Alexander's Disease

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Background    Gross Pathology    Histopathology & Immunohistochemistry    Differential Diagnosis

BACKGROUND AND CLINICAL INFORMATION: Head  

Summary: Alexander's disease is a leukodystrophy that is seen most commonly in infants or later childhood and is clinically a progressive, sometimes very slow, process with dementia, seizures and spasticity. Pathologically, it is a degenerative disorder of the CNS characterized by diffuse demyelination and rarefaction of the white matter, with little or no sparing of the arcuate fibers, and widespread accumulation of Rosenthal fibers. Generalized changes are most frequently seen but localized forms are also reported.

Genetics: Probably a genetically inherited disease but the pattern of inheritance has not been established. Sequence analysis of DNA samples from patients representing different Alexander disease phenotypes revealed that most cases are with non-conservative mutations in the coding region of GFAP. Alexander disease is the first disease that is known to be associated with GFAP mutations [Brenner M, et al., 2001].

Clinical features: Canavan disease, Alexander disease and Aicardi-Goutières syndrome are the three leukodystrophy that typically present with megalencephaly. Most cases of Alexander disease have onset in infancy, however, onset in older ages has also been described.

• Infantile form: present between aged 6 months to 2 years with megalencephaly and/or hydrocephalus, seizures, developmental delay, and spastic paresis. Death occurs from 2 months to 7 years after onset of symptoms. Bilateral symmetrical lesions in the white matter especially in the frontal lobe, subependymal and deep white matters. Posterior fossa structures are less affected. There is also dilatation of lateral ventricles.

• Juvenile form: onset between the ages of 7 and 14 years. Seizures are less common. Brain stem features with dysphagia and psychological disturbance have been reported. There is marked dilatation of the lateral and third ventricles and white matter lesions particularly in the frontal lobe.

• Adult form: variable in clinical and pathologic manifestation. Some patients may have a waxing and waning neurologic course similar to that seen in MS and others suffer from a progressive neurologic disorder. Patients show bulbar symptoms, spastic paraparesis or quadriparesis, and varying degrees of cognitive dysfunction.

GROSS PATHOLOGY: Head  

The brain shows a somewhat indurated, uniformly white, cortical ribbon. The subjacent white matter is discoloured and may be loosened in texture, soft, jelly-like, collapsed or broken down.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head  

Rosenthal fibers are initially accumulated in the astrocytic cell body in the early stages but eventually located at the end-feet. They are associated with gliosis, extensive myelin disintegration. They are found throughout CNS but are most commonly seen in subpial, subependymal, and perivascular sites and their distribution does not always correlate with the myelin loss and can be found in areas without myelin abnormalities such as pontine tegmentum. Astrocytes contain eosinophilic globules with ultrastructural features of Rosenthal material.

Macrophages are characteristically absent.

Axonal loss is widespread.

Pleomorphism: astrocytes in Alexander's disease show moderate nuclear and cytoplasmic pleomorphism.                                                              

EM: Perivascular processes are astrocytic processes distended by irregular osmiophilic densities covered by glial filaments.

DIFFERENTIAL DIAGNOSIS: Head  

Pilocytic astrocytoma may suggest localized Alexander's disease.

NeuroLearn NeuroHelp Muscle For Comment: KarMing-Fung@ouhsc.edu

Background    Gross Pathology    Histopathology & Immunohistochemistry    Differential Diagnosis