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Role of Oxidative Stress in the Worsening of Neurologic Wilson Disease Following Chelating Therapy

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Abstract

Patients with neurologic Wilson disease (NWD) may worsen on treatment, but there is no study evaluating the role of oxidative stress. We report the role of plasma glutathione (GSH), total antioxidant capacity (TAC) and malondialdehyde (MDA) in the worsening of NWD following treatment. Fifty-one treatment-naïve NWD patients were subjected to detailed clinical evaluation. The severity of NWD was noted, and dystonia was measured by Burke–Fahn–Marsden (BFM) score. Their hematological, serum chemistry, ultrasound abdomen and cranial MRI changes were noted. Plasma GSH, TAC and MDA, serum free copper (Cu) and 24-h urinary Cu were measured at admission and at 3 and 6 months after treatment. The patients were considered worsened if there was one or more grade deterioration in severity scale, >10 % deterioration in BFM score or appearance of new neurologic signs. The median age of the patients was 11 (5–37) years, and 12 were females. Following treatment, 25 patients improved, 12 worsened, and 14 had stationary course. The worsened group at 3 months had lower GSH (1.99 ± 0.17 vs. 2.30 ± 0.30 mg/dl; P = 0.004) and TAC (1.59 ± 0.12 vs. 1.82 ± 0.17 mmol Trolox equivalent/L; P = 0.001) and higher MDA (5.24 ± 0.22 vs. 4.34 ± 0.46 nmol/ml; P < 0.001) levels compared to the improved group. These changes were associated with increased serum free Cu (41.81 ± 3.31 vs. 35.62 ± 6.40 µg/dl; P = 0.02) and 24-h urinary Cu (206.42 ± 41.61 vs. 121.99 ± 23.72 µg/24 h; P < 0.001) in the worsened compared to the improved group. All the patients having worsening were on penicillamine. Worsening following chelating treatment in NWD may be due to oxidative stress which is induced by increased serum free Cu. These results may have future therapeutic implication and needs further study.

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Abbreviations

BFM:

Burke–Fahn–Marsden

CNS:

Central nervous system

Cu:

Copper

GSH:

Glutathione

LPO:

Lipid peroxidation

MRI:

Magnetic resonance imaging

MDA:

Malondialdehyde

NWD:

Neurologic Wilson disease

TAC:

Total antioxidant capacity

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Acknowledgments

We are thankful to Mr. Deepak for secretarial help.

Funding

This work was funded by Intramural grant from the Sanjay Gandhi Post Graduate Medical Sciences, Lucknow, India (39:287), and Mr. Vijay Kumar received fellowship from Indian Council of Medical research, Government of India (ICMR-JRF, 3/1/3/JRF-2009/MPD 31381).

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  1. Department of Neurology, Sanjay Gandhi Post Graduate Medical Sciences, Raebareily Road, Lucknow, 226014, India

    Jayantee Kalita, Vijay Kumar, Abhay Ranjan & Usha K. Misra

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  1. Jayantee Kalita
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  2. Vijay Kumar
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  3. Abhay Ranjan
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  4. Usha K. Misra
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Correspondence to Jayantee Kalita.

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The research has been approved by the Institutional Ethics Committee, SGPGIMS, Lucknow (Ethic No A-03:PGI/IMP/IEC/56/19.08.2011).

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Supplementary figure 1

Error bar diagram shows plasma glutathione (GSH), total antioxidant capacity (TAC) and malondialdehyde (MDA) levels of the worsened Wilson disease patients at baseline, the time of worsening (3 months) and at stabilization (6 months) after stopping penicillamine. Eight patients received zinc and four received zinc and trientine (TIFF 651 kb)

Supplementary material 2 (DOC 73 kb)

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Kalita, J., Kumar, V., Ranjan, A. et al. Role of Oxidative Stress in the Worsening of Neurologic Wilson Disease Following Chelating Therapy. Neuromol Med 17, 364–372 (2015). https://doi.org/10.1007/s12017-015-8364-8

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