 |
|
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
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. Most individuals present with nonspecific neurologic signs and symptoms. The two most common forms are infantile (about 63% of affected individuals) and juvenile (about 24%); however, neonatal and adult forms are also recognized. The infantile form initially presents in the first two years of life. Individuals typically have 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 a few weeks to several years. The juvenile form usually presents between four and ten years of age, occasionally in the mid-teens. Survival is variable, ranging from the early teens to the 20s-30s. Affected individuals can present with bulbar/pseudobulbar signs, ataxia, gradual loss of intellectual function, seizures, megalencephaly, and breathing problems. The neonatal form is characterized by onset within the first month of life with rapid progression leading to severe disability or death within the first two years of life. Characteristics include seizures, hydrocephalus, severe motor and mental retardation, severe white matter abnormalities, involvement of the basal ganglia and cerebellum, and elevated CSF protein concentration. The adult form is the most variable and least common.
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 currently known to be associated with Alexander disease. Molecular genetic testing is available on a clinical basis.
Management. No specific therapy is currently available for Alexander disease. Treatment is supportive and includes attention to general care and nutritional requirements; antibiotic treatment for intercurrent infection; antiepileptic drugs (AEDs) for seizure control; and assessment for learning disabilities and cognitive impairment. Surveillance includes 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 upon the genetic status of the proband's parents. If a parent is affected or has a mutation in the GFAP gene, the risk to the sibs of inheriting the GFAP mutation is 50%. Sibs of a proband with unaffected parents are at low risk for developing Alexander disease; however, the possibility of germline mosaicism exists. Prenatal molecular genetic testing may be available for families in which the disease-causing mutation has been identified in an affected family member.
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 [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.
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.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. GFAP is the only gene currently known to be associated with 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 uses
Confirmatory diagnostic testing
Clinical testing
Sequence analysis of coding region. In research studies, 49 out of 52 (94%) individuals with a diagnosis of Alexander disease had detectable mutations in GFAP [Aoki et al 2001, Brenner et al 2001, Rodriguez et al 2001, Shiroma et al 2001, Gorospe et al 2002, Li et al 2002, Meins et al 2002, Okamoto et al 2002, Sawaishi et al 2002].
Research testing
Sequence analysis of select exons. In research studies, 90% (47/52) of individuals with a diagnosis of Alexander disease (histologically proven or based on characteristic imaging studies) had mutations in exons 1, 4, and 8 [Aoki et al 2001, Brenner et al 2001, Rodriguez et al 2001, Shiroma et al 2001, Gorospe et al 2002, Li et al 2002, Meins et al 2002, Okamoto et al 2002, Sawaishi et al 2002].
Table 1 summarizes molecular genetic testing for this disorder.
| Test Methods | Mutations Detected | Mutation Detection Frequency | Test Availability |
|---|---|---|---|
| Sequence analysis of coding region | Mutations in GFAP coding region | 94% | Clinical
 |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
No other phenotypes have been associated with mutations in GFAP.
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. The infantile form of Alexander disease is the most common, accounting for 63% (86/137) of reported individuals with an identifiable GFAP mutation [Aoki et al 2001; Brenner et al 2001; Rodriguez et al 2001; Shiroma et al 2001; Gorospe et al 2002; Meins et al 2002; Shiihara et al 2002; Bassuk et al 2003; Brockmann, Dechent et al 2003; Shiroma et al 2003; Suzuki et al 2004, Shiihara et al 2004; Kawai et al 2006; Li et al 2005, van der Knaap et al 2005; Dinopoulos et al, in press].
It has been suggested that a subset of individuals with infantile-onset Alexander disease who present in the neonatal period constitute a separate, neonatal form of the disease [Springer et al 2000].
The juvenile form accounts for 24% (33/137) of reported individuals with an identificable GFAP mutation [Brenner et al 2001, Gorospe et al 2002, Sawaishi et al 2002, Guthrie et al 2003, Stumpf et al 2003, Kyllerman et al 2005, Li et al 2005, van der Knaap 2005, van der Knaap 2006].
The adult form accounts for 10% (18/137) of reported individuals with an identifiable GFAP mutation [Okamoto et al 2002; Namekawa et al 2002; Brockmann, Meins et al 2003; Kinoshita et al 2003; Stumpf et al 2003; Li et al 2005; van der Knaap et al 2005; Salvi et al 2005; Kyllerman et al 2005].
Neonatal form. Springer et al (2000) suggested the presence of a neonatal form 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 mental retardation, 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 and least common. It can be similar to the juvenile form with later onset and slower progression [Martidis et al 1999; Okamoto et al 2002; Namekawa et al 2002; Brockmann, Meins et al 2003; Kinoshita et al 2003; Stumpf et al 2003]. Survival is variable, ranging 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 [Johnson 1996]. A report of molecularly confirmed familial cases supports the existence of asymptomatic adults with Alexander disease [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
Hemi- or quadriparesis/plegia
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 [Takanashi et al 1998]. Increased levels of glial fibrillary acidic protein, astrocyte (GFAP) 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.
Post-term delivery, hypotonia, frequent syncopal episodes, unusual nevi, hypothyroidism [Gorospe et al 2002]
Hypertension and diabetes mellitus [Brockmann, Meins et al 2003]
Arched palate and short neck [Stumpf et al 2003]
Linear growth failure [Gorospe et al 2002, van der Knaap et al 2006]
Precocious puberty [van der Knaap et al 2006]
Vertebral anomalies:
Scoliosis [Nonomura et al 2002, Okamoto et al 2002]
Kyphosis [Stumpf et al 2003, van der Knaap et al 2006]
Lordosis [van der Knaap et al 2006]
Some asymptomatic individuals have been identified as having a GFAP mutation with suggestive MRI findings discovered incidentally while being evaluated for other unrelated conditions (e.g., accidental eye injury, short stature) [Gorospe et al 2002, Guthrie et al 2003].
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.
The most common mutations (R239, n=34; R79, n=25) have been seen almost exclusively in the infantile form (Table 2) (pdf).
Ten mutations (M73R, K86_V87delinsQF, Q93P, R126_L127dup, E207K, E207Q, L235P, K279E, L359V, E362D) have been seen only in the juvenile form.
Five mutations (K63Q, R70W, V87G, E223Q, and R276L) have been found exclusively in the adult form.
Six mutations (R79C, R78H, R88C, R239C, R238H, A244V) have been seen in both the infantile and juvenile forms, while one mutation (D78E) was seen in a family in which both the juvenile and adult forms were seen. Only one mutation (R416W) has been seen in all forms of Alexander disease.
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 parents and sibs of affected individuals have a GFAP mutation, is more frequently observed in familial adult cases [Okamoto et al 2002, Namekawa et al 2002, Messing & Brenner 2003a, Stumpf et al 2003, Thyagarajan et al 2004, van der Knaap 2006].
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 450 have been reported. GFAP mutations have been confirmed in 137 reported individuals. The disorder is known to occur in diverse ethnic and racial groups [reviewed in Gorospe & Maletkovic 2006].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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 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.
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 the MLC1 gene 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.
Another individual with MRI findings similar to Alexander disease had no identifiable mutations either in GFAP or in the coding regions of NDUFV1 [Gorospe et al 2002].
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.
Complete neurologic assessment
Formal, age-appropriate developmental assessment
Assessment of feeding/eating, digestive problems (including constipation and gastro-esophageal 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
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.
Nutritional intervention (i.e., gastrostomy tube placement) for those with severe feeding difficulties
Speech and swallowing assessments to identify problems amenable to intervention
Physical and occupational therapy when assessment reveals the need for adaptive measures to maximize strength and motor capabilities
Early recognition of 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.
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.
Genetics clinics are a source of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Alexander disease is inherited in an autosomal dominant manner.
Parents of a proband
The infantile and juvenile forms of Alexander disease are caused by a de novo mutation in GFAP. Typically, the parents of individuals with molecularly confirmed infantile and juvenile form do not have clinical features of Alexander disease or an identified GFAP mutation [Brenner et al 2001, Rodriguez et al 2001, Gorospe et al 2002].
Individuals with the slowly progressive adult form have been reported to have an affected parent [Okamoto et al 2002, Namekawa et al 2002, Stumpf et al 2003, Thyagarajan et al 2004, van der Knaap et al 2006].
A recent study on unrelated individuals with Alexander disease revealed that the GFAP mutation was on the paternal chromosome in a majority of individuals (24 of 28), suggesting that most mutations occur during spermatogenesis rather than in the embryo [Li et al 2006].
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
The risk to the sibs of the proband depends upon the genetic status of the proband's parents.
If a parent is affected or has a mutation in the GFAP gene, the risk to the sibs of inheriting the GFAP mutation is 50%.
Sibs of a proband with the infantile or juvenile forms are at low risk for developing Alexander disease when neither parent has a disease-causing mutation.
If a disease-causing mutation cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband.
Reports of neuropathologically and molecularly proven Alexander disease that runs in families in which the parents are neurologically intact suggest the possibility of germline mosaicism [Messing et al 2001, Namekawa et al 2002, Messing & Brenner 2003a].
The expected risk to sibs of being affected (<1/200, or 0.5%) is accounted for by the possibility of germline mosaicism.
Offspring of a proband
Individuals with the infantile or juvenile form of Alexander disease 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 upon the genetic status of the proband's parents. If a parent is found to be affected or have a GFAP mutation, his or her family members are at risk.
Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for Alexander disease is clinically available. 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. 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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.
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 available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|
| GFAP | 17q21 | Glial fibrillary acidic protein, astrocyte |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| Gene Symbol | Entrez Gene | HGMD |
|---|---|---|
| GFAP | 2670 (MIM No. 137780) | GFAP |
For a description of the genomic databases listed, click here.
The GFAP gene 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]. In one recent study, the aggregation of GFAP filament proteins appears to result from lowered expression of plectin [Tian et al 2006]. Whatever the triggering mechanism, the altered protein resulting from GFAP mutations 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.
Normal allelic variants: The GFAP gene comprises nine exons distributed over 9.8 kb, transcribed into a 3-kb mRNA.
Pathologic allelic variants: To date, 49 different mutations in GFAP have been reported in 137 individuals with Alexander disease. See Table 2 (pdf). Almost all of the mutations (94%) have been missense mutations resulting in the change of a single amino acid residue. Exceptions include three mutations: 349HLins [Li et al 2005], K86_V87delinsQF, and R126_L127dup [van der Knaap et al 2006]. Forty-six of the mutations (94%) are located in three exons (exons 1, 4, and 6); no mutations have been identified in exons 2, 3, 7, and 9 of the GFAP gene.
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.
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: All mutations identified to date are the result of de novo heterozygous single amino acid changes that alter the charge of the protein. Table 2 (pdf) shows the amino acid changes and their distribution among the forms of Alexander disease (see also Li et al 2002). Of the 49 different mutations that have been identified, 14 involve an arginine residue, and mutations at two of these sites (at amino acids 79 and 239) account for 43% (59/137) of all cases.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
National Library of Medicine Genetics Home Reference
Alexander disease
The Waisman Center Alexander Disease
www.waisman.wisc.edu/alexander/index.html
Hunter's Hope Foundation
6368 West Quaker Street
Orchard Park NY 14127
Phone: 877-984-4673 (toll-free); 716-667-1200
Fax: 716-667-1212
Email: info@huntershope.org
www.huntershope.org
United Leukodystrophy Foundation (ULF)
2304 Highland Drive
Sycamore IL 60178
Phone: 800-728-5483; 815-895-3211
Fax: 815-895-2432
Email: office@ulf.org
www.ulf.org
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
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
