Alexander disease
Template:Short description Template:Infobox medical condition
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. The most common type is the infantile form that usually begins during the first two 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.
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 disease was first documented in 1949 by W. Stewart Alexander, who treated a 15 month-old infant presenting with megalencephaly, hydrocephaly, seizures, and developmental delays. Between 1949 and 1964, 15 more cases with similar symptoms were observed, leading to suggestions that the cases were the same disease and that the disease be named after Alexander.<ref name=":0">Template:Cite journal</ref>
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>Template:Cite web Template:PD-notice</ref>
Presentation
Symptoms observed include 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">Template:Cite book</ref> Symptoms vary greatly between patients.<ref name="Messing 2010" />
In cases of early-onset or neonatal Alexander disease, symptoms include seizures, fluid buildup in the brain, high protein levels in cerebrospinal fluid, and severe motor and intellectual impairment. In cases of type I Alexander disease, where the condition appears before age 4, symptoms include seizures, enlarged brain and head, stiffness in the limbs, delayed intellectual and physical development, recurrent vomiting, and difficulties with gaining weight. In cases of type II Alexander disease, where the condition appears after the age of 4, symptoms include speech problems, difficulty swallowing, poor coordination, scoliosis, recurrent vomiting, and difficulties with gaining weight.<ref>Template:Cite web</ref>
Classification
Traditionally, Alexander disease has been classified by age at onset and is divided into infantile, juvenile, and adult forms.<ref name=":1">Template:Cite journal</ref> In line with this method of classification, some researchers have proposed adding an additional neonatal division for cases where the disease began before birth.<ref name="Singh 2012">Template:Cite journal</ref> These divisions have the following characteristics:
| Form | Age at Onset | Symptoms/Pathology |
|---|---|---|
| Neonatal | < 1 month<ref name="Singh 2012" /> | hydrocephalus, developmental delays, seizures, no ataxia<ref name="Singh 2012" /> |
| Infantile | 0–2 years<ref name=":0" /> | megalencephaly, developmental delays, seizures,<ref>Template:Cite journal</ref> failure to thrive<ref name=":2">Template:Cite journal</ref> |
| Juvenile | 2–12 years<ref name=":0" /> | ataxia, gait disturbance, basal ganglia and thalamus abnormalities<ref name=":2" /> |
| Adult | > 12 years<ref name=":0" /> | brainstem and spinal cord abnormalities,<ref name=":4">Template:Cite journal</ref> bulbar symptoms<ref name=":2" /> |
Other researchers have adopted a classification system with two divisions, Type I and Type II. The divisions have the following major characteristics:<ref name=":1" />
| Type | Onset | Symptoms/Pathology | MRI Features |
|---|---|---|---|
| Type I | early | seizures, megalencephaly | typical |
| Type II | late | brainstem features | atypical |
Cause
Alexander disease is a genetic disorder primarily 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">Template:Cite journal</ref><ref name="Quinlan 2007">Template:Cite journal</ref><ref name="Messing 2012">Template:Cite journal</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">Template:NINDS</ref><ref name="BBC">Template:Cite news</ref>
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 gain-of-function mutation in the gene encoding GFAP.<ref name="Gene" /><ref name="NINDS" /><ref name="Li 2002" /><ref name="Quinlan 2007" /><ref name="Adult">Template:Cite journal</ref><ref name="news.wisc.edu">Template:Cite web</ref><ref name=":3">Template:Cite journal</ref>Template:Excessive citations inline The mutation causes protein aggregates called Rosenthal fibers to form in astrocytes' cytoplasm,<ref>Template:Cite journal</ref> but the exact method of this formation mechanism is not well understood.<ref name=":3" /> Rosenthal fibers appear not to be present in healthy people,<ref name="NINDS" /><ref name="Alexander">Template:Cite web</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 name="news.wisc.edu" /> The Rosenthal fibers found in Alexander disease do not share the distribution or concentration of other diseases and disorders.<ref name="NINDS" />
A CT scan of a patient with Alexander disease typically shows:
- Decreased density of white matter
- Frontal lobe predominance
- Dilated lateral ventricles may present
An MRI scan of a patient with Alexander disease typically shows:
- Periventricular white matter change
- Medullar atrophy
- Signal change in the spinal cord<ref name=":1" />
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">Template:Cite journal</ref><ref>Template:Cite journal</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">Template:Cite journal</ref><ref name="Sawaishi 2009">Template:Cite journal</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" /> However, due to the similarity of symptoms to other diseases such as multiple sclerosis, many adults experience misdiagnosis until they receive an MRI scan confirming Alexander disease pathology.<ref name=":4" />
Treatment
There is no known cure for Alexander disease.<ref name="Messing 2010" /> Treatment varies greatly between patients, and treatment plans consist of therapies for specific symptoms, such as shunts to relieve pressure caused by hydrocephalus,<ref name="Alexander" /> or antiepileptic medications to treat seizures.<ref name="Messing 2010" />
Recent studies have tested experimental treatments, but none have been approved for clinical use. A University of Wisconsin study shows promise with gene editing of the astrocytes.<ref name="Gene" /><ref name="NINDS" /><ref name="news.wisc.edu" /> A phase III clinical trial of an antisense therapy, sponsored by Ionis Pharmaceuticals, began in 2021.<ref>Template:Cite web</ref> A bone marrow transplant has been attempted on a child, but it made no improvement.<ref name="Staba 1997">Template:Cite journal</ref><ref name="Messing 2010">Template:Cite journal</ref>
Prognosis
The prognosis is generally poor. Individuals with the infantile form usually die before the age of seven.<ref>Template:Cite web</ref> The average duration of the infantile form is usually about three years. Duration of the juvenile form is about six years.<ref name=":0" /> Usually, the later the disease occurs, the slower its course.<ref name="Gene" /><ref name="NINDS" />
Prevalence
Its occurrence is very rare, with an estimated 1 in 2.7 million prevalence. More Type I cases have been reported than Type II cases, but researchers believe this may be due to high rates of misdiagnosis in adults.<ref name=":0" /><ref name=":4" />
See also
References
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
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