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Journal of Trace Elements in Medicine... Jul 2019Menkes diseases (MD) is an X-linked recessive neurodegenerative disorder of copper metabolism, characterized by progressive multisystemic involvement. Death in the early...
Menkes diseases (MD) is an X-linked recessive neurodegenerative disorder of copper metabolism, characterized by progressive multisystemic involvement. Death in the early childhood is usually observed in classical patients. Although a definite cure has not been established, copper replacement therapy administered parenterally may modify the severity of MD and permitted survival into adolescence. Subcutaneous copper-histidine supplementation is the current choice of therapy, and long-term administration is not desirable because of the expected nephrotoxicity. We report here the case of a 29-year-old male with MD who tolerated long-term intravenous copper therapy initiated at 2 months. Molecular analysis revealed hemizygous deletion mutation of ATP7A previously reported in classical MD. Although neurodevelopement is poor, no major event of central nervous system is observed, and he enjoys a good social life by interacting using gestures. Optimum management is unknown, and closed follow-up is mandatory for clarification of this phenotype.
Topics: Administration, Intravenous; Adult; Copper; Drug Administration Schedule; Humans; Male; Menkes Kinky Hair Syndrome
PubMed: 31109608
DOI: 10.1016/j.jtemb.2019.04.020 -
Gaceta Medica de Mexico 2019Menkes disease is a neurodegenerative and lethal pathology caused by gene mutations of the copper-transporting ATP-7A enzyme; it manifests itself by neurological...
Menkes disease is a neurodegenerative and lethal pathology caused by gene mutations of the copper-transporting ATP-7A enzyme; it manifests itself by neurological symptoms and connective tissue changes of varying severity. Timely subcutaneous use of copper histidinate (Cu-His) is determinant for quality of life. We report the first experiences in Mexico on Cu-His synthesis and its safe use in 3 cases where hypocupremia and hypoceruloplasminemia were corroborated. With advice of the Hospital for Sick Children of Toronto Canada, we prepared a 500 µg/mL solution. In all three cases were 250 µg of Cu-His applied without relevant undesirable effects for 30 days. Serum copper (Cu, expressed in µg/L) and ceruloplasmin (Cp, in mg/dL) were determined: case 1, Cu days 0 and 30, 8 and 504 µg/L; Cp days 0 and 30, 4 and 10.75 mg/dL; case 2, Cu days 0 and 30, <50 and 502 µg/L; Cp days 0 and 30, 2 and 15 mg/dL; case 3, Cu days 0 and 30, 3 and 84.2 µg/L; Cp days 0 and 30, 4 and 10.7 mg/dL. In Mexico, it is possible to safely synthesize Cu-His and treat MD, which must be intentionally sought.
Topics: Child, Preschool; Copper; Drug Compounding; Histidine; Humans; Infant; Menkes Kinky Hair Syndrome; Mexico; Organometallic Compounds; Pharmaceutical Solutions; Quality of Life
PubMed: 31056589
DOI: 10.24875/GMM.18004310 -
Fatal Exsanguination Following Rupture of an Iliac Artery Aneurysm in an Infant With Menkes Disease.Pediatric and Developmental Pathology :... Oct 2019Menkes disease (MD) usually presents in infancy with respiratory and neurological complications. Severe isolated vasculo-connective tissue involvement in infancy is...
Menkes disease (MD) usually presents in infancy with respiratory and neurological complications. Severe isolated vasculo-connective tissue involvement in infancy is rare, and hence the precise and timely diagnosis is difficult. We report a case of an 8-week-old male infant who succumbed to acute, severe exsanguination, and hemorrhagic shock secondary to a large retroperitoneal hematoma due to rupture of a right iliac artery aneurysm. Perimortem musculoskeletal findings raised suspicion of nonaccidental injury. However, postmortem review of facial traits raised the suspicion of MD. MD was subsequently confirmed on genetic testing. Child health clinicians must remain aware of MD as a rare cause of infant vasculopathy or atypical skeletal abnormalities.
Topics: Aneurysm, Ruptured; Exsanguination; Fatal Outcome; Humans; Iliac Aneurysm; Infant; Male; Menkes Kinky Hair Syndrome
PubMed: 30935272
DOI: 10.1177/1093526619841152 -
JAMA Dermatology Apr 2019
Topics: Adult; Diagnosis, Differential; Female; Gastric Bypass; Hair Diseases; Humans; Malnutrition; Menkes Kinky Hair Syndrome; Rare Diseases; Risk Assessment
PubMed: 30810707
DOI: 10.1001/jamadermatol.2018.4677 -
Pediatrics International : Official... Apr 2019Menkes disease (MNK; MIN 309400) is an X-linked recessive lethal disorder of copper metabolism caused by mutations in ATP7A (MIM 300011), which encodes a transmembrane...
BACKGROUND
Menkes disease (MNK; MIN 309400) is an X-linked recessive lethal disorder of copper metabolism caused by mutations in ATP7A (MIM 300011), which encodes a transmembrane copper-transporting P-type ATPase. This study assessed mutations in ATP7A in Japanese patients with MNK and their families using gene analysis.
METHODS
A total of 66 patients with MNK born between 1975 and 2013 in Japan were investigated in this study. Definite diagnosis of MNK was carried out on polymerase chain reaction (PCR) amplification and direct sequencing of each exon. Genetic analysis was also performed on 39 women for carrier diagnosis, and on nine fetuses and 10 neonates for the diagnosis of MNK.
RESULTS
We detected 55 different mutations, of which 20 were de novo mutations. The mutations were located around the six copper binding sites, first to third and six transmembrane domains, and the ATP binding site. Of 30 mothers, 23 (76.7%) were carriers. Approximately half of the male siblings of patients with MNK were also diagnosed with MNK.
CONCLUSION
Mutations in ATP7A varied widely across patients, although approximately half of the mutations were located in exons 4, 9, 10, and 15. Approximately 23% of patients did not inherit the mutations from their mothers, but had de novo mutations. An early definite diagnosis is necessary for the early treatment of MNK, and gene analysis serves as an effective method for detecting mutations in ATP7A.
Topics: Asian People; Copper-Transporting ATPases; Female; Genetic Testing; Humans; Infant, Newborn; Japan; Male; Menkes Kinky Hair Syndrome; Mutation
PubMed: 30809870
DOI: 10.1111/ped.13817 -
Ceska a Slovenska Farmacie : Casopis... 2018This paper presents an overview of the physiological properties of copper (Cu), an essential trace element playing an important role in the human metabolism, primarily... (Review)
Review
This paper presents an overview of the physiological properties of copper (Cu), an essential trace element playing an important role in the human metabolism, primarily as a cofactor of many metalloenzymes. The maintenance of Cu homeostasis is required for proper functioning of the human body. However, when the disturbance of Cu homeostasis occurs, strong pathological manifestations may develop. Wilsons disease and idiopathic toxicosis are examples of severe chronic liver diseases that are the results of genetic predisposition to the hepatic accumulation of copper. Conversely, congenital Menkes disease is manifested as serious Cus nutritional deficiency. Although Cu is necessary for many life processes, it is also a powerful weapon used since the ancient times against many microorganisms. Finally, the theories of Cu antimicrobial and antiviral mechanisms of action are summarized, including contemporary and potential future utilizations in medical and non-medical fields of human life. Key words: copper metalloenzymes copper toxicity copper deficiency copper-related diseases copper applications.
Topics: Copper; Hepatolenticular Degeneration; Homeostasis; Humans; Menkes Kinky Hair Syndrome; Trace Elements
PubMed: 30646728
DOI: No ID Found -
Journal of Korean Medical Science Jan 2019Menkes disease (MD) is a rare X-linked hereditary multisystemic disorder that is caused by dysfunction of copper metabolism. Patients with MD typically present with...
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 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.
Topics: Child, Preschool; Copper-Transporting ATPases; DNA Mutational Analysis; Diverticulum; Female; Genotype; Humans; Male; Menkes Kinky Hair Syndrome; Phenotype; Prognosis; Retrospective Studies; Ultrasonography; Urinary Bladder
PubMed: 30618512
DOI: 10.3346/jkms.2019.34.e4 -
Molecular Genetics and Metabolism Jan 2019Menkes disease is a rare X-linked neurodegenerative disorder caused by defect in copper metabolism. Parenteral copper supplementation has been used as a potential...
Menkes disease is a rare X-linked neurodegenerative disorder caused by defect in copper metabolism. Parenteral copper supplementation has been used as a potential disease-modifying treatment of Menkes disease for decades. However, recent evidence suggests its efficacy only when treatment is started within days after birth, which also has important implications related to the techniques that enable early diagnosis. We aim at proposing a guideline for prenatal and neonatal diagnosis and for disease-modifying treatment of Menkes disease, guided by a systematic review of the literature, and built in conjunction with medical experts, methodologists and patient representatives. Thirteen articles were used for our recommendations that were based on GRADE system. Reviewed evidence suggests that prenatal genetic diagnosis in families with previous diagnosis of Menkes disease is feasible; analysis of plasma catecholamine levels is accurate for neonatal diagnosis of Menkes disease; treatment with copper-histidine is effective to increase survival and reduce neurologic burden of the disease if initiated in the neonatal period; and, treatment indication should not be guided by patient's genotype. In conclusion, our guideline can contribute to standardize some aspects of the clinical care of patients with Menkes disease, especially reducing disease burden and mortality and providers' and families' anxiety.
Topics: Catecholamines; Clinical Trials as Topic; Copper; Early Diagnosis; Female; Humans; Male; Menkes Kinky Hair Syndrome; Mutation; Practice Guidelines as Topic; Pregnancy; Prenatal Diagnosis
PubMed: 30594472
DOI: 10.1016/j.ymgme.2018.12.005 -
The Journal of Pediatrics Mar 2019
Topics: Brain; Hair; Humans; Infant; Male; Menkes Kinky Hair Syndrome
PubMed: 30529134
DOI: 10.1016/j.jpeds.2018.09.069 -
Nature Nov 2018Following Cas9 cleavage, DNA repair without a donor template is generally considered stochastic, heterogeneous and impractical beyond gene disruption. Here, we show that...
Following Cas9 cleavage, DNA repair without a donor template is generally considered stochastic, heterogeneous and impractical beyond gene disruption. Here, we show that template-free Cas9 editing is predictable and capable of precise repair to a predicted genotype, enabling correction of disease-associated mutations in humans. We constructed a library of 2,000 Cas9 guide RNAs paired with DNA target sites and trained inDelphi, a machine learning model that predicts genotypes and frequencies of 1- to 60-base-pair deletions and 1-base-pair insertions with high accuracy (r = 0.87) in five human and mouse cell lines. inDelphi predicts that 5-11% of Cas9 guide RNAs targeting the human genome are 'precise-50', yielding a single genotype comprising greater than or equal to 50% of all major editing products. We experimentally confirmed precise-50 insertions and deletions in 195 human disease-relevant alleles, including correction in primary patient-derived fibroblasts of pathogenic alleles to wild-type genotype for Hermansky-Pudlak syndrome and Menkes disease. This study establishes an approach for precise, template-free genome editing.
Topics: Alleles; Base Sequence; CRISPR-Associated Protein 9; CRISPR-Cas Systems; DNA Repair; Fibroblasts; Gene Editing; HCT116 Cells; HEK293 Cells; Hermanski-Pudlak Syndrome; Humans; K562 Cells; Machine Learning; Menkes Kinky Hair Syndrome; Reproducibility of Results; Substrate Specificity; Templates, Genetic
PubMed: 30405244
DOI: 10.1038/s41586-018-0686-x