Alexander Disease

Clinical characteristics.

Alexander disease, a progressive disorder of cerebral white matter caused by a heterozygous GFAP pathogenic variant, comprises a continuous clinical spectrum most recognizable in infants and children and a range of nonspecific neurologic manifestations in adults. This chapter discusses the spectrum of Alexander disease as four forms: neonatal, infantile, juvenile, and adult.

The neonatal form begins in the first 30 days after birth with neurologic findings (e.g., hypotonia, hyperexcitability, myoclonus) and/or gastrointestinal manifestations (e.g., gastroesophageal reflux, vomiting, failure to thrive), followed by severe developmental delay and regression, seizures, megalencephaly, and typically death within two years.

The infantile form is characterized by variable developmental issues: initially some have delayed or plateauing of acquisition of new skills, followed in some by a loss of gross and fine motor skills and language during in the first decade or in others a slow disease course that spans decades. Seizures, often triggered by illness, may be less frequent/severe than in the neonatal form.

The juvenile form typically presents in childhood or adolescence with clinical and imaging features that overlap with the other forms. Manifestations in early childhood are milder than those in the infantile form (e.g., mild language delay may be the only developmental abnormality or, with language acquisition, hypophonia or nasal speech may alter the voice, often prior to appearance of other neurologic features). Vomiting and failure to thrive as well as scoliosis and autonomic dysfunction are common.

The adult form is typically characterized by bulbar or pseudobulbar findings (palatal myoclonus, dysphagia, dysphonia, dysarthria or slurred speech), motor/gait abnormalities with pyramidal tract signs (spasticity, hyperreflexia, positive Babinski sign), or cerebellar abnormalities (ataxia, nystagmus, or dysmetria). Others may have hemiparesis or hemiplegia with a relapsing/remitting course or slowly progressive quadriparesis or quadriplegia. Other neurologic features can include sleep apnea, diplopia or disorders of extraocular motility, and autonomic dysfunction.

Diagnosis/testing.

The diagnosis of Alexander disease is established in a proband with suggestive clinical and neuroimaging findings and a heterozygous pathogenic variant in GFAP identified by molecular genetic testing.

Management.

Treatment of manifestations: Treatment is supportive and focuses on management by multidisciplinary specialists to manage general care, feeding, and nutrition; antiepileptic drugs for seizure control; physical and occupational therapy; speech and language therapy; and appropriate educational services.

Surveillance: Monitoring for progression of neurologic manifestations, developmental progress, and educational needs as well as need for services as they relate to physical therapy and occupational therapy, nutrition and safety of oral feeding, speech and language, gastrointestinal involvement, bladder function, evidence of autonomic dysfunction, pulmonary function, psychological/psychiatric manifestations, and sleep.

Genetic counseling.

Alexander disease is inherited in an autosomal dominant manner. To date, most reported individuals with molecularly confirmed Alexander disease have the disorder as the result of a de novo GFAP pathogenic variant; however, familial cases have been reported, including individuals with slowly progressive adult Alexander disease who have an affected parent. Individuals with Alexander disease with significant neurologic and cognitive impairment typically do not reproduce, whereas each child of an adult with slowly progressing Alexander disease has a 50% chance of inheriting the GFAP pathogenic variant. Once the GFAP pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Alexander disease are possible.

Suggestive Findings

Alexander disease should be suspected in individuals with the following age-related clinical and brain MRI findings.

Establishing the Diagnosis

The diagnosis of Alexander disease is established in a proband with suggestive clinical and neuroimaging findings and a heterozygous pathogenic variant in GFAP identified by molecular genetic testing (see Table 2).

Note: Identification of a heterozygous GFAP variant of uncertain significance does not establish or rule out the diagnosis of Alexander disease.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Alexander disease has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

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).

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.

Genotype-Phenotype Correlations

A number of genotype-phenotype correlations have been observed for some recurrent variants, albeit with a limited number of affected individuals (see Table 3 [pdf] for references and Table 11). It is possible that given the variable expressivity of the disorder, exceptions may occur.

• Infantile form. Recurrent pathogenic variants commonly (but not necessarily exclusively) observed in this form include: p.Met73Thr (c.218T>C), p.Leu76Phe (c.226C>T), p.Asn77Ser (c.230A>G), p.Arg79Cys (c.235C>T), p.Arg88Cys (c.262C>T), p.Leu97Pro (c.290T>C), p.Arg239Cys (c.715C>T), p.Arg239His (c.716G>A), p.Arg239Leu (c.716G>T), p.Arg239Pro (c.716G>C), p.Leu352Pro (c.1055T>C), p.Glu373Lys (c.1117G>A), p.Asp417MetfsTer15 (c.1249delG).
• Juvenile form. Recurrent pathogenic variants commonly (but not necessarily exclusively) observed in this form include: p.Arg79Cys (c.235C>T), p.Arg88Cys (c.262C>T), p.Glu210Lys (c.628G>A), p.Leu235Pro (c.704T>C), p.Arg239Cys (c.715C>T), p.Arg416Trp (c.1246C>T).
• Adult form. Recurrent pathogenic variants commonly (but not necessarily exclusively) observed in this form include: p.Arg66Gln (c.197G>A), p.Arg70Trp (208C>T), p.Arg70Gln (c.209G>A), p.Met74Thr (c.221T>C), p.Glu205Lys (c.613G>A), p.Arg258Cys (c.772C>T), p.Arg276Leu (c.827G>T), p.Leu359Pro (c.1076T>C), p.Ala364Thr (c.1090G>C), p.Ser393Ile (c.1178G>T), p.Arg416Trp (c.1246C>T).

Penetrance

Penetrance appears to be nearly 100% in individuals with the infantile and juvenile forms [Li et al 2002, Messing & Brenner 2003a, Messing 2018].

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].

Nomenclature

Prevalence

The prevalence of Alexander disease is not known, but hundreds of affected individuals with heterozygous GFAP pathogenic variants have been reported.

The only population-based prevalence estimate is one in 2.7 million [Yoshida et al 2011].

The disorder is known to occur in diverse ethnic and racial groups [Gorospe & Maletkovic 2006].

Differential Diagnosis in Neonates, Infants, and Juveniles