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; anti-seizure medication; 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

Differential Diagnosis in Adults

Multiple sclerosis (MS). Similar to Alexander disease, MS is characterized by relapsing and remitting hemiparesis or hemiplegia, dysarthria, and ataxia. On MRI, MS is associated with mild frontal white matter involvement, periventricular rim, and brain stem or cervical cord signal abnormalities. Unlike Alexander disease, MS is not inherited in an autosomal dominant manner and, on MRI, MS is associated with generalized brain atrophy (rather than symmetric brain stem signal abnormalities with medullary and cord atrophy as in Alexander disease).

Hereditary disorders in the differential diagnosis of the adult form of Alexander disease are summarized in Table 7.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Alexander disease, the evaluations summarized in Table 8 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

No specific therapy is currently available for Alexander disease; however, clinicians and families should routinely check ClinicalTrials.gov or other experts regarding potential experimental therapies [Hagemann et al 2018].

Management is supportive and includes attention to general care, feeding and nutrition, anti-seizure medication (ASM) for seizure control, physical and occupational therapy, speech and language therapy, and appropriate educational services. The management by multidisciplinary specialists as outlined in Table 9 is recommended.

Surveillance

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Alexander disease is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• To date, most reported individuals with molecularly confirmed Alexander disease have the disorder as the result of a de novo GFAP pathogenic variant, though familial cases have occurred [Messing 2018].
• A study on unrelated individuals with Alexander disease revealed that the GFAP pathogenic variant was on the paternal chromosome in a majority of individuals (24/28), suggesting that most instances of de novo mutation occur during spermatogenesis rather than in the embryo [Li et al 2006].
• Some individuals with slowly progressive adult Alexander disease have an affected parent [Namekawa et al 2002, Okamoto et al 2002, Stumpf et al 2003, Thyagarajan et al 2004, van der Knaap et al 2006, Messing et al 2012].
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant (i.e., a proband who appears to be the only affected family member).
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. * Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. Sib recurrence of neuropathologically and molecularly proven Alexander disease in families in which the parents are neurologically intact suggest the possibility of germline mosaicism in one of the parents [Messing et al 2012, Messing 2018].
    * An individual with somatic and germline mosaicism for a GFAP pathogenic variant may be mildly/minimally affected [Flint et al 2012].
• Some individuals with Alexander disease may appear to be the only affected family member because of failure to recognize the disorder in other family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Variable expressivity may occur in heterozygous family members (see Genotype-Phenotype Correlations and Penetrance).
• If the GFAP pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Messing 2018].
• If the parents have not been tested for the GFAP pathogenic variant but are clinically unaffected, the risk to the sibs of a proband with Alexander disease appears to be lower than 1:200 (i.e., <0.5%) because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.

Offspring of a proband

• Individuals with Alexander disease with significant neurologic and cognitive impairment typically do not reproduce.
• Each child of an adult with slowly progressing Alexander disease has a 50% chance of inheriting the GFAP pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the GFAP pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Predictive testing for Alexander disease (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the GFAP pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of Alexander disease, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e. the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the GFAP pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Alexander disease are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

GFAP encodes glial fibrillary acidic protein, the main intermediate filament protein expressed in mature astrocytes of the central nervous system. GFAP is a homotetramer, consisting of two dimers of paired alpha-helices and stabilized by a vast array of intermolecular interactions [Kim et al 2018]. As a cytoskeletal protein providing structural stability, GFAP appears to be important in modulating the morphology and motility of astrocytes [Eng et al 2000, Messing & Brenner 2003b]; however, it may have other as-yet unknown functions.

Mechanism of disease causation. Gain of function. The cellular mechanism causing the Alexander disease phenotype remains unresolved; however, abnormal protein oligomerization that alters either the oligomerization or the solubility of the protein has been proposed [Hsiao et al 2005, Der Perng et al 2006]. Proteins encoded by pathogenic variants in GFAP may interfere with the intermolecular interactions necessary to stabilize the protein, leading to increased protein aggregation [Kim et al 2018, Viedma-Poyatos et al 2018]. Expression of an abnormal protein may result in disturbance of the normal interaction between astrocytes and oligodendrocytes, resulting in hypomyelination or demyelination. See Messing et al [2001], Gorospe & Maletkovic [2006], and Sosunov et al [2018].

Consistent with a gain-of-function mechanism, the majority of disease-associated variants are missense or in-frame variants [Li et al 2005, van der Knaap et al 2006, Murakami et al 2008, Ayaki et al 2010, Flint et al 2012, Schmidt et al 2013].

GFAP-specific laboratory technical considerations. The most common pathogenic variants occur at three amino acid residues (p.Arg79, p.Arg88, and p.Arg239).

Most GFAP pathogenic variants have been reported on transcript NM_002055.4; however, a heterozygous variant (p.Arg430His) presently only on the transcript NM_001131019.2 has been identified in multiple individuals [Melchionda et al 2013, Karp et al 2019, Helman et al 2020] (see Table 11).

Author Notes

Website for Amy Waldman at the Children's Hospital of Philadelphia
www.chop.edu/doctors/waldman-amy

Website for Siddharth Srivastava at Boston Children's Hospital
www.childrenshospital.org/directory/physicians/s/siddharth-srivastava

Clinical trial pertaining to outcome measures of Alexander disease at the Children's Hospital of Philadelphia
www.research.chop.edu/axd-outcomes

Author History

J Rafael Gorospe, MD, PhD; NIH – National Center for Research Resource (2002-2015)
Sakkubai Naidu, MD (2015-present)
Siddharth Srivastava, MD (2015-present)
Amy Waldman, MD, MSCE (2020-present)

Revision History

• 12 November 2020 (bp) Comprehensive update posted live
• 8 January 2015 (me) Comprehensive update posted live
• 22 April 2010 (me) Comprehensive update posted live
• 9 March 2007 (cd,jrg) Revision: sequence analysis of select exons and targeted mutation analysis no longer clinically available
• 2 October 2006 (me) Comprehensive update posted live
• 28 September 2004 (me) Comprehensive update posted live
• 5 May 2003 (cd,jrg) Revision: molecular genetic testing clinically available
• 15 November 2002 (me) Review posted live
• 24 April 2002 (jrg) Original submission

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