Jayalakshmi Narayan BHAT, Paul MAERTENS

Low function of natural killer cells in treated classic Menkes disease

Background. Menkes disease (MD) is a rare lethal X-linked, multisystem disorder of copper metabolism resulting from mutations in the ATP7A gene. Features such as Ehlers- Danlos syndrome, trichopoliodystrophy, urologic and skeletal changes have been reported. We present a case of classic MD treated with copper infusions who suffered from persistent natural killer (NK) cell dysfunction.Case. A 2-year-old, Caucasian male child presented at 8-month-old of age with persistent hypotonia, kinky hair and developmental regression. Diagnosis of MD was based on low serum levels of copper [5 mg/dl (18-37)] and ceruloplasmin [18 ug/dl (75-153)] and gene-targeted deletion/duplication analysis performed by the reference laboratory. Brain MRI showed mild hypoplasia of the cerebellar vermis and vascular tortuosity typical of MD. Copper chloride treatment was immediately initiated. The child became more alert with excellent eye contact and purposeful movements. The child was hospitalized for recurrent respiratory infections, each time caused by enterovirus as confirmed by multiplex polymerase chain reaction (PCR). Extensive immunologic studies were negative, except for a severe NK cell dysfunction on multiple occasions (0.6 NK lytic Units; N >2.6). Conclusion. We postulate that NK cell dysfunction in a classic MD can be explained by the deficient incorporation of copper in the endoplasmic reticulum resulting in an abnormal Fenton chemistry within phagosomes.

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1. Holloway ZG, Velayos-Baeza A, Howell GJ, et al. Trafficking of the Menkes copper transporter ATP7A is regulated by clathrin-, AP-2-, AP-1-, and Rab22- dependent steps. Mol Biol Cell 2013; 24: 1735-1748.

2. Kaler SG, Liew CJ, Donsante A, Hicks JD, Sato S, Greenfield JC. Molecular correlates of epilepsy in early diagnosed and treated Menkes disease. J Inherit Metab Dis 2010; 33: 583-589.

3. Olivares JL, Bueno I, Gallati S, Ramos FJ. Late-onset treatment in Menkes disease: is there a correlation between genotype and response to therapy? Clin Genet 2006; 69: 363-366.

4. Kaler SG, Holmes CS, Goldstein DS, et al. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med 2008; 358: 605-614.

5. Christodoulou J, Danks DM, Sarkar B, et al. Early treatment of Menkes disease with parenteral copper-histidine: long term follow-up of four treated patients. Am J Med Genet 1998; 76: 154-164.

6. Friberg DD, Bryant JL, Whiteside TL. Measurements of Natural Killer (NK) activity and NK-cell quantification. Methods 1996; 9: 316-326.

7. Tümer Z, Møller LB. Menkes disease. Eur J Hum Genet 2010; 18: 511-518.

8. Prohaska JR, Lukasewycz OA. Copper deficiency suppresses the immune response of mice. Science 1981; 31: 559-561.

9. White C, Lee J, Kambe T, Fritsche K, Petris MJ. A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity. J Biol Chem 2009; 284: 33949-33956.

10. Stafford SL, Bokil NJ, Achard ME, et al. Metal ions in macrophage antimicrobial pathways: emerging roles for zinc and copper. Biosci Rep 2013; 33: e00049.