Alexander disease: Difference between revisions
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==Classification== | ==Classification== | ||
* Alexander disease | * Alexander disease is classified according to the age of onset and clinical course as: | ||
** | ** Type I (infantile). The most common, with an age of onset before 4 years of age. It presents with seizures, macrocephaly, developmental delay, failure to thrive, intractable vomiting, and encephalopathy.<ref name="pmid281120503">{{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> | ||
** Type II (juvenile and adult). With an age of onset after 4 years of age. It presents with bulbar dysfunction, palatal myoclonus, autonomic dysfunction, but no significant encephalopathy.<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> | |||
** | |||
<br /> | <br /> | ||
==Pathophysiology== | ==Pathophysiology== | ||
Alexander disease is a heritable cerebral white matter disorder caused by dominant missense mutations in 1 allele of the glial fibrillary acidic protein (GFAP) gene.<ref name="pmid28112050" /><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> | |||
Alexander disease belongs to [[leukodystrophies]], | Alexander disease belongs to a 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" /> | ||
The destruction of [[white matter]] in the [[brain]] 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">{{cite web |url=https://www.ninds.nih.gov/disorders/all-disorders/alexander-disease-information-page |title=Alexander Disease Information Page | National Institute of Neurological Disorders and Stroke |format= |work= |accessdate=}}</ref> | |||
===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. | 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. | ||
==Causes== | ==Causes== | ||
* The cause of Alexander disease is a mutation in the gene GFAP, encoding glial fibrillary acidic protein.<ref name="pmid29478608" /> | |||
==Differentiating {{PAGENAME}} from Other Diseases== | ==Differentiating {{PAGENAME}} from Other Diseases== | ||
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* Frontal lobe predominance | * Frontal lobe predominance | ||
* +/- Dilated lateral ventricles | * +/- Dilated lateral ventricles | ||
=== MRI Findings === | |||
* Type I Alexander disease is distinguished on an MRI due to:<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> | |||
** 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 | |||
===Imaging Findings=== | ===Imaging Findings=== | ||
Revision as of 00:16, 26 July 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 which results from a genetic mutation and mostly affects infants and children, causing developmental delay and changes in physical characteristics.
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 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.[1]
- By the decade of 1960´s, the presence of Rosenthal fibers accompanied by the destruction of white matter and progressive neurologic imapairment was recognized as the hallmark of patients with Alexander disease.[2][1][3]
- 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.[4][1]
Classification
- Alexander disease is classified according to the age of onset and clinical course as:
- Type I (infantile). The most common, with an age of onset before 4 years of age. It presents with seizures, macrocephaly, developmental delay, failure to thrive, intractable vomiting, and encephalopathy.[5]
- Type II (juvenile and adult). With an age of onset after 4 years of age. It presents with bulbar dysfunction, palatal myoclonus, autonomic dysfunction, but no significant encephalopathy.[6]
Pathophysiology
Alexander disease is a heritable cerebral white matter disorder caused by dominant missense mutations in 1 allele of the glial fibrillary acidic protein (GFAP) gene.[7][8]
Alexander disease belongs to a group of disorders called leukodystrophies, which affect growth or development of the myelin sheath.[9]
The destruction of white matter in the brain is accompanied by the formation of fibrous, eosinophilic deposits known as Rosenthal fibers.[9]
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 17q21. It is inherited in an autosomal dominant manner.
Causes
- The cause of Alexander disease is a mutation in the gene GFAP, encoding glial fibrillary acidic protein.[1]
Differentiating Alexander disease from Other Diseases
Epidemiology and Demographics
Alexander disease has a prevalence of 1 in 2.7 million population studied.[1][10]
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.
There is no economic predilection to Alexander disease.
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.
Risk Factors
Screening
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.
Diagnosis
Diagnostic Criteria
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
Laboratory Findings
CT Findings
- Decreased density of white matter
- Frontal lobe predominance
- +/- Dilated lateral ventricles
MRI Findings
- Type I Alexander disease is distinguished on an MRI due to:[7]
- 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
Imaging Findings
Other Diagnostic Studies
Treatment
There is neither cure nor standard treatment for Alexander disease. All treatment is symptomatic and supportive, for example antibiotics for intercurrent infection and anticonvulsants for seizure control are usually used.
Medical Therapy
Surgery
Prevention
See also
External links
- alexander at NIH/UW GeneTests
- The Stennis Foundation - Registered charity committed to raising awareness and funds for Leukodystrophies research
- The Stennis Foundation's MySpace site
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Messing A (2018). "Alexander disease". Handb Clin Neurol. 148: 693–700. doi:10.1016/B978-0-444-64076-5.00044-2. PMID 29478608.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 7.0 7.1 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.
- ↑ 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.
- ↑ 9.0 9.1 "Alexander Disease Information Page | National Institute of Neurological Disorders and Stroke".
- ↑ 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.