Menkes disease: what a multidisciplinary approach can do

Abstract

Disorders of copper homeostasis are currently recognized across the life span. Their recognition and links to human disease have spanned several decades, beginning with the recognition of a degenerative disorder in the offspring of sheep grazing in copper-deficient pastures, through to the description of infants suffering from a progressive neurodegenerative disorder characterized by epileptic seizures, developmental regression, failure to thrive, and an unusual hair quality (giving the condition its distinctive label of “kinky hair disease”). In this review, we trace the historical background and describe the biochemistry and physiology of copper metabolism and transport, inheritance patterns, molecular genetics, and genotype–phenotype correlations based on current understanding of the disorder. It is clear from the clinical presentations and variants that disorders of copper homeostasis include phenotypes ranging from mild occipital horn syndrome to intermediate and severe forms of classical Menkes disease. The symptoms involve multiple organ systems such as brain, lung, gastrointestinal tract, urinary tract, connective tissue, and skin. A multisystem disorder needs a multidisciplinary approach to care, as treatment interventions permit longer survival for some individuals. Animal models have been developed to help screen treatment options and provide a better understanding of these disorders in the laboratory. Finally, we propose a multidisciplinary approach to promote continued research (both basic and clinical) to improve survival, quality of life, and care for these conditions.

Membrane transport proteins in melanosomes: Regulation of ions for pigmentation

“…The defect of ATP7A does not cause albinism but causes Menkes disease. Symptoms of the Menkes patients vary but include abnormalities in hair and skin [62]. TPC2 defect leads to abnormalities of melanin production and pigmentation [63]; however, their corresponding disease was not reported (Table 1).…”

“…ATP7A is ubiquitously expressed in most tissues and plays a central role in controlling Cu 2+ balance in the cells. Cu 2+ is an essential cofactor for enzymatic functions, however, excessive amounts of Cu 2+ lead to tissue toxicity such as liver diseases and neurological defects [62,127,128]. Accordingly, cells need to restrict cellular Cu 2+ homeostasis, and thus, ATP7A is critical.…”

“…At the bloodbrain barrier, ATP7A is trafficked to the basolateral membrane to promote Cu 2+ delivery to the brain. ATP7A plays important roles in neuron activation, angiotensin-II-associated hypertension, cisplatin resistance and hepatic Cu 2+ mobilization [62].…”

“…Because ATP7A is located on the Xchromosome, the vast majority of Menkes disease patients are male. Since ATP7A is ubiquitously expressed and Cu 2+ has wide functionality, the patients have various degrees of symptoms ranging from mild to death clinical syndromes [62,138,139]. Complete disrupting the protein function (immature protein or deletion) may lead to childhood fatality [140].…”

“…The classical form phenotype is characterized by progressive neurological degeneration, osteoporosis, connective tissue defect, spare hypopigmented hair, hypopigmented skin, and retinal degradation. The milder form is termed OHS, which has connective tissue abnormalities [62]. At present, more than 100 mutations have been reported.…”