Prenatal Treatment of Mosaic Mice (Atp7a mo-ms) Mouse Model for Menkes Disease, with Copper Combined by Dimethyldithiocarbamate (DMDTC)

Abstract

Menkes disease is a fatal neurodegenerative disorder in infants caused by mutations in the gene ATP7A which encodes a copper (Cu) transporter. Defects in ATP7A lead to accumulated copper in the small intestine and kidneys and to copper deficiencies in the brain and the liver. The copper level in the kidney in postnatal copper-treated Menkes patients may reach toxic levels. The mouse model, mosaic Atp7a mo-ms recapitulates the Menkes phenotype and die about 15.75±1.5 days of age. In the present study we found that prenatal treatment of mosaic murine fetuses throughout gestation days 7, 11, 15 and 18 with a combination of CuCl2 (50 mg/kg) and dimethyldithiocarbamate (DMDTC) (280 mg/kg) leads to an increase in survival to about 76±25.3 days, whereas treatment with CuCl2 alone (50 mg/kg) only leads to survival for about 21 days ±5 days. These copper-DMDTC treated mutants showed an improved locomotor activity performance and a gain in body mass. In contrast to treatment with CuCl2 alone, a significant increase in the amount of copper was observed in the brain after prenatal copper-DMDTC treatment as well as a decrease in the amount of accumulated copper in the kidney, both leading towards a normalization of the copper level. Although copper-DMDTC prenatal treatment only leads to a small increase in the sub-normal copper concentration in the liver and to an increase of copper in the already overloaded small intestine, the combined results suggest that prenatal copper-DMDTC treatment also should be considered for humans.

Characterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes disease

“…The observed effects of the 36 ATP7A missense mutations are summarized in Figs 2 and 11.

Figure 11Distribution and effect of ATP7A disease-causing missense mutations. The mutations, presented in this study, are plotted as spheres in a previously established homology model of ATP7A 7 , based on the crystal structure of the homologous protein LpCopA from Legionella pneumophila 3 . The various domains of ATP7A are colored as in Fig.

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“…The mutations, presented in this study, are plotted as spheres in a previously established homology model of ATP7A 7 , based on the crystal structure of the homologous protein LpCopA from Legionella pneumophila 3 . The various domains of ATP7A are colored as in Fig.…”

Menkes disease: Oral administration of glyoxal-bis(N(4)-methylthiosemicarbazonato)-copper(II) rescues the macular mouse

“…In mosaic (Atp7a mo-ms) mice, another mouse model of Menkes disease, neuromotor deterioration manifests at 2 weeks old but is ameliorated by prenatal copper supplementation. 6 In this study, CuGTSM treatment started at 5 days old, which may be late for intact brain development.…”

“…1 To facilitate copper distribution to the brain, copper chelators such as diethyldithiocarbamate (DEDTC) and dimethyldithiocarbamate (DMDTC) have been proposed in combination with copper injections. [5][6][7] These compounds form lipophilic complexes with copper in the body and can penetrate the blood-brain barrier to increase copper levels and copper-dependent enzyme activity in the brain.…”

Biometals in rare neurodegenerative disorders of childhood

“…These mice are called mottled mice and different mutations in the atp7a gene cause different neurological and connective tissue anomalies. The two mottled mice mutations mottled brindled (Mo br ) and mottled macular (Mo ml ) show severe reductions in copper within the liver (Hunt and Clarke, 1983), and die within 1–3 weeks of birth (Lenartowicz et al, 2012). This premature death can be prevented with injected copper within the first week of birth, as well as transgenic over expression of atp7a (Danks, 1986).…”