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Alexander Disease

, MD, PhD
Medical Officer, NIH-National Center for Research Resources
Bethesda, Maryland

Initial Posting: ; Last Update: April 22, 2010.

Summary

Disease characteristics. Alexander disease is a disorder of cortical white matter that predominantly affects infants and children and usually results in death within ten years after onset. The infantile form comprises about 51% of affected individuals, the juvenile form about 23%, and the adult form about 24%. 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, severe white-matter abnormalities, involvement of the basal ganglia and cerebellum, and elevated CSF protein concentration.
  • The infantile form presents in the first two years of life, typically with progressive psychomotor retardation with loss of developmental milestones, megalencephaly and frontal bossing, seizures, hyperreflexia and pyramidal signs, ataxia, and 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, megalencephaly, and breathing problems. Survival ranges from the early teens to the 20s-30s.
  • The adult form is the most variable.

Diagnosis/testing. Diagnosis of Alexander disease is based on MRI findings. Prior to the availability of molecular genetic testing the diagnosis was confirmed by the detection of astrocytic inclusion bodies (Rosenthal fibers) on brain histology. GFAP, which encodes glial fibrillary acidic protein, is the only gene in which mutation is currently known to cause Alexander disease.

Management. 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: Attention to nutritional status, swallowing ability, early signs of scoliosis.

Surveillance: Examinations 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.

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 mutation in GFAP, the risk to the sibs of inheriting the GFAP mutation is 50%. Sibs of a proband with unaffected parents are at low risk for Alexander disease; however, the possibility of germline mosaicism exists. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation has been identified in an affected family member.

Diagnosis

Clinical Diagnosis

The clinical presentation of Alexander disease is nonspecific.

Neural imaging studies. From a multi-institutional retrospective survey of MRI studies of 217 individuals with leukoencephalopathy, van der Knaap et al [2001] suggest that the presence of four of the five following criteria establish 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.

Recent 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 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.

Testing

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.

Note: The availability of molecular genetic testing practically eliminates the need for immunohistochemical staining of brain biopsy material as a diagnostic tool even in very young infants.

Molecular Genetic Testing

Gene. GFAP is the only gene in which mutation is currently known to cause Alexander disease.

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

Clinical testing

  • Sequence analysis of coding region. Sequence analysis of the coding region and flanking intronic junctions detects about 97% of mutations (see Table 1). Published reports indicate that mutations in six of the nine exons of GFAP can be found in those with the diagnosis of Alexander disease based on histologic or imaging studies (see Table 2). No mutations have been seen in exons 2, 7, and 9.

Table 1. Summary of Molecular Genetic Testing Used in Alexander Disease

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
GFAPSequence analysisSequence variants 497% 5

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Based on published reports in which 189 out of 195 (97%) individuals with a diagnosis of Alexander disease had detectable mutations in GFAP. See Table 2 (pdf) and Table 3.

Interpretation of test results. The diagnosis of Alexander disease is highly likely if a sequence variant found in a proband:

  • Involves a highly conserved site in GFAP across species (orthologs)
  • Involves a highly conserved site in similar domain motifs across other human intermediate filament proteins (paralogs)
  • Shows altered astrocyte function in functional studies in animals or cell culture systems

Testing Strategy

To confirm/establish the diagnosis in a proband. Individuals who meet four of the five criteria or show any of the atypical MRI findings described in Clinical Diagnosis, Neural imaging studies are candidates for GFAP molecular genetic testing.

  • The diagnosis is established when a GFAP sequence variant that has been previously reported as disease-causing is found in the proband.
  • If a sequence variant that has not been previously reported is identified in the proband, molecular genetic testing of both parents establishes the diagnosis if the sequence variant found in the proband is not seen in either parent. However, if the sequence variant is found in either parent and that parent has no clinical or imaging abnormalities consistent with Alexander disease, it is likely a normal variant. If the parents are not available for testing, see Molecular Genetic Testing, Interpretation of test results.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Alexander disease is a disorder of cortical white matter that predominantly affects infants and children and usually results in death within ten years after onset. 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 51% (97/189) of reported individuals with an identifiable GFAP mutation (see Table 2).The juvenile form accounts for 23% (44/189) and the adult form 24% (45/189) (see Table 2).

Three individuals from 189 cases (2%) with an identifiable GFAP mutation were reported to be asymptomatic [Stumpf et al 2003, Shiihara et al 2004]. As the data were unpublished, the 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
  • Megalencephaly and frontal bossing
  • 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 from 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]. Affected individuals can present with one or more of the following signs and symptoms:

  • 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.

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 mutation is unknown.

Some asymptomatic individuals have been identified as having a GFAP mutation 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].

Genotype-Phenotype Correlations

The number of individuals confirmed as having mutations in GFAP is currently too small to make any conclusive genotype-phenotype correlations.

  • Disparate clinical presentations between males and females with identical mutations suggest that gender may modulate disease progression.
  • Disparate clinical presentations among affected members within the same family suggest that modifier genes and other factors may play a role in expression of the clinical phenotype.
  • A total of 72 distinct mutations have been identified to date (see Table 2). Of this number, 51 (71%) are private mutations that have been reported only in single patients or families. The remaining number (21/72 [29%]) are recurring mutations that have been seen in multiple individuals and/or families. The most common recurring mutations involve the arginine residues at amino acid positions 79, 88, 239, and 416.
  • Eight recurrent mutations (p.Met73Thr, p.Leu76Phe, p.Asn77Ser, p.Leu97Pro, p.Arg239His, p.Leu352Pro, p.Glu373Lys, and g.1247delG) have been seen only in the infantile form (see Table 2 for references related to these mutations).
  • Four recurrent mutations (p.Arg70Trp, p.Arg70Gln, p.Glu205Lys, and p.Leu359Pro) have been found exclusively in the adult form (see Table 2 for references related to these mutations).
  • Six recurrent mutations (p.Arg79Cys, p.Arg79His, p.Arg239Cys, p.Arg239Pro, p.Arg239His, p.Ala244Val) have been seen in both the infantile and juvenile forms, while two mutations (p.Glu210Lys and p.Ser393Ile) were seen in both the juvenile and adult forms. Only one mutation (p.Arg416Trp) has been seen in all forms of Alexander disease (see Table 2 for references related to these mutations).

Penetrance

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 [Gorospe et al 2002, Guthrie et al 2003].

Incomplete penetrance, in which asymptomatic or mildly affected parents and sibs of affected individuals have a GFAP mutation, is more frequently observed in familial adult cases [Namekawa et al 2002, Okamoto et al 2002, Messing & Brenner 2003a, Brockmann et al 2003, Stumpf et al 2003, Shiihara et al 2004, Thyagarajan et al 2004, van der Knaap et al 2006].

Prevalence

Although Alexander disease is thought to be rare, actual prevalence figures have not been reported. Since the description of the first affected individual, no more than 550 cases have been reported. GFAP mutations have been confirmed in 189 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 glutaricaciduria type I (see Organic Acidemias) 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 rostro-caudal 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, commencing at the arcuate fibers, Canavan disease. See also Leukodystrophy Overview.

Vacuolating megalencephalic leukoencephalopathy with subcortical cysts (MLC). MLC is an autosomal recessive disorder characterized by accelerated head growth in the first year of life leading to macrocephaly (head circumference 4-8 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. Mutations in MLC1 are causative in the majority of individuals [Leegwater et al 2001, Leegwater et al 2002, Gorospe et al 2004]; about 30% of cases may result from mutations in at least one other gene [Blattner et al 2003, Patrono et al 2003].

In a female with a clinical presentation reported to resemble Alexander disease, the molecular basis for the leukodystrophy was found to be a homozygous mutation in NDUFV1, 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.

Six individuals with MRI findings similar to those observed in Alexander disease had no identifiable GFAP mutations [Brenner et al 2001, Rodriguez et al 2001, Gorospe et al 2002, Li et al 2005, Huttner et al 2007].

Rosenthal fibers. 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, 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.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease 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 vertebral anomalies (i.e., scoliosis)
  • Assessment of family and social structure to determine availability of adequate support system

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:

  • Nutritional intervention (i.e., gastrostomy tube placement) for those with severe feeding difficulties
  • Speech and swallowing assessments to identify problems amenable to intervention
  • Early recognition of spinal problems (i.e., scoliosis) in order to prevent long-term complications

Surveillance

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 ClinicalTrials.gov 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, or incomplete penetrance.

Sibs of a proband

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 mutation.

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 mutation, his or her family members are at risk.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for Alexander disease is possible. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for Alexander disease, an affected family member should be tested first to identify the GFAP mutation.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of Alexander disease, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider include implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals who are identified as having a GFAP mutation need arrangements for long-term follow-up and evaluations.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or undisclosed adoption could also be explored.

Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified in an affected family member.

Resources

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.

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 symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Alexander Disease (View All in OMIM)

137780GLIAL FIBRILLARY ACIDIC PROTEIN; GFAP
203450ALEXANDER DISEASE

Molecular Genetic Pathogenesis

GFAP encodes glial fibrillary acidic protein, the main intermediate filament protein expressed in mature astrocytes of the central nervous system. All mutations 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 mutations 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 mutant 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], Gorospe & Maletkovic [2006] for more detailed discussion.

Gene structure. GFAP comprises nine exons distributed over 9.8 kb, transcribed into a 3-kb mRNA. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. GFAP pathogenic variants have been reported in individuals with Alexander disease (see Table 2). Almost all (68/72, 94%) have been missense mutations resulting in the change of a single amino acid residue. Exceptions include four variants: p.Lys86_Val87delinsGluPhe [van der Knaap et al 2006], p.Arg126_Leu127dup [van der Knaap et al 2006], p.Tyr349_Gln350insHisLeu [Li et al 2005], and p.Asp417MetfsTer15 [Murakami et al 2008].

No mutations have been identified in exons 2, 7, and 9 of GFAP.

While no splicing mutations have been found, alternate transcripts of glial fibrillary acidic protein can be formed from different RNA start sites or by alternate splicing [Condorelli et al 1999, Nielsen et al 2002]. It is conceivable that splicing mutations can cause the disorder if mutant proteins with greatly altered chemical and physical properties are synthesized from abnormal transcripts. Additionally, increased expression of glial fibrillary acidic protein has been seen in a variety of human and animal CNS disorders characterized by gliosis [reviewed in Messing et al 2001]. Thus, mutations 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)
Protein Amino Acid ChangeReference Sequences
c.209G>Ap.Arg70GlnNM_002055​.3
NP_002046​.1
c.208C>Tp.Arg70Trp
c.218T>Cp.Met73Thr
c.226C>Tp.Leu76Phe
c.230A>Gp.Asn77Ser
c.235C>Tp.Arg79Cys
c.236G>Ap.Arg79His
c.256_259delinsGAGTp.Glu86_Glu87delinsGluGlu
c.290T>Cp.Leu97Pro
c.376_381dupGCGGCTp.Arg126_Leu127dup
c.613G>Ap.Glu205Lys
c.628G>Ap.Glu210Lys
c.715C>Tp.Arg239Cys
c.716G>Ap.Arg239His
c.716G>Cp.Arg239Pro
c.731C>Tp.Ala244Val
c.1047_1048insCACTTGp.Tyr349_Gln350insHisLeu
c.1055T>Cp.Leu352Pro
c.1076T>Cp.Leu359Pro
c.1117G>Ap.Glu373Lys
c.1178G>Tp.Ser393Ile
c.1249delG
(1247_1249delGGGinsGG)
p.Asp417MetfsTer15

Note on variant classification: Variants listed in the table have been provided by the author(s). 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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

See Table 2 for references related to these mutations.

1. Variant designation that does not conform to current naming conventions

Normal gene product. 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. Table 2 shows the amino acid changes and their distribution among the forms of Alexander disease. Of the 72 different mutations that have been identified, 68 are missense mutations involving 48 different amino acid residues. Mutations at three amino acid residues (Arg79, Arg88, and Arg239) account for 42% (80/189) of all molecularly confirmed cases.

References

Literature Cited

  1. Blattner R, Von Moers A, Leegwater PA, Hanefeld FA, Van Der Knaap MS, Kohler W. Clinical and genetic heterogeneity in megalencephalic leukoencephalopathy with subcortical cysts (MLC). Neuropediatrics. 2003;34:215–8. [PubMed: 12973664]
  2. Brenner M, Johnson AB, Boespflug-Tanguy O, Rodriguez D, Goldman JE, Messing A. Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. Nat Genet. 2001;27:117–20. [PubMed: 11138011]
  3. Brockmann K, Meins M, Taubert A, Trappe R, Grond M, Hanefeld F. A novel GFAP mutation and disseminated white matter lesions: adult Alexander disease? Eur Neurol. 2003;50:100–5. [PubMed: 12944715]
  4. Condorelli DF, Nicoletti VG, Barresi V, Conticello SG, Caruso A, Tendi EA, Giuffrida Stella AM. Structural features of the rat GFAP gene and identification of a novel alternative transcript. J Neurosci Res. 1999;56:219–28. [PubMed: 10336251]
  5. Delnooz CC, Schelhaas JH, van de Warrenburg BP, de Graaf RJ, Salomons GS. Alexander disease causing hereditary late-onset ataxia with only minimal white matter changes: A report of two sibs. Mov Disord. 2008;23:1613–5. [PubMed: 18581469]
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Suggested Reading

  1. Barkovich AJ, Messing A. Alexander disease: not just a leukodystrophy anymore. Neurology. 2006;66:468–9. [PubMed: 16505295]
  2. 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]
  3. Sawaishi Y. Review of Alexander disease: beyond the classical concept of leukodystrophy. Brain Dev. 2009;31:493–8. [PubMed: 19386454]

Chapter Notes

Revision History

  • 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 to live Web site
  • 28 September 2004 (me) Comprehensive update posted to live Web site
  • 5 May 2003 (cd,jrg) Revision: molecular genetic testing clinically available
  • 15 November 2002 (me) Review posted to live Web site
  • 24 April 2002 (jrg) Original submission
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