Clinical manifestations

Presentation and course

The presentation of children with the more common, infantile form of Alexander disease is often insidious and variable and may not immediately suggest the diagnosis. The typical features of the infantile form combine developmental delay, macrocephaly due to megalencephaly, and seizures (01; 05; 02; 39; 20). Usually, the onset is during the first or second year of life; rarely, however, onset may not occur until 6 years of age. A neonatal form is known as well (24). Both sexes are affected (the earlier suggestion of male predominance probably resulted from the small number of cases).

The initial signs are followed by loss of developmental milestones with progressive neurologic regression of both motor and mental skills, and spastic quadriparesis. Feeding problems are common. Some infants have a more acute onset of symptoms early in the first year that are often accompanied by hydrocephalus with increased intracranial pressure. In a few cases, megalencephaly may be present from birth; yet, in rare cases are not megalencephalic. Seizures and even infantile spasms may rarely occur (52). Death usually occurs between 2 years of age and 10 years of age, but children having a more acute onset or exhibiting obstructive hydrocephalus may die in the first or second year of life (48).

The less common juvenile form of Alexander disease generally occurs between the ages of 6 years of age and the middle teens, but may occur in infancy (43; 05; 39; 20). It is manifested by predominant bulbar or pseudobulbar signs, especially dysphagia, vomiting, difficulty talking and also ataxia and hyperreflexia; and spastic paraparesis or quadriparesis, often more severe in the lower extremities. These signs are all slowly progressive and are more important than age of onset for differentiating the juvenile from the infantile form. Mental function often remains intact for much of the illness, and usually megalencephaly is not present. The duration of the juvenile form tends to be prolonged ranging from 4 years to 10 years or more. Presentation as a tumor-like lesion, often mistaken for an astrocytoma, is well known (28; 49).

The adult onset form of Alexander disease was thought to be rare (10; 17; 45; 06; 35; 36). Data suggest that it is more common than previously thought (37; 57). The clinical picture is not specific, but adult-onset Alexander disease must be considered in patients of any age with lower brainstem signs. When present, palatal myoclonus is strongly suggestive (46). Pyramidal involvement, cerebellar ataxia, and urinary disturbances are common. The disease sometimes presents as brainstem glioma (41). Less frequent findings include sleep disorders and dysautonomia (37). Its pathology closely resembles the pathology of Alexander disease in children, with widespread Rosenthal fibers. However, the adult disorder is varied, and has been described in adults from their late teens to 82 years of age, both with and without clinical neurologic symptoms. The presentations are highly variable and sometimes resemble multiple sclerosis, a tumor, or spastic paraplegia (38). Generally, the adult onset Alexander disease cases have later onset and longer survival, compared with individuals suffering from the others forms of this disorder.

The infantile and juvenile forms are usually sporadic. In adult onset cases, there is a much greater tendency toward familial incidence, and in some cases there may be autosomal dominant inheritance (17; 36; 51). But other cases of adult onset are sporadic (06).

A study used the age of disease onset and the GFAP mutation site to identify statistically only 2 clinical types of Alexander disease: type I characterized by early onset, seizures, macrocephaly, motor delay, encephalopathy, failure to thrive, paroxysmal deterioration, and typical MRI features and type II characterized by later onset, autonomic dysfunction, ocular movement abnormalities, bulbar symptoms, and atypical MRI features (40).

Prognosis and complications

Whether of the infantile, juvenile, or adult onset form, Alexander disease is inexorably progressive, but the rate of functional loss is variable. It is generally slowest in the adult and juvenile forms, where mental function may be retained for much of the course. The major complications are seizures, respiratory infection, urinary tract infection, and scoliosis. Some children with the infantile form have obstructive hydrocephalus that may require surgery.

Clinical vignette

A girl was the product of a normal pregnancy and delivery. The parents were nonconsanguineous, there was no family history of neurologic disease, and a younger brother was normal. The child had appeared normal for the first few months after birth. However, following her first immunization at 3 months of age, she developed seizures, and an enlarged head circumference was noted. Laboratory examinations including cultures, leukocyte lysosomal enzymes, and toxoplasmosis, rubella, cytomegalovirus, and herpes studies were negative. CT showed bilateral frontal changes suggestive of a leukodystrophy.

Over the next few months, the child exhibited developmental delay, with limited acquisition of skills, and she developed a mild motor deficit. A repeat CT at 6 months of age revealed marked progression of the white matter changes, especially in the frontal lobes.

An enlarged, cystic cavum septum pellucidum was noted. CT with contrast showed prominent enhancement bilaterally.

By 8 months of age, she was alert, responsive, and happy, but had a full, tense fontanelle and a spastic rigid paraparesis with upgoing toes. Her head circumference was 48 cm. Funduscopic examination, hearing, blood chemistries, and cerebrospinal fluid were normal. A diagnostic brain biopsy revealed numerous Rosenthal fibers with the typical distribution found in Alexander disease. By 22 months of age, the child was quadriparetic and spastic, and she exhibited a markedly enlarged head with frontal bossing.

The circumference was now 51 cm and she had almost no head control. CT at 28 months of age revealed extensive further progression of the white matter degeneration.

She never learned to talk, but appeared to understand simple language and for a number of years was interactive with people in a pleasant way. At 7 years 9 months of age, tasks associated with daily living had become progressively burdensome, and MRI showed that both frontal lobes and the left parietal lobe were cystic with encephalomalacia.

She now had dislocated hips and scoliosis. Despite severe mental and physical disability, she remained responsive and seemingly happy almost until the end. She died at 8 years 6 months of age, and an autopsy confirmed the biopsy diagnosis of infantile Alexander disease. Her head circumference had reached 59 cm, and her brain weighed 1535 g.

Biological basis

Etiology and pathogenesis

Almost all cases of childhood Alexander disease (infantile and juvenile) are sporadic and are believed to be caused by a de novo, dominant mutation in 1 of the alleles of the gene for the astrocytic intermediate filament protein, GFAP (06; 42; 11; 27). The events leading up to this finding were reviewed (21). The initial results were obtained in the United States and Europe, and similar findings have since been reported from Japan (47). Based on The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff, currently 68 missense/nonsense GFAP mutations are listed as well as 1 small deletion, 1 small insertion, and 1 small insertion/deletion in Alexander disease patients. An in-frame deletion of exon 5 has been described suggesting abnormal secondary structure and/or solubility characteristics analogous to the presumed pathology of the more commonly reported GFAP missense mutations (13). However, in 2 of these studies, no GFAP mutation was found in 1 case each of a pathologically proven infantile case studied by sequencing (06; 42). Thus, there may be additional causes of Alexander disease. In adult onset cases also, there is a dominant heterozygous mutation in the gene for GFAP (06; 35; 36). However, the rare occurrence of affected siblings has been reported for the infantile form and for a set of siblings with either juvenile-age or adult-onset disease (56; 10). Alexander disease has also been reported in 2 sets of monozygotic twins (29; 47). Because the adult onset form can be inherited, but the parents of infantile and juvenile cases do not have the mutation present in their child, it seems likely that the disorder originates in a germline mutation. The occurrence of affected siblings could then be explained by gonadal mosaicism. Only if the effect of the mutation gives rise to adult onset cases will the mutation possibly be passed on (23).

The underlying basis of almost all Alexander disease cases, infantile, juvenile and adult onset forms, appears to be the result of a heterozygous, dominant mutation in the gene for GFAP (06; 32; 42; 11; 29; 35; 36; 47; 30). To date, there are at least 40 different mutations, and many of the mutations are predicted to cause replacement of an arginine by another amino acid (23). The great majority of these mutations occur in exon 1, exon 4, or exon 8. The severity of disease does not strictly parallel the particular mutation present, but in some instances a general correlation exists (42).

How the mutations in GFAP lead to the disease and the pathogenesis of this disorder are poorly understood. They seem to be associated with a marked increased GFAP turnover in the cell (34). All 3 clinical forms are characterized pathologically by the presence of widely distributed Rosenthal fibers and by greatly increased numbers of astrocytic intermediate filaments. In the infantile form especially, the brain exhibits a pronounced lack of myelin. The brain in infantile cases is heavy for the age and shows the greatest involvement bilaterally in the frontal lobes, where the white matter is discolored, shrunken, and may show cystic degeneration and cavitation. The lesions frequently extend to involve the subcortical U or arcuate fibers. The basal ganglia are also affected early, but relative sparing of the occipital lobes and cerebellum occurs. Children with severe hydrocephalus have extensive Rosenthal fiber involvement of the periaqueductal area, which may cause obstruction. The neurons are generally not affected, but in advanced cases there may be some axonal loss. In juvenile cases, the greatest involvement is in the brainstem, with plentiful Rosenthal fibers and less severe, but variable, hypomyelination or demyelination. Adult onset cases may show axonal loss with brainstem and medullary shrinkage, cerebellar involvement, and scattered Rosenthal fibers.

Rosenthal fibers are cytoplasmic inclusions that occur only in astrocytes. In the light microscope, Rosenthal fibers appear as round or elongated hyaline bodies that are stained with eosin, Luxol Fast blue, Heidenhain hematoxylin, and phosphotungstic acid-hematoxylin.

In the electron microscope, Rosenthal fibers are electron dense, osmiophilic, granular, nonmembrane-bound bodies up to 50 microns or more in size.

The Rosenthal fibers are surrounded by and intimately related to dense aggregates of glial intermediate filaments that often penetrate into the Rosenthal fibers. In Alexander disease, Rosenthal fibers are present both in astrocytic processes and end-feet, and also in perikarya, where they are small and frequently multiple. They are characteristically found in subpial, subependymal, and perivascular locations in Alexander disease, as well as diffusely in the white matter.

In addition to the astrocytes with Rosenthal fibers, other astrocytes may be enlarged and have a bizarre appearance, and there may be a fibrillary gliosis.

The particular GFAP mutation present does not appear to have any effect on the appearance or qualities of the Rosenthal fibers. The child in the clinical vignette section had a heterozygous p.Arg416Trp mutation in GFAP, the child in the light microscopic illustration of Rosenthal fibers had a heterozygous p.Arg239Cys mutation, and the child in the ultrastructural illustration had a heterozygous p.Arg79Cys mutation (06; Brenner and Johnson, unpublished data).

Rosenthal fibers are not unique to Alexander disease because they also sometimes occur, but with a more localized distribution, in other conditions (astrocytomas, chronic glial scars, tuberous sclerosis and hamartomas, multiple sclerosis, and Alzheimer disease). Although Rosenthal fibers may be perivascular in these other conditions, subependymal and subpial collections are not generally found. The widespread and characteristic distribution of Rosenthal fibers throughout the neuraxis is unique to Alexander disease.

Much about the composition of Rosenthal fibers has been learned over the past 15 years, but their relation to the myelin deficits in Alexander disease is unclear, and no difference has been noted between the composition of Rosenthal fibers in Alexander disease and in other conditions. Rosenthal fibers can be difficult to label immunocytochemically at the light microscope level, probably due to poor penetrability. However, at the electron microscope level, Rosenthal fibers in Alexander disease are immunoreactive for GFAP (22; 50).

They also contain ubiquitin and 2 small heat shock proteins, alphaB-crystallin and HSP27 (50). AlphaB-crystallin has been purified from isolated Rosenthal fibers and appears to be a major constituent. Because elevated levels of these heat shock proteins can occur in astrocytes without Rosenthal fibers and in other glia, their presence is not unique to Rosenthal fibers or to Alexander disease. Heat shock proteins are believed to function as chaperones and increase in reaction to stress (15). Animal studies in mouse models that over-express Gfap crossed with Cryab (alphaB-crystallin) knockout mice show that AlphaB-crystallin plays a critical role in tempering Alexander disease pathology. In Alexander disease, some unidentified stress (possibly caused by the mutated GFAP) leads to up-regulation of these heat shock proteins and to the formation of the Rosenthal fibers. In addition, Rosenthal fibers in Alexander disease are immunoreactive for advanced glycation and lipid peroxidation end products, which suggests a role for oxidative stress (07).

Alexander disease is considered an example of a positive dominant disease. Evidence suggests that the basic pathology results from a combination of overexpression of GFAP in certain brain regions and the toxic effect of the mutated protein (31). Various models suggest that to eliminate toxicity, one has to reduce the expression of mutated allele to a level as close as possible to zero (31). The basis of the myelin defect in Alexander disease is not known. It is particularly severe in the infantile form and in areas of white matter with abundant Rosenthal fibers. It can be considered, in large part, as a deficiency of normal myelination or hypomyelination, rather than demyelination. Little evidence exists of macrophage or microglial reaction or of sudanophilia, indicating that myelin destruction is not likely to be the primary process. One hypothesis on the cause of hypomyelination posits that the involvement of the astrocytes by the underlying abnormality interferes with their supportive role in myelination, and that the timing of this involvement in infantile cases coincides with the time of frontal lobe myelination. This is consistent with the more normal presence of myelin in the lower neuraxis and posterior cerebrum and the frontal predominance of hypomyelination in young cases. The same hypothesis can also be invoked to explain the less severe degree of a lack of myelin in the juvenile and adult onset forms because myelin may have already been formed before the astrocytic involvement became severe. It has also been proposed that a defect is located in the blood-brain barrier, which could be caused by the astrocytic abnormality. Increased endothelial pinocytic activity has been reported as an early finding in the periventricular frontal lobe and basal ganglia of infantile cases, areas that are affected early in the disease process. Likewise, early in the course of the infantile form, CT contrast enhancement is often present in the same areas that also show increased density in unenhanced scans as well as intense Rosenthal fiber deposition.

This suggests that the presence of Rosenthal fibers and the increased vascularity and pinocytic activity may be related. In contrast to other intermediate filaments mutation disorders, the GFAP mutations appear to cause a gain of function (27). Astrocytes derived from Alexander disease patient-induced pluripotent cells inhibit proliferation of human oligodendrocyte progenitor cells in coculture and reduce their myelination potential (26). The secreted glycoprotein CHI3L plays a role in that noncell autonomous inhibitory effect (26).

Epidemiology

All 3 forms of Alexander disease are rare disorders, but the most common of the 3 forms is the infantile form. The juvenile form is rarer, and the adult form even rarer. None of the forms shows an association with any particular ethnic group.

Prevention

The cause of de novo genetic mutations is unknown; thus, no form of prevention is available. Although prenatal testing can be performed in families where the spontaneous mutation in the GFAP gene is identified, the utility of this testing is likely to be extremely limited because familial cases of Alexander disease are so rare.

Differential diagnosis

Alexander disease in children needs to be differentiated from nonprogressive disorders that may give rise to developmental delay and mental retardation, such as cerebral palsy, as well as from other leukodystrophies and causes of hydrocephalus or seizures. In particular, disorders accompanied by megalencephaly, such as Canavan disease, Tay-Sachs disease and glutaric aciduria type I, need to be ruled out. Megalencephalic leukoencephalopathy with subcortical cysts can be clinically similar to Alexander disease, but is much more slowly progressive, is autosomal recessive, and often can be diagnosed by MRI or a genetic test (25). Also to be differentiated is a second autosomal recessive leukodystrophy, usually without megalencephaly, called childhood ataxia with central hypomyelination, or vanishing white matter disease. However, these other leukodystrophies do not manifest either Rosenthal fibers or mutations in GFAP. Benign familial macrocephaly and the rare cerebral gigantism should also be considered. If a brain biopsy is performed, Alexander disease must be differentiated from other entities associated with Rosenthal fibers, such as hamartomas and tumors. In addition, because some cases of childhood Alexander disease exhibit abnormalities of mitochondrial function, they need to be differentiated from primary mitochondrial disorders. Adult cases need to be distinguished from multiple sclerosis and tumors.

Diagnostic workup

Almost all cases of all 3 forms of Alexander disease can now be diagnosed by genetic analysis for mutations in GFAP. In addition, the MRI is often diagnostic, and a previously affected offspring has a proven mutation (44). The typical MRI abnormalities include extensive cerebral white matter changes with frontal predominance, a periventricular rim with high signal on T1-weighted images and low signal on T2-weighted images, abnormalities of basal ganglia and thalami, brainstem abnormalities, and contrast enhancement of particular gray and white matter structures (53). Lower brainstem and cervical atrophy are very common in Alexander disease and may be the sole abnormality on brain MRI in patients with the adult-onset form (44; 08). Less common MRI variants include predominantly posterior fossa lesions, especially multiple tumor-like brainstem lesions (28), asymmetrical frontal white matter and basal ganglia abnormalities as well as ventricular garlands (55; 54), or even focal central lesions (03). Also, a tigroid pattern of white matter changes in a 10-year-old boy with a slowly progressive disease (04). CT scan can be helpful (02; 53). Bilateral frontal predominance of the lesions and frontal cystic changes, along with relative sparing of the occipital lobe and cerebellum, support a diagnosis of infantile Alexander disease. When the lesions are in the brainstem, magnetic resonance spectroscopy may help differentiate between a glioma and Alexander disease (09). Routine studies on blood, urine, and cerebrospinal fluid are normal in Alexander disease, but GFAP is elevated in the CSF of most patients and sometimes in the blood as well (18). The absence of urinary organic acid abnormalities, elevated N-acetylaspartic acid, and a normal leukocyte hexosaminidase facilitate the dismissal of other megaloencephalic disorders considered, such as glutaric aciduria type I, Canavan disease, and Tay-Sachs disease. The electroencephalogram may present slow waves in the frontal region but is not diagnostic (39). Tests for other leukodystrophies, such as adult autosomal dominant leukodystrophy caused by duplication of the LMNB1 gene, adrenoleukodystrophy, Krabbe disease, metachromatic leukodystrophy, and perhaps Pelizaeus-Merzbacher disease, should also be performed to rule out these other disorders. However, definitive adult onset cases may show atrophy of the medulla and cervicothoracic spinal cord as well as shrunken pyramids (12). Signal change on FLAIR in the medulla and spinal cord as well as middle cerebellar peduncle and pia have been confirmed (12). Definitive diagnosis during life no longer requires brain biopsy, but biopsy can be diagnostic. Routine studies on blood, urine, and cerebrospinal fluid are normal in Alexander disease but GFAP protein and mRNA levels are frequently elevated (19). This biomarker will be evaluated in the spinal fluid and in blood in the coming years.

Management

No specific treatment is available. The care of patients with Alexander disease is entirely supportive and dictated by the current condition and any complications that have arisen. Treatment for seizures is usually required. Assisted feeding procedures often become necessary as the disease progresses. Current evidence suggests that reducing the expression of the mutated GFAP allele by using antisense oligonucleotides to reverse the neuropathology may be the most direct therapeutic approach (14). However, at present, the antisense oligonucleotides reduce the expression of both the wild type and the mutated allele (31).

Special considerations

Pregnancy

Not applicable to the infantile and juvenile forms. No information is available on the adult onset form.

Anesthesia

With pre-evaluation and caution concerning the possibilities of seizures, gastroesophageal reflux (with possible aspiration), and respiratory-pharyngeal muscle weakness, anesthesia can be safe.