Skip to Main Content

At a glance

A degenerative disorder of the nervous system caused by leukodystrophy. Affects mostly males and usually begins at approximately 6 months of age. Symptoms include mental and physical retardation, enlargement of the brain and head, seizures, and spasticity in arms and legs.

Synonyms

Demyelinogenic Leukodystrophy; Dysmyelinogenic Leukodystrophy; Fibrinoid Leukodystrophy; Fibrinoid Degeneration of Astrocytes; Megalencephaly with Hyaline Panneuropathy; Macrocephaly with Feeble Mindedness; and Encephalopathy with Peculiar Deposits.

History

First described in 1949 by William Stewart Alexander, a pathologist from New Zealand working in the United Kingdom.

Incidence

Has been estimated in the range of 1:2,700,000. Approximately 500 cases without any racial preference have been reported. Males are affected about 2.5 times more frequently than females.

Genetic inheritance

AD is a transmissible astrocytic abnormality with varying expression. Inheritance is autosomal dominant, but most cases are considered de novo mutations. The genetic defect has been mapped to chromosome 17q21 and more than 20 different mutations have been identified. This gene encodes the glial fibrillary acidic protein (GFAP), which is the main intermediate filament protein synthesized in mature astrocytes. Most likely, GFAP in AD is defective and hinders the normal interaction between astrocytes and oligodendrocytes, finally resulting in dys- and demyelination.

Pathophysiology

Non-neoplastic white matter expansion with neuronal dysfunction and astrocyte proliferation associated with demyelination occur. Histopathology reveals widespread reactive gliosis and hyaline inclusions in astrocytes of up to 30 microns in length, so-called Rosenthal fibers (RF; named after W. Rosenthal, a German pathologist who first described them in 1898 in a astrocytic scar in a patient with syringomyelia). RFs consist mainly of big aggregations of alpha-B-crystallin (a stress protein), heat shock protein, and glial fibrillary acidic protein. They are often found in subpial, periventricular, and perivascular brain areas. Their occurrence in brainstem and spinal cord is less frequent. The distribution of RFs is closely correlated with areas of demyelination and loss of oligodendroglia. While RF are not pathognomonic for AD, their abundance and distribution (particularly in subpial and subependymal regions) in AD is characteristic. Although extensive and progressive frontal white matter demyelination occurs, no inflammatory cells can be found. These areas may degenerate into brain lacunae. Signs of storage disease are absent.

Diagnosis

Brain biopsy and histology demonstrate perivascular hyaline, eosinophilic, and argyrophilic RFs. Abnormal astrocytes with functional demyelination are the prominent feature. No enzyme defect has been identified. Progressive megalencephaly in the first year of life is a very common finding. The disease is associated with progressive spasticity and dementia. Molecular genetic testing is available to confirm the diagnosis of AD, thus a brain biopsy is no longer mandatory and prenatal diagnosis is possible. Brain imaging (MRI) shows progressive white matter reduction and cystic changes predominantly in the frontal lobes. The ...

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.