Osteolathyrism

Osteolathyrism is a collagen cross-linking deficiency brought on by dietary over-reliance on the seeds of Lathyrus sativus or grass pea, a legume often grown as a famine crop in Asia and East Africa.^[1] Other members of the genus are also known to cause the disease, including L. sylvestris, L. cicera, and L. clymenum.^[1] L. sativus grows well under famine conditions, often severe drought, where it is cultivated.^[1] The condition results in damage to bone and mesenchymal connective tissues.^[1]It is seen in people in combination with neurolathyrism and angiolathyrism in areas where famine demands reliance on a crop with known detrimental effects. It occurs in cattle and horses with diets overreliant upon the grass pea. Osteolathyrism is caused by a variety of osteolathyrogenic compounds, specifically excitatory amino-compounds. The most widely-studied of these compounds is beta-aminopropionitrile (BAPN), which exerts its deleterious effect by an unknown yet potently irreversible mechanism.^[2] Other instigators are ureides, semicarbazides and thiosemicarbazides, which are believed to chelate the prosthetic Cu(II)-bipyridine cofactor complex in the enzyme lysyl oxidase.^[3]

Cause

Lysyl oxidase is an important enzyme for the creation of crosslinks between collagen triple-helices in connective tissue. By oxidizing the terminal amino group of lysine, an aldehyde is created. This aldehyde can undergo several reactions with neighboring aldehydes or amines to create strong covalent cross-links between collagen tertiary structures in bone and cartilage. The main product of these reactions is the aldimine compound dehydrohydroxylysinonorleucine.^[4] This unique crosslink can be formed by the Schiff base mechanism in which the lone pair of electrons on a primary amine react with the carbonyl carbon of an aldehyde. Other crosslinks include the formation of an α,β-unsaturated ketone via aldol condensation and hydroxylysinonorleucine.

If these crosslinks are not formed, as in the case of osteolathyrism, the synthesis of strong mesenchymal and mesodermal tissue is inhibited. Symptoms of osteolathyrism include weakness and fragility of connective tissue (i.e., skin, bones, and blood vessels (angiolathyrism) and the paralysis of the lower extremities associated with neurolathyrism. For these reasons, compounds containing lathyrogens should be avoided during pregnancy and growth of a child.

References

1. Rosenthal, Gerald (2003). "Toxic Constituents and their Related Metabolites". Plant Nonprotein Amino and Imino Acids: Biological, Biochemical, and Toxicological Properties. Elsevier. ISBN 9780323157742.
2. Wilmarth KR, Froines JR (November 1992). "In Vitro and In Vivo Inhibition of Lysyl Oxidase by Aminopropionitriles". Journal of Toxicology and Environmental Health 37 (3): 411-423
3. Dawson DA, Rinaldi AC, Poch G (August 2002). "Biochemical and toxicological evaluation of agent-cofactor reactivity as a mechanism of action for osteolathyrism". Toxicology 177 (2-3): 267-284.
4. Bailey AJ, Peach CM (1971). "The Chemistry of the Collagen Cross-Links: The Absence of Reduction of Dehydrolysinonorleucine and Dehydrohydroxylysinonorleucine in Vivo". The Biochemical Journal 121: 257-259.