As an indispensable trace element in the human body,copper plays an important role in various physiological and biochemical reactions.The dyshomeostasis of copper leads to the disorder of copper metabolism and the occurrence of related diseases.Cuproptosis,a newly proposed regulatory cell death mode,is different from the known apoptosis,pyroptosis,necroptosis,and ferroptosis.Recent studies have found that the dyshomeostasis of copper has been observed in a variety of cancers.Therefore,targeting copper for disease treatment may become a new strategy and a new idea.This article systematically summarizes the fundamental properties of copper,copper dyshomeostasis-related diseases (Menkes syndrome,Wilson's disease,and cancer) and their treatment,and reviews the research progress in cuproptosis.
Humans ; Copper/metabolism* ; Homeostasis ; Neoplasms/metabolism* ; Hepatolenticular Degeneration/metabolism* ; Menkes Kinky Hair Syndrome/metabolism*

OBJECTIVE: To explore the clinical characteristics and genetic etiology of three children with Menkes disease. METHODS: Three children who had presented at the Children's Medical Center, the Affiliated Hospital of Guangdong Medical University from January 2020 to July 2022 were selected as the study subjects. Clinical data of the children were reviewed. Genomic DNA was extracted from peripheral blood samples of the children, their parents and sister of child 1. Whole exome sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing, copy number variation sequencing (CNV-seq), and bioinformatic analysis. RESULTS: Child 1 was a 1-year-and-4-month male, and children 2 and 3 were monozygotic twin males aged 1-year-and-10-month. The clinical manifestations of the three children have included developmental delay and seizures. WES showed that child 1 has harbored a c.3294+1G>A variant of the ATP7A gene. Sanger sequencing confirmed that his parents and sister did not carry the same variant, suggesting that it was de novo. Children 2 and 3 had carried a c.77266650_77267178del copy number variation. CNV-seq results showed that their mother has carried the same variant. By searching the HGMD, OMIM and ClinVar databases, the c.3294+1G>A was known to be pathogenic. No carrier frequency has been recorded in the 1000 Genomes, ESP, ExAC and gnomAD databases. Based on the Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics (ACMG), the ATP7A gene c.3294+1G>A variant was predicted to be pathogenic. The c.77266650_77267178del variant has involved exons 8 to 9 of the ATP7A gene. ClinGen online system score for it was 1.8, which was also considered to be pathogenic. CONCLUSION The c.3294+1G>A and c.77266650_ 77267178del variants of the ATP7A gene probably underlay the Menkes disease in the three children. Above finding has enriched the mutational spectrum of Menkes disease and provided a basis for clinical diagnosis and genetic counseling.
Humans ; Male ; Computational Biology ; Copper-Transporting ATPases/genetics* ; DNA Copy Number Variations ; Exons ; Menkes Kinky Hair Syndrome/genetics* ; Mutation ; Peptide Fragments ; Seizures ; Infant

OBJECTIVE: To explore the clinical characteristics and variants of ATP7A gene in a child with Menkes disease. METHODS: A child with Menkes disease diagnosed at the West China Second Hospital of Sichuan University and its family members in March 2022 was selected as the study subjects. Clinical manifestations and results of laboratory tests and genetic testing were summarized. RESULTS: The main manifestations of the child included seizures, global development delay, facial dysmorphism, sparse and curly hair, increased lactate and pyruvate, and significantly decreased cuprin. EEG showed frequent issuance of multifocal spikes, spines, polyspines (slow) and polymorphic slow waves. Multiple tortuous vascular shadows were observed on cranial MRI. Whole exome sequencing revealed that the child has harbored a hemizygous c.3076delA (p.ile1026*) variant of the ATP7A gene, which was inherited from his mother. The variant may lead to premature termination of protein translation. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted as pathogenic (PVS1+PM2+PP4). CONCLUSION The c.3076delA (p.Ile1026*) variant of the ATP7A gene probably underlay the Menkes disease in this child. Above finding has provided evidence for clinical diagnosis. The significantly increased lactic acid and pyruvate can be used as a reference for the diagnosis and management of Menkes disease. Microscopic abnormalities in the hair of the carriers may also facilitate their diagnosis.
Child ; Humans ; Copper-Transporting ATPases/genetics* ; East Asian People ; Menkes Kinky Hair Syndrome/genetics* ; Mutation ; Pedigree ; Peptide Fragments ; Pyruvic Acid

OBJECTIVE: To explore the genetic basis for three children with Menkes disease. METHODS: The patients were subjected to next-generation sequencing (NGS) to detect potential variants of the ATP7A gene. Suspected variants were verified by Sanger sequencing of their family members and 200 healthy individuals. Multiplex ligation-dependent probe amplification (MLPA) was also carried out to detect potential deletions in their family members and 20 healthy individuals. RESULTS: Variants of the ATP7A gene were detected in all of the three families, including a novel c.1465A>T nonsense variant in family 1, a novel c.3039_3043del frame-shifting variant in family 2, and deletion of exons 3 to 23 in family 3, which was reported previously. Based on the standards and guidelines of American College of Medical Genetics and Genomics, the c.1465A>T and c.3039_3043del variants of ATP7A gene were predicted to be likely pathogenic (PVS1+PM2). CONCLUSION Variants of the ATP7A gene may underlay the Menkes disease in the three children. Above findings have facilitated clinical diagnosis and enriched the spectrum of genetic variants of Menkes disease.
Case-Control Studies ; Child ; Copper-Transporting ATPases/genetics* ; Exons ; Family Health ; High-Throughput Nucleotide Sequencing ; Humans ; Menkes Kinky Hair Syndrome/genetics* ; Mutation ; Pedigree

OBJECTIVE: To carry out genetic testing for a male infant suspected for Menkes disease. METHODS: Genomic DNA of the proband and his parents were extracted and subjected to family trio whole exome sequencing (WES). Microduplication and microdeletion of the ATP7A gene were detected by multiplex ligation-dependent probe amplification (MLPA). Suspected variants were subjected to bioinformatic analysis and verified by Sanger sequencing. RESULTS: The proband was found to harbor a de novo c.1870 -13T>G variation of the ATP7A gene, which may alter a splice site and affect its protein product. CONCLUSION The patient was diagnosed with Menkes disease due to the c.1870 -13T>G variant of the ATP7A gene. Whole exome sequencing of family trios is a powerful tool for the diagnosis of diseases with strong phenotypic heterogeneity.
Copper-Transporting ATPases ; genetics ; Genetic Testing ; Humans ; Infant ; Male ; Menkes Kinky Hair Syndrome ; genetics ; Multiplex Polymerase Chain Reaction ; Mutation ; Whole Exome Sequencing

OBJECTIVE: To explore the genetic etiology of a pedigree affected with tricho-rhino-phalangeal syndrome. METHODS: Next-generation sequencing (NGS) using a gene panel for hereditary osteopathies was carried out for the proband. Suspected mutation was validated in the proband and her parents by Sanger sequencing. RESULTS: A heterozygous frameshift variation c.1995dupA (p.Gly666Argfs*20) of the TRPS1 gene was detected in the proband but not in her parents. CONCLUSION The novel c.1995dupA (p.Gly666Argfs*20) mutation of the TRPS1 gene probably underlies the disease in the proband.
DNA-Binding Proteins ; genetics ; Female ; Fingers ; abnormalities ; Frameshift Mutation ; Hair Diseases ; genetics ; Humans ; Langer-Giedion Syndrome ; genetics ; Nose ; abnormalities ; Pedigree ; Transcription Factors ; genetics

BACKGROUND: The modified Ferriman-Gallwey (mFG) score is the gold standard for the clinical evaluation of hirsutism. However, racial variations in terminal hair growth limit this tool. This study aimed to determine the mFG cut-off score among Filipino women and its association with biochemical hyperandrogenism.METHODS: A total of 128 Filipino women were included in this prospective cross-sectional study and were divided into two groups: a polycystic ovary syndrome (PCOS) group (n=28) and a non-PCOS group (n=100). The participants underwent mFG score determination, ovarian ultrasound conducted by a single sonographer, and hormone testing. The mFG cut-off score was determined based on the 95th percentile of the non-PCOS group. Logistic regression was used to analyze the relationship between mFG score and biochemical hyperandrogenism.RESULTS: Although the mFG score was generally low in both the PCOS and non-PCOS groups, the former exhibited a higher mean score than the latter (4.3±3.0 vs. 2.0±2.2, P<0.001). Normal values for the total mFG score ranged from 0 to 7. Using a cut-off score of 7, a higher proportion of hirsute women (mFG score ≥7) was observed in the PCOS group versus the non-PCOS group (17.9% vs. 5.0%, P=0.025). Elevated calculated free testosterone (FT) was also found to be significantly associated with hirsutism (odds ratio, 6.2; 95% confidence interval, 1.2 to 32.4 pmol/L; P=0.030).CONCLUSION: A score of 7 and above constitutes hirsutism in this population of Filipino women. Hirsute women are more likely than non-hirsute women to have elevated calculated FT.
Cross-Sectional Studies ; Female ; Gonadal Disorders ; Hair ; Hirsutism ; Humans ; Hyperandrogenism ; Logistic Models ; Polycystic Ovary Syndrome ; Prospective Studies ; Reference Values ; Testosterone ; Ultrasonography

BACKGROUND: Menkes disease (MD) is a rare X-linked hereditary multisystemic disorder that is caused by dysfunction of copper metabolism. Patients with MD typically present with progressive neurodegeneration, some connective tissue abnormalities, and characteristic “kinky” hair. In addition, various types of urological complications are frequent in MD because of underlying connective tissue abnormalities. In this study, we studied the clinical features and outcomes of MD, focusing on urological complications. METHODS: A total of 14 unrelated Korean pediatric patients (13 boys and 1 girl) with MD were recruited, and their phenotypes and genotypes were analyzed by retrospective review of their medical records. RESULTS: All the patients had early-onset neurological deficit, including developmental delay, seizures, and hypotonia. The girl patient showed normal serum copper and ceruloplasmin levels as well as milder symptoms. Mutational analysis of the ATP7A gene revealed 11 different mutations in 12 patients. Bladder diverticula was the most frequent urological complication: 8 (57.1%) in the 14 patients or 8 (72.7%) in the 11 patients who underwent urological evaluation. Urological imaging studies were performed essentially for the evaluation of accompanying urinary tract infections. Four patients had stage II chronic kidney disease at the last follow-up. CONCLUSION: Urologic problems occurred frequently in MD, with bladder diverticula being the most common. Therefore, urological imaging studies and appropriate management of urological complications, which may prevent or reduce the development of urinary tract infections and renal parenchymal damage, are required in all patients with MD.
Ceruloplasmin ; Connective Tissue ; Copper ; Diverticulum ; Female ; Follow-Up Studies ; Genotype ; Hair ; Humans ; Medical Records ; Menkes Kinky Hair Syndrome* ; Metabolism ; Muscle Hypotonia ; Phenotype ; Renal Insufficiency, Chronic ; Retrospective Studies ; Seizures ; Urinary Bladder ; Urinary Tract Infections

Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder characterized by the formation of hair follicle tumors, kidney tumors, and pulmonary cysts with recurrent spontaneous pneumothorax. A 44-year-old woman visited Wonkwang University Hospital with mild dyspnea. A chest X-ray on admission revealed pneumothorax in both lung fields. Chest computed tomography (CT) revealed both pneumothorax and multiple, irregularly shaped, variable-sized cysts in both lung fields. Upon physical examination, white dome-shaped papules were observed on the face. Histological examination of the skin lesion confirmed fibrofolliculoma, and genetic studies revealed a folliculin gene mutation. Abdominal CT revealed a 1-cm small solid renal mass at the lower pole of the right kidney. We surgically removed the renal tumor, and a histological diagnosis of oncocytoma was made. Here, we report a case of BHD that demonstrated all three clinical manifestations; this is the first case report of its kind in Korea.
Adenoma, Oxyphilic ; Adult ; Birt-Hogg-Dube Syndrome ; Diagnosis ; Dyspnea ; Estrone ; Female ; Hair Follicle ; Humans ; Kidney ; Kidney Neoplasms ; Korea ; Lung ; Physical Examination ; Pneumothorax ; Skin ; Thorax ; Tomography, X-Ray Computed

Klippel-Feil syndrome is characterized by congenital fusion of two or more cervical vertebrae, a low hair line at the back of the head, restricted neck mobility, and other congenital anomalies. We report a 16-year-old young man with Klippel-Feil syndrome, Sprengel deformity of the right scapula, thoracic kyphoscoliosis, and mandibular prognathism with an anterior open bite. He was treated with orthodontic treatment and maxillofacial surgery. An anticipated difficult airway due to a short neck with restricted neck movements and extrinsic restrictive lung disease due to severe thoracic kyphoscoliosis increased his anesthesia risk. Due to his deviated nasal septum and contralateral inferior turbinate hypertrophy, we chose awake fiber optic orotracheal intubation followed by submental intubation. Considering the cervical vertebral fusion, he was carefully positioned during surgery to avoid potential spinal injury. He recovered well and his postoperative course was uneventful.
Adolescent ; Anesthesia ; Cervical Vertebrae ; Congenital Abnormalities ; Female ; Genioplasty ; Hair ; Head ; Humans ; Hypertrophy ; Intubation ; Klippel-Feil Syndrome ; Lung Diseases ; Mandible ; Nasal Septum ; Neck ; Open Bite ; Orthognathic Surgery ; Osteotomy ; Prognathism ; Scapula ; Spinal Injuries ; Surgery, Oral ; Turbinates