Deficiencies of different
proteins involved in
copper metabolism have been reported to cause human diseases. Well-known syndromes, for example, are Menkes and Wilson diseases. Here we report a patient presenting with congenital
cataract, severe
muscular hypotonia, developmental delay,
sensorineural hearing loss and
cytochrome-c oxidase deficiency with repeatedly low
copper and
ceruloplasmin levels. These findings were suggestive of a
copper metabolism disorder. In support of this, the patient's fibroblasts showed an increased
copper uptake with normal retention. Detailed follow-up examinations were performed. Immunoblotting for several
proteins including ATP7A (MNK or Menkes
protein), ATP7B (Wilson
protein) and SOD1 showed normal results, implying a
copper metabolism defect other than Wilson or
Menkes disease. Sequence analysis of ATOX1 and genes coding for
proteins that are known to play a role in the mitochondrial
copper metabolism (COI-III, SCO1, SCO2, COX11, COX17, COX19) revealed no mutations. Additional disease genes that have been associated with
cytochrome-c oxidase deficiency were negative for mutations as well. As beneficial effects of
copper histidinate supplementation have been reported in selected disorders of
copper metabolism presenting with low serum
copper and
ceruloplasmin levels, we initiated a
copper histidinate supplementation. Remarkable improvement of clinical symptoms was observed, with complete restoration of
cytochrome-c oxidase activity in skeletal muscle.