Alexander disease

Alexander disease (AD), 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 recognised. 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:

  1. infantile/childhood onset
  2. juvenile onset
  3. adult onset (AOAD)

Childhood onset Alexander disease is sporadic and typically presents with macrocephaly, rapid neurological deterioration, seizures and spasticity, and retarded psychomotor development.

In some cases, the gene for glial fibrillary acidic protein (GFAP): mapped to chromosome 17q21: has been implicated. Histologically the disease is characterised by the accumulation of large numbers of Rosenthal fibres 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).

It generally presents in infants and adolescents. Macrocephaly is typically present, and other clinical features include progressive quadriparesis and intellectual failure.

Most of the cases are sporadic. However, familial disease has also been reported. A heterozygous mutation in the coding region of GFAP, an astrocyte specific intermediate filament protein, are associated with most cases of infantile sporadic onset.

Histologic examination reveals Rosenthal fibres in the brain, ependyma and pia. Intracellular deposition of these fibres 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 characterised by contrast enhancing cystic leukomalacia.

MRI

  • T2: increased signal in
    • bifrontal white matter which tends to be symmetrical 
    • caudate head > globus pallidus > thalamus > brain stem
    • periventricular rim
  • 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.

Adult-onset Alexander disease (AOAD) only recognised with any frequency after GFAP was recognised as the mutation has markedly different imaging findings and presentation. It has been described as autosomally inherited in some pedigrees, presenting with prominent bulbar symptoms (dysphagia, dysphonia or dysarthria), sleep disturbance and impairment of autonomic function.

MRI
  • T2: increased T2 signal (demyelination)  and atrophy of the
    • 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
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Article information

rID: 5267
Section: Pathology
Tag: rewrite
Synonyms or Alternate Spellings:
  • Alexander's disease
  • Fibrinoid leukodystrophy

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Cases and figures

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    Figure 1: gross pathology : Alexander disease autopsy
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    Case 1: AOAD
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    Figure 2: histology : H &amp; E stain
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