Early treatment of Menkes disease with parenteral Cooper-Histidine: Long-term follow-up of four treated patients

Abstract

We report on the long-term clinical course of 4 boys with Menkes disease, treated from early infancy with parenteral copper-histidine, with follow-up over 10-20 years. Three of the 4 had male relatives with a severe clinical course compatible with classical Menkes disease. As a consequence of early treatment, our patients have normal or near-normal intellectual development, but have developed many of the more severe somatic abnormalities of the related disorder, occipital horn syndrome, including severe orthostatic hypotension in 2. In addition, 1 boy developed a previously unreported anomaly, namely, massive splenomegaly and hypersplenism as a consequence of a splenic artery aneurysm. Previously reported molecular studies in 2 of these patients had shown gene defects which would have predicted a truncated and probably nonfunctional gene product. Despite the favorable effects on the neurological symptoms, parenteral copper treatment for Menkes disease should still be regarded as experimental. The development of more effective treatments must await a more precise delineation of the role which the Menkes protein plays in intracellular copper trafficking.

Menkes disease

“…58 All these patients clearly exhibited a milder neurological course without seizures, mildto-moderate ataxia, and near-normal intellectual development. Some problems related to autonomic failure, such as postural hypotension and chronic diarrhea, persisted, and in one patient these symptoms could be corrected by L-DOPS.…”

“…Among the available copper compounds, copper histidine has proved to be the most effective. [57][58] Positive outcome of copper-histidine supplementation is dependent on early initiation and presence of at least partially functional ATP7A.…”

Clinical utility gene card for: Menkes disease

“…If an MD patient can be diagnosed within the first weeks of life, parenteral administration of copper can be initiated. 12 Early initiation of treatment may have a beneficial effect on neurodevelopment, but does not remove all the symptoms. It has to be kept in mind that the long-term benefits of copper treatment have only been documented in very few patients.…”

The Mild Form of Menkes Disease: A 34 Year Progress Report on the Original Case

“…Other manifestations include autonomic dysfunction, skin laxity, bladder diverticuli, pili torti hair changes and characteristic facies. Untreated boys with classical Menkes succumb in the first few years of life; however, early treatment with parenteral copper-histidinate may normalise the developmental outcomes in patients with residual enzyme activity (Kaler et al 2008;Christodoulou et al 1998). The occipital horn syndrome manifests with prominent connective tissue abnormalities as well as pathognomonic occipital exostoses; mild intellectual impairment may be seen (Tsukahara et al 1994).…”