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ARTICLES: P. Kaufmann, K. Engelstad, Y. Wei, S. Jhung, M. C. Sano, D. C. Shungu, W. S. Millar, X. Hong, C. L. Gooch, X. Mao, J. M. Pascual, M. Hirano, P. W. Stacpoole, S. DiMauro, and D. C. De Vivo Dichloroacetate causes toxic neuropathy in MELAS: A randomized, controlled clinical trial Neurology 2006; 66: 324-330 [Abstract] [Full text] [PDF]

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Dichloroacetate causes toxic neuropathy in MELAS: A randomized, controlled clinical trial

Irina A. Anselm, Basil T. Darras   (6 June 2006)

Reply from the Authors

Petra Kaufmann, Darryl DeVivo   (6 June 2006)

Dichloroacetate causes toxic neuropathy in MELAS: A randomized, controlled clinical trial

Heikki Savolainen   (28 March 2006)

Reply from the authors

Petra Kaufmann, Darryl C. De Vivo   (28 March 2006)

Dichloroacetate causes toxic neuropathy in MELAS: A randomized, controlled clinical trial 6 June 2006
Irina A. Anselm, Children's Hospital Boston 300 Longwood Avenue, Boston MA 02115, Basil T. Darras Send Correspondence to journal: Re: Dichloroacetate causes toxic neuropathy in MELAS: A randomized, controlled clinical trial irina.anselm{at}childrens.harvard.edu Irina A. Anselm, et al.	We read the report by Kaufmann et al with interest.[1] The investigators studied the efficacy of dichloroacetate (DCA) in the treatment of 30 patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). At a DCA dose of 25 mg/kg/day, they detected no therapeutic benefit and documented peripheral nerve toxicity resulting in premature study termination. They conclude that peripheral nerve toxicity overshadows any potential benefit from DCA in patients harboring the A3243G mutation. The high rate of DCA-induced peripheral neuropathy in the Kaufmann study was unexpected because previous studies in a sample of 97 patients with congenital lactic acidosis (including 10 MELAS patients) did not reveal a high incidence of peripheral nerve toxicity. [2, 3] The new information raises the possibility that patients with MELAS with the A3243G mutation are exceptionally susceptible to DCA toxicity, with diabetes mellitus potentially being a contributing factor. During the last 12 years, on a compassionate basis we treat patients with chronic lactic acidosis with DCA using an IRB-approved protocol. Of 13 enrolled patients with cerebral lactic acidosis, peripheral lactic acidosis, or both, three had MELAS and harbored the A3243G mutation, but one of these was taken off DCA due to noncompliance. The other two patients with MELAS are still actively enrolled in the protocol and have taken DCA for 7 and 9 years. Both patients developed moderate to severe axonal length-dependent sensorimotor neuropathy manifested primarily as distal weakness in lower extremities. Ten patients enrolled in our DCA protocol had lactic acidosis due to various metabolic disorders [Leigh syndrome, Kearns-Sayre syndrome (KSS), pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, and single or multiple oxidative phosphorylation defects detected enzymatically in biopsied skeletal muscle]. Immediately after starting DCA, a single patient with KSS developed subjective symptoms of peripheral neuropathy with severe extremity pain and numbness, and DCA was discontinued. The remaining nine patients, some treated with DCA at a dose of 25-50 mg/kg/day for as long as 12 years, show no clinical or electrophysiological evidence of peripheral neuropathy. Per protocol, all patients are followed closely clinically and with nerve conduction studies every 6-12 months. Despite the small size of our patient sample, our findings seem to confirm the conclusion reached by Kaufmann et al that DCA causes toxic neuropathy in patients with MELAS. We are about to resubmit our DCA study protocol to the Children’s Hospital Boston IRB for renewal and will include in the application the findings of the Kaufmann et al study. We are wondering, however, whether the MELAS A3243G patients should be excluded from receiving DCA treatment or be assessed on a case-by-case basis. Since a correlation exists between cerebral lactic acidosis and neurologic impairment in MELAS [4], would it be advisable to enroll selected MELAS patients with severe cerebral lactic acidosis? References 1. Kaufmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology 2006;66:324-330. 2. Stacpoole PW, Barnes CL, Hurbanis MD, Cannon SL, Kerr DS. Treatment of congenital lactic acidosis with dichloroacetate. Arch Dis Child 1997;77:535-541. 3. Stacpoole PW, Perkins LA, Neiberger NE, Theriaque DW, Hutson AD. Dichloroacetate treatment of congenital lactic acidosis: preliminary outcome results of the DCA/CLA clinical trial (abstr). Presented at the 84th annual meeting of The Endocrine Society; San Francisco, CA; June 2002. 4. Kaufmann P, Shungu DC, Sano MC, et al. Cerebral lactic acidosis correlates with neurological impairment in MELAS. Neurology 2004;62:1297-1302. Disclosure: The authors report no conflicts of interest.
Reply from the Authors 6 June 2006
Petra Kaufmann, Columbia University 710 W 168th Street, New York NY 10032, Darryl DeVivo Send Correspondence to journal: Re: Reply from the Authors pk88{at}columbia.edu Petra Kaufmann, et al.	We thank Drs. Anselm and Darras for their comments and agree that MELAS 3243 patients may have an underlying vulnerability of the peripheral nervous system making them particularly susceptible to dichloroacetate toxicity. Due to this toxicity, we could not evaluate for any possible benefit in our study. Discerning drug effects from the natural history of metabolic disease can be challenging without concurrent controls. Therefore, we agree that if dichloroacetate is used, patients should be monitored very closely, both electrophysiologically and clinically, for signs of peripheral neuropathy. Disclosure: The authors report no conflicts of interest.
Dichloroacetate causes toxic neuropathy in MELAS: A randomized, controlled clinical trial 28 March 2006
Heikki Savolainen, Department of Occupational Safety and Health POB 536, FIN-33101 Tampere, Finland Send Correspondence to journal: Re: Dichloroacetate causes toxic neuropathy in MELAS: A randomized, controlled clinical trial heikki.savolainen{at}stm.fi Heikki Savolainen	This careful investigation by Kaufmann et al [1] shows that decreasing the lactate anion concentration does not ameliorate the nervous system's biochemical complications. It may be due to the toxicity of the treatment as Kaufmann et al suggest or because the inhibition of lactate accumulation does not necessarily correct the acidosis caused by excessive protons for malfunctioning respiratory chain. Acidosis in itself is an important factor in formic acid toxicity [2] and circulating anions from the tricarboxylic acid cycle [3] may have important regulatory effects, such as upregulation of hypoxia inducible factor (HIF-1). [4] It seems that treating the acidosis is even more important than trying to remove only the lactate anions. References 1. Kaufmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in MELAS. Neurology 2006;66:324-330. 2. Liesivuori J, Savolainen H. Methanol and formic acid toxicity: Biochemical mechanisms. Pharmacol Toxicol 1991;69:157-163. 3. Forni LG, McKinnon W, Lord GA, Treacher DF, Peron J-MR, Hilton PJ. Circulating anions usually associated with the Krebs cycle in patients with metabolic acidosis. Crit Care 2005;9:R591-R595. 4. Brière JJ, Favier J, Benit P, et al. Mitochondrial succinate is instrumental for HIF 1 alpha nuclear translocation in SDHA-mutant fibroblasts under normoxic conditions. Hum Mol Genet 2005;14:3263-3269. Disclosure: The author reports no conflicts of interest.
Reply from the authors 28 March 2006
Petra Kaufmann, Columbia University 710 W 168th Street, New York, NY 10032, Darryl C. De Vivo Send Correspondence to journal: Re: Reply from the authors pk88{at}columbia.edu Petra Kaufmann, et al.	We thank Dr. Savolainen for his comments. DCA did not lower lactate under the conditions of our trial. [1] Therefore, our study does not allow conclusions on the clinical effects of lowering lactate in MELAS. We have previously shown that elevated brain lactate is associated with neurological impairment [5] and we maintain that lowering lactate may be beneficial in MELAS. We presume that elevated brain lactate is associated with acidosis, but this is not proven. Dr. Savolainen’s hypothesis that lowering lactate may not correct acidosis cannot be evaluated on the basis of our data. We concur that chronic cerebral acidosis is disadvantageous to brain cells, but low brain pH has to be documented in MELAS. References 5. Kaufmann P, Shungu DC, Sano MC, et al. Cerebral lactic acidosis correlates with neurological impairment in MELAS. Neurology 2004;62:1297-1302. Disclosure: The authors report no conflicts of interest.