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Alexander disease, also known as fibrinoid leukodystrophy, is a rare fatal leukodystrophy, which usually becomes clinically evident in the infantile period, although neonatal, juvenile and even adult variants are recognized. As with many other diseases with variable age of presentation, the earlier it manifests the more fulminant the clinical course.
There are three clinical forms:
infantile/childhood-onset (most common)
adult onset (AOAD)
Childhood-onset Alexander disease
Childhood-onset Alexander disease typically manifests in infants and adolescents. It is typically sporadic, although in some cases, the gene for glial fibrillary acidic protein (GFAP) has been implicated.
Macrocephaly is typically present, and other clinical features include progressive quadriparesis and spasticity, seizures, and intellectual disability.
Most of the cases are sporadic. However, familial disease has also been reported. A heterozygous mutation in the coding region, mapped to chromosome 17q21, of GFAP, an astrocyte-specific intermediate filament protein, is associated with most cases of infantile sporadic onset.
Histologically the disease is characterized by the accumulation of large numbers of Rosenthal fibers and eosinophilic granular bodies (large accumulations agglomerations of astrocytic processes) in the degenerated (demyelinated) white matter which is a product of GFAP. This is on its own a non-specific finding, as they are also seen in slow-growing or benign astrocytomas (e.g. pilocytic astrocytomas). Intracellular deposition of Rosenthal fibers may cause abnormal functioning of the oligodendrocytes.
The disease begins in the frontal region and extends posteriorly. Subcortical U-fibers are somewhat initially spared but affected relatively early in the course of the disease. End-stage disease is characterized by contrast-enhancing cystic leukomalacia.
T2: increased signal in
bifrontal white matter which tends to be symmetrical
caudate head > globus pallidus > thalamus > brainstem
T1 C+ (Gd): enhancement may be seen in the same areas
Obstructive hydrocephalus secondary to periaqueductal involvement and swelling of basal ganglia may be seen.
Juvenile/adult-onset Alexander disease
Adult-onset Alexander disease (AOAD), which was only recognized with any frequency after GFAP was recognized as the mutation, has markedly different imaging findings and presentation. It has been described as having an autosomal pattern of inheritance in some pedigrees.
Adult-onset Alexander disease presents with prominent bulbar symptoms (dysphagia, dysphonia or dysarthria), sleep disturbance and impairment of autonomic function.
T2: increased T2 signal (representing demyelination) and atrophy affecting multiple regions
medulla and upper cervical cord
occasional involvement of inferior cerebellar peduncles
pons, middle and superior cerebellar peduncles (rare)
supratentorial (typically periventricular) may be seen in patients <40 years of age
T1 C+ (Gd): patchy enhancement uncommonly seen in adult patients
History and etymology
The condition is named after New Zealand pathologist William Stewart Alexander who first described it in a 1949 case report.
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