-
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 -
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 -
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 -
BMJ Case Reports May 2018Menkes disease is a rare neurodegenerative metabolic disease with a reported incidence of 1 per 300 000 live births. It occurs due to mutations in ATP7A gene located... (Review)
Review
Menkes disease is a rare neurodegenerative metabolic disease with a reported incidence of 1 per 300 000 live births. It occurs due to mutations in ATP7A gene located on X-chromosome leading to deficiency of several copper-containing enzymes. The patient presents with history of neuroregression with characteristic kinky hair. MRI is the imaging modality of choice. Characteristic imaging findings are: bilateral subdural hygromas, cerebral and cerebellar atrophy, white matter changes and tortuous intracranial vessels on angiography. The rarity of this condition prompted us to report this case of Menkes disease along with the characteristic neuroimaging findings and brief review of literature.
Topics: Copper; Fatal Outcome; Humans; Infant; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Male; Menkes Kinky Hair Syndrome; Neuroimaging
PubMed: 29789304
DOI: 10.1136/bcr-2017-223858 -
Turkish Journal of Haematology :... Aug 2019
Topics: Bone Marrow; Child, Preschool; Erythroid Cells; Humans; Male; Menkes Kinky Hair Syndrome; Myeloid Cells; Vacuoles
PubMed: 29716882
DOI: 10.4274/tjh.galenos.2018.2018.0104 -
Metallomics : Integrated Biometal... Mar 2018Copper is essential for eukaryotic life, and animals must acquire this nutrient through the diet and distribute it to cells and organelles for proper function of...
Copper is essential for eukaryotic life, and animals must acquire this nutrient through the diet and distribute it to cells and organelles for proper function of biological targets. Indeed, mutations in the central copper exporter ATP7A contribute to a spectrum of diseases, including Menkes disease, with symptoms ranging from neurodegeneration to lax connective tissue. As such, a better understanding of the fundamental impacts of ATP7A mutations on in vivo copper distributions is of relevance to those affected by these diseases. Here we combine metal imaging and optical imaging techniques at a variety of spatial resolutions to identify tissues and structures with altered copper levels in the Calamity zebrafish model of Menkes disease. Rapid profiling of tissue slices with LA-ICP-MS identified reduced copper levels in the brain, neuroretina, and liver of Menkes fish compared to control specimens. High resolution nanoSIMS imaging of the neuroretina, combined with electron and confocal microscopies, identified the megamitochondria of photoreceptors as loci of copper accumulation in wildtype fish, with lower levels of megamitochondrial copper observed in Calamity zebrafish. Interestingly, this localized copper decrease does not result in impaired photoreceptor development or altered megamitochondrial morphology, suggesting the prioritization of copper at sufficient levels for maintaining essential mitochondrial functions. Together, these data establish the Calamity zebrafish as an optically transparent in vivo model for the study of neural copper misregulation, illuminate a role for the ATP7A copper exporter in trafficking copper to the neuroretina, and highlight the utility of combining multiple imaging techniques for studying metals in whole organism settings with spatial resolution.
Topics: Animals; Copper; Copper-Transporting ATPases; Disease Models, Animal; Laser Therapy; Menkes Kinky Hair Syndrome; Mitochondria; Multimodal Imaging; Mutation; Nanotechnology; Phenotype; Photoreceptor Cells, Vertebrate; Spectrometry, Mass, Electrospray Ionization; Spectrometry, Mass, Secondary Ion; Zebrafish
PubMed: 29507920
DOI: 10.1039/c7mt00349h -
Medicine Feb 2018Menkes disease (MD), also known as Menkes kinky hair disease, is a fatal neurodegenerative disease caused by a defect in copper metabolism. The symptoms involve multiple...
RATIONALE
Menkes disease (MD), also known as Menkes kinky hair disease, is a fatal neurodegenerative disease caused by a defect in copper metabolism. The symptoms involve multiple organ systems, such as the brain, lung, gastrointestinal tract, urinary tract, connective tissue, and skin. There is currently no cure for this disease entity, and patients with the classic form of MD usually die from complications between 6 months and 3 years of age. Intracranial hemorrhage secondary to tortuous intracranial arteries is a well-known complication of MD, but spontaneous retroperitoneal hemorrhage, to the best of our knowledge, has never been reported in a patient with MD. Herein, we describe the first case of retroperitoneal hematoma as a complication of MD in a 4-year-old boy.
PATIENT CONCERNS
A 4-year-old Taiwanese male patient with MD was referred to the hospital and presented with a palpable epigastric mass.
DIAGNOSES
On the basis of the findings of ultrasonography and enhanced computed tomography, the diagnosis was retroperitoneal hematoma.
INTERVENTIONS
Interventions included laparotomy with evacuation of the hematoma, manual compression, and suture of the bleeding vessels.
OUTCOMES
There were no postoperative complications.
LESSONS
This case emphasizes that bleeding in patients with MD is possible at any site in the body owing to the unstable structure of the connective tissues. Timely diagnosis with proper imaging studies can lead to prompt and appropriate management and save patients from this life-threatening condition.
Topics: Child, Preschool; Hematoma; Hemostasis, Surgical; Humans; Laparotomy; Male; Menkes Kinky Hair Syndrome; Retroperitoneal Space; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography
PubMed: 29419699
DOI: 10.1097/MD.0000000000009869 -
Cell Systems Mar 2018Rare neurological diseases shed light onto universal neurobiological processes. However, molecular mechanisms connecting genetic defects to their disease phenotypes are...
Rare neurological diseases shed light onto universal neurobiological processes. However, molecular mechanisms connecting genetic defects to their disease phenotypes are elusive. Here, we obtain mechanistic information by comparing proteomes of cells from individuals with rare disorders with proteomes from their disease-free consanguineous relatives. We use triple-SILAC mass spectrometry to quantify proteomes from human pedigrees affected by mutations in ATP7A, which cause Menkes disease, a rare neurodegenerative and neurodevelopmental disorder stemming from systemic copper depletion. We identified 214 proteins whose expression was altered in ATP7A fibroblasts. Bioinformatic analysis of ATP7A-mutant proteomes identified known phenotypes and processes affected in rare genetic diseases causing copper dyshomeostasis, including altered mitochondrial function. We found connections between copper dyshomeostasis and the UCHL1/PARK5 pathway of Parkinson disease, which we validated with mitochondrial respiration and Drosophila genetics assays. We propose that our genealogical "omics" strategy can be broadly applied to identify mechanisms linking a genomic locus to its phenotypes.
Topics: Adenosine Triphosphatases; Animals; Cation Transport Proteins; Computational Biology; Copper; Copper-Transporting ATPases; Disease Models, Animal; Drosophila; Female; Fibroblasts; Homeostasis; Humans; Male; Menkes Kinky Hair Syndrome; Mice; Mice, Inbred C57BL; Mitochondria; Mutation; Pedigree; Phenotype; Proteomics; Rare Diseases; Ubiquitin Thiolesterase
PubMed: 29397366
DOI: 10.1016/j.cels.2018.01.008 -
Nihon Eiseigaku Zasshi. Japanese... 2018The deficiency or excess intake of trace elements, including zinc, copper, selenium and iodine, has often been reported. Zinc deficiency is often observed in infants fed... (Review)
Review
The deficiency or excess intake of trace elements, including zinc, copper, selenium and iodine, has often been reported. Zinc deficiency is often observed in infants fed breast milk with low zinc concentration, individuals administered chelating medicines, athletes and patients with diabetes mellitus, hepatic cirrhosis or nephrosis syndrome. Menkes disease is associated with severe copper deficiency, and there is no effective treatment. Deficiencies of selenium and iodine are observed in patients who receive special formulas of milk and enteral formula with low selenium and iodine concentrations, respectively. In contrast, neonatal transient hypothyroidism due to excess intake of iodine in pregnant women has also reported in Japan. It is expected that collaborative studies by researchers and clinicians will contribute to clarify the detail mechanism, diagnosis and treatment of these abnormalities.
Topics: Clinical Medicine; Copper; Female; Hepatolenticular Degeneration; Humans; Hypothyroidism; Infant, Newborn; Japan; Male; Menkes Kinky Hair Syndrome; Pregnancy; Selenium; Trace Elements; Zinc
PubMed: 29386451
DOI: 10.1265/jjh.73.75 -
AJNR. American Journal of Neuroradiology Oct 2017Menkes disease is a rare multisystem X-linked disorder of copper metabolism. Despite an early, severe, and progressive neurologic involvement, our knowledge of brain... (Review)
Review
Menkes disease is a rare multisystem X-linked disorder of copper metabolism. Despite an early, severe, and progressive neurologic involvement, our knowledge of brain involvement remains unsatisfactory. The first part of this retrospective and review MR imaging study aims to define the frequency rate, timing, imaging features, and evolution of intracranial vascular and white matter changes. According to our analysis, striking but also poorly evolutive vascular abnormalities characterize the very early phases of disease. After the first months, myelination delay becomes evident, often in association with protean focal white matter lesions, some of which reveal an age-specific brain vulnerability. In later phases of the disease, concomitant progressive neurodegeneration might hinder the myelination progression. The currently enriched knowledge of neuroradiologic finding evolution provides valuable clues for early diagnosis, identifies possible MR imaging biomarkers of new treatment efficacy, and improves our comprehension of possible mechanisms of brain injury in Menkes disease.
Topics: Brain; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Male; Menkes Kinky Hair Syndrome; Neuroimaging; Retrospective Studies; White Matter
PubMed: 28495946
DOI: 10.3174/ajnr.A5186