Alexander disease
Synonyms and keywords: Dysmyelogenic leukodystrophy, Dysmyelogenic leukodystrophy-megalobare, Fibrinoid degeneration of astrocytes, Fibrinoid leukodystrophy, Hyaline panneuropathy, Leukodystrophy with Rosenthal fibers, Megalencephaly with hyaline inclusion, Megalencephaly with hyaline panneuropathy

# Overview
Alexander disease is a slowly progressing and fatal neurodegenerative disease. It is a very rare disorder that results from a genetic mutation and mostly affects infants and children, causing developmental delay and changes in physical characteristics.

# Historical Perspective
- Alexander disease was first described in 1949 by the New Zealand pathologist William Alexander in London, England under his paper "Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant", where he reported a case of a 16-month old child who died after presenting a history of increasing macrocephaly and developmental delay.
- In 1959, Wohwill et al. reported the case of siblings with Alexander disease phenotype and suggested the possibility of an autosomal recessive transmission.
- By the decade of 1960 s, the presence of Rosenthal fibers accompanied by the destruction of white matter and progressive neurologic imapairment was recognized as the hallmark of patients with Alexander disease.
- In 2001, Brenner et. al discovered that mutations in GFAP encoding for glial fibrillary acidic protein, could be the causant of most of the cases of Alexander disease.

# Classification
- Alexander disease is classified according to the age of onset and clinical course as:
Type I (infantile). The most common type of Alexander disease, usually caused by de novo mutations, with an age of onset before 4 years of age. It presents with seizures, macrocephaly, developmental delay, failure to thrive, intractable vomiting, encephalopathy, and classic imaging findings.
Type II (juvenile and adult). Often familial, with an age of onset after 4 years of age. It presents with bulbar dysfunction, palatal myoclonus, autonomic dysfunction, less significant encephalopathy, and atypical imaging findings.
- Type I (infantile). The most common type of Alexander disease, usually caused by de novo mutations, with an age of onset before 4 years of age. It presents with seizures, macrocephaly, developmental delay, failure to thrive, intractable vomiting, encephalopathy, and classic imaging findings.
- Type II (juvenile and adult). Often familial, with an age of onset after 4 years of age. It presents with bulbar dysfunction, palatal myoclonus, autonomic dysfunction, less significant encephalopathy, and atypical imaging findings.
- Some authors propose the inclusion of a neonatal form in the classification of Alexander disease to describe patients with the onset of symptoms within the first month of life.

# Pathophysiology
- Alexander disease is an astrocytopathy that belongs to the group of disorders called leukodystrophies, which affect growth or development of the myelin sheath.
- Alexander disease is characterized by a white matter destruction in the midbrain and cerebellum.
- The destruction of white matter destruction in the central nervous system (CNS) is accompanied by the formation of fibrous, eosinophilic deposits known as Rosenthal fibers.
- Mutated glial fibrillary acidic protein accumulates which in turn aggregates astrocytes to form the so called Rosenthal fibers.
- Rosenthal fibers are known to be the major contributer in the pathogenesis of Alexander disease and its accumulation in especific sites may cause obstructive hydrocephalus.
- Glial fibrillary acidic protein accumulation causes an overload of long-chain fatty acids in the brain, which induces T-cells infiltrates that destroy the myelin sheath.

## Pathogenesis
- The most accepted proposed mechanism to explain Alexander disease is as follows:
- The accumulation of glial fibrillary acidic protein and the consequent formation of characteristic aggregates, called Rosenthal fibers in various cell types, and especially astrocytes.
- The accumulation appears to be due to a gain in function due to the mutation that partially blocks the assembly of the GFAP filaments.
- Subsequent sequestration of ubiquitin and the -B-crystalline chaperone proteins and HSP27 in the Rosenthal fibers.
- Activation of both the Jnk protein and the stress response.

## Genetics
- Individuals with Alexander disease present a mutation in the gene GFAP that maps to chromosome 17q21.
- GFAP gene comprises nine exons distributed over 9.8 kb, transcribed into a 3-kb mRNA.
- When inherited, Alexander disease is transmitted in an autosomal dominant manner.
- Penetrance appears to be close to 100% in patients with Alexander disease type I.

## Gross Pathology
- The main features in brain biopsies of patients with Alexander disease are Rosenthal fibers accumulation (mostly in the superficial cortex) and loss of myelin from the white matter.
- It may be challenging to differentiate mass-like lesions in Alexander disease from low-grade astrocytomas due to the proliferative nature of the astrocytic lesions; one finding that may separate Alexander disease is the presence of biphasic morphology and eosinophylic granular bodies.

# Causes
- The cause of Alexander disease is a mutation in one or more exons of the gene GFAP, encoding for glial fibrillary acidic protein:
Exon 1 (45.5% of cases)
Exon 3 (3.3% of cases)
Exon 4 (27.2% of cases)
Exon 5 (1.8% of cases)
Exon 6 (16.0% of cases)
Exon 7 (<1% of cases)
Exon 8 (7.5% of cases).
- Exon 1 (45.5% of cases)
- Exon 3 (3.3% of cases)
- Exon 4 (27.2% of cases)
- Exon 5 (1.8% of cases)
- Exon 6 (16.0% of cases)
- Exon 7 (<1% of cases)
- Exon 8 (7.5% of cases).

# Differentiating Alexander disease from Other Diseases
- Alexander disease must be differentiated from other disorders that affect the white matter such as:
X-linked adrenoleukodystrophy
Krabbe disease
Canavan disease
Arylsulfatase A deficiency
Megalencephalic leukoencephalopathy
- X-linked adrenoleukodystrophy
- Krabbe disease
- Canavan disease
- Arylsulfatase A deficiency
- Megalencephalic leukoencephalopathy

# Epidemiology and Demographics
- Alexander disease is a rare condition; since the description of the first affected individual until 2015, only 550 cases have been reported.
- The incidence of Alexander disease has not been reported.
- The prevalence world-wide of Alexander disease has not been reported. In a study made by Yoshida et al. in 2012 in Japan, they estimated a prevalence of 1 in 2.7 million population studied.
- Patients of all age groups may develop Alexander disease, but it infantile (type I) form is more common, with presentation appearing usually before 2 years of age.
- There is no gender predilection to Alexander disease.
- There is no racial predilection to Alexander disease.
- There is no geographic predilection to Alexander disease.
- There is no economic predilection to Alexander disease.

# Risk Factors
- There are no established risk factors for developing Alexander disease.
- The risk to other family members depends on the genetic status of the proband's parents (if they present with a GFAP pathogenic variant).

# Screening
- According to the van der Knaap et al. (2001),genetic testing screening for Alexander disease by searching for GFAP mutations is recommended among patients with classic MRI features.
- Guidelines for GFAP mutations screening in individuals with suspected atypical MRI findings do not exist for Alexander disease type II.
- It is recommended to screen parents of children with Alexander disease to rule-out familial type of late onset.
- Testing of asymptomatic siblings is still on debate and will depend on their age and inquiery of the parents. Probability of a second de novo mutation is extremely low.
- When testing for exonic mutations is negative, you should always consider splice-site mutations.

# Natural History, Complications and Prognosis
- Life expectancy in individuals with Alexander disease is variable.
- In some cases of the adult form, patients present no symptoms.
- Individuals with type I of Alexander disease typically do not reproduce.
- The prognosis of individuals with Alexander disease is generally poor. With early-onset, death usually occurs within 10 years after the onset of symptoms in infantile forms (type I). Usually, the later the disease occurs, the slower its course is.
- Common complications of Alexander disease are included in the "History and Symptoms" section.

# Diagnosis

## Diagnostic Study of Choice
- The diagnosis of Alexander disease is made when genetic testing confirms a heterozygous pathogenic variant of GFAP gene in a proband, although, first step is to suspect the disorder by clinical presentation and back it up with CNS imaging (signal abnormalities or atrophy of the medulla or spinal cord have sufficient weight to warrant a genetic study).

## History and Symptoms

### History
- There is not a single specific clinical presentation of Alexander disease, since it varies among the age of onset.

### Common symptoms
- Common symptoms of Alexander disease include:
Type I:
Seizures
Encephalopathy
Paroxysmal deterioration
Failure to thrive
Developemental delay
Focal mass-like symptoms
Type II:
Autonomic dysfunction
Bulbar symptoms
Ocular movement abnormalities
Palatal myoclonus
- Type I:
Seizures
Encephalopathy
Paroxysmal deterioration
Failure to thrive
Developemental delay
Focal mass-like symptoms
- Seizures
- Encephalopathy
- Paroxysmal deterioration
- Failure to thrive
- Developemental delay
- Focal mass-like symptoms
- Type II:
Autonomic dysfunction
Bulbar symptoms
Ocular movement abnormalities
Palatal myoclonus
- Autonomic dysfunction
- Bulbar symptoms
- Ocular movement abnormalities
- Palatal myoclonus

### Less common symptoms
- Less common symptoms of Alexander disease include:
- Dysarthria
- Sleep disturbance
- Dysphonia
- Gait disturbance
- Frequent emesis
- Hiccups
- Frequent vomiting
- Dementia

## Physical Examination
- Physical examination will also vary depending on the age of presentation; the most typical findings that make Alexander disease more suspicious are:
Infantile: progressive psychomotor retardation, developmental regression, megalencephaly with frontal bossing, seizures, pyramidal signs, ataxia, and occasional hydrocephalus secondary to aqueductal stenosis.
Juvenile: bulbar/pseudobulbar signs with nasal speech, lower limb spasticity, ataxia, gradual loss of intellectual function, seizures, megalencephaly, and breathing problems.
Adults: bulbar/pseudobulbar signs, pyramidal tract signs, cerebellar signs, dysautonomia, sleep disturbance, gait disturbance, hemiparesis/hemiplegia or quadriparesis/quadriplegia, seizures, and diplopia.
- Infantile: progressive psychomotor retardation, developmental regression, megalencephaly with frontal bossing, seizures, pyramidal signs, ataxia, and occasional hydrocephalus secondary to aqueductal stenosis.
- Juvenile: bulbar/pseudobulbar signs with nasal speech, lower limb spasticity, ataxia, gradual loss of intellectual function, seizures, megalencephaly, and breathing problems.
- Adults: bulbar/pseudobulbar signs, pyramidal tract signs, cerebellar signs, dysautonomia, sleep disturbance, gait disturbance, hemiparesis/hemiplegia or quadriparesis/quadriplegia, seizures, and diplopia.

## Laboratory Findings
- Molecular genetic testing used to evaluate GFAP mutations in Alexander disease are sequence analysis and deletion/duplication analysis.
- CSF may disclose an increased levels of glial fibrillary acidic protein and -crystallin and heat shock protein 27 in individuals with Alexander disease.

## Electrocardiogram
- There are no ECG findings associated with Alexander disease.

## X-ray
- There are no x-ray findings associated with Alexander's disease. However, an x-ray may be helpful in the diagnosis of complications, which include scoliosis and frontal bossing.

## Echocardiography or Ultrasound
- There are no echocardiography/ultrasound findings associated with Alexander disease.

## CT scan
- Alexander disease may show the following findings in a head CT scan:
Decreased density of white matter
Frontal lobe predominance
+/- Dilated lateral ventricles
- Decreased density of white matter
- Frontal lobe predominance
- +/- Dilated lateral ventricles

## MRI
- Type I Alexander disease has the following findings on MRI of the CNS, known as the classic Alexander disease findings:
Frontal predominance of central white matter involvement manifested by T2 hyperintensity and T1 hypointensity
Periventricular rim of T2 hypointensity and T1 hyperintensity
Abnormal T2 signal, swelling or atrophy of basal ganglia/thalamus
Abnormal T2 signal of the brain stem
Contrast enhancement of selected structures
- Frontal predominance of central white matter involvement manifested by T2 hyperintensity and T1 hypointensity
- Periventricular rim of T2 hypointensity and T1 hyperintensity
- Abnormal T2 signal, swelling or atrophy of basal ganglia/thalamus
- Abnormal T2 signal of the brain stem
- Contrast enhancement of selected structures
- Other MRI findings, known as atypical, can be identified, especially in patients with type II Alexander disease, these are:
Predominant or isolated involvement of posterior fossa structures
Multifocal tumor-like brain stem lesions and brain stem atrophy
Slight, diffuse signal changes involving the basal ganglia and/or thalamus
Garland-like feature along the ventricular wall
Characteristic pattern of contrast enhancement
Any other findings that suggest, but do not meet, the strict criteria
- Predominant or isolated involvement of posterior fossa structures
- Multifocal tumor-like brain stem lesions and brain stem atrophy
- Slight, diffuse signal changes involving the basal ganglia and/or thalamus
- Garland-like feature along the ventricular wall
- Characteristic pattern of contrast enhancement
- Any other findings that suggest, but do not meet, the strict criteria

## Other Imaging Findings
- There are no other imaging findings associated with Alexander's disease.

## Other Diagnostic Studies
- Electroencephalogram in Alexander disease may show slow activity, which is much more prominent over the anterior than posterior regions.

# Treatment

## Medical Therapy
- There is neither cure nor standard treatment for Alexander disease. All treatment is symptomatic and supportive, for example antibiotics for intercurrent infection and anticonvulsants for seizure control are usually used.

## Surgery
- There are no surgical interventions specific for Alexander disease. Some complications such as scoliosis may require surgical correction in severe cases.

## Primary Prevention
- There are no established measures for the primary prevention of Alexander disease.

## Secondary Prevention
- Multidisciplinary care should be implemented in regular visits to early detect and treat progression of nutritional status, swallowing ability, strength, mobility, and early signs of scoliosis in patients with Alexander disease.