Alexander disease

Alexander disease
Synonyms
Pronounce
Field
Symptoms
Complications
Onset
Duration
Types
Causes
Risks
Diagnosis
Differential diagnosis
Prevention
Treatment
Medication
Prognosis
Frequency
Deaths

Alexander disease

Alexander disease is a very rare autosomal dominant leukodystrophy, which are neurological conditions caused by anomalies in the myelin which protects nerve fibers in the brain. According to the National Institute of Neurological Disorders and Stroke, the destruction of white matter is accompanied by the formation of Rosenthal fibers—abnormal clumps of protein that accumulate in astrocytes in the brain.

The most common type of Alexander disease is the infantile form that usually begins during the first 2 years of life. Symptoms include mental and physical developmental delays, followed by the loss of developmental milestones, an abnormal increase in head size and seizures.

The juvenile form of Alexander disease has an onset between the ages of 2 and 13 years. These children may have excessive vomiting, difficulty swallowing and speaking, poor coordination, and loss of motor control.

Adult-onset forms of Alexander disease are less common. The symptoms sometimes mimic those of Parkinson’s disease or multiple sclerosis, or may present primarily as a psychiatric disorder.

The disease occurs in both males and females, and no ethnic, racial, geographic or cultural/economic differences are seen in its distribution. Alexander disease is a progressive and often fatal disease.<ref>

Alexander Disease Information Page(link). {{{website}}}. National Institute of Neurological Disorders and Stroke.

 This article incorporates text from this source, which is in the public domain.</ref>

Presentation

Delays in development of some physical, psychological and behavioral skills; progressive enlargement of the head (macrocephaly), seizures, spasticity, and in some cases also hydrocephalus, idiopathic intracranial hypertension, and dementia.<ref name="Gene">GeneReviews/NCBI/NIH/UW entry on Alexander disease</ref>

Autopsy, Alexander disease

Cause

Alexander disease is a genetic disorder affecting the midbrain and cerebellum of the central nervous system. It is caused by mutations in the gene for glial fibrillary acidic protein (GFAP)<ref name="Li 2002">,

 GFAP mutations in Alexander disease, 
 Int. J. Dev. Neurosci., 
 2002,
 Vol. 20(Issue: 3–5),
 pp. 259–68,
 DOI: 10.1016/s0736-5748(02)00019-9,
 PMID: 12175861,</ref><ref name="Quinlan 2007">, 
 GFAP and its role in Alexander disease, 
 Exp. Cell Res., 
 
 Vol. 313(Issue: 10),
 pp. 2077–87,
 DOI: 10.1016/j.yexcr.2007.04.004,
 PMID: 17498694,
 PMC: 2702672,</ref><ref name="Messing 2012">, 
 Alexander disease, 
 J. Neurosci., 
 
 Vol. 32(Issue: 15),
 pp. 5017–23,
 DOI: 10.1523/JNEUROSCI.5384-11.2012,
 PMID: 22496548,
 PMC: 3336214,</ref> that maps to chromosome 17q21. It is inherited in an autosomal dominant manner, such that the child of a parent with the disease has a 50% chance of inheriting the condition, if the parent is heterozygotic. However, most cases arise de novo as the result of sporadic mutations.<ref name="Gene" />

Alexander disease belongs to leukodystrophies, a group of diseases that affect the 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.<ref name="Gene" /><ref name="NINDS">alexander_disease at NINDS</ref><ref name="BBC">"Cause of brain disease found" -BBC News</ref> Rosenthal fibers appear not to be present in healthy people,<ref name="NINDS" /><ref name="Alexander">

Archived copy(link). {{{website}}}.

Accessed 2010-06-14.

</ref> but occur in specific diseases, like some forms of cancer, Alzheimer’s, Parkinson’s, Huntington’s, and ALS.<ref name="NINDS" /><ref name="Alexander" /><ref>

Mutation in common protein triggers tangles, chaos inside brain cells(link). news.wisc.edu.

Accessed 2018-11-16.

</ref> The Rosenthal fibers found in Alexander disease do not share the distribution or concentration of other diseases and disorders.<ref name="NINDS" />

Pathology

Alexander disease causes the gradual loss of bodily functions and the ability to talk. It also causes an overload of long-chain fatty acids in the brain, which destroy the myelin sheath. The cause of Alexander disease is a mutation in the gene encoding GFAP.<ref name="Gene" /><ref name="NINDS" /><ref name="Li 2002" /><ref name="Quinlan 2007" /><ref name="Adult">,

 Can MR imaging diagnose adult-onset Alexander disease?, 
 AJNR Am J Neuroradiol, 
 
 Vol. 29(Issue: 6),
 pp. 1190–6,
 DOI: 10.3174/ajnr.A1060,
 PMID: 18388212,</ref><ref>

Mutation in common protein triggers tangles, chaos inside brain cells(link). news.wisc.edu.

Accessed 2018-11-16.

</ref>

A CT scan shows:

• Decreased density of white matter
• Frontal lobe predominance
• Dilated lateral ventricles may present

Diagnosis

Detecting the signs of Alexander disease is possible with magnetic resonance imaging (MRI), which looks for specific changes in the brain that may be tell-tale signs for the disease.<ref name="Labauge 2009">Labauge P,

 Magnetic resonance findings in leucodystrophies and MS, 
 Int MS J, 
 
 Vol. 16(Issue: 2),
 pp. 47–56,
 
 PMID: 19671368,</ref><ref>, 
 Alexander disease: diagnosis with MR imaging, 
 AJNR Am J Neuroradiol, 
 
 Vol. 22(Issue: 3),
 pp. 541–52,
 
 PMID: 11237983,
 
 
 Full text,</ref> It is even possible to detect adult-onset Alexander disease with MRI.<ref name="Adult" /> Alexander disease may also be revealed by genetic testing for its known cause.<ref name="Johnson 2002">Johnson AB, 
 Alexander disease: a review and the gene, 
 Int. J. Dev. Neurosci., 
 2002,
 Vol. 20(Issue: 3–5),
 pp. 391–4,
 DOI: 10.1016/S0736-5748(02)00045-X,
 PMID: 12175878,</ref><ref name="Sawaishi 2009">Sawaishi, Y, 
 Review of Alexander disease: beyond the classical concept of leukodystrophy, 
 Brain Dev., 
 
 Vol. 31(Issue: 7),
 pp. 493–8,
 DOI: 10.1016/j.braindev.2009.03.006,
 PMID: 19386454,</ref> A rough diagnosis may also be made through revealing of clinical symptoms, including enlarged head size, along with radiological studies, and negative tests for other leukodystrophies.<ref name="Alexander" />

Treatment

No cure or standard procedure for treatment is known, although a University of Wisconsin study shows promise with gene editing of the astrocytes.<ref name="Gene" /><ref name="NINDS" /><ref>

Mutation in common protein triggers tangles, chaos inside brain cells(link). news.wisc.edu.

Accessed 2018-11-16.

</ref> A bone marrow transplant has been attempted on a child, but it made no improvement.<ref name="Staba 1997">,

 Allogeneic bone marrow transplantation for Alexander's disease, 
 Bone Marrow Transplant., 
 
 Vol. 20(Issue: 3),
 pp. 247–9,
 DOI: 10.1038/sj.bmt.1700871,
 PMID: 9257894,</ref><ref name="Messing 2010">, 
 Strategies for treatment in Alexander disease, 
 Neurotherapeutics, 
 
 Vol. 7(Issue: 4),
 pp. 507–15,
 DOI: 10.1016/j.nurt.2010.05.013,
 PMID: 20880512,
 PMC: 2948554,</ref> Hydrocephalus may be seen in younger patients and can be relieved with surgery or by implanting a shunt to relieve pressure.<ref>

Alexander Disease - United Leukodystrophy Foundation United Leukodystrophy Foundation(link). ulf.org.

Accessed 2016-11-08.

</ref>

Prognosis

The prognosis is generally poor. With early onset, death usually occurs within 10 years from the onset of symptoms. Individuals with the infantile form usually die before the age of seven.<ref>

Alexander Disease Information Page: National Institute of Neurological Disorders and Stroke (NINDS)(link). www.ninds.nih.gov.

Accessed 2016-11-03.

</ref> Usually, the later the disease occurs, the slower its course.<ref name="Gene" /><ref name="NINDS" />

Prevalence

Its occurrence is very rare. The infantile form occurs from birth to 2 years of age.<ref name="Messing 2012" /> The average duration of the infantile form is usually about 3 years. Onset of the juvenile form presents between 2 and 12 years of age.<ref name="Messing 2012" /> Duration of this form is in most cases about 6 years. The adult form occurs after 12 years.<ref name="Messing 2012" /> In younger patients, seizures, megalencephaly, developmental delay, and spasticity are usually present. Neonatal onset is also reported.<ref name="Singh 2012">,

 Alexander's disease: reassessment of a neonatal form, 
 Childs Nerv Syst, 
 
 Vol. 28(Issue: 12),
 pp. 2029–31,
 DOI: 10.1007/s00381-012-1868-8,
 PMID: 22890470,</ref> 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.<ref name="Gene" /> No more than 500 cases have been reported.<ref name="Gene" />

See also

• The Myelin Project
• The Stennis Foundation

External links

• OMIM entries on Alexander disease
• Infantile-onset Alexander disease in a child with long-term follow-up by serial magnetic resonance imaging: a case report
• Alexander Disease: New Insights From Genetics