メンケス病

A 7-month-old intact male Cavalier King Charles Spaniel was presented for persistent glucosuria despite normoglycemia, failure to thrive, chronic diarrhea, and cerebellar ataxia. Fanconi syndrome was diagnosed, but the neurologic abnormalities were not fully explained. As a consequence of the early onset Fanconi syndrome, a hereditary process was suspected. Whole genome sequencing identified a private hemizygous SINE-like insertion into the ATP7A gene, at the end of intron 13, near the start of exon 14. In humans, variants in ATP7A are associated with Menkes disease, a disorder of copper metabolism associated with a spectrum of clinical signs including progressive neurodegeneration and connective tissue abnormalities. Clinically affected dogs with variants in ATP7A have not been reported previously. Although this case appears to represent a mild phenotypic presentation of Menkes-like disease, it raises the possibility that copper disorders aside from copper-associated hepatitis might exist in dogs. Further genetic screening and phenotypic characterization of rare genetic variants associated with copper metabolism would be beneficial to expand our knowledge of copper disorders in dogs and allow potential early intervention and modeling for metabolic diseases in humans.

Copper (Cu) is essential to life as an enzymatic cofactor, powering a plethora of biological processes. However, cells teeter on a delicate balance where both too much and too little Cu can lead to dysfunction. These risks are exemplified by Menkes disease patients, where Cu deficiency leads to neurodevelopmental delay and early childhood mortality, and those affected by Wilson's disease, where Cu overload results in liver damage, behavioural changes and movement disorders. Cu is also a major cellular stressor, with roles in many other pathologies including neurodegeneration and cancer. Consequently, cells tightly regulate Cu load by highly conserved import, export, and distribution mechanisms. While these have been well documented, less is known about how cells sense and respond to Cu deviations. This function may lie in the extensive post-translational modifications (PTMs) that control the Cu transport proteins, where a chorus of glycosylation, phosphorylation, and ubiquitination affects their activity, intracellular trafficking, and stability. Cu also affects the machinery that applies these PTMs, providing a potential mechanism by which cells 'sense' Cu levels. This review explores this hypothesis, examining our current knowledge of how PTMs are modulated by Cu, and how they control the responses of the Cu transporters to fluctuating Cu load. Further probing of how cells sense and respond to Cu deviations may aid the pursuit of effective diagnosis and treatment of the many disorders associated with mismanaged Cu levels.

Menkes disease is a rare X-linked recessive multisystem copper metabolism disorder first reported in 1962.Recent studies have shown that its incidence and mortality rates may be underestimated due to miscarriages and early deaths.The clinical manifestations of Menkes disease are closely related to copper metabolism disorder，mainly characterized by neurodegeneration and vascular and connective tissue abnormalities.These symptoms stem from copper transport disorders and abnormal activity of copper-dependent enzymes caused by copper metabolism disorder.By integrating clinical symptoms and mechanism analysis，this paper reveals the core role of copper metabolism disorder in the multisystem damage of Menkes disease，providing a theoretical basis for early diagnosis and intervention.

Metabolic diseases caused by transporter dysfunction are inherited disorders resulting from defects in membrane transport proteins. These proteins allow the passage of nutrients, ions, and other molecules across cell membranes. If there is a malfunction, substances do not enter the cell, are not reabsorbed, or are not distributed correctly, even if present in normal amounts. Intracellular metabolism is normal; the problem lies in the movement of the molecule. These diseases are caused by mutations in genes that encode transporters and impair intestinal absorption (Menkes disease), renal reabsorption (cystinuria), or the passage of substances to specific tissues such as the brain (type I glucose transporter deficiency), muscle (mitochondrial carnitine transporter deficiency), or liver (Wilson disease). They are generally autosomal recessive inherited diseases with highly varied clinical manifestations, including seizures, developmental delay, intellectual disability, autism, and movement disorders. In the text we review some of the most common diseases of interest to neuropediatricians. Many of these diseases have early biochemical or molecular diagnosis and therapeutic options that improve the prognosis.

BACKGROUND: Osteoporosis is a prevalent metabolic bone disorder driven by an imbalance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, and current pharmacological options remain limited by adverse effects and incomplete mechanistic targeting. Copper, an essential trace element, has long been linked to bone mineral density through population-level dietary surveys, but whether and how copper mechanistically shapes osteoblast and osteoclast function at the subcellular level has not been systematically reviewed. METHODS: We synthesised genetic, clinical, and cell-biological evidence-including copper-transporter mutation models (Menkes and Wilson disease), organelle-specific trafficking studies, and mechanistic work on copper-dependent enzymes and chaperones-to construct an organelle-resolved account of copper handling in bone cells, extending beyond the mitochondria and trans-Golgi network to include the endoplasmic reticulum and the lysosomal/endosomal system. RESULTS: Copper regulates bone metabolism through distinct, organelle-specific, and cell-type-specific mechanisms. In mitochondria, physiological copper supports oxidative phosphorylation and osteogenesis, whereas copper overload can trigger cuproptosis, a mechanistically distinct form of cell death mediated by FDX1-dependent aggregation of lipoylated tricarboxylic acid cycle proteins; whether this pathway selectively affects osteoclasts remains an open, and in part contested, question, since the hypoxic bone marrow niche may confer glycolysis-associated protection. In the trans-Golgi network, ATP7A/ATP7B-dependent maturation of lysyl oxidase supports collagen cross-linking, while COMMD1 restrains NF-κB-driven osteoclastogenesis. Emerging evidence implicates copper-dependent PERK activity in endoplasmic reticulum proteostasis relevant to osteoblast secretory function, and lysosomal CTR2-mediated copper release as a candidate regulator of mTORC1-autophagy signalling in osteoclasts, although direct evidence in bone cells for both pathways is still lacking. CONCLUSION: Copper acts as a compartment-specific and cell-type-specific regulator of bone remodelling rather than a uniform, dose-dependent factor. Trans-Golgi-network-targeted strategies to enhance lysyl oxidase maturation are the most mechanistically mature translational direction, whereas mitochondria- and lysosome-targeted approaches remain hypothesis-generating and require direct validation in osteoblasts and osteoclasts before therapeutic development can reasonably proceed.