The neuropathology of cerebrotendinous xanthomatosis revisited: a case report and review of the literature.

Cerebrotendinous xanthomatosis (CTX), a rare autosomal-recessive lipid storage disease, has been well characterized clinically and biochemically, and recently also from the molecular biological aspect. However, only a very few publications deal with its neuropathology, and views on its pathogenesis vary. Based on a recently examined case, we propose that central-peripheral distal axonopathy is the major pathogenetic mechanism of nervous system injury in CTX. The latter is characterized by white matter pathology, typically in form of long tract involvement with the more distal parts of the tract more severely affected. Most severely affected are the cerebellar white matter, the optic pathways and the long tracts of the brain stem and spinal cord, particularly the pyramidal tracts, although there is hardly a CNS region which does not display some form of pathology. Lesions are characterized by loss of myelinated fibers and accumulation of lipid products in form of foamy macrophages, clear oil-red-O-positive spaces and crystalline clefts, accompanied by gliosis, occasional axonal spheroids, and in the cerebellum--the most severely affected structure--also by multi-nucleated foreign body giant cells. Demyelination is not seen, and ultrastructurally myelin sheaths are normally structured. Signs of axonal degeneration are also present in the spinal roots. We hypothesize that the basic enzymatic defect in CTX leads to accumulation of metabolites in the brain which may be neurotoxic and may impair the metabolic apparatus of neurons with resultant axonopathy and subsequent nonspecific lipid deposition in the injured tracts.