Clinical Description
Alexander disease is a progressive disorder of cerebral white matter that predominantly affects infants and children. Life expectancy is variable. 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 42% (124/293) of reported individuals with an identifiable GFAP pathogenic variant (see Table 2). The juvenile form accounts for 22% (63/293) and the adult form 33% (96/293) (see Table 2).
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.
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
Frontal bossing and megalencephaly including enlargement of cerebellum and brain stem
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 following 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, Messing et al 2012, Wada et al 2013]. Based on a retrospective study of 13 individuals with late-onset Alexander disease, brain stem and/or spinal cord involvement may be common, resulting in symptoms such as nystagmus, dysphagia, dysarthria, spasticity/hyperreflexia, positive Babinski sign, gait abnormality, and weakness, though individual-to-individual and intrafamilial variability is seen [Graff-Radford et al 2014]. The full set of signs and symptoms variably seen in affected individuals comprises the following:
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. Focal epileptiform discharges may also be seen [Gordon 2003].
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 pathogenic variant is unknown.
Post-term delivery, hypotonia, frequent syncopal episodes, unusual nevi, hypothyroidism [
Gorospe et al 2002]
Mood disturbances, osteopenia, microcoria, primary ovarian failure, hypothyroidism [
Sreedharan et al 2007]
Vertebral anomalies:
Some asymptomatic individuals have been identified as having a GFAP pathogenic variant 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]. Due to lack of follow-up studies, it is not clear whether these individuals remain asymptomatic, or whether symptoms will emerge gradually with time.
Histologic studies. Prior to the definition of the molecular genetic basis of Alexander disease, the demonstration of enormous numbers of Rosenthal fibers on brain biopsy or at autopsy was the only method for definitive diagnosis of the disease. Rosenthal fibers are intracellular inclusion bodies composed of aggregates of glial fibrillary acidic protein, vimentin, αβ-crystallin, and heat shock protein 27 found exclusively in astrocytes. Rosenthal fibers increase in size and number during the course of the disease.