Neurological aspects of osteopetrosis

Neuropathol Appl Neurobiol. 2003 Apr;29(2):87-97. doi: 10.1046/j.1365-2990.2003.00474.x.


The osteopetroses are caused by reduced activity of osteoclasts which results in defective remodelling of bone and increased bone density. They range from a devastating neurometabolic disease, through severe malignant infantile osteopetrosis (OP) to two more benign conditions principally affecting adults [autosomal dominant OP (ADO I and II)]. In many patients the disease is caused by defects in either the proton pump [the a3 subunit of vacuolar-type H(+)-ATPase, encoded by the gene variously termed ATP6i or TCIRG1] or the ClC-7 chloride channel (ClCN7 gene). These pumps are responsible for acidifying the bone surface beneath the osteoclast. Although generally thought of as bone diseases, the most serious consequences of the osteopetroses are seen in the nervous system. Cranial nerves, blood vessels and the spinal cord are compressed by either gradual occlusion or lack of growth of skull foramina. Most patients with OP have some degree of optic atrophy and many children with severe forms of autosomal recessive OP are rendered blind; optic decompression is frequently attempted to prevent the latter. Auditory, facial and trigeminal nerves may also be affected, and hydrocephalus can develop. Stenosis of both arterial supply (internal carotid and vertebral arteries) and venous drainage may occur. The least understood form of the disease is neuronopathic OP [OP and infantile neuroaxonal dystrophy, MIM (Mendelian inheritance in man) 600329] which causes rapid neurodegeneration and death within the first year. Although characterized by the finding of widespread axonal spheroids and accumulation of ceroid lipofuscin, the biochemical basis of this disease remains unknown. The neurological complications of this disease and other variants are presented in the context of the latest classification of the disease.

Publication types

  • Review

MeSH terms

  • Animals
  • Blindness / etiology
  • Child
  • Cranial Nerve Diseases / etiology
  • Hematologic Diseases / etiology
  • Humans
  • Models, Animal
  • Nervous System Diseases / etiology*
  • Optic Atrophy / etiology
  • Osteopetrosis / complications*
  • Osteopetrosis / diagnostic imaging
  • Osteopetrosis / genetics
  • Osteopetrosis / physiopathology*
  • Psychomotor Disorders / etiology
  • Radiography

Associated data

  • OMIM/259710
  • OMIM/600329