Early treatment of Menkes disease with parenteral copper-histidine: long-term follow-up of four treated patients.

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.

Variability in clinical expression of Menkes syndrome.

Six patients with Menkes syndrome are described, who differ from patients with the classical form of Menkes syndrome because of their longer survival; some of them also exhibited a milder manifestation of symptoms. Based on the present data and a summary of seven case reports describing Menkes patients with long survival, it may be possible to divide these patients into two subgroups: one group of severely affected patients with long survival and another group of very mildly affected patients with late onset of symptoms. Perhaps only the latter represents a true subgroup of Menkes syndrome. The possible benefits of copper therapy are discussed.

Ontogeny of iminoglycine transport in mammalian kidney.

Renal tubular absorption of proline, hydroxyproline, and glycine by the newborn of most mammals is inefficient compared to that of the adult. Cortex slices from seven-day-old rat kidney also transport proline and glycine at reduced initial rates compared to mature kidney. Nonetheless, newborn slices achieve higher intracellular concentrations during prolonged incubation; the latter reflects a reduced rate of efflux, a characteristic peculiar to the membrane of postnatal kidney. The postnatal reduction of initial uptake rates is observed clearly only at substrate concentrations in or below the physiological range; it correlates with the absence of two high-affinity systems which normally serve proline and glycine transport independently at these concentrations in mature kidney, in conjunction with a "common" low-affinity system. The low-affinity system alone performs the observed uptake in the newborn kidney. Specific activity of the high-affinity systems for proline and glycine increases asynchronously after birth, suggesting independent genetic control of the three systems for iminoglycine transport in mammalian kidney.