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

Template:DiseaseDisorder infobox

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.[1]
  • In 1959, Wohwill et al. reported the case of sibilings 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.[2][1][3]
  • 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.[4][1]

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, 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.[5][6]
    • 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.[5][6]

Pathophysiology

  • Alexander disease is an astrocytopathy that belongs to the group of disorders called leukodystrophies, which affect growth or development of the myelin sheath.[7]
  • Alexander disease is characterized by a white matter destruction in the midbrain and cerebellum.[5][8]
  • 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.[7]
  • Mutated glial fibrillary acidic protein accumulates which in turn aggregates astrocytes to form the so called Rosenthal fibers.[9]
  • 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.[10][11][12]
  • 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.[13][5]

Pathogenesis

  • The most accepted proposed mechanism to explain Alexander disease is as follows:[14]
  1. The accumulation of glial fibrillary acidic protein (PAFG) and the consequent formation of characteristic aggregates, called Rosenthal fibers in various cell types, and especially astrocytes.
  2. The accumulation appears to be due to a gain in function due to the mutation that partially blocks the assembly of the PAFG filaments.[15]
  3. Subsequent sequestration of ubiquitin and the α-B-crystalline chaperone proteins and HSP27 in the Rosenthal fibers.
  4. Activation of both the Jnk protein and the stress response.

Genetics

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.[17]
  • 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.[5]

Causes

  • The cause of Alexander disease is a mutation in one exon of the gene GFAP, encoding for glial fibrillary acidic protein:[1][5][6]
    • 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 diseases that cause .


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.[18]

Alexander disease has a prevalence of 1 in 2.7 million population studied.[1][19]

There is no gender predilection to Alexander disease.[1]

There is no racial predilection to Alexander disease.[1]

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.

OR

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

OR

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

OR

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

There is no racial predilection to [disease name].

OR

[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.

OR

[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].

OR

[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].

OR

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].

OR

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

OR

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

Diagnostic Criteria

History and Symptoms


Physical Examination

Laboratory Findings

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:[20]
    • 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

Imaging Findings

Other Diagnostic Studies


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].

OR

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].

OR

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

History and Symptoms

History

Common symptoms

  • Common symptoms of Alexander disease include:[6][10][21]
    • Type I:
      • Seizures
      • Macrocephaly
      • Encephalopathy
      • Paroxysmal deterioration
      • Failure to thrive
      • Developemental delay
      • Focal mass-like lesions
    • Type II:
      • Atonomic dysfunction
      • Bulbar symptoms
      • Ocular movement abnormalities
      • Palatal myoclonus

Less common symptoms

Less common symptoms of Alexander disease include:[6]

Dysarthria

Sleep disturbance

Dysphonia

Gait disturbance

Frequent emesis

Hiccups

Frequent vomiting




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

OR

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].

OR

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].

OR

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].

OR

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].

OR

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].

OR

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].

OR

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].

OR

[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].

OR

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].

OR

[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].

OR

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

Electroencephalogram in Alexander disease shows slow activity, whichis much more prominent over the anterior than posterior regions.[17]

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

OR

[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].

OR

[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].

OR

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.

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

See also

External links

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Messing A (2018). "Alexander disease". Handb Clin Neurol. 148: 693–700. doi:10.1016/B978-0-444-64076-5.00044-2. PMID 29478608.
  2. ↑ Seil, Fredrick J. (1968). "Alexander's Disease in an Adult". Archives of Neurology. 19 (5): 494. doi:10.1001/archneur.1968.00480050064006. ISSN 0003-9942.
  3. ↑ Balbi, Pietro; Salvini, Silvana; Fundarò, Cira; Frazzitta, Giuseppe; Maestri, Roberto; Mosah, Dibo; Uggetti, Carla; Sechi, GianPietro (2010). "The clinical spectrum of late-onset Alexander disease: a systematic literature review". Journal of Neurology. 257 (12): 1955–1962. doi:10.1007/s00415-010-5706-1. ISSN 0340-5354.
  4. ↑ Brenner, Michael; Lampel, Keith; Nakatani, Yoshihiro; Mill, John; Banner, Carl; Mearow, Karen; Dohadwala, Mariam; Lipsky, Robert; Freese, Ernst (1990). "Characterization of human cDNA and genomic clones for glial fibrillary acidic protein". Molecular Brain Research. 7 (4): 277–286. doi:10.1016/0169-328X(90)90078-R. ISSN 0169-328X.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Tavasoli A, Armangue T, Ho CY, Whitehead M, Bornhorst M, Rhee J, Hwang EI, Wells EM, Packer R, van der Knaap MS, Bugiani M, Vanderver A (February 2017). "Alexander Disease". J. Child Neurol. 32 (2): 184–187. doi:10.1177/0883073816673263. PMID 28112050.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Prust M, Wang J, Morizono H, Messing A, Brenner M, Gordon E, Hartka T, Sokohl A, Schiffmann R, Gordish-Dressman H, Albin R, Amartino H, Brockman K, Dinopoulos A, Dotti MT, Fain D, Fernandez R, Ferreira J, Fleming J, Gill D, Griebel M, Heilstedt H, Kaplan P, Lewis D, Nakagawa M, Pedersen R, Reddy A, Sawaishi Y, Schneider M, Sherr E, Takiyama Y, Wakabayashi K, Gorospe JR, Vanderver A (September 2011). "GFAP mutations, age at onset, and clinical subtypes in Alexander disease". Neurology. 77 (13): 1287–94. doi:10.1212/WNL.0b013e3182309f72. PMC 3179649. PMID 21917775.
  7. ↑ 7.0 7.1 "Alexander Disease Information Page | National Institute of Neurological Disorders and Stroke".
  8. ↑ Johnson AB (May 2004). "Alexander disease: a leukodystrophy caused by a mutation in GFAP". Neurochem. Res. 29 (5): 961–4. doi:10.1023/b:nere.0000021240.30518.2c. PMID 15139294.
  9. ↑ Rodriguez D, Gauthier F, Bertini E, Bugiani M, Brenner M, N'guyen S, Goizet C, Gelot A, Surtees R, Pedespan JM, Hernandorena X, Troncoso M, Uziel G, Messing A, Ponsot G, Pham-Dinh D, Dautigny A, Boespflug-Tanguy O (November 2001). "Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation". Am. J. Hum. Genet. 69 (5): 1134–40. doi:10.1086/323799. PMC 1274357. PMID 11567214.
  10. ↑ 10.0 10.1 Vázquez, E.; Macaya, A.; Mayolas, N.; Arévalo, S.; Poca, M.A.; Enríquez, G. (2008). "Neonatal Alexander Disease: MR Imaging Prenatal Diagnosis". American Journal of Neuroradiology. 29 (10): 1973–1975. doi:10.3174/ajnr.A1215. ISSN 0195-6108.
  11. ↑ Garcia, Leonardo; Gascon, Generoso; Ozand, Pinar; Yaish, Hassan (2016). "Increased Intracranial Pressure in Alexander Disease: A Rare Presentation of White-Matter Disease". Journal of Child Neurology. 7 (2): 168–171. doi:10.1177/088307389200700206. ISSN 0883-0738.
  12. ↑ Lee JM, Kim AS, Lee SJ, Cho SM, Lee DS, Choi SM, Kim DK, Ki CS, Kim JW (October 2006). "A case of infantile Alexander disease accompanied by infantile spasms diagnosed by DNA analysis". J. Korean Med. Sci. 21 (5): 954–7. doi:10.3346/jkms.2006.21.5.954. PMC 2722014. PMID 17043438.
  13. ↑ Olabarria M, Putilina M, Riemer EC, Goldman JE (October 2015). "Astrocyte pathology in Alexander disease causes a marked inflammatory environment". Acta Neuropathol. 130 (4): 469–86. doi:10.1007/s00401-015-1469-1. PMID 26296699.
  14. ↑ Quinlan RA, Brenner M, Goldman JE, Messing A (June 2007). "GFAP and its role in Alexander disease". Exp. Cell Res. 313 (10): 2077–87. doi:10.1016/j.yexcr.2007.04.004. PMC 2702672. PMID 17498694.
  15. ↑ Johnson AB (2002). "Alexander disease: a review and the gene". Int. J. Dev. Neurosci. 20 (3–5): 391–4. doi:10.1016/s0736-5748(02)00045-x. PMID 12175878.
  16. ↑ Messing A, Brenner M (February 2003). "Alexander disease: GFAP mutations unify young and old". Lancet Neurol. 2 (2): 75. doi:10.1016/s1474-4422(03)00301-6. PMID 12849260.
  17. ↑ 17.0 17.1 Pridmore, Clare L.; Baraitser, Michael; Harding, Brian; Boyd, Stewart G.; Kendall, Brian; Brett, Edward M. (2016). "Alexander's Disease: Clues to Diagnosis". Journal of Child Neurology. 8 (2): 134–144. doi:10.1177/088307389300800205. ISSN 0883-0738.
  18. ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean L, Stephens K, Amemiya A, Srivastava S, Naidu S. PMID 20301351. Vancouver style error: initials (help); Missing or empty |title= (help)
  19. ↑ Yoshida, Tomokatsu; Nakagawa, Masanori (2012). "Clinical aspects and pathology of Alexander disease, and morphological and functional alteration of astrocytes induced by GFAP mutation". Neuropathology. 32 (4): 440–446. doi:10.1111/j.1440-1789.2011.01268.x. ISSN 0919-6544.
  20. ↑ Tavasoli A, Armangue T, Ho CY, Whitehead M, Bornhorst M, Rhee J, Hwang EI, Wells EM, Packer R, van der Knaap MS, Bugiani M, Vanderver A (February 2017). "Alexander Disease". J. Child Neurol. 32 (2): 184–187. doi:10.1177/0883073816673263. PMID 28112050.
  21. ↑ Johnson AB (2002). "Alexander disease: a review and the gene". Int. J. Dev. Neurosci. 20 (3–5): 391–4. doi:10.1016/s0736-5748(02)00045-x. PMID 12175878.

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