Alexander disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Moises Romo M.D.

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 which 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.
• 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, 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). With an age of onset after 4 years of age. It presents with bulbar dysfunction, palatal myoclonus, autonomic dysfunction, less significant encephalopathy, atypical imaging findings.

Pathophysiology

Alexander disease is a heritable cerebral white matter disorder caused by dominant missense mutations in 1 allele of the glial fibrillary acidic protein (GFAP) gene.

Alexander disease belongs to a group of disorders called leukodystrophies, which affect growth or development of the myelin sheath.

The destruction of white matter in the brain is accompanied by the formation of fibrous, eosinophilic deposits known as Rosenthal fibers.

The exact pathogenesis of [disease name] is not fully understood.

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It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].

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[Pathogen name] is usually transmitted via the [transmission route] route to the human host.

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Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.

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[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].

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The progression to [disease name] usually involves the [molecular pathway].

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The pathophysiology of [disease/malignancy] depends on the histological subtype.

Causes

Disease name] may be caused by [cause1], [cause2], or [cause3].

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Common causes of [disease] include [cause1], [cause2], and [cause3].

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The most common cause of [disease name] is [cause 1]. Less common causes of [disease name] include [cause 2], [cause 3], and [cause 4].

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The cause of [disease name] has not been identified. To review risk factors for the development of [disease name], click here.

Genetics

Alexander disease is a genetic disorder affecting the central nervous system (midbrain and cerebellum). It is caused by mutations in the gene for glial fibrillary acidic protein (GFAP) that maps to chromosome 17q21. It is inherited in an autosomal dominant manner.

Causes

• The cause of Alexander disease is a mutation in the gene GFAP, encoding glial fibrillary acidic protein.

Differentiating Alexander disease from Other Diseases

[Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as [differential dx1], [differential dx2], and [differential dx3].

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[Disease name] must be differentiated from [[differential dx1], [differential dx2], and [differential dx3].

Epidemiology and Demographics

Alexander disease has a prevalence of 1 in 2.7 million population studied.

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.

The infantile form (80% of all cases) starts usually at the age of six months or within the first two years. The average duration of the infantile form of the illness is usually about 3 years. Onset of the juvenile form (14% of all cases) presents usually between four to ten years of age. Duration of this form is in most cases about 8 years. In younger patients, seizures, megalencephaly, developmental delay, and spasticity are usually present. Neonatal onset is also reported. Onset in adults is least frequent. In older patients, bulbar or pseudobulbar symptoms and spasticity predominate. Symptoms of the adult form may also resemble multiple sclerosis.

The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.

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In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.

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In [year], the incidence of [disease name] is approximately [number range] per 100,000 individuals with a case-fatality rate of [number range]%.

Patients of all age groups may develop [disease name].

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The incidence of [disease name] increases with age; the median age at diagnosis is [#] years.

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[Disease name] commonly affects individuals younger than/older than [number of years] years of age.

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[Chronic disease name] is usually first diagnosed among [age group].

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[Acute disease name] commonly affects [age group].

There is no racial predilection to [disease name].

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[Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].

[Disease name] affects men and women equally.

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[Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1.

The majority of [disease name] cases are reported in [geographical region].

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[Disease name] is a common/rare disease that tends to affect [patient population 1] and [patient population 2].

Risk Factors

There are no established risk factors for [disease name].

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The most potent risk factor in the development of [disease name] is [risk factor 1]. Other risk factors include [risk factor 2], [risk factor 3], and [risk factor 4].

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Common risk factors in the development of [disease name] include [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].

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Common risk factors in the development of [disease name] may be occupational, environmental, genetic, and viral.

Screening

There is insufficient evidence to recommend routine screening for [disease/malignancy].

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According to the [guideline name], screening for [disease name] is not recommended.

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According to the [guideline name], screening for [disease name] by [test 1] is recommended every [duration] among patients with [condition 1], [condition 2], and [condition 3].

Natural History, Complications and Prognosis

The prognosis is generally poor. With early onset, death usually occurs within 10 years after the onset of symptoms. Usually, the later the disease occurs, the slower its course is.

If left untreated, [#]% of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].

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Common complications of [disease name] include [complication 1], [complication 2], and [complication 3].

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Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with [disease name] is approximately [#]%.

Diagnosis

History and Symptoms

• Delays in development of some physical, psychological and behavioral skills
• Progressive enlargement of the head (macrocephaly)
• Seizures
• Spasticity
• Hydrocephalus
• Dementia
• Clumsy movements.

CT Findings

• Decreased density of white matter
• Frontal lobe predominance
• +/- Dilated lateral ventricles

MRI Findings

• Type I Alexander disease is distinguished on an MRI due to:
  • 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

Diagnostic Study of Choice

The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: [criterion 1], [criterion 2], [criterion 3], and [criterion 4].

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The diagnosis of [disease name] is based on the [criteria name] criteria, which include [criterion 1], [criterion 2], and [criterion 3].

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The diagnosis of [disease name] is based on the [definition name] definition, which includes [criterion 1], [criterion 2], and [criterion 3].

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There are no established criteria for the diagnosis of [disease name].

History and Symptoms

Common symptoms

Common symptoms of Alexander disease include:

Type I:

Seizures

Macrocephaly

Encephalopathy

Paroxysmal deterioration

Failure to thrive

Developemental delay

Type II:

Atonomic 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

The majority of patients with [disease name] are asymptomatic.

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The hallmark of [disease name] is [finding]. A positive history of [finding 1] and [finding 2] is suggestive of [disease name].

The most common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].

Common symptoms of [disease] include [symptom 1], [symptom 2], and [symptom 3].

Less common symptoms of [disease name] include [symptom 1], [symptom 2], and [symptom 3].

Physical Examination

Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].

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Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].

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The presence of [finding(s)] on physical examination is diagnostic of [disease name].

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The presence of [finding(s)] on physical examination is highly suggestive of [disease name].

Laboratory Findings

An elevated/reduced concentration of serum/blood/urinary/CSF/other [lab test] is diagnostic of [disease name].

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Laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

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[Test] is usually normal among patients with [disease name].

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Some patients with [disease name] may have elevated/reduced concentration of [test], which is usually suggestive of [progression/complication].

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There are no diagnostic laboratory findings associated with [disease name].

Electrocardiogram

There are no ECG findings associated with [disease name].

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An ECG may be helpful in the diagnosis of [disease name]. Findings on an ECG suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

X-ray

There are no x-ray findings associated with [disease name].

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An x-ray may be helpful in the diagnosis of [disease name]. Findings on an x-ray suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

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There are no x-ray findings associated with [disease name]. However, an x-ray may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with [disease name].

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Echocardiography/ultrasound may be helpful in the diagnosis of [disease name]. Findings on an echocardiography/ultrasound suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

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There are no echocardiography/ultrasound findings associated with [disease name]. However, an echocardiography/ultrasound may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

CT scan

There are no CT scan findings associated with [disease name].

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[Location] CT scan may be helpful in the diagnosis of [disease name]. Findings on CT scan suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

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There are no CT scan findings associated with [disease name]. However, a CT scan may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

MRI

There are no MRI findings associated with [disease name].

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[Location] MRI may be helpful in the diagnosis of [disease name]. Findings on MRI suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

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There are no MRI findings associated with [disease name]. However, a MRI may be helpful in the diagnosis of complications of [disease name], which include [complication 1], [complication 2], and [complication 3].

Other Imaging Findings

There are no other imaging findings associated with [disease name].

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[Imaging modality] may be helpful in the diagnosis of [disease name]. Findings on an [imaging modality] suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

There are no other diagnostic studies associated with [disease name].

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[Diagnostic study] may be helpful in the diagnosis of [disease name]. Findings suggestive of/diagnostic of [disease name] include [finding 1], [finding 2], and [finding 3].

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Other diagnostic studies for [disease name] include [diagnostic study 1], which demonstrates [finding 1], [finding 2], and [finding 3], and [diagnostic study 2], which demonstrates [finding 1], [finding 2], and [finding 3].

Treatment

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.

See also

• The Myelin Project
• The Stennis Foundation
• Glial fibrillary acidic protein

External links

• alexander at NIH/UW GeneTests
• The Stennis Foundation - Registered charity committed to raising awareness and funds for Leukodystrophies research
• The Stennis Foundation's MySpace site