Penicillamine Neurotoxicity: An Hypothesis

Penicillamine, dimethyl cysteine, thiovaline, remains the drug of choice for the treatment of patience with Wilson disease. It is also of value in the treatment of cysteinuria and rheumatoid arthritis, it has also been suggested that it has value in the management of other rare diseases. It also has multiple toxicities. The majority of these can be explained as chemical toxicity, for instance its weak antipyridoxine action and its ability to interfere with lysyloxidea resulting in skin lesions. More important are its ability to induce immune reactions such as SLE, immune complex nephritis, the Ehlers Danlos syndrome and Goodpasture's syndrome. However the sudden increase in neurological signs which may occur in a small number of patients remains unexplained. The theory is proposed that this is due to lethal synthesis. In susceptible patients the–SH radical is liberated from penicillamine and will inhibit–SH dependent enzymes in the Krebs cycle leading to death in neurones. Other toxic metabolites may also be produced such as methyl mercaptan and ethyl mercaptan either of which could produce a similar metabolic block.