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Alexander Disease

, MD and , MD.

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Initial Posting: ; Last Update: January 8, 2015.

Estimated reading time: 24 minutes


Clinical characteristics.

Alexander disease is a progressive disorder of cerebral white matter that predominantly affects infants and children and has variable life expectancy. The later-onset forms present with a slower clinical course. The infantile form comprises about 42% of affected individuals, the juvenile form about 22%, and the adult form about 33%. A neonatal form is also recognized.

  • The neonatal form leads to severe disability or death within two years. Characteristics include seizures, hydrocephalus, severe motor and intellectual disability, and elevated CSF protein concentration. MRI shows severe white matter abnormalities with involvement of the basal ganglia and cerebellum.
  • The infantile form presents in the first two years of life, typically with progressive psychomotor retardation with loss of developmental milestones, megalencephaly, frontal bossing, and seizures. Other findings include hyperreflexia and pyramidal signs, ataxia, and occasional hydrocephalus secondary to aqueductal stenosis. Affected children survive weeks to several years.
  • The juvenile form usually presents between ages four and ten years, occasionally in the mid-teens. Findings can include bulbar/pseudobulbar signs, ataxia, gradual loss of intellectual function, seizures, normocephaly or megalencephaly, and breathing problems. Survival ranges from the early teens to the 20s-30s.
  • The adult form is the most variable.


Diagnosis of Alexander disease is based on clinical findings, and confirmed with MRI changes and identification of a heterozygous pathogenic variant in GFAP, which encodes glial fibrillary acidic protein.


Treatment of manifestations: Treatment is supportive and includes attention to general care and nutritional requirements, antibiotic treatment for intercurrent infection, antiepileptic drugs (AEDs) for seizure control, assessment for learning disabilities and cognitive impairment, and physical and occupational therapy as needed.

Prevention of secondary complications: It is essential to pay attention to nutritional status, swallowing ability, and early signs of scoliosis.

Surveillance: Examinations at regular intervals by a multidisciplinary team with particular attention to growth, gastrointestinal function/nutritional intake, orthopedic and neurologic status, strength and mobility, communication skills, and psychological complications.

Genetic counseling.

Alexander disease is inherited in an autosomal dominant manner. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If a parent is affected or has a pathogenic variant in GFAP, the risk to the sibs of inheriting the GFAP pathogenic variant is 50%. Sibs of a proband are at low risk for Alexander disease if the pathogenic variant is de novo (as is usually the case); however, the possibility of germline mosaicism exists. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.


The clinical presentation of Alexander disease is nonspecific and depends on age of presentation.

Suggestive Findings

Diagnosis of Alexander disease should be suspected in individuals with the following clinical and neuroimaging findings:

Clinical findings by age of presentation

  • Children under age two years may present with progressive psychomotor retardation, developmental regression, megalencephaly with frontal bossing, seizures, pyramidal signs, ataxia, and occasional hydrocephalus secondary to aqueductal stenosis.
  • Children age two to ten years, up to the mid-teens, may present with bulbar/pseudobulbar signs with nasal speech, lower limb spasticity, ataxia, gradual loss of intellectual function, seizures, megalencephaly, and breathing problems.
  • Adults may present with bulbar/pseudobulbar signs, pyramidal tract signs, cerebellar signs, dysautonomia, sleep disturbance, gait disturbance, hemiparesis/hemiplegia or quadriparesis/quadriplegia, seizures, and diplopia.

Neuroimaging findings. From a multi-institutional retrospective survey of MRI studies of 217 individuals with leukoencephalopathy [van der Knaap et al 2001], it has been suggested that the presence of four of the five following criteria establishes an MRI-based diagnosis of Alexander disease:

  • Extensive cerebral white-matter abnormalities with a frontal preponderance
  • A periventricular rim of decreased signal intensity on T2-weighted images and elevated signal intensity on T1-weighted images
  • Abnormalities of the basal ganglia and thalami that may include any of the following:
    • Elevated signal intensity and swelling
    • Atrophy
    • Elevated or decreased signal intensity on T2-weighted images
  • Brain stem abnormalities, particularly involving the medulla and midbrain
  • Contrast enhancement of one or more of the following: ventricular lining, periventricular rim, frontal white matter, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, brain stem

Rodriguez et al [2001] determined that individuals who exhibited these typical findings on MRI were more likely than not to have the diagnosis of Alexander disease confirmed by molecular genetic testing.

Studies of individuals with molecularly confirmed Alexander disease have expanded the MRI findings to include the following atypical MRI findings [van der Knaap et al 2005, van der Knaap et al 2006]:

  • Predominant or isolated involvement of posterior fossa structures
  • Multifocal tumor-like brain stem lesions and brain stem atrophy
  • Slight, diffuse signal changes involving the basal ganglia and/or thalamus
  • Garland-like feature along the ventricular wall
  • Characteristic pattern of contrast enhancement
  • Any other findings that suggest, but do not meet, the strict criteria

Note: (1) It has been suggested that signal abnormalities or atrophy of the medulla or spinal cord are sufficient findings to warrant molecular genetic testing of GFAP [Salvi et al 2005, van der Knaap et al 2006]. (2) Atypical MRI findings were more commonly observed in juvenile- and adult-onset Alexander disease, indicating that these forms have more variable disease manifestations.

Establishing the Diagnosis

The diagnosis of Alexander disease is established in a proband by detection of a heterozygous pathogenic variant of GFAP (see Table 1).

Approaches to molecular genetic testing can include the following:

  • Sequence analysis of GFAP. If no pathogenic variant is found, deletion/duplication analysis could be considered.
  • Use of a multigene panel that includes GFAP and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if single-gene testing (and/or use of a multigene panel that includes GFAP) fails to confirm a diagnosis in an individual with features of Alexander disease. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Summary of Molecular Genetic Testing Used in Alexander Disease

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
GFAPSequence analysis 298% 3
Deletion/duplication analysis 4None reported
Unknown 5NA

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Based on published reports in which 293 out of 299 (98%) individuals with a diagnosis of Alexander disease had detectable pathogenic variants in GFAP. See Table 2 (pdf) and Table 3.


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


It is not clear whether individuals with Alexander disease phenotypes in whom molecular genetic testing does not detect pathogenic variants in the GFAP coding region have a genetically unrelated disorder, or current testing methods are unable to detect a subset of GFAP pathogenic variants.

Clinical Characteristics

Clinical Description

Alexander disease is a progressive disorder of cerebral white matter that predominantly affects infants and children. Life expectancy is variable. Most individuals with Alexander disease present with nonspecific neurologic signs and symptoms.

Three forms are typically recognized: infantile, juvenile, and adult. It has been suggested that the subset of infants with neonatal onset (i.e., within 30 days of birth) constitutes a separate neonatal form [Springer et al 2000].

The infantile form of Alexander disease accounts for 42% (124/293) of reported individuals with an identifiable GFAP pathogenic variant (see Table 2). The juvenile form accounts for 22% (63/293) and the adult form 33% (96/293) (see Table 2).

Ten (3%) of the 293 individuals with an identifiable GFAP pathogenic variant were reported to be asymptomatic [Stumpf et al 2003, Shiihara et al 2004, Yoshida et al 2011, Messing et al 2012, Wada et al 2013]. The current clinical status of these individuals is unknown.

Neonatal form. Springer et al [2000] suggested that the neonatal form is characterized by the following:

  • Onset within the first month of life
  • Rapid progression leading to severe disability or death with the first two years of life. Regression may be difficult to identify at such an early age and may be manifest as loss of sucking.
  • Seizures as an early and obligatory symptom. Seizures are generalized, frequent, and often intractable.
  • Hydrocephalus with raised intracranial pressure, primarily caused by aqueductal stenosis
  • Severe motor and intellectual disability, without prominent spasticity or ataxia
  • Severe white-matter abnormalities with frontal predominance and extensive pathologic periventricular enhancement demonstrated on neuroradiologic contrast imaging
  • Involvement of the basal ganglia and cerebellum
  • Elevated CSF protein concentration

Infantile form. Onset of the infantile form occurs during the first two years of life. Affected children survive a few weeks to several years, but usually not beyond the early teens. Variable presentations, in decreasing order of frequency, include the following:

  • Progressive psychomotor retardation with loss of developmental milestones
  • Frontal bossing and megalencephaly including enlargement of cerebellum and brain stem
  • Seizures
  • Hyperreflexia and pyramidal signs
  • Ataxia
  • Hydrocephalus secondary to aqueductal stenosis

Juvenile form. The juvenile form of Alexander disease usually presents between age four and ten years, occasionally in the mid-teens. Sometimes the initial presentation suggests a focal brain stem lesion, such as tumor. Survival is variable, ranging from the early teens to the 20s-30s. Affected children can present with one or more of the following signs and symptoms, ordered by decreasing frequency:

  • Bulbar/pseudobulbar signs including speech abnormalities, swallowing difficulties, frequent vomiting
  • Lower limb spasticity
  • Poor coordination (ataxia)
  • Gradual loss of intellectual function
  • Seizures
  • Megalencephaly
  • Breathing problems

Adult form. The adult form of Alexander disease is the most variable. It can be similar to the juvenile form with later onset and slower progression [Martidis et al 1999, Namekawa et al 2002, Okamoto et al 2002, Brockmann et al 2003, Kinoshita et al 2003, Stumpf et al 2003]. Survival ranges from a few years to a number of decades following the onset of symptoms. Some individuals have been diagnosed incidentally during autopsy for other conditions. Reports of molecularly confirmed familial cases support the existence of asymptomatic adults with Alexander disease [Stumpf et al 2003, Shiihara et al 2004, Messing et al 2012, Wada et al 2013]. Based on a retrospective study of 13 individuals with late-onset Alexander disease, brain stem and/or spinal cord involvement may be common, resulting in symptoms such as nystagmus, dysphagia, dysarthria, spasticity/hyperreflexia, positive Babinski sign, gait abnormality, and weakness, though individual-to-individual and intrafamilial variability is seen [Graff-Radford et al 2014]. The full set of signs and symptoms variably seen in affected individuals comprises the following:

  • Bulbar/pseudobulbar signs: palatal myoclonus, dysphagia, dysphonia, dysarthria, slurred speech
  • Pyramidal tract signs: spasticity, hyperreflexia, positive Babinski sign
  • Cerebellar signs: ataxia, nystagmus, dysmetria
  • Dysautonomia: incontinence, constipation, pollakiuria (urinary frequency), urinary retention, impotence, sweating abnormality, hypothermia, orthostatic hypotension
  • Sleep disturbance: sleep apnea
  • Gait disturbance
  • Hemiparesis/hemiplegia or quadriparesis/quadriplegia
  • Seizures
  • Diplopia
  • Fluctuating course

EEG. Electroencephalographic studies are nonspecific, usually showing slow waves over the frontal areas of the brain. Focal epileptiform discharges may also be seen [Gordon 2003].

CSF studies. Increased levels of αβ-crystallin and heat shock protein 27 have been observed in cerebrospinal fluid (CSF) of individuals with Alexander disease. Increased levels of glial fibrillary acidic protein were documented in the CSF of individuals with a molecularly confirmed diagnosis [Kyllerman et al 2005].

Other. The causal relationship of the following other findings observed in individuals with a GFAP pathogenic variant is unknown.

Some asymptomatic individuals have been identified as having a GFAP pathogenic variant with suggestive MRI findings discovered incidentally during evaluation for other unrelated conditions (e.g., accidental eye injury, short stature) [Gorospe et al 2002, Guthrie et al 2003]. Due to lack of follow-up studies, it is not clear whether these individuals remain asymptomatic, or whether symptoms will emerge gradually with time.

Histologic studies. Prior to the definition of the molecular genetic basis of Alexander disease, the demonstration of enormous numbers of Rosenthal fibers on brain biopsy or at autopsy was the only method for definitive diagnosis of the disease. Rosenthal fibers are intracellular inclusion bodies composed of aggregates of glial fibrillary acidic protein, vimentin, αβ-crystallin, and heat shock protein 27 found exclusively in astrocytes. Rosenthal fibers increase in size and number during the course of the disease.

Genotype-Phenotype Correlations

The number of individuals with confirmed pathogenic variants in GFAP is too small to make any conclusive genotype-phenotype correlations. Currently, the following observations hold true, but given the variable expressivity of the disorder, exceptions may occur:


Penetrance appears to be nearly 100% in individuals with the infantile and juvenile forms [Li et al 2002, Messing & Brenner 2003a].

Asymptomatic, neurologically intact individuals with the juvenile form of Alexander disease are occasionally diagnosed after evaluation for other conditions, as illustrated in the following three cases. Note, however, that long-term follow up has not been reported.

  • In a prospective study in which 12 of 13 patients suspected of having Alexander disease were found to have a GFAP pathogenic variant, two were minimally affected [Gorospe et al 2002]. One underwent brain MRI after eye injury. Before the accident, he performed well in school except in mathematics, and he had no neurologic symptoms except for clumsiness and incoordination reported by the parents. The second individual had high normal head circumference and short stature, for which an endocrinologist had ordered a brain MRI to assess the pituitary gland.
  • Similar to the latter case of Gorospe et al [2002], Guthrie et al [2003] reported a third case: a child with normal development except for macrocephaly and growth retardation whose brain MRI findings and GFAP testing were consistent with Alexander disease.

In some instances, variable expressivity may masquerade as incomplete penetrance.


Alexander disease is thought to be rare; actual prevalence figures have not been reported. Since the description of the first affected individual, more than 550 cases have been reported. GFAP pathogenic variants have been confirmed in 293 reported individuals (see Table 2).

The disorder is known to occur in diverse ethnic and racial groups [Gorospe & Maletkovic 2006].

Differential Diagnosis

The clinical presentation of Alexander disease often overlaps that of other neurologic disorders. It is usually considered in the differential diagnosis of infants who present with megalencephaly, developmental delay, spasticity, and seizures, or in older individuals who have a preponderance of brain stem signs and spasticity with or without megalencephaly or seizures.

Because of their nonspecificity, signs and symptoms of Alexander disease can be confused with those found in organic acidurias, lysosomal storage disorders, and peroxisomal biogenesis disorders, Zellweger syndrome spectrum. In glutaric aciduria type I and in 50% of individuals with L-2 hydroxyglutaric aciduria, early accelerated head growth can precede neurologic deterioration. Even in the absence of seizures, Canavan disease should be seriously considered. In individuals with Alexander disease, laboratory testing for these other disorders is normal.

Leukodystrophy. MRI studies can help distinguish the leukodystrophies. The finding of marked frontal predominance of white matter changes with a rostrocaudal progression of myelin loss on serial imaging studies in individuals with Alexander disease contrasts with the MRI findings in individuals with other leukodystrophies and megalencephalies. Affected individuals may have hyperintensity of the basal ganglia with brain stem and cerebellar involvement. The white matter involvement in individuals with X-linked adrenoleukodystrophy is most severe in the parietal and occipital lobes and progresses anteriorly. Centripetal spread of white matter involvement is observed in individuals with arylsulfatase A deficiency (metachromatic leukodystrophy), Krabbe disease, and Canavan disease, commencing at the arcuate fibers. See also Leukodystrophy Overview.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC). MLC is characterized by accelerated head growth in the first year of life leading to macrocephaly (head circumference 4-6 SD above the mean) and mild delay in gross motor milestones followed by slowly progressive ataxia and spastic paraparesis. Seizures are common but mild. Cognition is in the low-normal to normal range. Dystonia, dysarthria, and athetosis can appear in the second and third decades. Brain MRI shows diffuse cerebral white matter swelling with appearance of subcortical cysts, particularly in the frontotemporal regions. In older individuals, ventriculomegaly and diffuse cortical atrophy are observed. When associated with biallelic pathogenic variants in MLC1, the classic MLC phenotype is known as MLC1; when caused by biallelic pathogenic variants in HEPACAM it is known as MLC2A. MLC1 and MLC2A are inherited in an autosomal recessive manner. The improving phenotype associated with heterozygous mutation of HEPACAM is known as MLC2B and is inherited in an autosomal dominant manner. De novo pathogenic variants are common. Pathogenic variants in MLC1 are observed in approximately 75% of persons with MLC with typical MRI changes; pathogenic variants in HEPACAM are found in approximately 20%.


  • In a female with a clinical presentation reported to resemble Alexander disease, the molecular basis for the leukodystrophy was found to be a homozygous pathogenic variant in NDUFV1 (OMIM 161015), a nuclear gene encoding a mitochondrial enzyme in complex I [Schuelke et al 1999]. However, no brain specimen was obtained from this individual to evaluate for the presence of Rosenthal fibers. It is likely that this individual has an unrelated autosomal recessive neurodegenerative disorder.
  • Rosenthal fibers are not unique to Alexander disease. They have been observed at autopsy in individuals without neurologic manifestations of Alexander disease or evidence of demyelination [Messing et al 2001, Jacob et al 2003] and with systemic illnesses such as cancer (lymphoma, ovarian cancer), cardiac and respiratory insufficiency, and diabetes mellitus. They can also be observed in old glial scars, in pilocytic astrocytomas, or in the walls of syrinx cavities. However, the preponderance of Rosenthal fibers in the brains of individuals with Alexander disease is striking compared to findings in these other conditions.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Alexander disease, the following evaluations are recommended:

  • Complete neurologic assessment
  • Formal, age-appropriate developmental assessment
  • Assessment of feeding/eating, digestive problems (including constipation and gastroesophageal reflux), and nutrition using history, growth measurements, and, if needed, gastrointestinal investigations
  • Video/EEG monitoring to obtain definitive information about the occurrence of seizures and the need for antiepileptic drugs
  • Psychological assessment for older patients to determine their awareness and understanding of the disease and its consequences
  • Examination for possible scoliosis
  • Assessment of family and social structure to determine availability of adequate support system
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No specific therapy is currently available for Alexander disease.

Management is supportive and includes attention to general care, nutritional requirements, antibiotic treatment for intercurrent infection, and antiepileptic drugs (AED) for seizure control.

Learning disabilities and other cognitive impairments are addressed as in individuals who do not have Alexander disease.

Physical and occupational therapy are indicated when assessment reveals the need for adaptive measures to maximize strength and motor capabilities.

Prevention of Secondary Complications

The following are appropriate:

  • Swallow studies and nutritional intervention (i.e., gastrostomy tube placement) for those with severe feeding difficulties
  • Speech assessments to identify problems amenable to interventions such as assistive communication devices
  • Early recognition of abnormal tone and spinal problems (i.e., scoliosis) in order to prevent long-term complications


Depending on age, affected individuals should be examined at regular intervals by a multidisciplinary team with particular attention to growth, nutritional intake, orthopedic and neurologic status, gastrointestinal function, strength and mobility, communication skills, and psychological complications.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Alexander disease is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Note: Although individuals diagnosed with the adult form of Alexander disease may have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, germline mosaicism in the parent, or incomplete penetrance.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

Offspring of a proband

  • Individuals with the infantile or juvenile form of Alexander disease typically do not reproduce.
  • Each child of an individual with the slowly progressing adult form of Alexander disease has a 50% chance of inheriting the pathogenic variant.

Other family members

  • The risk to other family members depends on the genetic status of the proband's parents.
  • If a parent is affected or has a GFAP pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adult relatives of individuals with Alexander disease is possible after molecular genetic testing has identified the specific pathogenic variants in the family. Such testing should be performed in the context of formal genetic counseling. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. Testing of asymptomatic at-risk individuals with nonspecific or equivocal symptoms is predictive testing, not diagnostic testing.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant (i.e., the pathogenic variant is not detected in leukocyte DNA) or clinical evidence of the disorder, the pathogenic variant likely occurred de novo. However, possible non-medical considerations include alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the GFAP pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for Alexander disease are possible.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Institute of Neurological Disorders and Stroke (NINDS)
  • National Library of Medicine Genetics Home Reference
  • Waisman Center for Alexander Disease
    University of Wisconsin-Madison
    1500 Highland Avenue
    Room 277
    Madison WI 53705
    Phone: 608-263-5776
    Fax: 608-263-0529
  • Hunter's Hope Foundation
    6368 West Quaker Street
    PO Box 643
    Orchard Park NY 14127
    Phone: 877-984-4673 (toll-free); 716-667-1200
    Fax: 716-667-1212
  • United Leukodystrophy Foundation (ULF)
    224 North Second Street
    Suite 2
    DeKalb IL 60115
    Phone: 800-728-5483 (toll-free); 815-748-3211
    Fax: 815-748-0844
  • Myelin Disorders Bioregistry Project

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Alexander Disease: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Alexander Disease (View All in OMIM)


Gene structure. The longest GFAP transcript (NM_002055.4) comprises nine exons distributed over 9.8 kb, transcribed into a 3-kb mRNA. Typically, this is the sequence that is analyzed by standard screening. However, a heterozygous variant (p.Arg430His) was recently identified in alternative exon 7A of transcript NM_001131019.2 [Melchionda et al 2013] (see Table 3).

For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. A total of 110 distinct pathogenic variants have been identified to date (a pathogenic variant in which the nucleotide change is unreported is considered distinct only if there are no other reported variants that have the same amino acid change).

Of the 110 different pathogenic variants that have been identified, 90 are single missense pathogenic variants involving 61 different amino acid residues. Pathogenic variants at three amino acid residues (Arg79, Arg88, and Arg239) account for 34% (101/293) of all molecularly confirmed cases. See Table 2 (pdf) and Table 3 for references related to these pathogenic variants.

The remaining 20 of the 110 pathogenic variants are as follows:

A c.1289G>A (see Table 3 and footnote 3) variant in exon 7A of the transcript encoding the alternative GFAP-ε isoform has been described in affected half-sibs sharing the same healthy mother (who is suspected of having germinal mosaicism) [Melchionda et al 2013].

Additionally, increased expression of GFAP protein has been seen in a variety of human and animal CNS disorders characterized by gliosis [reviewed in Messing et al 2001]. Thus, pathogenic variants in the promoter or enhancer regions of GFAP that result in overexpression of the protein may also result in Alexander disease. While mRNA or expression studies can help exclude these possibilities, the difficulty in obtaining appropriate tissue for study (brain biopsy from already neurologically compromised individuals) frequently precludes their performance.

Table 3.

Selected GFAP Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein Change
(Alias 1)
Reference Sequences
c.[988C>G;994G>A]p.[Arg330Gly;Glu332Lys] 2
c.1289G>A 3p.Arg430HisNM_001131019​.2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

See Table 2 (pdf) for references related to these pathogenic variants.


Variant designation that does not conform to current naming conventions


Two variants on the same allele (in cis)


Variant in alternative exon7A; reference sequences for alternative transcript and protein isoform are given.

Normal gene product. GFAP encodes glial fibrillary acidic protein, the main intermediate filament protein expressed in mature astrocytes of the central nervous system. Translation of the mRNA results in a protein with 432 amino acid residues. The protein is an intermediate filament protein. As a cytoskeletal protein providing structural stability, glial fibrillary acidic protein appears to be important in modulating the morphology and motility of astrocytes [Eng et al 2000, Messing & Brenner 2003b]; however, it may have other, as-yet unknown, functions.

Abnormal gene product. All pathogenic variants identified to date appear to exert a dominant toxic gain of function, but the exact mechanism by which the Alexander disease phenotype is expressed remains unresolved. It is believed that GFAP pathogenic variants do not affect protein synthesis but result in a defective protein that alters either the oligomerization or the solubility of the protein synthesized from the normal allele [Hsiao et al 2005, Der Perng et al 2006]. Further, the mutated GFAP oligomers appear to inhibit proteasomal activity in astrocytes [Tang et al 2010]. The ensuing pathophysiology presumably disturbs the normal interaction between astrocytes and oligodendrocytes, resulting in hypomyelination or demyelination. See Messing et al [2001], and Gorospe & Maletkovic [2006] for more detailed discussion.


Literature Cited

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Suggested Reading

  • Barkovich AJ, Messing A. Alexander disease: not just a leukodystrophy anymore. Neurology. 2006;66:468–9. [PubMed: 16505295]
  • Quinlan RA, Brenner M, Goldman JE, Messing A. GFAP and its role in Alexander disease. Exp Cell Res. 2007;313:2077–87. [PMC free article: PMC2702672] [PubMed: 17498694]
  • Sawaishi Y. Review of Alexander disease: beyond the classical concept of leukodystrophy. Brain Dev. 2009;31:493–8. [PubMed: 19386454]

Chapter Notes

Author History

J Rafael Gorospe, MD, PhD; NIH – National Center for Research Resource (2002-2015)
Sakkubai Naidu, MD (2015-present)
Siddharth Srivastava, MD (2015-present)

Revision History

  • 8 January 2015 (me) Comprehensive update posted live
  • 22 April 2010 (me) Comprehensive update posted live
  • 9 March 2007 (cd,jrg) Revision: sequence analysis of select exons and targeted mutation analysis no longer clinically available
  • 2 October 2006 (me) Comprehensive update posted live
  • 28 September 2004 (me) Comprehensive update posted live
  • 5 May 2003 (cd,jrg) Revision: molecular genetic testing clinically available
  • 15 November 2002 (me) Review posted live
  • 24 April 2002 (jrg) Original submission
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