Clinical Description
Alexander disease is a progressive disorder affecting cerebral white matter. It is most readily recognized in infants and children. Adults can also be affected, but manifestations and diagnosis may be under-recognized. Life expectancy is variable. Many individuals with Alexander disease present with nonspecific neurologic manifestations.
Previous classification recognized four forms: neonatal (sometimes considered a subset of the infantile form), infantile, juvenile, and adult. Based on a prior review of reports of GFAP variants, the infantile form of Alexander disease accounts for 42% (124/293) of reported individuals with an identifiable GFAP pathogenic variant; the juvenile form accounts for 22% (63/293); and the adult form accounts for 33% (96/293) (see Table 3 [pdf]). Ten (3%) of the 293 individuals with an identifiable GFAP pathogenic variant were reported to be asymptomatic [Stumpf et al 2003, Shiihara et al 2004, Yoshida et al 2011, Messing et al 2012, Wada et al 2013]. The current clinical status of these individuals is unknown.
Additional case series have suggested a two-group classification system (Type I and Type II) [Prust et al 2011] or a three-group classification system (cerebral, bulbospinal, intermediate) [Yoshida et al 2011].
See Table 4 for a comparison of select features seen in the different forms (based on age of onset).
Table 4.
Alexander Disease: Comparison of Forms by Select Features
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| Neonatal | Infantile | Juvenile | Adult |
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Typical age at presentation
| 1st mo of life | Infancy or childhood | Childhood or adolescence | Adolescence or adulthood |
Core neurologic manifestations
| Lack of developmental progression; motor impairment w/o spasticity; seizures; megalencephaly; hydrocephalus | Developmental delay or developmental regression; seizures; megalencephaly | Bulbar/pseudobulbar signs w/nasal speech, dysphagia, dysphonia; failure to thrive; intractable vomiting; scoliosis; autonomic dysfunction | Pyramidal involvement; bulbar dysfunction; autonomic dysfunction |
Other findings
| Feeding difficulties (failure to thrive) | Failure to thrive | Short stature | Cerebellar involvement; palatal myoclonus; normocephaly |
The forms described in Table 4 and below likely represent a phenotypic continuum rather than distinct classifications. However, subgrouping is intended to help clinicians care for affected individuals and explain the disorder to them and/or their families.
Neonatal form. Neurologic manifestations (e.g., hypotonia, hyperexcitability, myoclonus) and/or gastrointestinal manifestations (e.g., gastroesophageal reflux, vomiting, failure to thrive) begin within 30 days of birth [Springer et al 2000]. Affected children fail to achieve early milestones, and if they do, may show developmental regression (though developmental regression may be difficult to identify at such an early age and may manifest only as loss of sucking reflex). Following these initial findings, seizures occur during the neonatal period or infancy. Seizures may be generalized, frequent, and/or intractable. Megalencephaly, with frontal bossing or over-proportional head growth compared to weight and length, occurs over the first several months of life. In this age group specifically, children should be monitored for hydrocephalus with raised intracranial pressure, primarily caused by aqueductal stenosis. Neurologic examination is notable for severe cognitive, language, and motor delay without prominent spasticity or ataxia. Rapid progression may occur, leading to severe disability or death, typically within two years.
Infantile form. Affected children typically present with developmental delay or plateau (failure to gain additional skills). The acquisition of developmental milestones is variable. While some children learn to walk and speak in phrases or sentences, others do not achieve independent ambulation and demonstrate limited spoken language ability. Dysarthria is frequently present in individuals who achieve expressive language.
Most children are referred to neurology after an initial seizure, often leading to brain MRI that reveals characteristic features (see Table 1) and recognition of the disorder. Seizures (often triggered by illness) may be less frequent/severe than in the neonatal form.
Frontal bossing and megalencephaly are not universally present. Macrocephaly is not always noted at the time of other neurologic manifestations (e.g., seizures, developmental delay) and may be detected through serial measurement of the head circumference many years after the initial neurologic manifestations and diagnosis.
While developmental regression may occur after a seizure or mild head trauma, some individuals can regain skills over time. Disease progression is also variable, with some individuals losing gross and fine motor as well as language skills in the first decade of life, while others follow a very slow disease course that spans decades.
Juvenile form. Children may present with a combined or intermediate [Yoshida et al 2011] phenotype with clinical and imaging features overlapping those of the other forms. Onset is usually in childhood or adolescence.
Compared to the infantile form, affected children have milder manifestations in early childhood. For example, mild language delay may be the only developmental abnormality or, with language acquisition, a change in voice (hypophonia or nasal speech) may develop, often prior to other neurologic features. Children and adolescents with this phenotype frequently have vomiting and failure to thrive as well as scoliosis and autonomic dysfunction.
Some individuals with Alexander disease present with vomiting as the only manifestation of bulbar dysfunction (i.e., dysphagia and dysphonia may not be present initially) [Namekawa et al 2012]. Anorexia is frequently present as well, and affected individuals may be diagnosed with an eating disorder. Over time, individuals have failure to thrive (poor weight gain) and delayed physical growth (short stature). Progressive scoliosis occurs in some individuals.
It is possible that this phenotype represents a spectrum of disease with other presentations. Longitudinal evaluations of individuals with Alexander disease have deidentified those with isolated brain stem lesions whose symptoms spontaneously resolved and who subsequently developed medullary and cervical cord atrophy as noted in the adult phenotype [Namekawa et al 2012].
Adult form. Adults typically present with bulbar or motor manifestations reflecting the prominent infratentorial involvement in this form. Bulbar or pseudobulbar manifestations include palatal myoclonus, dysphagia, dysphonia, dysarthria, or slurred speech. Other individuals present with gait abnormalities and are noted to have pyramidal tract signs (spasticity, hyperreflexia, positive Babinski sign) or cerebellar abnormalities (ataxia, nystagmus, or dysmetria). While some individuals have hemiparesis or hemiplegia and may have a relapsing remitting course [Ayaki et al 2010], others have a slowly progressive quadriparesis or quadriplegia. Other features include sleep apnea, diplopia or disorders of extraocular motility (impaired smooth pursuit, gaze-evoked horizontal nystagmus, slowed saccades, or ocular myoclonus) [Martidis et al 1999], and autonomic dysfunction (incontinence, constipation, pollakiuria [urinary frequency], urinary retention, impotence, sweating abnormality, hypothermia, orthostatic hypotension) [Spritzer et al 2013].
Variable expressivity is most frequently observed in affected individuals within a family in which mildly affected parents and sibs of affected individuals have a GFAP pathogenic variant [Messing 2018].
In contrast, in one family all three individuals with a GFAP pathogenic variant had mild manifestations: a boy age 16 months had macrocephaly; his mother (age 34 years) and sister (age 7 years) had normal physical and neurologic examinations, including head circumference. However, their brain MRIs showed abnormal signal intensities in the deep frontal white matter and caudate [Shiihara et al 2004]. Clinical follow up has not been reported.
EEG. Electroencephalographic studies are nonspecific. While some individuals may have a normal EEG, others may show slow waves over the frontal areas. Focal epileptiform discharges have been reported, and may be related to cortical abnormalities [Gordon 2003], although generalized patterns have also occurred, likely due to thalamic involvement.
Histologic studies. Prior to the definition of the molecular genetic basis of Alexander disease, the demonstration of enormous numbers of Rosenthal fibers on brain biopsy or at autopsy was the only method for definitive diagnosis. 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. Some individuals with mass-like lesions have been biopsied, and the presence of Rosenthal fibers has led to genetic confirmation of Alexander disease.