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Alexander disease

Alexander disease
Literature review current through: Sep 2023.
This topic last updated: Apr 18, 2022.

INTRODUCTION — Alexander disease (MIM #203450) is one of a group of neurologic disorders, collectively referred to as leukodystrophies, which predominantly affect the central nervous system white matter. These disorders are caused by defects in the synthesis (ie, dysmyelination) or maintenance of the myelin sheath that insulates the nerves. While leukodystrophy is the predominant abnormality in the neonatal and infantile forms of Alexander disease, advances in genetics and imaging have revealed a broad phenotypic variability that includes juvenile and adult forms of the disorder without obvious leukodystrophy [1].

Prior to the identification of the genetic features, other names were used to describe the clinical features and pathology of Alexander disease, such as hyaline panneuropathy and dysmyelinogenic leukodystrophy [2]. These terms are no longer used.

This topic will review the pathology, pathogenesis, clinical features, and diagnosis of Alexander disease.

PATHOLOGY — Alexander disease was first described in 1949, when W. Stewart Alexander reported a 15-month-old child with megalencephaly, hydrocephalus, and psychomotor retardation [3]. The child died eight months later, and the brain pathology revealed "a progressive fibrinoid degeneration of fibrillary astrocytes." These astrocytic inclusions were later found to be identical to Rosenthal fibers [4]. The presence of glial fibrillary acidic protein (GFAP) in Rosenthal fibers led to the identification of pathogenic variants of the gene encoding GFAP as the cause of Alexander disease [5]. (See 'Pathogenesis' below.)

Rosenthal fibers, which are hyaline eosinophilic rods, are present in Alexander disease throughout the central nervous system. These intracytoplasmic astrocytic inclusions are the hallmark of Alexander disease [6]. They are commonly seen in subpial, subependymal, and perivascular regions. They are present in the perikarya, processes, and end-feet of astrocytes and appear round or oblong, with extensive glial intermediate filaments seen on electron microscopy. They also contain GFAP. In addition, alpha B-crystallin, heat shock protein 27, and ubiquitin are present in Rosenthal fibers [7-11].

Rosenthal fibers are not specific for Alexander disease; focal Rosenthal fibers are found in other conditions, including astrocytomas, hamartomas, glial scars, and even in multiple sclerosis. However, the focal nature of Rosenthal fibers in these disorders stands in sharp contrast to Alexander disease, where the Rosenthal fibers are diffuse and abundant [12].

Myelin loss and/or failure of normal myelin development in Alexander disease are variable. In the infantile form, the myelin loss is severe. Patients with juvenile or adult-onset Alexander disease can have mild and patchy myelin loss [2].

PATHOGENESIS — In 2001, nonconservative mutations were identified in the regions of chromosome 17q21 that encode the GFAP gene from patients representing different Alexander disease phenotypes [5]. GFAP is an intermediate filament protein found in mature astrocytes that is rapidly synthesized during central nervous system injury and reactive astrogliosis [13]. Astrocytes also help maintain the blood-brain barrier [2,12] and have many additional functions.

Pathogenic variants of the GFAP gene are thought to result in a gain of function phenotype that disrupts dimerization of GFAP [14]. This leads to cytoskeletal collapse and abnormal protein aggregation [15]. Alternatively, the accumulation of a toxic substance could interrupt filament assembly [14]. However, the precise interactions between the GFAP pathogenic variants and the cellular responses of astrocytes remain unknown.

EPIDEMIOLOGY — Alexander disease is rare, but its true incidence and prevalence are unknown. In a population-based study from Japan, the estimated the prevalence was 1 in 2.7 million individuals [16]. In a series from Germany, Alexander disease accounted for 1.6 percent of all leukodystrophies [17]. In a study of eight genetic laboratories in the United States performing next-generation sequencing, Alexander disease was identified in 22 of 664 (3.3 percent) positive leukodystrophy diagnoses [18].

Alexander disease predominantly affects infants and children but it can affect adults [19]. The predominance of infants and children may be due in part to referral bias, as the classic form is most recognizable. This same bias may reduce the likelihood that adults with Alexander disease receive a correct diagnosis, especially since imaging findings can be subtle.

CLINICAL FEATURES — The clinical features and imaging findings in Alexander disease represent a spectrum across the age span, although some symptoms are more common in certain phenotypes, which can be helpful to the clinician in confirming a diagnosis. Three classification schemes have been proposed: a traditional age-based grouping (four subtypes), a two-group revised system based on clinical and imaging features, and a three-group system that accounts for overlap between the two-group system.

Traditional (age-based) classification — Four subtypes of Alexander disease (neonatal, infantile, juvenile, and adult) are traditionally recognized. However, the traditional clinical classification of Alexander disease does not predict the disease severity and progression with reliability [20].

The classification should not be based upon age alone; clinical and radiologic features are key determinants.

Neonatal — The neonatal form is associated with hydrocephalus and increased intracranial pressure secondary to aqueductal stenosis, as well as elevated cerebrospinal fluid protein, intractable seizures, severe delay in acquisition of motor milestones (even in the absence of upper motor neuron signs), and intellectual disability. In contrast to the infantile form, ataxia and hyperreflexia are not present [21]. In the neonatal form, death usually occurs within the first few weeks to two years of life, although some affected infants survive until the end of the first decade [2,19].

Infantile — The infantile form is the most common, accounting for approximately 42 percent of all cases [19]. The onset occurs during infancy or childhood [22]. Infants and young children have delayed acquisition of psychomotor milestones, followed by a plateau or the gradual loss of developmental milestones, spasticity, and feeding difficulties. Affected infants may have head enlargement (macrocephaly) secondary to brain enlargement (megalencephaly), frontal bossing, seizures, and hydrocephalus. Death may occur in the first decade of life, although many children with infantile-onset Alexander disease progress slowly and survive for decades [19].

Juvenile — The juvenile phenotype, seen in approximately 22 percent of affected patients, typically presents during childhood and adolescence [19,23]. It is associated with pseudobulbar and bulbar signs, including swallowing and speech difficulties. Patients may have vomiting, ataxia, spasticity (principally affecting the lower extremities), and kyphoscoliosis. There have been three case reports of children with Alexander disease who presented with symptoms suggestive of anorexia nervosa (including failure to thrive, nocturnal vomiting, and weight loss) at ages 6, 7, and 11, respectively [24-26]. Persistent vomiting in a pediatric patient should warrant imaging to explore the possibility of brainstem disease.

Unlike in the infantile form, children with juvenile Alexander disease are typically normocephalic, and have a slow deterioration of cognitive abilities. Although progressive and fatal, the manifestations are usually milder and deterioration is often slower than the infantile form [19].

Adult — In patients with Alexander disease, adult-onset is seen in approximately 33. In a cohort of 85 adult patients with Alexander disease and pathogenic GFAP variants, symptom onset occurred after age 65 years in 11 percent [27].

Gait disturbance, pyramidal involvement (spasticity, quadriparesis), and ataxia are common presenting features. Others present with bulbar symptoms (mainly palatal myoclonus, dysarthria, dysphagia, and dysphonia), disturbances of ocular movement (nystagmus, saccadic pursuit, diplopia), sphincter abnormalities, or dysautonomia [19,27-31]. Dysmorphic features may also be present. Sleep disorders (such as sleep apnea) are common. Additional manifestations include mood disturbances (anxiety, depression), episodic hypothermia (dysautonomia) [30], and parkinsonism [32].

Some adults patients may be asymptomatic but suspected of having Alexander disease after a brain MRI is obtained for other indications [33]. Imaging abnormalities, particularly in the brainstem (eg, atrophy of the medulla) and cerebellum, may precede the clinical symptoms [34]. (See 'Brain MRI' below.)

The neuro-ophthalmologic and oculomotor findings reflect dysfunction in the pons and cerebellum, consistent with neuroimaging studies. The adult form may result from a sporadic pathogenic variant; however, familial cases have been reported more commonly among adult-onset patients than in the infantile or juvenile forms. (See 'Inheritance' below.)

Revised (two-group) classification — The classification of Alexander disease was revised in 2011 on the basis of a statistical method called latent class analysis (LCA) [35]. Using data from 215 patients with genetically confirmed Alexander disease, LCA modeling was applied to define clinically coherent subtypes of Alexander disease with similar outcomes. The result suggested that the optimal number of Alexander disease subtypes is two (types I and II). Of note, the LCA models predict trends but do not allow type classification of individual cases with absolute certainty [35].

Common features of types I and II are reviewed in the next sections.

Type I — Type I Alexander disease is characterized by the following features [35]:

Early onset (often but not always before age four years)

Seizures

Macrocephaly

Motor delay

Encephalopathy

Failure to thrive

Developmental delay

Paroxysmal deterioration

Typical neuroimaging features (see 'Brain MRI' below)

Type I Alexander disease is generally more severe than type II, with a reduced median survival from onset (14 versus 25 years) and a nearly twofold increase in mortality for type I compared with type II.

Type II — Type II Alexander disease is characterized by the following features [35]:

Manifests across the lifespan, usually but not always age four years or older

Autonomic dysfunction

Eye movement abnormalities

Bulbar symptoms

Palatal myoclonus

Often lacking neurocognitive or developmental deficits

Atypical neuroimaging features (see 'Atypical neuroimaging features' below)

As noted above, type II Alexander disease is generally less severe and has a longer median survival than type I (see 'Type I' above).

Three-group classification — A three-group classification accounts for overlap between the two-group system (see 'Revised (two-group) classification' above) and includes cerebral (type I), bulbospinal (type II), and intermediate (type III) groups [16].

Cerebral (type I) – The cerebral group is characterized by the following features [16]:

Core neurologic features: Psychomotor developmental delay, intellectual disability, convulsions, macrocephaly

Supportive neurologic features: Dysarthria, dysphagia, dysphonia, hyperreflexia, cerebellar ataxia, sphincter abnormalities, scoliosis

Core MRI findings: Cerebral white matter abnormalities with frontal lobe predominance

Supportive MRI findings: Signal abnormalities with swelling or atrophy of basal ganglia and thalami, periventricular rim, brainstem lesions, contrast enhancement

Bulbospinal (type II) – The bulbospinal group is characterized by the following features [16]:

Core neurologic features: Muscle weakness, hyperreflexia (sometimes hypo- or areflexia), positive Babinski sign, dysarthria, dysphagia, dysphonia

Infrequent but specific neurologic feature: Palatal myoclonus

Supportive neurologic features: Cerebellar ataxia nystagmus, scoliosis, sleep disorder (eg, sleep apnea syndrome, REM behavior disorder), parkinsonism, dementia, psychosis, sphincter abnormalities

Core MRI findings: Signal abnormalities or atrophy of medulla oblongata and/or cervical cord

Supportive MRI findings: Signal abnormalities and/or atrophy of cerebellum, white matter lesion, signal abnormalities of basal ganglia and thalami, contrast enhancement

Intermediate form (type III) The intermediate group is characterized by a combination of features of the cerebral and bulbospinal forms [16]:

Neurologic features: At least one of the core features in cerebral (type I) and at least one of the core features in bulbospinal (type II)

MRI findings: Core findings of type I and core feature of type II

For a case satisfying any of the above-mentioned types, a definite diagnosis is based on pathologic findings (existence of numerous Rosenthal fibers in addition to gliosis and loss of myelin) and genetic analysis demonstrating a pathogenic GFAP variant [16]. (See 'Diagnosis' below.)

GENETICS — Up to 98 percent of the cases of Alexander disease are associated with pathogenic variants in the coding region of GFAP [5,19]. Hundreds of GFAP pathogenic variants have been reported in the literature [19,36]. In an analysis of 215 patients with genetically confirmed Alexander disease, more than one-half of the patients had pathogenic variants affecting one of four GFAP peptide sequences (R79, R88, R239, and R416) [35]. An updated list of GFAP pathogenic variants associated with Alexander disease is available online from the Waisman Center [36].

Sequence analysis detects GFAP pathogenic variants in 90 to 98 percent of patients [19,37]. Pathogenic variants are most commonly found in exons 1, 4, and 6 [35].

Inheritance — Pathogenic GFAP variants found in phenotypes with early onset usually arise de novo. Most affected individuals with infantile and juvenile onset Alexander disease do not live until child-bearing age and do not reproduce, indicating that the majority of cases are sporadic [17]. In addition, GFAP pathogenic variants are seldom detected in parents that have been tested, although mosaicism can occur [14].

However, there are some familial cases of Alexander disease, mostly in adults [28,34,38,39].

Genotype-phenotype correlations — As mentioned earlier, more than one-half of patients with Alexander disease have pathogenic variants affecting one of four GFAP peptide sequences (R79, R88, R239, and R416) [35].

Pathogenic variants of R79 and R239 GFAP are the most common, and are associated with early onset and with type I Alexander disease (see 'Revised (two-group) classification' above) [35]. Earlier studies found that patients with R79 pathogenic variants may have a milder clinical course, with some who presented as neonates reported to be alive at ages ranging from 2 to 20 years [40-42].

R239 pathogenic variants, specifically R239H and R239C, are associated with more severe phenotypes [35,43].

R88 and R416 pathogenic variants have not been associated with specific clinical features [35].

NEUROIMAGING — Cerebral white matter changes are seen with both brain magnetic resonance imaging (MRI) and head computed tomography (CT), but MRI is more sensitive than CT and is therefore the preferred imaging study for patients with a suspected diagnosis of Alexander disease or any leukodystrophy.

Brain MRI — The classically recognized abnormalities on MRI in Alexander disease include extensive frontal white matter signal changes and swelling (image 1). Similarly, abnormalities are frequently seen in the basal ganglia and thalami, including signal abnormalities and swelling (image 2). With time and progression of disease, serial MRI scans demonstrate increasing frontoparietal white matter atrophy with cystic degeneration, enlargement of the lateral ventricles, and atrophy of the basal ganglia and thalami (image 3). There is relative sparing of occipital and temporal lobe white matter (image 4) [44].

MRI criteria — In a report published in 2001, diagnostic criteria for Alexander disease in children based upon brain MRI were proposed [44]. These were derived from three children with autopsy-proven diagnosis, and were retrospectively validated in a cohort of 217 children with leukoencephalopathy of unknown origin.

Five MRI criteria were defined [44]:

Extensive cerebral white matter changes with frontal predominance (image 1 and image 2 and image 3 and image 4 and image 5)

A periventricular rim of high signal on T1-weighted sequences and low signal on T2-weighted sequences (image 1 and image 2 and image 3 and image 4 and image 5)

Abnormalities of the basal ganglia and thalami (image 1 and image 2 and image 3 and image 4 and image 5)

Abnormalities of the brainstem, mainly involving the midbrain and medulla (image 2 and image 4 and image 6)

Contrast enhancement involving one or more of the following gray and white matter structures (image 1 and image 2 and image 5 and image 7):

Ventricular lining

Periventricular tissue

Frontal white matter

Optic chiasm

Fornix

Basal ganglia

Thalamus

Dentate nucleus

Brainstem

These criteria allow for the diagnosis in infants, in whom the identification of abnormal white matter can be difficult, as well as in patients who do not receive contrast when the MRI is performed. In addition, there is evidence that the MRI imaging pattern encompassed by these criteria is specific for distinguishing Alexander disease from other white matter disorders [44,45]. (See 'Differential diagnosis' below.)

Atypical neuroimaging features — Some patients with Alexander disease have atypical or unusual neuroimaging features.

A fetal MRI at 33 weeks gestation showed asymmetrically enlarged ventricles with thickening of the fornices and possible white matter abnormalities. Alexander disease was confirmed after birth by genetic testing [46].

In one report, 10 patients with juvenile or neonatal-onset Alexander disease and Rosenthal fibers on histologic examination did not meet the previously established MRI criteria for the disease [47]. In eight of these, MRI showed mainly posterior fossa lesions, particularly multifocal brainstem lesions resembling multiple tumors.

In a study of seven patients with juvenile-onset Alexander disease and pathogenic variants of GFAP, MRI abnormalities (signal change or atrophy) were seen predominantly in the medulla and cervical spinal cord (image 6) [48]. A novel finding was the description of ventricular garlands in four patients.

A 12-year-old girl with juvenile-onset Alexander disease had focal brainstem and cervical cord lesions without white matter changes [49].

A 20-year-old man with adult-onset Alexander disease presented with episodic dysphagia and dysphonia, and transient gaze-evoked nystagmus; he later developed diplopia because of a right cranial nerve VI palsy [50]. Abnormalities on MRI included T2 hyperintensity in the medulla and upper cervical spinal cord, with areas of contrast enhancement and progressive brainstem atrophy on serial scans. In addition, there was a rim of increased periventricular signal with garland-like aspects on fluid-attenuated inversion recovery (FLAIR) and T2-weighted images.

In one family, a 26-year-old woman presented with a cerebellar mass lesion by head CT, which on biopsy was notable for neuronal loss, gliosis, and Rosenthal fibers characteristic of Alexander disease [51]. Similarly, her 11-year-old brother presented with a brainstem lesion that was found on biopsy to be a manifestation of Alexander disease.

MRI characteristics appear to vary by age of disease onset. In comparison with the infantile form, the juvenile and adult forms of Alexander disease do not have as clear a predilection for the cerebral white matter but rather involve infratentorial structures (ie, brainstem, specifically the medulla, and cerebellum).

Adults have less frequent supratentorial involvement than juveniles or infants, but the degree of involvement can range from no evidence of cerebral white matter demyelination, to periventricular hyperintensities on T2-weighted and FLAIR sequences [28,34]. In contrast, adults typically have marked atrophy of the infratentorial structures on brain MRI, most notably involving the medulla, but also involving the remainder of the brainstem, cerebellum, and cervical spinal cord [23,33].

DIAGNOSIS — The diagnosis of Alexander disease can be established based upon clinical and radiographic (magnetic resonance imaging [MRI]) features. In addition, the diagnosis is confirmed by demonstrating a pathogenic variant of GFAP. Although genetic testing is not necessarily required for the diagnosis, genetic confirmation should always be attempted due to the heterogeneity of the disease and its presentation.

In children with typical clinical features of Alexander disease, the diagnosis can be established by brain MRI if patients fulfill four of the five MRI diagnostic criteria [44]. (See 'MRI criteria' above.)

These MRI criteria remain useful for proving the diagnosis in situations in which genetic testing is equivocal (eg, discovery of novel GFAP sequence variants that are potentially uncommon benign polymorphisms rather than causative pathogenic variants). However, MRI criteria alone cannot exclude the diagnosis in children with atypical imaging features, and are not helpful for confirming or refuting the diagnosis in adults. Therefore, when Alexander disease is suspected in adults, or in children with atypical imaging features, the diagnosis is confirmed by genetic testing.

Demonstration of Rosenthal fibers on brain biopsy or at autopsy is diagnostic, but has been superseded by the availability of MRI and genetic testing.

Other laboratory studies are not useful for the diagnosis of Alexander disease.

Prenatal diagnosis — While prenatal diagnosis for adult-onset Alexander disease is theoretically available through amniocentesis and chorionic villus sampling, the affected allele within a family member must be known. In a family with adult-onset, autosomal dominant transmission of a pathogenic GFAP variant, one child with the same pathogenic variant developed symptoms before the age of 10 years [28].

Differential diagnosis — The differential diagnosis of Alexander disease involves consideration of other disorders that present with macrocephaly and/or cerebral white matter changes (algorithm 1). While many of these disorders share some of the clinical or neuroimaging characteristics of Alexander disease, none shares all of them [44]. Thus, they can be distinguished from Alexander disease by MRI criteria and/or clinical criteria [52].

Adrenoleukodystrophy is an X-linked disorder. Brain MRI of symptomatic boys demonstrates mild to severe cerebral white matter demyelination. Lesions are usually bilateral, with predominant involvement of the occipitoparietal region, but the frontal lobes may also be affected. Disease progression correlates with the presence of contrast enhancement on T1-weighted MR images. (See "Clinical features, evaluation, and diagnosis of X-linked adrenoleukodystrophy".)

Canavan disease is a neurodegenerative disease characterized by leukodystrophy and spongy degeneration of the brain. It is caused by a deficiency of aspartoacylase, which leads to increased N-acetylaspartic acid (NAA) levels in the brain. Clinical onset is typically in early infancy with macrocephaly, hypotonia, and optic atrophy. Later, hypertonia, seizures, and progressive neurologic deterioration occur. On neuroimaging, there is diffuse cerebral white matter degeneration without a frontal predominance. Unlike Alexander disease, there is no contrast enhancement. (See "Aspartoacylase deficiency (Canavan disease)".)

Megalencephalic leukoencephalopathy with subcortical cysts presents with macrocephaly in the first year of life [53,54]. Other symptoms include mild developmental delay, ataxia, spasticity, and seizures. Cognition is relatively spared. The disorder is caused by pathogenic variants in MLC1 and HEPACAM. MRI reveals diffuse supratentorial white matter abnormalities, edema, and cystic brain lesions, mostly in the frontoparietal border zone region and anterior-temporal subcortical white matter [53]. In contrast, the cysts in Alexander disease are mostly located in the deep frontal white matter [44].

Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease that is usually caused by decreased levels of the enzyme arylsulfatase A and is divided into late infantile, early, and late juvenile, and adult forms. As the disease progresses, bulbar symptoms, spasticity, quadriparesis, and optic atrophy occur. (See "Metachromatic leukodystrophy".)

On MRI, the cerebral white matter is diffusely and symmetrically hyperintense on T2-weighted images, with a frontal predominance. Unlike Alexander disease, contrast enhancement on neuroimaging is not associated with MLD [44]. The presence of a demyelinating peripheral neuropathy, which is usually present in the late infantile or juvenile forms, also distinguishes MLD from Alexander disease.

Classic (merosin deficient) congenital muscular dystrophy is associated with demyelination of the cerebral hemispheres without structural central nervous system anomalies. MRI shows extensive cerebral white matter changes, but the occipital white matter is relatively spared [55]. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Congenital muscular dystrophies'.)

Adult-onset Alexander disease can mimic multiple sclerosis (MS) [56], a central nervous system demyelinating disorder. Patients with MS frequently have gait disturbances, ataxia, visual changes, and autonomic dysfunction, with a relapsing and remitting course. Lesions on the MRI are typically periventricular and asymmetric. (See "Manifestations of multiple sclerosis in adults".)

As an example, the first patient with histologically proven adult-onset Alexander disease was initially diagnosed with MS. At age 32, he developed left arm paralysis for five days, which improved with time to only mild weakness. His other symptoms waxed and waned, including diplopia, difficulty walking, impaired proprioception, and occasional lightheadedness [57]. This patient had three daughters, and all had progressive palatal myoclonus, spastic weakness, hyperreflexia, mild cerebellar dysfunction, and ocular motor abnormalities [58]. The autopsy of one daughter revealed widespread Rosenthal fiber deposition and demyelination, consistent with Alexander disease.

Organic acidemias are characterized by the excretion of non-amino organic acids in urine, from defective amino acid catabolism. They vary in severity and age of onset. The neonatal variants, such as isovaleric acidemia and maple syrup urine disease, present in the first few days of life with vomiting, poor feeding, seizures, hypotonia, and lethargy. Glutaric acidemia type I and L-2 hydroxyglutaric aciduria may present with accelerated head growth. In the older child or adolescent, affected individuals can have loss of intellectual function, ataxia, or other focal neurologic signs. MRI abnormalities have been described in the white matter and basal ganglia. (See "Organic acidemias: An overview and specific defects".)

TREATMENT — Treatment of Alexander disease remains supportive. However, a multidisciplinary team and a comprehensive treatment plan can improve function and quality of life for affected individuals [59]. Antiseizure medications are used to control seizures. Spasticity and hypertonia may improve with medications such as baclofen and benzodiazepines, and with physical therapy. Properly fitted equipment, such as ankle braces, may help improve mobility; wheelchairs and other seating devices may be required for non-ambulatory individuals or those with significant hypotonia and scoliosis. In the neonatal and infantile forms associated with obstructive hydrocephalus, a ventriculoperitoneal shunt may be required. Dysphagia is a frequent symptom across the age span and consultation with a feeding specialist or speech and language pathologist is indicated to evaluate safety and efficiency with oral intake. Gastrointestinal symptoms, such as reflux and vomiting, are common in Alexander disease and may improve with acid blockade or proton pump inhibitors. Enteral feeding may be required, especially in children with failure to thrive. Urinary retention and incontinence are also common and can be managed by medications, bladder training, and catheterization under the guidance of a urologist.

One adult with Alexander disease demonstrated clinical stabilization after prolonged treatment with intravenous ceftriaxone [60]. During the first two years of treatment, disability worsened, as measured by the modified Rankin scale. However, after two years, there were improvements in gait and speech intelligibility, with continued improvement at four years [61]. Of note, the symptoms in Alexander disease may wax and wane, which may explain some of the clinical improvement demonstrated in this individual. Other medications or therapies during the treatment may have also contributed to improved symptoms. The mechanism of action and utility of beta lactams in this setting has not been clearly elucidated and requires further investigation [62,63].

The clinical and radiographic progression in Alexander disease is variable, with many children surviving several decades longer than published life expectancies. With symptom management and a comprehensive, multidisciplinary team, it may be possible to pursue educational and employment opportunities.

SUMMARY AND RECOMMENDATIONS — Alexander disease (MIM #203450) is a rare genetic disorder that predominantly affects infants and children and is associated with cerebral white matter disease.

Intracytoplasmic astrocytic inclusions known as Rosenthal fibers are the hallmark of Alexander disease. (See 'Pathology' above.)

Sporadic pathogenic GFAP variants are the cause of most cases of Alexander disease. (See 'Pathogenesis' above and 'Genetics' above.)

Four subtypes of Alexander disease (neonatal, infantile, juvenile, and adult) are traditionally recognized (see 'Clinical features' above):

The neonatal form is associated with increased intracranial pressure, seizures, and severe motor retardation

The infantile form is characterized by megalencephaly, frontal bossing, seizures, hydrocephalus, psychomotor retardation with loss of developmental milestones, spasticity, and feeding difficulties

Children with juvenile Alexander disease are typically normocephalic, and the deterioration is often slower than the infantile form

Adult-onset Alexander disease has variable features

A revised classification of Alexander disease proposes two subtypes (types I and II) based upon statistical analyses (see 'Revised (two-group) classification' above):

Type I is characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, sudden deterioration, and typical neuroimaging features. (See 'Type I' above.)

Type II onset may occur across the lifespan, and is characterized by autonomic dysfunction, eye movement abnormalities, bulbar symptoms, and atypical neuroimaging features. (See 'Type II' above.)

An intermediate form of Alexander disease between type I (the cerebral form) and type II (the bulbospinal form) has the clinical and imaging features of both subtypes. (See 'Three-group classification' above.)

Typical magnetic resonance imaging (MRI) features of Alexander disease are as follows (see 'Brain MRI' above):

Extensive cerebral white matter changes with frontal predominance

Periventricular rim of high T1 signal and low T2 signal

Basal ganglia and thalamic abnormalities

Brainstem abnormalities

Contrast enhancement of selected gray and white matter structures

Less common MRI features of Alexander disease include (see 'Brain MRI' above):

Multifocal brainstem lesions resembling multiple tumors

Medullary and cervical spinal cord signal abnormalities or atrophy

Ventricular garlands

The diagnosis of Alexander disease can be established based upon clinical and radiographic (MRI) features. The diagnosis is usually confirmed by demonstrating a pathogenic GFAP variant. Although genetic testing is not necessarily required for the diagnosis, genetic confirmation should always be attempted due to the heterogeneity of the disease and its presentation. (See 'Diagnosis' above.)

The differential diagnosis of Alexander disease involves consideration of other disorders that present with macrocephaly and/or cerebral white matter changes. (See 'Differential diagnosis' above.)

Treatment of Alexander disease remains supportive. (See 'Treatment' above.)

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Topic 1695 Version 17.0

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