In decreasing order of frequency, 3 forms of Alexander disease are recognized, based on age of onset: infantile, juvenile, and adult. Younger patients typically present with seizures, megalencephaly, developmental delay, and spasticity. In older patients, bulbar or pseudobulbar ... In decreasing order of frequency, 3 forms of Alexander disease are recognized, based on age of onset: infantile, juvenile, and adult. Younger patients typically present with seizures, megalencephaly, developmental delay, and spasticity. In older patients, bulbar or pseudobulbar symptoms predominate, frequently accompanied by spasticity. The disease is progressive, with most patients dying within 10 years of onset. Imaging studies of the brain typically show cerebral white matter abnormalities, preferentially affecting the frontal region (Gorospe et al., 2002). All 3 forms have been shown to be caused by mutations in the GFAP gene.
Van der Knaap et al. (2001) proposed specific MRI criteria for the diagnosis of Alexander disease: extensive, symmetric white matter abnormalities with frontal preponderance; periventricular signal changes; basal ganglia and thalamic signal changes; brainstem lesions; and contrast enhancement ... Van der Knaap et al. (2001) proposed specific MRI criteria for the diagnosis of Alexander disease: extensive, symmetric white matter abnormalities with frontal preponderance; periventricular signal changes; basal ganglia and thalamic signal changes; brainstem lesions; and contrast enhancement of multiple areas throughout the brain. Van der Knaap et al. (2005) reported 9 patients with Alexander disease confirmed by genetic analysis who had atypical MRI features. Alexander disease was not the initial diagnosis for any of the patients, and none of the patients met the MRI-based criteria proposed by van der Knaap et al. (2001). MRI in 8 patients showed predominantly posterior fossa lesions, especially multiple tumor-like brainstem lesions. One patient had asymmetric frontal white matter abnormalities and basal ganglia abnormalities. Van der Knaap et al. (2005) concluded that DNA diagnostics is warranted in patients with atypical MRI features that are only suggestive of Alexander disease. Van der Knaap et al. (2006) reported 7 patients with genetically confirmed Alexander disease who had no or inconspicuous cerebral white matter abnormalities and no or minimal contrast enhancement on brain MRI. All had juvenile disease onset with signs of brainstem or spinal cord dysfunction, including bladder and gait disturbances. MRI findings were predominantly signal changes or atrophy of the medulla and spinal cord. Four patients had a kind of 'garland' along the ventricular wall. Van der Knaap et al. (2006) concluded that Alexander disease is not invariably a leukoencephalopathy, and that patients with later onset of the disorder may have more unusual phenotypic variation.
This disorder, first described by Alexander (1949), is characterized clinically by development of megalencephaly in infancy accompanied by progressive spasticity and dementia. The features are similar to those of Canavan disease (271900).
Gorospe et al. (2002) ... This disorder, first described by Alexander (1949), is characterized clinically by development of megalencephaly in infancy accompanied by progressive spasticity and dementia. The features are similar to those of Canavan disease (271900). Gorospe et al. (2002) reported 12 genetically confirmed cases of Alexander disease. Seven of the 12 had onset in infancy (range 2-18 months), with seizures being the most common presenting sign, followed by failure to thrive and delayed motor development. Five patients had juvenile onset (between 5 and 9 years) and presented with variable symptoms ranging from asymptomatic (2 patients) to linear growth failure, excessive sleepiness and vomiting. Patients in both groups showed megalencephaly, bulbar or pseudobulbar signs, spasticity, cognitive deficits and developmental delay. In addition, all patients showed diffuse and symmetric white matter abnormalities in the frontal regions of the brain. Gorospe et al. (2002) suggested that GFAP gene analysis be included in the diagnostic evaluation of patients presenting with frontal leukoencephalopathy by MRI. Bassuk et al. (2003) reported an infant with Alexander disease who presented with poor feeding on the first day of life, followed by emesis and weight loss. MRI on day 21 of life showed signal abnormalities in the frontal lobes and basal ganglia. Over the next 12 days, the patient became increasingly somnolent and hypotonic, and developed seizures on day 33. Magnetic resonance spectroscopy (MRS) performed 14 days apart demonstrated an interval 2-fold increase in the lipid/lactate peak over the right basal ganglia. Over the course of 25 days, head growth increased from the 50th to the 75th percentile. The child died on day 38 from prolonged seizures and respiratory failure. Mutation analysis detected a heterozygous mutation in the GFAP gene (137780.0012). Bassuk et al. (2003) commented on several unusual aspects of the case, including the rapid clinical decline, the rapid head growth, and the demonstration of progressive lactate elevation in the brain by MRS. Stumpf et al. (2003) reported a family with an autosomal dominant adult form of Alexander disease. The clinical phenotype varied in severity, but the pattern of evolution was similar in all affected members. Although sleep disturbances and dysautonomia, primarily constipation, began in childhood, the major neurologic features began in the third or fourth decade of life. Features included bulbar signs, ataxia, and pyramidal signs. All patients also had mild dysmorphic features, including progressive kyphosis, arched palate, and short neck. MRI of the older patients showed atrophy of the medulla without signal abnormalities. A mutation in the GFAP gene (137780.0013) was identified in all affected members. Li et al. (2005) reported detailed clinical features of 44 patients with Alexander disease, including 26 with infantile onset, 15 with juvenile onset, and 3 with adult onset. The most common features among the patients with infantile onset included seizures (92%), cognitive defects (82%), macrocephaly (62%), bulbar signs (62%), ataxia (58%), and spasticity (52%). The phenotype of juvenile- and adult-onset cases was less severe. Features of juvenile patients included bulbar signs (73%), cognitive defects (60%), spasticity (53%), ataxia (47%), seizures (27%), and macrocephaly (20%). None of the patients with adult onset had macrocephaly, seizures, or cognitive defects. There was a suggestion of male predominance for the disorder. Sreedharan et al. (2007) reported an unusual case of a 38-year-old woman with Alexander disease. She presented with a 2-year history of progressive reading difficulty with oscillopsia, slurring dysarthria, choking, and stumbling. Past medical history was significant for endocrine disturbances with an episode of amenorrhea, hypothyroidism, depression, and hypothermic episodes associated with ataxia, facial twitching and drowsiness. Physical examination showed torsional nystagmus and palatal, tongue, and jaw tremor. She had symptomatic microcoria, mild left arm dysmetria, ataxia, and lower limb hyporeflexia. Brain MRI showed brainstem atrophy and symmetric signal changes in the medulla and cerebellum. Her father reportedly had microcoria but refused participation. Genetic analysis identified a heterozygous GFAP mutation in the proband. Sreedharan et al. (2007) commented that this case represented an unusually slowly progressive form of adult-onset Alexander disease. - Pathologic Findings Histologically, Alexander disease is characterized by Rosenthal fibers, homogeneous eosinophilic masses which form elongated tapered rods up to 30 microns in length, which are scattered throughout the cortex and white matter and are most numerous in the subpial, perivascular and subependymal regions. These fibers are located in astrocytes, cells that are closely related to blood vessels. Demyelination is present, usually as a prominent feature. A few cases have had hydrocephalus (Alexander, 1949). Rosenthal fibers are commonly found in astrocytomas, optic nerve gliomas and states of chronic reactive gliosis, but they are especially conspicuous in Alexander disease. Herndon et al. (1970) expressed the view that Rosenthal fibers found in this situation are the result of degenerative changes in the cytoplasm and cytoplasmic processes of astrocytic glial cells. Iwaki et al. (1989) found that alpha-B-crystallin (CRYAB; 123590) accumulates in the brain in Alexander disease.
Mutations were found in the infantile form of Alexander disease by Brenner et al. (2001), in the juvenile form by Sawaishi et al. (2002), and in the adult form by Namekawa et al. (2002).
Brenner et ... Mutations were found in the infantile form of Alexander disease by Brenner et al. (2001), in the juvenile form by Sawaishi et al. (2002), and in the adult form by Namekawa et al. (2002). Brenner et al. (2001) identified de novo, heterozygous mutations in the GFAP gene in 10 of 11 patients with Alexander disease (137780.0001-137780.0005). Rodriguez et al. (2001) likewise identified de novo heterozygous missense GFAP mutations in exon 1 or exon 4 of 14 of 15 patients who were candidates for Alexander disease on the basis of suggestive neuroimaging abnormalities. These included patients without macrocephaly. Affected sibs whose parents were unaffected, including 1 family with neuropathologically proved Alexander disease (Wohlwill et al., 1959), could represent autosomal recessive transmission or germinal mosaicism for a dominant mutation. Therefore, Rodriguez et al. (2001) suggested that after the birth of a patient with Alexander disease with a de novo GFAP mutation, prenatal diagnosis should be proposed for all subsequent pregnancies. It remained to be determined whether the heritable dominant forms of Alexander disease described in 2 families, both of which had late onsets after age 25 years (Howard et al., 1993; Schwankhaus et al., 1995), also had GFAP mutations as the cause. Of 13 patients with MRI white matter abnormalities consistent with Alexander disease, 12 were found by Gorospe et al. (2002) to have GFAP mutations. Four of the 9 changes identified were novel mutations. Li et al. (2006) determined that the paternal chromosome carried the GFAP mutation in 24 of 28 unrelated cases of Alexander disease analyzed, suggesting that most mutations occur during spermatogenesis rather than in the embryo. No effect of paternal age was observed. In 13 unrelated Italian patients with Alexander disease, including 8 with the infantile, 2 with the juvenile, and 3 with the adult form, Caroli et al. (2007) identified 11 different mutations in the GFAP gene (see, e.g., 137780.0005), including 4 novel mutations. Ten mutations occurred in the rod domains and 1 in the tail domain.
The clinical presentation of Alexander disease is nonspecific....
Diagnosis
Clinical DiagnosisThe 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.TestingHistologic 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 TestingGene. 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 testingSequence 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 DiseaseView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityGFAPSequence analysis
Sequence variants 297% 3Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. 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. For issues to consider in interpretation of sequence analysis results, click here.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.Genetically Related (Allelic) DisordersNo 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....
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. Post-term delivery, hypotonia, frequent syncopal episodes, unusual nevi, hypothyroidism [Gorospe et al 2002] Hypertension and diabetes mellitus [Brockmann 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]Mood disturbances, osteopenia, microcoria, primary ovarian failure, hypothyroidism [Sreedharan et al 2007] Vertebral anomalies: Scoliosis [Nonomura et al 2002, Okamoto et al 2002, Hinttala et al 2007] Kyphosis [Stumpf et al 2003, van der Knaap et al 2006, Delnooz et al 2008] Lordosis [van der Knaap et al 2006] 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].
The number of individuals confirmed as having mutations in GFAP is currently too small to make any conclusive genotype-phenotype correlations....
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).
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. ...
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. 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.
To establish the extent of disease in an individual diagnosed with Alexander disease, the following evaluations are recommended:...
Management
Evaluations Following Initial DiagnosisTo 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 ManifestationsNo 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 ComplicationsThe 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 SurveillanceDepending 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 InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGFAP17q21.31
Glial fibrillary acidic proteinHuman Intermediate Filament Database GFAP GFAP homepage - Mendelian genesGFAPData 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) View in own window 137780GLIAL FIBRILLARY ACIDIC PROTEIN; GFAP 203450ALEXANDER DISEASEMolecular Genetic PathogenesisGFAP 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.Normal allelic variants. GFAP comprises nine exons distributed over 9.8 kb, transcribed into a 3-kb mRNA. Abnormal allelic variants. GFAP mutations have been reported in individuals with Alexander disease (see Table 2). Almost all of the mutations (68/72, 94%) have been missense mutations resulting in the change of a single amino acid residue. Exceptions include four mutations: 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.Asp417Metfs*15 [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 Pathologic Allelic VariantsView in own windowDNANucleotide Change (Alias 1)Protein Amino Acid Change Reference Sequencesc.209G>Ap.Arg70GlnNM_002055.3 NP_002046.1c.208C>Tp.Arg70Trpc.218T>Cp.Met73Thrc.226C>Tp.Leu76Phec.230A>Gp.Asn77Serc.235C>Tp.Arg79Cysc.236G>Ap.Arg79Hisc.256_259delinsGAGTp.Glu86_Glu87delinsGluGluc.290T>Cp.Leu97Proc.376_381dupGCGGCTp.Arg126_Leu127dupc.613G>Ap.Glu205Lysc.628G>Ap.Glu210Lysc.715C>Tp.Arg239Cysc.716G>Ap.Arg239Hisc.716G>Cp.Arg239Proc.731C>Tp.Ala244Valc.1047_1048insCACTTGp.Tyr349_Gln350insHisLeuc.1055T>Cp.Leu352Proc.1076T>Cp.Leu359Proc.1117G>Ap.Glu373Lysc.1178G>Tp.Ser393Ilec.1249delG (1247_1249delGGGinsGG)p.Asp417Metfs*15See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). See Table 2 for references related to these mutations.1. Variant designation that does not conform to current naming conventionsNormal 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.