This distinctive disease shares certain features with the leukodystrophies and also with gray matter diseases (poliodystrophies), both clinically and pathologically. The onset is in infancy with a failure to thrive, psychomotor retardation, spasticity of the craniospinal musculature, and seizures. An early and progressive macrocephaly has been a consistent feature. Alexander was the first to call attention to the enlargement of the brain, the extensive loss of cerebral white matter, and highly characteristic inclusions (the so-called Rosenthal fibers noted below) in astrocytes, and subpial and periventricular regions.
Pathologically, there are severe destructive changes in the cerebral white matter, most intense in the frontal lobes. Distinctive eosinophilic hyaline bodies, most prominent just below the pia and around blood vessels, are seen throughout the cerebral cortex, brainstem, and spinal cord. These have been identified as Rosenthal fibers and probably represent glial degradation products.
The astrocytic changes have been traced to a mutation in the glial fibrillary acidic protein (GFAP), as described by Gorospe and colleagues. It is usually inherited in an autosomal dominant pattern, and gives rise to the intermediate filament protein in astrocytes and, presumably, to the Rosenthal fiber inclusions. On the basis of this and related gene mutations, apparent milder forms of Alexander disease have been reported in juveniles and adults. They differed clinically in lacking the cerebral leukoencephalopathy. Instead, after a long period of constipation, sleep disorder, and orthostatic hypotension during adolescence, bulbar symptoms (dysarthria, dysphonia, and dysphagia), seizures, and in some cases ataxia gradually emerged during adult years. The myelin changes and atrophy of the medulla seen in MRI were confirmed by postmortem examination and the Rosenthal fibers; GFAP fibers were present in two autopsied cases.
This is a progressive disease of the cerebral gray matter, known also as progressive cerebral poliodystrophy or diffuse cerebral degeneration in infancy. A familial form (probably autosomal recessive) as well many sporadic cases has been reported. In both groups there is a certain uniformity of clinical features—loss of smile and disinterest in the surroundings, sweating attacks, seizures, and diffuse myoclonic jerks beginning in early infancy and followed by incoordination of movements; progressive spasticity of limb, trunk, and cranial muscles; blindness and optic atrophy; growth retardation and increasing microcephaly; and finally virtual decortication (see Alpers original description). In some instances, the late onset of jaundice and fatty degeneration or cirrhosis of the liver have been described (Alpers-
Huttenlocher syndrome). By the age of 4 years, these patients are hypotonic, anemic, and thrombocytopenic. They also show fragile hair follicles that break at thickened nodes (trichorrhexis nodosa).