Menkes Disease Research Articles

External Occipital Protuberance Enlargement in Children: A Benign Anatomic Variant with Rare Associations

Objective − The aim of this study is to raise awareness about External Occipital Protuberance (EOP) enlargement in children, its typically benign anatomical variant, and the importance of considering associated conditions in diagnosis and management.Case Report − We reviewed the cases of four male patients, presenting with EOP enlargement. Among the cases, one involved a newborn diagnosed with Menkes disease, a rare genetic disorder affecting copper transport, which was associated with occipital exostosis. The other three cases involved adolescents with varying degrees of EOP enlargement, linked to factors such as prior trauma and excessive screen time. Conclusion − While EOP enlargement is generally a benign anatomical variant, this study underscores the importance of differential diagnosis, particularly in the pediatric population. Clinicians should be aware of the potential, albeit rare, associations with serious conditions such as Menkes disease. A comprehensive approach to diagnosis and management is recommended, especially in symptomatic cases.

Copper and Colorectal Cancer.

Minerals constitute only 5% of the typical human diet but are vital for health and functionality. Copper, a trace element, is absorbed by the human gut at 30-40% from diets typical of industrialized countries. The liver produces metallothioneins, which store copper. Copper is crucial for mitochondrial respiration, pigmentation, iron transport, antioxidant defense, hormone production, and extracellular matrix biosynthesis. Copper deficiency, often caused by mutations in the ATP7A gene, results in Menkes disease, an X-linked recessive disorder. On the contrary, Wilson disease is characterized by toxic copper accumulation. Cuproptosis, a unique form of cell death regulated by copper, is a subtype of necrosis induced by enhanced mitochondrial metabolism and intracellular copper accumulation. This process can reduce the malignant potential of tumor cells by inhibiting glucose metabolism. Therapeutically, copper and its complexes have shown efficacy in malignancy treatments. The disruption of copper homeostasis and excessive cuproplasia are significant in colorectal cancer development and metastasis. Therefore, manipulating copper status presents a potential therapeutic target for colorectal cancer, using copper chelators to inhibit copper formation or copper ion carriers to promote cuproptosis. This review highlights the role of copper in human physiology and pathology, emphasizing its impact on colorectal cancer and potential therapeutic strategies. Future AI-based approaches are anticipated to accelerate the development of new compounds targeting cuproptosis and copper disruption in colorectal cancer.

CT-based measurement and analysis of distal humerus morphology in healthy adults from Northern China

BackgroundThis study aims to investigate the morphological characteristics of the distal humerus in healthy adults from northern China using computed tomography and three-dimensional reconstruction techniques and compared whether there were diferences in morphology among populations from diferent geographical regions.MethodsThe CT data of 80 patients were imported into Mimics software for three-dimensional reconstruction and measurement. The differences in distal humeral morphological parameters between different genders and sides were compared, and the correlation between the parameters was explored. The distal humeral morphological parameters between Western and Chinese populations based on current and previous pooled results were compared.ResultsThirty-one morphological parameters were measured and analyzed in this study. The average (and standard deviation) of capitellum depth, capitellum width, capitellum height, distal humerus width, epitrochlea width, and humeral metaphyseal width was 10.83 ± 1.18 mm, 17.60 ± 2.06 mm, 21.10 ± 2.03 mm, 44.38 ± 4.07 mm, 12.02 ± 1.90 mm and 58.95 ± 4.86 mm, these parameters were significantly higher (P < 0.001*) in males than females. The capitellum width (r = -0.300, P = 0.007*), anterior lateral trochlear depth (r =-0.227, P = 0.043*), medial crest coronal tangential angle (r = 0.307, P = 0.006*), olecranon fossa volume (r = -0.408, P < 0.001*), olecranon fossa surface area (r = -0.345, P = 0.002*) and coronoid fossa surface area (r = -0.279, P = 0.012*) were significantly correlated with the age of the subjects. In the comparison of people from different regions, the capitellum height, lateral trochlear high, trochlear groove high, trochlear depth and medial trochlear high of the Western population were 23.25 ± 2.56 m, 21.6 ± 2.20 mm, 17.8 ± 2.00 mm, 17.80 ± 2.00 mm, 29.9 ± 4.10 mm, are significantly higher than those in the Chinese population. while capitellum width (15.55 ± 2.68 mm) and capitellum depth (9.00 ± 1.00 mm) were slightly lower.ConclusionThe findings provide a basis for the design of distal humeral orthopaedic implants, ensuring greater alignment with the anatomical structure of the distal humerus and improved surgical outcomes. Furthermore, the study provides a reference point for the diagnosis and classification of distal humeral diseases, as well as guidance for patient rehabilitation.

Adaptive protein synthesis in genetic models of copper deficiency and childhood neurodegeneration.

Copper dysregulation is present in neurodevelopmental, neurodegenerative, and neurological conditions ranging from rare conditions such as Menkes disease and CTR1 deficiency to more common diseases like Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. However, the precise mechanisms through which copper deficiency leads to pathology and the survival mechanisms by which the brain exhibits resilience remain unknown. We demonstrate that in a human cell line, Drosophila , and the mouse cerebellum, copper-depleted neuronal cells exhibit increased protein synthesis through two distinct signaling pathways: mTORC1 activation and decreased PERK (EIF2AK3) activity. This upregulation of protein synthesis facilitates resilience of neuronal cells to copper deficiency, including partial restoration of dendritic arborization. Our findings offer a new framework for understanding copper deficiency-related pathology in neurological disorders.

MAMMALIAN COPPER HOMEOSTASIS: PHYSIOLOGIC ROLES AND MOLECULAR MECHANISMS.

In the past decade, evidence for numerous roles of copper (Cu) in mammalian physiology has grown exponentially. The discoveries of Cu involvement in cell signaling, autophagy, cell motility, differentiation, and regulated cell death (cuproptosis) have markedly extended the list of already known functions of Cu, such as a cofactor of essential metabolic enzymes, a protein structural component, and a regulator of protein trafficking. Novel and unexpected functions of Cu transporting proteins and enzymes have been identified, and new disorders of Cu homeostasis have been described. Significant progress has been made in the mechanistic studies of two classic disorders of Cu metabolism, Menkes disease and Wilson disease, which paved ways to novel approaches to their treatment. Discovery of cuproptosis and the role of Cu in cells metastatic growth have markedly increased interest in targeting Cu homeostatic pathways to treat cancer. In this review, we summarize the established concepts in the field of mammalian Cu physiology, and discuss how new discoveries of the past decade expand and modify these concepts. The roles of Cu in brain metabolism, in cells' functional speciation and a recently discovered regulated cell death have attracted significant attention and are highlighted in this review.

Insights Into the Role of Copper in Neurodegenerative Diseases and the Therapeutic Potential of Natural Compounds.

Neurodegenerative diseases encompass a collection of neurological disorders originating from the progressive degeneration of neurons, resulting in the dysfunction of neurons. Unfortunately, effective therapeutic interventions for these diseases are presently lacking. Copper (Cu), a crucial trace element within the human body, assumes a pivotal role in various biological metabolic processes, including energy metabolism, antioxidant defense, and neurotransmission. These processes are vital for the sustenance, growth, and development of organisms. Mounting evidence suggests that disrupted copper homeostasis contributes to numerous age-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Wilson's disease (WD), Menkes disease (MD), prion diseases, and multiple sclerosis (MS). This comprehensive review investigates the connection between the imbalance of copper homeostasis and neurodegenerative diseases, summarizing pertinent drugs and therapies that ameliorate neuropathological changes, motor deficits, and cognitive impairments in these conditions through the modulation of copper metabolism. These interventions include Metal-Protein Attenuating Compounds (MPACs), copper chelators, copper supplements, and zinc salts. Moreover, this review highlights the potential of active compounds derived from natural plant medicines to enhance neurodegenerative disease outcomes by regulating copper homeostasis. Among these compounds, polyphenols are particularly abundant. Consequently, this review holds significant implications for the future development of innovative drugs targeting the treatment of neurodegenerative diseases.

Phenotypic and mutational spectrum of 17 Chinese patients with Menkes Disease.

Menkes Disease (MD) is a fatal X-linked recessive disorder caused by mutations in the ATP7A gene. Severe cases typically die before the age of three. Mild MD and occipital horn syndrome are variants of MD characterized by a less severe phenotype and longer survival. This case series aims to validate previous findings, expand the clinical phenotype, identify novel ATP7A mutations of MD patients. Observational data with follow-up were collected from 17 genetically diagnosed Chinese MD patients. All 17 patients exhibited neurological symptoms, including delayed motor milestones (100%) and seizures (58.8%). Unspecific pregnancy or delivery complications occurred in 9 patients (52.9%). The most prevalent connective tissue problems were abnormal hair (76.5%), followed by skeletal and dental abnormalities (52.9%), skin problems (41.2%) and hernia (35.3%). Sensorineural hearing loss (17.6%) was previously unreported. Coronary artery aneurysm and patent foramen ovale (5.9%) were infrequent. One 16-year-old boy carries pathological exon 3-4 deletion, presents novel mild phenotype including short stature and cerebellar ataxia. Out of 13 patients with follow-up (median: 24 months), 7 patients (53.8%) died with median survival of 40 months (range: 21-48 months), 3 patients (23.1%) show severe motor development delay and 2 (15.4%) have refractory epilepsy, only the mild MD patient shows improved cerebellar ataxia. Sixteen ATP7A mutations were identified including 6 small indels (37.5%), 5 nonsense mutations (31.2%), 2 missense mutations (12.5%), 2 exon deletions (12.5%), and 1 splice site mutation (6.25%). Fourteen mutations were novel. Our study further broadens the phenotypic and genotypic spectrums of Menkes disease.

Pili Torti: A Clue to Life-threatening Illness – A Rare Case Report

Menkes kinky hair disease (MKHD) is a rare inherent error of copper metabolism presenting during early infancy with multi-system involvement. It is associated with high morbidity and mortality in early childhood. Characteristic hair changes mirror internal metabolic alterations. Here, we report a case of 13-month-old male child who presented with peculiar changes of skin and hair along with convulsion and high-grade fever. Dermatoscopy and hair mount examination showing pili torti with pigmentary dilution pointed toward the diagnosis of MKHD, which was further enforced with blood investigations showing low copper and ceruloplasmin levels. Cutaneous findings play a crucial role in early diagnosis, thereby reducing morbidity with timely treatment.

Comprehensive insights into Menkes disease: Genetics, pathophysiology, animal models, diagnosis, and therapeutic strategies

Menkes disease (MD) is an inherited disorder affecting primarily the males which is X-linked recessive in inheritance pattern due to mutation in ATP7A gene that codes for copper transporter protein. This results in neurological complications and connective tissue lesions that make affected males succumb to death. MD can be classified as the classical and Occipital Horn Syndrome (OHS) varieties, though the severity and early presentation of the classical MD is more pronounced. Diagnostic assays include determination of serum copper and ceruloplasmin concentrations; neurochemical studies are also performed. The standard treatment usually entails the use of copper supplements with copper – Histidine being one of the most effective. Therefore, it is necessary to investigate the molecular pathophysiology of ATP7A disorder to come up with different therapies. Animal models such as zebrafish, fruit flies etc. are beneficial to know about MD pathology to get treatment. In summary, the early and accurate diagnosis of MD, followed by immediate treatment, plays a critical role in successful management of the disorder.

Brain and the whole-body bone imaging appearances in Menkes disease: a case report and literature review

BackgroundMenkes disease (MD) is a rare, inherited, multisystemic copper metabolism disorder. Classical Menkes disease is characterized by low serum copper and ceruloplasmin concentrations, leading to multiple abnormalities in the whole-body, especially in connective tissue and central nervous system. However, serum copper and ceruloplasmin levels are not reliable diagnostic biomarkers due to the low concentrations in healthy newborns either. The featured imaging manifestations play an important role in diagnosing Menkes disease. To our knowledge, there are few reports on the systemic imaging manifestations of Menkes disease.Case presentationA 4-month-old male patient presented with recurrent seizures. He had cognitive, intellectual, growth, gross motor, precision movement, and language developmental lags. The patient’s hemoglobin and serum ceruloplasmin level were low. On MRI, increased intracranial vascular tortuosity, cerebral and cerebellar atrophy, white matter changes, and basal ganglia abnormalities were observed. Plain radiograph revealed wormian bones, rib flaring, metaphyseal spurring, and periosteal reactions in the long bones of the limbs. A pathogenic variant in ATP7A gene was identified in the patient, so he was confirmed the diagnosis of Menkes disease. His symptoms did not improve despite symptomatic and supportive treatment during his hospitalization. Unfortunately, the infant died 3 months after leaving hospital.ConclusionA comprehensive and intuitive understanding of the disease’s imaging manifestations can help clinicians to identify the disease and avoid delays in care.

Unraveling Copper Exchange in the Atox1-Cu(I)-Mnk1 Heterodimer: A Simulation Approach.

Copper, an essential metal for various cellular processes, requires tight regulation to prevent cytotoxicity. Intracellular pathways crucial for maintaining optimal copper levels involve soluble and membrane transporters, namely, metallochaperones and P-type ATPases, respectively. In this study, we used a simulation workflow based on free-energy perturbation (FEP) theory and parallel bias metadynamics (PBMetaD) to predict the Cu(I) exchange mechanism between the human Cu(I) chaperone, Atox1, and one of its two physiological partners, ATP7A. ATP7A, also known as the Menkes disease protein, is a transmembrane protein and one of the main copper-transporting ATPases. It pumps copper into the trans-Golgi network for the maturation of cuproenzymes and is also essential for the efflux of excess copper across the plasma membrane. In this analysis, we utilized the nuclear magnetic resonance (NMR) structure of the Cu(I)-mediated complex between Atox1 and the first soluble domain of the Menkes protein (Mnk1) as a starting point. Independent free-energy simulations were conducted to investigate the dissociation of both Atox1 and Mnk1. The calculations revealed that the two dissociations require free energy values of 6.3 and 6.2 kcal/mol, respectively, following a stepwise dissociation mechanism.

Role of copper in central nervous system physiology and pathology.

Copper is a transition metal and an essential element for the organism, as alterations in its homeostasis leading to metal accumulation or deficiency have pathological effects in several organs, including the central nervous system. Central copper dysregulations have been evidenced in two genetic disorders characterized by mutations in the copper-ATPases ATP7A and ATP7B, Menkes disease and Wilson's disease, respectively, and also in multifactorial neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. This review summarizes current knowledge about the role of copper in central nervous system physiology and pathology, reports about unbalances in copper levels and/or distribution under disease, describes relevant animal models for human disorders where copper metabolism genes are dysregulated, and discusses relevant therapeutic approaches modulating copper availability. Overall, alterations in copper metabolism may contribute to the etiology of central nervous system disorders and represent relevant therapeutic targets to restore tissue homeostasis.

The physiological and pathophysiological roles of copper in the nervous system.

Copper is a critical trace element in biological systems due the vast number of essential enzymes that require the metal as a cofactor, including cytochrome c oxidase, superoxide dismutase and dopamine-β-hydroxylase. Due its key role in oxidative metabolism, antioxidant defence and neurotransmitter synthesis, copper is particularly important for neuronal development and proper neuronal function. Moreover, increasing evidence suggests that copper also serves important functions in synaptic and network activity, the regulation of circadian rhythms, and arousal. However, it is important to note that because of copper's ability to redox cycle and generate reactive species, cellular levels of the metal must be tightly regulated to meet cellular needs while avoiding copper-induced oxidative stress. Therefore, it is essential that the intricate system of copper transporters, exporters, copper chaperones and copper trafficking proteins function properly and in coordinate fashion. Indeed, disorders of copper metabolism such as Menkes disease and Wilson disease, as well as diseases linked to dysfunction of copper-requiring enzymes, such as SOD1-linked amyotrophic lateral sclerosis, demonstrate the dramatic neurological consequences of altered copper homeostasis. In this review, we explore the physiological importance of copper in the nervous system as well as pathologies related to improper copper handling.

Emergence of kinky hair in Menkes disease

Emergence of kinky hair in Menkes disease

Features of damage to the central nervous system in children with Menkes disease. Clinical case

Features of damage to the central nervous system in children with Menkes disease. Clinical case

MENKES DISEASE: A LITERATURE REVIEW AND CLINICAL CASE

Menkes Kinky Hair Disease (MKHD) is characterized by an abnormality in copper metabolism caused by a mutation in the ATP7A gene, which is located on Xq13.3 and has 23 exons. In addition, this gene encodes 1500 amino acids and is expressed in large quantities in various organs. It’s worth mentioning that about 357 diff erent mutations have been identifi ed in the ATP7A gene. It is a relatively rare disease with an incidence of 1 case per 100,000 to 250,000 live births. MKHD is an X-linked recessive trait that almost exclusively aff ects boys.The diagnosis of this rare disease is based on the genetic- molecular study of a metabolic disease panel, including the ATP7A gene and the biochemical phenotype (a decrease in serum copper and ceruloplasmin levels).In developing therapeutic strategies for individuals with Menkes disease, three fundamental problems are being addressed: 1) unlocking the absorption of copper in the intestine; 2) making copper available to enzymes in cells that require it as a cofactor; and 3) identifying infants with Menkes disease and initiating treatment at a very early stage of life, before irreversible neurodegeneration occurs. This article presents a clinical case of Menkes disease in a 7-month-old boy. The diagnosis was confi rmed by molecular genetic testing (NGS) of the Neurometabolic Disorders Panel, which included the ATP7A gene and biochemical phenotype. The described case illustrates the complexity of diagnosing Menkes disease in the neonatal period due to the non-specifi city of disease symptoms (lethargy, weak sucking, weight loss, etc.) and the importance of biochemical and molecular genetic methods of fetal investigation in subsequent pregnancies or in a newborn sibling for early diagnosis and treatment. This case will be published with the consent of the mother in accordance with bioethical principles.

Synthesis and Biological Activities of Some Metal Complexes of Peptides: A Review.

Peptides, both natural and synthetic, are well suited for a wide range of purposes and offer versatile applications in different fields such as biocatalysts, injectable hydrogels, tumor treatment, and drug delivery. The research of the better part of the cited papers was conducted using various database platforms such as MetalPDB. The rising prominence of therapeutic peptides encompasses anticancer, antiviral, antimicrobial, and anti-neurodegenerative properties. The metals Na, K, Mg, Ca, Fe, Mn, Co, Cu, Zn, and Mo are ten of the twenty elements that are considered essential for life. Crucial for understanding the biological role of metals is the exploration of metal-bound proteins and peptides. Aside from essential metals, there are other non-essential metals that also interact biologically, exhibiting either therapeutic or toxic effects. Irregularities in metal binding contribute to diseases like Alzheimer's, neurodegenerative disorders, Wilson's, and Menkes disease. Certain metal complexes have potential applications as radiopharmaceuticals. The examination of these complexes was achieved by preforming UV-Vis, IR, EPR, NMR spectroscopy, and X-ray analysis. This summary, although unable to cover all of the studies in the field, offers a review of the ongoing experimentation and is a basis for new ideas, as well as strategies to explore and gain knowledge from the extensive realm of peptide-chelated metals and biotechnologies.

Preimplantation genetic testing for monogenic disorders (PGT-M) offers an alternative strategy to prevent children from being born with hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes: a retrospective study.

Preimplantation genetic testing for monogenic disorders (PGT-M) is now widely used as an effective strategy to prevent various monogenic or chromosomal diseases. In this retrospective study, couples with a family history of hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes and/or carrying the pathogenic genes underwent PGT-M to prevent children from inheriting disease-causing gene mutations from their parents and developing known genetic diseases. After PGT-M, unaffected (i.e., normal) embryos after genetic detection were transferred into the uterus of their corresponding mothers. A total of 43 carrier couples with the following hereditary neurological diseasesor metabolic diseases dominated by nervous system phenotypesunderwent PGT-M: Duchenne muscular dystrophy (13 families); methylmalonic acidemia (7 families); spinal muscular atrophy (5 families); infantile neuroaxonal dystrophyand intellectual developmental disorder(3 families each); Cockayne syndrome(2 families); Menkes disease, spinocerebellar ataxia, glycine encephalopathy with epilepsy,Charcot-Marie-Tooth disease, mucopolysaccharidosis, Aicardi-Goutieres syndrome, adrenoleukodystrophy, phenylketonuria, amyotrophic lateral sclerosis, and Dravet syndrome (1 family each). After 53 PGT-M cycles,the final transferable embryo rate was 12.45%, the clinical pregnancy rate was 74.19%, and the live birth rate was 89.47%;a total of 18 unaffected (i.e., healthy) children were born to these families. This study highlights the importance of PGT-M in preventing children born with hereditary neurological diseases or metabolic diseases dominated by nervous system phenotypes.

Cuproptosis: Unraveling the Mechanisms of Copper-Induced Cell Death and Its Implication in Cancer Therapy

Copper, an essential element for various biological processes, demands precise regulation to avert detrimental health effects and potential cell toxicity. This paper explores the mechanisms of copper-induced cell death, known as cuproptosis, and its potential health and disease implications, including cancer therapy. Copper ionophores, such as elesclomol and disulfiram, increase intracellular copper levels. This elevation triggers oxidative stress and subsequent cell death, offering potential implications in cancer therapy. Additionally, copper ionophores disrupt mitochondrial respiration and protein lipoylation, further contributing to copper toxicity and cell death. Potential targets and biomarkers are identified, as copper can be targeted to those proteins to trigger cuproptosis. The role of copper in different cancers is discussed to understand targeted cancer therapies using copper nanomaterials, copper ionophores, and copper chelators. Furthermore, the role of copper is explored through diseases such as Wilson and Menkes disease to understand the physiological mechanisms of copper. Exploring cuproptosis presents an opportunity to improve treatments for copper-related disorders and various cancers, with the potential to bring significant advancements to modern medicine.

Mechanism of Cu entry into the brain: many unanswered questions.

Brain tissue requires high amounts of copper (Cu) for its key physiological processes, such as energy production, neurotransmitter synthesis, maturation of neuropeptides, myelination, synaptic plasticity, and radical scavenging. The requirements for Cu in the brain vary depending on specific brain regions, cell types, organism age, and nutritional status. Cu imbalances cause or contribute to several life-threatening neurologic disorders including Menkes disease, Wilson disease, Alzheimer's disease, Parkinson's disease, and others. Despite the well-established role of Cu homeostasis in brain development and function, the mechanisms that govern Cu delivery to the brain are not well defined. This review summarizes available information on Cu transfer through the brain barriers and discusses issues that require further research.