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Menkes disease (MD) is a rare inherited disease that leads to a severe multisystem disorder of copper metabolism, characterized by progressive neurodegeneration and marked connective tissue abnormalities, as well as abnormal, kinky, sparse hair. It is a chromosome X-linked disease (mutations in the ATP7A gene that codes for a copper transport protein) that mainly affects men and appears in the neonatal period, while women are usually unaffected carriers.

In the early neonatal period, patients may present prolonged jaundice, hypothermia, hypoglycemia, and feeding difficulties. The first sign may be an unusually sparse, dull scalp at 1 to 2 months of age. This characteristic hair is hypopigmented or depigmented and looks like steel wool. It is dull and brittle, especially in areas subject to friction. Additional symptoms include developmental delay, poor feeding, vomiting, and diarrhea. Patients develop gradual motor dysfunction and seizures. In early life, muscle tone is often reduced but is later replaced by spasticity and limb weakness. The clinical course is usually severe.

Although this disease has been known since Menkes described it in 1962, today (almost 60 years later) its treatment is still only symptomatic. It has been seen that the early parenteral administration of copper-histidine (Cu-His) can modify the progression of the disease and some symptoms by providing extra copper to the tissues and copper-dependent enzymes. Oral administration of copper is not effective since it is retained in the intestines. The prognosis is poor, and patients usually die in early childhood. However, careful medical attention and the possibility of administering Cu-His can lengthen the lives of these children.

As recently as 2020, a small molecule, elesclomol, that can escort copper has been described. It does it in the form of the Cu(elesclomol) complex, Cu-ES, which drives copper to the mitochondria and increase levels of cytochrome c oxidase-1 (copper-dependent protein) in the brain of spotted mice (Menkes models). Through this mechanism, Cu-ES was shown to be able to prevent deleterious neurodegenerative changes and improve survival in treated mice that had normal growth and survival. These showed normal serum copper levels, reduced but improved brain copper levels, and normal brain weight. Untreated mice exhibited hypopigmentation and death around postnatal day 14. The authors concluded that Cu-ES holds promise for the treatment of Menkes disease and the associated disorders of hereditary copper deficiency.

Our adventure begins here: in the fight against the progress of the disease and its neurodegenerative effects, the UAB-UB Bioinorganics group, in collaboration with the Pediatric Institute for Rare Diseases (IPER) of the Sant Joan de Déu Hospital (Drs. Natalia Serrano y Frances Palau) and the "Menkes International Association" and an international committee (“The Copper(Less) Committee”) that brings together world experts in the field of MD honorarily working for this purpose, has started a project to establish Cu-ES administration and follow-up protocols that should allow us to improve the living conditions of children with Menkes.

The Copper(Less) Committee

The administration of Cu-ES can obviously have positive effects in Menkes patients but also highly negative ones if certain copper concentration thresholds are exceeded. Copper metabolism in humans is different from that in mice. Therefore, although Cu-ES has been shown to relieve mice suffering from Menkes, it is not easy to establish an adequate dosage for a child as young as a few months old. For this reason, it is highly recommended to start treatment with lower doses than those necessary for the proper functioning of the body of these children and to follow, day by day, the levels of copper in their bodies with reliable measurements of the same. Based on these copper levels, the initial dosage would be increased until reaching those levels that maintained the correct copper concentration in the body of our little patients. Until now, free copper in the blood or the concentration of Cu-ceruloplasmin (copper transporter in the blood) have been used for this purpose, but they turn out to be inaccurate and precise for such a delicate undertaking as the one we intend to accept. According to the literature, being able to accurately determine the concentrations of metallothionein in the blood and urine of patients while they are being treated with Cu-ES could provide us with reliable guidelines for adapting the dosage of Cu-ES to each child.

Metallothioneins (MTs) were discovered in the middle of the 20th century and embrace a large family of metalloproteins, nowadays known to be ubiquitously found in almost all organisms. All of them share common features such as their low molecular weight and their richness in cysteine residues (close to 30%) which gives them their affinity for transition metals. Stunningly, after 65 years of study, their function is still a matter of debate although they have been linked to heavy metal detoxification and zinc and copper homeostasis, among other functions. Natively, they are found binding either Zn(II) or Cu(I), and mammals have 4 MT isoforms (MT1 to MT4), and many subisoforms, with different tissular localizations and metal binding properties.

The funding obtained to carry out this first line of action will make it possible to determine if metallothioneins can be used to monitor the copper levels of Menkes patients treated with Cu-ES to establish the appropriate dose of the drug that will provide these patients with the desired state of health, but it must also allow progress towards the efficiency, biosafety and toxicity tests of Cu-ES that are required to apply for a clinical trial.

Before the end of 2023, we want to have successfully reached an essential first stage to achieve the new treatment: To determine if metallothioneins can be used as biomarkers of copper levels in Menkes patients.

The project is headed by Dr. Capdevila, Professor of Inorganic Chemistry at the UAB Department of Chemistry, and an internationally recognized expert in the field of MTs research. The team has numerous collaborators, both from the UAB (Mª Isabel Pividori, Professor of Analytical Chemistry in the Department of Chemistry; Juan Hidalgo, Professor of the Department of Cellular Biology, Physiology and Immunology; Javier Carrasco, of the Molecular Biology service of the Institute of Neurosciences; and Òscar Palacios, Associate professor at the Department of Chemistry) and from the UB (Ricard Albalat, tenured professor in the Department of Genetics, Microbiology and Statistics).

This initiative, which started recently at the UAB with very limited resources, has benefited from this donation from MIa thanks to the support that the association has received from the Belgian Menkes Voor William Foundation, a Menkes child who unfortunately left this summer. His family has decided to promote scientific research in order to advance the cure for this rare disease and thus help other families like his. Thanks William!!!!

Menkes International Association (MIa) website: https://menkesinternational.com/