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. After more than 50 years of experience penicillamine remains the most effective treatment for patients with Wilson disease for which there is ample evidence [1, 2]. However it also has a wide variety of toxicities, most of these can be explained in terms of chemical or immunological reactions. But one, the great increase in the neurological deficit remains unexplained. The present theories are unsatisfactory and this paper proposes a new hypothesis for the neurotoxicity of penicillamine which, if correct, may lead to the introduction of a predictive test which will be of great value in deciding whether or not this drug can be used as an initial therapy. In 1948, when he established the role of copper in the pathogenesis of Wilson disease, Cumings [3] put possible therapy on a sound scientific basis by suggesting that the chelating agent BAL, British Antilewisite, might be beneficial in the management of this disease by removing the excess copper. This hypothesis was later supported by his own observations [4] and those of Denny Brown and Porter in Boston [5]. Later Denny Brown appeared to have abandoned the copper theory in favour of Uzman’s hypothesis that the disease was due to an abnormality of peptide metabolism and that copper was merely deposited as a secondary phenomenon in dying neurones [6–8]. How Denny Brown was able to continue to propagate the use of BAL as an effective therapy in view of his theories on pathogenesis remains