Alexander disease: Difference between revisions

Revision as of 03:53, 19 March 2025

Alexander disease is a rare, progressive neurodegenerative disorder that primarily affects the central nervous system. It is classified under the group of leukodystrophies, which are disorders characterized by the destruction of white matter in the brain. The disease is caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP), leading to the formation of abnormal protein aggregates known as Rosenthal fibers within astrocytes. These abnormalities impair the function of astrocytes, which are crucial for maintaining neuronal health, leading to progressive neurological decline.

Clinical Features

Alexander disease presents in different forms, classified based on the age of onset and severity:

Infantile Form:
The most common and severe form, manifesting within the first two years of life.
Symptoms include:
Developmental delay and intellectual disability.
Macrocephaly (enlarged head size) due to accumulation of abnormal astrocytic filaments.
Seizures and spasticity.
Dysphagia (difficulty swallowing).
Progressive white matter destruction leading to leukodystrophy.

Juvenile Form:
Onset occurs between ages 2 and 13 years.
Symptoms include:
Progressive ataxia (loss of coordination).
Dysarthria (difficulty speaking).
Dysphagia (swallowing difficulties).
Cognitive impairment and behavioral abnormalities.
Progressive muscle weakness.

Adult Form:
The rarest and mildest form, with onset after adolescence.
Symptoms can mimic those of multiple sclerosis or Parkinson’s disease.
Features include:
Mild spasticity.
Tremors and rigidity.
Psychiatric disturbances, such as depression or psychosis.

Pathophysiology

Alexander disease results from mutations in the GFAP gene, leading to the accumulation of Rosenthal fibers—abnormal aggregates of glial fibrillary acidic protein within astrocytes. These fibers impair astrocyte function, disrupting their roles in:

Maintaining the blood-brain barrier.
Regulating ion homeostasis in the brain.
Supporting neuronal metabolism and synaptic function.

This dysfunction leads to progressive demyelination, the hallmark of leukodystrophies. The loss of myelin disrupts neural signal transmission, resulting in the neurological symptoms observed in Alexander disease.

Diagnosis

The diagnosis of Alexander disease is based on a combination of clinical features, neuroimaging findings, and genetic testing.

Neuroimaging:
Magnetic Resonance Imaging (MRI) shows:
Extensive white matter abnormalities, especially in the frontal lobes.
Basal ganglia and brainstem involvement.
Rosenthal fibers accumulation.

Genetic Testing:
Identification of mutations in the GFAP gene confirms the diagnosis.
Testing is particularly useful in cases with atypical presentations.

Management

Currently, there is no cure for Alexander disease. Treatment is primarily supportive and focuses on managing symptoms:

Seizure Control:
Antiepileptic drugs are used to reduce seizure frequency.

Physical and Occupational Therapy:
Helps maintain motor function and prevent muscle contractures.

Nutritional Support:
In advanced cases, feeding tubes may be required to prevent malnutrition.

Speech Therapy:
Assists with communication difficulties and dysphagia management.

Research into targeted therapies, including gene therapy and pharmacological interventions to reduce GFAP accumulation, is ongoing.

Prognosis

The prognosis of Alexander disease varies depending on the age of onset:

Infantile form: Often leads to severe neurological disability and early mortality, typically within the first decade of life.
Juvenile form: Generally progressive but slower than the infantile form.
Adult form: Milder symptoms and a more prolonged disease course.

External Links

NIH genetic and rare disease info

NIH info on Alexander disease

Alexander disease is a rare disease.

ights From Genetics]

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-{{Infobox medical condition (new)
+[[File:Alexander autopsy.jpg|thumb|Brain of a 4-year-old boy with Alexander disease]]
-| name            = Alexander disease
+[[File:Alexander Disease HE 400x.jpg|alt=Alexander disease|thumb|Alexander disease]]
-| synonyms        =
+'''Alexander disease''' is a rare, progressive [[neurodegenerative disorder]] that primarily affects the [[central nervous system]]. It is classified under the group of [[leukodystrophies]], which are disorders characterized by the destruction of [[white matter]] in the brain. The disease is caused by mutations in the gene encoding [[glial fibrillary acidic protein]] ('''GFAP'''), leading to the formation of abnormal protein aggregates known as '''Rosenthal fibers''' within [[astrocytes]]. These abnormalities impair the function of [[astrocytes]], which are crucial for maintaining [[neuronal]] health, leading to progressive neurological decline.
-| image           = Alexander autopsy.jpg
-| caption         = Brain of a 4-year-old boy with Alexander disease showing [[macroencephaly]] and [[periventricular leukomalacia]] (note brownish discoloration around the cerebral [[ventricular system|ventricles]])
-| pronounce       =
-| field           =
-| symptoms        =
-| complications   =
-| onset           =
-| duration        =
-| types           =
-| causes          =
-| risks           =
-| diagnosis       =
-| differential    =
-| prevention      =
-| treatment       =
-| medication      =
-| prognosis       =
-| frequency       =
-| deaths          =
-}}
-[[File:Alexander Disease HE 400x.jpg|alt=Alexander disease|thumb|Alexander disease]]'''Alexander disease''' is a very rare [[autosomal dominant]] [[leukodystrophy]], which are neurological conditions caused by anomalies in the [[myelin]] which protects nerve fibers in the brain. According to the [[National Institute of Neurological Disorders and Stroke]], the destruction of white matter is accompanied by the formation of [[Rosenthal fiber]]s—abnormal clumps of protein that accumulate in [[astrocyte]]s in the brain.
+== Clinical Features ==
-The most common type of Alexander disease is the infantile form that usually begins during the first 2 years of life. Symptoms include mental and physical developmental delays, followed by the loss of developmental milestones, an abnormal [[Macrocephaly|increase in head size]] and seizures.
+Alexander disease presents in different forms, classified based on the age of onset and severity:
-The juvenile form of Alexander disease has an onset between the ages of 2 and 13 years. These children may have excessive vomiting, difficulty swallowing and speaking, poor coordination, and loss of motor control.
+* '''Infantile Form:'''
+* The most common and severe form, manifesting within the first two years of life.
+* Symptoms include:
+* [[Developmental delay]] and [[intellectual disability]].
+* [[Macrocephaly]] (enlarged head size) due to accumulation of abnormal astrocytic filaments.
+* [[Seizures]] and [[spasticity]].
+* [[Dysphagia]] (difficulty swallowing).
+* Progressive [[white matter]] destruction leading to [[leukodystrophy]].
-Adult-onset forms of Alexander disease are less common. The symptoms sometimes mimic those of [[Parkinson’s disease]] or [[multiple sclerosis]], or may present primarily as a [[psychiatric disorder]].
+* '''Juvenile Form:'''
+* Onset occurs between ages 2 and 13 years.
+* Symptoms include:
+* Progressive [[ataxia]] (loss of coordination).
+* [[Dysarthria]] (difficulty speaking).
+* [[Dysphagia]] (swallowing difficulties).
+* Cognitive impairment and behavioral abnormalities.
+* Progressive muscle weakness.
-The disease occurs in both males and females, and no ethnic, racial, geographic or cultural/economic differences are seen in its distribution. Alexander disease is a progressive and often fatal disease.<ref>{{cite web |url = https://www.ninds.nih.gov/Disorders/All-Disorders/Alexander-Disease-Information-Page |title = Alexander Disease Information Page |publisher = National Institute of Neurological Disorders and Stroke |year = 2018 }} {{PD-notice}}</ref>
+* '''Adult Form:'''
+* The rarest and mildest form, with onset after adolescence.
+* Symptoms can mimic those of [[multiple sclerosis]] or [[Parkinson’s disease]].
+* Features include:
+* Mild [[spasticity]].
+* [[Tremors]] and [[rigidity]].
+* Psychiatric disturbances, such as [[depression]] or [[psychosis]].
-== Presentation ==
+== Pathophysiology ==
-Delays in development of some physical, psychological and behavioral skills; progressive enlargement of the head ([[macrocephaly]]), [[seizures]], [[spasticity]], and in some cases also [[hydrocephalus]], [[idiopathic intracranial hypertension]], and [[dementia]].<ref name="Gene">[https://www.ncbi.nlm.nih.gov/books/NBK1172/ GeneReviews/NCBI/NIH/UW entry on Alexander disease]</ref>
-[[File:Alexander autopsy.jpg|alt=Autopsy, Alexander disease|thumb|Autopsy, Alexander disease]]
-==Cause==
-Alexander disease is a genetic disorder affecting the [[midbrain]] and [[cerebellum]] of the [[central nervous system]]. It is caused by [[mutation]]s in the [[gene]] for [[glial fibrillary acidic protein]] (GFAP)<ref name="Li 2002">{{cite journal |vauthors =Li R, Messing A, Goldman JE, Brenner M |title = GFAP mutations in Alexander disease |journal=Int. J. Dev. Neurosci. |volume=20 |issue=3–5 |pages=259–68 |year=2002 |pmid=12175861 |doi = 10.1016/s0736-5748(02)00019-9 |url = }}</ref><ref name="Quinlan 2007">{{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><ref name="Messing 2012">{{cite journal |vauthors = Messing A, Brenner M, Feany MB, Nedergaard M, Goldman JE |title = Alexander disease |journal=J. Neurosci. |volume=32 |issue=15 |pages=5017–23 |date=April 2012 |pmid=22496548 |pmc=3336214 |doi=10.1523/JNEUROSCI.5384-11.2012 |url=}}</ref> that maps to [[Chromosome 17 (human)|chromosome 17]]q21. It is inherited in an [[dominance (genetics)|autosomal dominant]] manner, such that the child of a parent with the disease has a 50% chance of inheriting the condition, if the parent is [[zygosity|heterozygotic]]. However, most cases arise ''de novo'' as the result of sporadic mutations.<ref name="Gene" />
-Alexander disease belongs to [[leukodystrophy|leukodystrophies]], a group of diseases that affect the 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 fiber]]s.<ref name="Gene" /><ref name="NINDS">{{NINDS|alexander_disease}}</ref><ref name="BBC">[http://news.bbc.co.uk/2/hi/health/1097277.stm "Cause of brain disease found" -BBC News]</ref> Rosenthal fibers appear not to be present in healthy people,<ref name="NINDS" /><ref name="Alexander">{{Cite web |url=http://www.ulf.org/types/Alexander.html |title=Archived copy |access-date=2010-06-14 |archive-url=https://web.archive.org/web/20100428072520/http://ulf.org/types/Alexander.html |archive-date=2010-04-28 |url-status=dead }}</ref> but occur in specific diseases, like some forms of [[cancer]], Alzheimer’s, Parkinson’s, Huntington’s, and ALS.<ref name="NINDS"  /><ref name="Alexander"  /><ref>{{Cite web|url=https://news.wisc.edu/mutation-in-common-protein-triggers-tangles-chaos-inside-brain-cells/|title=Mutation in common protein triggers tangles, chaos inside brain cells|website=news.wisc.edu|language=en-US|access-date=2018-11-16}}</ref> The Rosenthal fibers found in Alexander disease do not share the distribution or concentration of other diseases and disorders.<ref name="NINDS"  />
+Alexander disease results from mutations in the '''GFAP gene''', leading to the accumulation of '''Rosenthal fibers'''—abnormal aggregates of [[glial fibrillary acidic protein]] within [[astrocytes]]. These fibers impair astrocyte function, disrupting their roles in:
-== Pathology ==
+* Maintaining the [[blood-brain barrier]].
-Alexander disease causes the gradual loss of bodily functions and the ability to talk. It also causes an overload of long-chain [[fatty acid]]s in the brain, which destroy the myelin sheath. The cause of Alexander disease is a mutation in the gene encoding GFAP.<ref name="Gene" /><ref name="NINDS"  /><ref name="Li 2002"  /><ref name="Quinlan 2007" /><ref name="Adult">{{cite journal |vauthors =Farina L, Pareyson D, Minati L |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 |display-authors = etal }}</ref><ref>{{Cite web|url=https://news.wisc.edu/mutation-in-common-protein-triggers-tangles-chaos-inside-brain-cells/|title=Mutation in common protein triggers tangles, chaos inside brain cells|website=news.wisc.edu|language=en-US|access-date=2018-11-16}}</ref>
+* Regulating [[ion homeostasis]] in the [[brain]].
+* Supporting [[neuronal metabolism]] and [[synaptic function]].
-A [[X-ray computed tomography|CT scan]] shows:
+This dysfunction leads to [[progressive demyelination]], the hallmark of leukodystrophies. The loss of [[myelin]] disrupts [[neural signal transmission]], resulting in the neurological symptoms observed in Alexander disease.
-* Decreased density of white matter
-* [[Frontal lobe]] predominance
-* Dilated [[lateral ventricles]] may present
 == Diagnosis ==
-Detecting the signs of Alexander disease is possible with [[magnetic resonance imaging]] (MRI), which looks for specific changes in the brain that may be tell-tale signs for the disease.<ref name="Labauge 2009">{{cite journal |author =Labauge P |title = Magnetic resonance findings in leucodystrophies and MS |journal=Int MS J |volume=16 |issue=2 |pages=47–56 |date=June 2009 |pmid=19671368 |doi= }}</ref><ref>{{cite journal |vauthors =van der Knaap MS, Naidu S, Breiter SN |title=Alexander disease: diagnosis with MR imaging |journal=AJNR Am J Neuroradiol |volume=22 |issue=3 |pages=541–52 |date=March 2001 |pmid=11237983 |url = http://www.ajnr.org/content/22/3/541.full |display-authors=etal }}</ref> It is even possible to detect adult-onset Alexander disease with MRI.<ref name="Adult" /> Alexander disease may also be revealed by [[genetic testing]] for its known cause.<ref name="Johnson 2002">{{cite journal |author =Johnson AB |title=Alexander disease: a review and the gene |journal=Int. J. Dev. Neurosci. |volume=20 |issue=3–5 |pages=391–4 |year=2002 |pmid=12175878 |doi=10.1016/S0736-5748(02)00045-X }}</ref><ref name="Sawaishi 2009">{{cite journal |last = Sawaishi |first = Y |title=Review of Alexander disease: beyond the classical concept of leukodystrophy |journal=Brain Dev. |volume=31 |issue=7 |pages=493–8 |date=August 2009 |pmid=19386454 |doi = 10.1016/j.braindev.2009.03.006 }}</ref> A rough diagnosis may also be made through revealing of [[clinical symptom]]s, including enlarged head size, along with [[radiological studies]], and negative tests for other leukodystrophies.<ref name="Alexander" />
-==Treatment==
+The diagnosis of Alexander disease is based on a combination of clinical features, neuroimaging findings, and genetic testing.
-No cure or standard procedure for treatment is known, although a University of Wisconsin study shows promise with gene editing of the astrocytes.<ref name="Gene" /><ref name="NINDS"  /><ref>{{Cite web|url=https://news.wisc.edu/mutation-in-common-protein-triggers-tangles-chaos-inside-brain-cells/|title=Mutation in common protein triggers tangles, chaos inside brain cells|website=news.wisc.edu|language=en-US|access-date=2018-11-16}}</ref> A [[bone marrow transplant]] has been attempted on a child, but it made no improvement.<ref name="Staba 1997">{{cite journal |vauthors = Staba MJ, Goldman S, Johnson FL, Huttenlocher PR |title=Allogeneic bone marrow transplantation for Alexander's disease |journal=Bone Marrow Transplant. |volume=20 |issue=3 |pages=247–9 |date=August 1997 |pmid=9257894 |doi=10.1038/sj.bmt.1700871 }}</ref><ref name="Messing 2010">{{cite journal |vauthors =Messing A, LaPash Daniels CM, Hagemann TL |title=Strategies for treatment in Alexander disease |journal=Neurotherapeutics |volume=7 |issue=4 |pages=507–15 |date=October 2010 |pmid=20880512 |pmc=2948554 |doi = 10.1016/j.nurt.2010.05.013 |url= }}</ref> Hydrocephalus may be seen in younger patients and can be relieved with surgery or by implanting a shunt to relieve pressure.<ref>{{Cite web|url=http://ulf.org/alexander-disease|title=Alexander Disease - United Leukodystrophy Foundation United Leukodystrophy Foundation|website=ulf.org|access-date=2016-11-08}}</ref>
-==Prognosis==
+* '''Neuroimaging:'''
-The prognosis is generally poor. With early onset, death usually occurs within 10 years from the onset of symptoms. Individuals with the infantile form usually die before the age of seven.<ref>{{Cite web|url=http://www.ninds.nih.gov/disorders/alexander_disease/alexander_disease.htm|title=Alexander Disease Information Page: National Institute of Neurological Disorders and Stroke (NINDS)|website=www.ninds.nih.gov|access-date=2016-11-03|archive-url=https://web.archive.org/web/20120514085203/http://www.ninds.nih.gov/disorders/alexander_disease/alexander_disease.htm|archive-date=2012-05-14|url-status=dead}}</ref> Usually, the later the disease occurs, the slower its course.<ref name="Gene" /><ref name="NINDS"  />
+* [[Magnetic Resonance Imaging]] ('''MRI''') shows:
+* Extensive [[white matter]] abnormalities, especially in the [[frontal lobes]].
+* [[Basal ganglia]] and [[brainstem]] involvement.
+* [[Rosenthal fibers]] accumulation.
-==Prevalence==
+* '''Genetic Testing:'''
-Its occurrence is very rare. The infantile form occurs from birth to 2 years of age.<ref name="Messing 2012" /> The average duration of the infantile form is usually about 3 years. Onset of the juvenile form presents between 2 and 12 years of age.<ref name="Messing 2012" /> Duration of this form is in most cases about 6 years. The adult form occurs after 12 years.<ref name="Messing 2012" /> In younger patients, [[seizures]], [[megalencephaly]], [[developmental delay]], and [[spasticity]] are usually present. Neonatal onset is also reported.<ref name="Singh 2012">{{cite journal |vauthors =Singh N, Bixby C, Etienne D, Tubbs RS, Loukas M |title=Alexander's disease: reassessment of a neonatal form |journal=Childs Nerv Syst |volume=28 |issue=12 |pages=2029–31 |date=December 2012 |pmid=22890470 |doi=10.1007/s00381-012-1868-8 |url=}}</ref> 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]].<ref name="Gene" /> No more than 500 cases have been reported.<ref name="Gene" />
+* Identification of mutations in the '''GFAP gene''' confirms the diagnosis.
+* Testing is particularly useful in cases with atypical presentations.
-==See also==
+== Management ==
-* [[The Myelin Project]]
-* [[The Stennis Foundation]]
-==References==
+Currently, there is no cure for Alexander disease. Treatment is primarily supportive and focuses on managing symptoms:
-{{Reflist}}
-== External links ==
+* '''Seizure Control:'''
+* [[Antiepileptic drugs]] are used to reduce seizure frequency.
-* [https://www.ncbi.nlm.nih.gov/omim/137780,203450,137780,203450  OMIM entries on Alexander disease]
+* '''Physical and Occupational Therapy:'''
-* [https://jmedicalcasereports.biomedcentral.com/articles/10.1186/1752-1947-7-194 Infantile-onset Alexander disease in a child with long-term follow-up by serial magnetic resonance imaging: a case report]
+* Helps maintain motor function and prevent muscle contractures.
-* [https://academic.oup.com/jnen/article/60/6/563/2916220 Alexander Disease: New Insights From Genetics]
+* '''Nutritional Support:'''
+* In advanced cases, [[feeding tubes]] may be required to prevent [[malnutrition]].
+* '''Speech Therapy:'''
+* Assists with communication difficulties and [[dysphagia]] management.
+Research into targeted therapies, including [[gene therapy]] and pharmacological interventions to reduce GFAP accumulation, is ongoing.
+== Prognosis ==
+The prognosis of Alexander disease varies depending on the age of onset:
+* '''Infantile form:''' Often leads to severe [[neurological disability]] and early [[mortality]], typically within the first decade of life.
+* '''Juvenile form:''' Generally progressive but slower than the infantile form.
+* '''Adult form:''' Milder symptoms and a more prolonged disease course.
+== See Also ==
+* '''[[Leukodystrophy]]'''
+* '''[[Astrocyte]]'''
+* '''[[Demyelination]]'''
+* '''[[Neuromuscular disorders]]'''
+== External Links ==
+* [https://rarediseases.org/rare-diseases/alexander-disease/ National Organization for Rare Disorders - Alexander Disease]
+* [https://medlineplus.gov/genetics/condition/alexander-disease/ MedlinePlus - Alexander Disease]
+* [https://www.ncbi.nlm.nih.gov/books/NBK562242/ NCBI Bookshelf - Alexander Disease]
 {{-}}
 {{CNS diseases of the nervous system}}
 {{Cytoskeletal defects}}
+{{Rare diseases}}
 [[Category:Disorders causing seizures]]
 [[Category:Leukodystrophies]]
@@ Line 83: / Line 105: @@
 [[Category:Demyelinating diseases of CNS]]
 [[Category:Neurological disorders in children]]
-[[Category:Cytoskeletal defects]]
+[[Category:Cytoskeletal defects]]ights From Genetics]