondary to [[Cerebral aqueduct|aqueductal]] [[stenosis]].
** Juvenile: [[bulbar]]/pseudobulbar [[signs]] with nasal [[speech]], [[lower limb]] [[spasticity]], [[ataxia]], gradual loss of intellectual function, [[seizures]], [[megalencephaly]], and [[breathing]] problems.
** Adults: [[bulbar]]/pseudobulbar [[signs]], [[Corticospinal tract|pyramidal tract]] signs, [[Cerebellum|cerebellar]] [[signs]], [[dysautonomia]], [[Sleep disorder|sleep disturbance]], [[gait disturbance]], [[hemiparesis]]/[[hemiplegia]] or [[quadriparesis]]/[[quadriplegia]], [[seizures]], and [[diplopia]].
 
=== Laboratory Findings ===
 
*Molecular genetic testing used to evaluate [[Glial fibrillary acidic protein|GFAP]] [[mutations]] in Alexander disease are sequence analysis and [[deletion]]/duplication [[analysis]].<ref name="pmid18004641">{{cite journal |vauthors=Balbi P, Seri M, Ceccherini I, Uggetti C, Casale R, Fundarò C, Caroli F, Santoro L |title=Adult-onset Alexander disease : report on a family |journal=J. Neurol. |volume=255 |issue=1 |pages=24–30 |date=January 2008 |pmid=18004641 |doi=10.1007/s00415-007-0654-0 |url=}}</ref>
*[[CSF]] may disclose an increased levels of [[glial fibrillary acidic protein]] and αβ-crystallin and [[heat shock protein 27]] in individuals with Alexander disease.<ref name="pmid16217707">{{cite journal |vauthors=Kyllerman M, Rosengren L, Wiklund LM, Holmberg E |title=Increased levels of GFAP in the cerebrospinal fluid in three subtypes of genetically confirmed Alexander disease |journal=Neuropediatrics |volume=36 |issue=5 |pages=319–23 |date=October 2005 |pmid=16217707 |doi=10.1055/s-2005-872876 |url=}}</ref><ref name="pmid20301351" />
 
=== Electrocardiogram ===
 
* There are no [[ECG]] findings associated with Alexander disease.
 
=== X-ray ===
 
* 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 ===
 
* There are no [[echocardiography]]/[[ultrasound]] findings associated with Alexander disease.
 
=== CT scan ===
 
* Alexander disease may show the following findings in a head [[CT scan]]:
**Decreased density of [[white matter]]
**[[Frontal lobe]] predominance
** +/- Dilated [[lateral ventricles]]
 
=== MRI ===
 
* Type I Alexander disease has the following findings on [[MRI]] of the [[CNS]], known as the classic Alexander disease findings:<ref name="pmid28112050">{{cite journal |vauthors=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 |title=Alexander Disease |journal=J. Child Neurol. |volume=32 |issue=2 |pages=184–187 |date=February 2017 |pmid=28112050 |doi=10.1177/0883073816673263 |url=}}</ref><ref name="pmid11237983" />
**[[Frontal lobe|Frontal]] predominance of central [[white matter]] involvement manifested by T2 hyperintensity and T1 hypointensity
** Periventricular rim of T2 hypointensity and T1 hyperintensity
** Abnormal T2 signal, [[swelling]] or [[atrophy]] of [[basal ganglia]]/[[thalamus]]
** Abnormal T2 signal of the [[brain stem]]
**[[Contrast]] [[enhancement]] of selected structures
*Other MRI findings, known as atypical, can be identified, especially in patients with type II Alexander disease, these are:<ref name="urlAlexander Disease - GeneReviews® - NCBI Bookshelf" />
** Predominant or isolated involvement of [[posterior fossa]] structures
** Multifocal tumor-like [[brain stem]] [[Lesion|lesions]] and [[brain stem]] [[atrophy]]
** Slight, diffuse signal changes involving the [[basal ganglia]] and/or [[thalamus]]
**[[Garland's triad|Garland]]-like feature along the [[ventricular]] wall
** Characteristic pattern of [[Contrast medium|contrast]] enhancement
** Any other findings that suggest, but do not meet, the strict criteria
 
=== Other Imaging Findings ===
 
* There are no other [[imaging]] findings associated with Alexander's disease.
 
=== Other Diagnostic Studies ===
 
*[[Electroencephalography|Electroencephalogram]] in Alexander disease may show slow activity, which is much more prominent over the anterior than posterior regions.<ref name="PridmoreBaraitser2016" />


==Treatment==
==Treatment==
There is neither cure nor standard treatment for Alexander disease. All treatment is symptomatic and supportive, for example [[antibiotic]]s for intercurrent infection and [[anticonvulsant]]s for seizure control are usually used.
===Medical Therapy===
===Medical Therapy===


===Surgery===
* There is neither [[cure]] nor standard [[treatment]] for Alexander disease. All treatment is symptomatic and supportive, for example [[antibiotic]]s for intercurrent [[infection]] and [[anticonvulsant]]s for [[seizure]] control are usually used.
 
=== Surgery ===
 
* There are no [[Surgical procedure|surgical interventions]] specific for Alexander disease. Some complications such as [[scoliosis]] may require surgical correction in severe cases.
 
=== Primary Prevention ===
 
* There are no established measures for the [[primary prevention]] of Alexander disease.
 
=== Secondary Prevention ===


===Prevention===
* Multidisciplinary care should be implemented in regular visits to early detect and treat progression of [[nutritional]] status, [[swallowing]] ability, [[Strength training|strength]], [[mobility]], and early signs of [[scoliosis]] in patients with Alexander disease.<ref name="pmid20301351" />


==See also==
==See also==

Latest revision as of 17:33, 4 September 2020

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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

Template:DiseaseDisorder infobox

Overview

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

Classification

Pathophysiology

Pathogenesis

  • 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.

Genetics

Gross Pathology

Causes

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]

Screening

  • 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.

Diagnosis

Diagnostic Study of Choice

History and Symptoms

History

Common symptoms

Less common symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

  • There are no ECG findings associated with Alexander disease.

X-ray

  • 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

MRI

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]

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

See also

External links

References

  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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