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Science (New York, N.Y.) May 2020Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is...
Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is characterized by progressive neurological injury culminating in death, typically by 3 years of age. Severe copper deficiency leads to multiple pathologies, including impaired energy generation caused by cytochrome c oxidase dysfunction in the mitochondria. Here we report that the small molecule elesclomol escorted copper to the mitochondria and increased cytochrome c oxidase levels in the brain. Through this mechanism, elesclomol prevented detrimental neurodegenerative changes and improved the survival of the mottled-brindled mouse-a murine model of severe Menkes disease. Thus, elesclomol holds promise for the treatment of Menkes and associated disorders of hereditary copper deficiency.
Topics: Animals; Biological Transport; Brain; Cell Line; Copper; Copper Transporter 1; Disease Models, Animal; Electron Transport Complex IV; Hydrazines; Male; Menkes Kinky Hair Syndrome; Mice; Mice, Knockout; Mitochondria; Neurodegenerative Diseases; Rats
PubMed: 32381719
DOI: 10.1126/science.aaz8899 -
Science (New York, N.Y.) May 2020
Topics: Animals; Copper; Hydrazines; Menkes Kinky Hair Syndrome; Mice
PubMed: 32381707
DOI: 10.1126/science.abb6662 -
American Journal of Medical Genetics.... Jun 2020Classic Menkes disease is a rare X-linked recessive disorder of copper metabolism caused by pathogenic variants in the copper transporter gene, ATP7A. Untreated affected...
Classic Menkes disease is a rare X-linked recessive disorder of copper metabolism caused by pathogenic variants in the copper transporter gene, ATP7A. Untreated affected individuals suffer failure to thrive and neurodevelopmental delays that begin at 6-8 weeks of age and progress inexorably to death, often within 3 years. Subcutaneous injections of Copper Histidinate (US Food and Drug Administration IND #34,166, Orphan product designation #12-3663) are associated with improved survival and neurological outcomes, especially when commenced within a month of birth. We previously identified internal jugular vein phlebectasia (IJP) in four Menkes disease subjects. This feature and other connective tissue abnormalities appear to be consequences of deficient activity of lysyl oxidase, a copper-dependent enzyme. Here, we report results from a prospective study of IJP based on 178 neck ultrasounds in 66 Menkes subjects obtained between November 2007 and March 2018. Nine patients met the criterion for IJP (one or more cross-sectional area measurements exceeding 2.2 cm ) and five subjects had clinically apparent neck masses that enlarged over time. Our prospective results suggest that IJP occurs in approximately 14% (9/66) of Menkes disease patients and appears to be clinically benign with no specific medical or surgical actionability. We surveyed the medical literature for prior reports of IJP in pediatric subjects and identified 85 individuals and reviewed the distribution of this abnormality by gender, sidedness, and underlying etiology. Taken together, Menkes disease accounts for 16% (15/94) of all reported IJP individuals. Neck masses from IJP represent underappreciated abnormalities in Menkes disease.
Topics: Adolescent; Child; Child, Preschool; Copper-Transporting ATPases; Failure to Thrive; Female; Genetic Predisposition to Disease; Humans; Infant; Jugular Veins; Male; Menkes Kinky Hair Syndrome; Mutation; Neurodevelopmental Disorders; Ultrasonography
PubMed: 32293788
DOI: 10.1002/ajmg.a.61572 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Apr 2020To carry out genetic testing for a male infant suspected for Menkes disease.
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.
Topics: Copper-Transporting ATPases; Genetic Testing; Humans; Infant; Male; Menkes Kinky Hair Syndrome; Multiplex Polymerase Chain Reaction; Mutation; Exome Sequencing
PubMed: 32219842
DOI: 10.3760/cma.j.issn.1003-9406.2020.04.029 -
Frontiers in Immunology 2019Neutrophil extracellular traps (NETs) contribute to pathological disorders, and their release was directly linked to numerous diseases. With intravital microscopy (IVM),...
Neutrophil extracellular traps (NETs) contribute to pathological disorders, and their release was directly linked to numerous diseases. With intravital microscopy (IVM), we showed previously that NETs also contribute to the pathology of systemic inflammation and are strongly deposited in liver sinusoids. Over a decade since NET discovery, still not much is known about the metabolic or microenvironmental aspects of their formation. Copper is a vital trace element essential for many biological processes, albeit its excess is potentially cytotoxic; thus, copper levels are tightly controlled by factors such as copper transporting ATPases, ATP7A, and ATP7B. By employing IVM, we studied the impact of copper on NET formation during endotoxemia in liver vasculature on two mice models of copper excess or deficiency, Wilson (ATP7B mutants) and Menkes (ATP7A mutants) diseases, respectively. Here, we show that respective ATP7 mutations lead to diminished NET release during systemic inflammation despite unaltered intrinsic capacity of neutrophils to cast NETs as tested . In Menkes disease mice, the effect is mostly due to diminished neutrophil infiltration of the liver as unmutated mice with a subchronic copper deficiency release even more NETs than their controls during endotoxemia, whereas in Wilson disease mice, excess copper directly diminishes the capacity to release NETs, and this was further confirmed by studies on isolated neutrophils co-cultured with exogenous copper and a copper-chelating agent. Taken together, the study extends our understanding on how microenvironmental factors affect NET release by showing that copper is not a prerequisite for NET release but its excess affects the trap casting by neutrophils.
Topics: Animals; Copper; Copper-Transporting ATPases; Disease Models, Animal; Extracellular Traps; Hepatolenticular Degeneration; Humans; Male; Menkes Kinky Hair Syndrome; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Neutrophils
PubMed: 32010131
DOI: 10.3389/fimmu.2019.03021 -
Urology Feb 2020Menkes disease, or Kinky Hair Syndrome, is a rare disorder of copper metabolism that causes fatal neurodegenerative disease in infancy. This X-linked disorder results... (Review)
Review
Menkes disease, or Kinky Hair Syndrome, is a rare disorder of copper metabolism that causes fatal neurodegenerative disease in infancy. This X-linked disorder results from mutations in the ATP7A gene. Along with neurological decline, characteristic coarse appearance of the hair is seen. Urological issues are prevalent in this patient population, with bladder diverticula being the most common. Herein, we describe a unique male patient with genetic mosaicism and osseous metaplasia found in a ruptured bladder diverticulum.
Topics: Bone Diseases; Bone and Bones; Child; Diverticulum; Humans; Male; Menkes Kinky Hair Syndrome; Metaplasia; Mosaicism; Urinary Bladder
PubMed: 31758979
DOI: 10.1016/j.urology.2019.10.024 -
Neuromuscular Disorders : NMD Oct 2019We describe a novel ATP7A gene mutation associated with distal motor neuropathy, mild connective tissue abnormalities and autonomic disturbances. Next-generation...
We describe a novel ATP7A gene mutation associated with distal motor neuropathy, mild connective tissue abnormalities and autonomic disturbances. Next-generation sequencing analysis of a lower-motor neuron diseases gene panel was performed in two sibs presenting with distal motor neuropathy plus an autonomic dysfunction, which main manifestations were retrograde ejaculation, diarrhea and hyperhydrosis. Probands underwent dysmorphological, neurological, electrophysiological as well as biochemical evaluations and somatic and autonomic innervation studies on skin biopsies. A novel missense mutation (p.A991D) was identified in the X-linked ATP7A gene, segregating in both brothers and inherited from their healthy mother. Biochemical studies on patients' blood samples showed reduced serum copper and ceruloplasmin levels. Clinical and neurophysiological evaluation documented dysautonomic signs. Quantitative evaluation of skin innervation disclosed a small fiber neuropathy with prevalent autonomic involvement. Mutations in the ATP7A gene, encoding for a copper-transporting ATPase, have been associated with the severe infantile neurodegenerative Menkes disease and in its milder variant, the Occipital Horn Syndrome. Only two ATP7A mutations were previously reported as causing, a pure axonal distal motor neuropathy (dHMN-SMAX3). The phenotype we report represents a further example of this rare genotype-phenotype correlation and highlights the possible occurrence in SMAX3 of autonomic disturbances, as described for Menkes disease and Occipital Horn Syndrome.
Topics: Adenosine Triphosphatases; Aged; Copper-Transporting ATPases; Cutis Laxa; Ehlers-Danlos Syndrome; Genetic Association Studies; Humans; Male; Menkes Kinky Hair Syndrome; Middle Aged; Motor Neuron Disease; Muscular Atrophy, Spinal; Mutation
PubMed: 31558336
DOI: 10.1016/j.nmd.2019.08.008 -
Brain & Development Nov 2019Menkes disease (MD) is a lethal infantile neurodegenerative disorder with X-linked inheritance, characterized by progressive neurodegenerative symptoms caused by...
Menkes disease (MD) is a lethal infantile neurodegenerative disorder with X-linked inheritance, characterized by progressive neurodegenerative symptoms caused by pathogenic variants in the ATP7A. Early diagnosis and treatment are important, although the diagnosis is difficult prior to 2 months of age. We present an unusually severe case of MD with skull fractures at the birth and repeated fractures during the neonatal period, with further examinations leading to diagnosis. The patient died due to hemorrhagic shock, due to multiple arterial occlusion despite initiation of copper-histidine therapy in early infancy. Bone fracture at birth and multiple arterial occlusion are very rare findings in MD. This unusual and severe presentation emphasizes the importance of early diagnosis and treatment. A congenital bone fracture should be considered as a possible presentation of MD, especially in cases without birth complications.
Topics: Arterial Occlusive Diseases; Cerebral Infarction; Fractures, Bone; Humans; Infant, Newborn; Male; Menkes Kinky Hair Syndrome
PubMed: 31279518
DOI: 10.1016/j.braindev.2019.06.005 -
Molecular Genetics & Genomic Medicine Aug 2019Koolen-de Vries (KdV) syndrome is caused by a 17q21.31 deletion leading to clinical symptoms of hypotonia and developmental delay and can present with abnormal hair...
BACKGROUND
Koolen-de Vries (KdV) syndrome is caused by a 17q21.31 deletion leading to clinical symptoms of hypotonia and developmental delay and can present with abnormal hair texture. Menkes disease is an X-linked recessive inherited disease caused by pathogenic variants in ATP7A, which leads to profound copper deficiency.
METHOD
We identified an infant male who presented with prematurity, hypotonia, and dysmorphic features for whom a family history of clinical Menkes disease was revealed after discussion with the clinical genetics team.
RESULTS
Although initial first-tier genetic testing identified Kdv syndrome (17q21.31 syndrome), the family history led the team to consider a second diagnostic possibility, and testing of ATP7A revealed a pathogenic variant (c.601C>T, p.R201X).
CONCLUSION
Menkes disease and KdV syndrome may both present with hypotonia and abnormal hair, in addition to seizures and failure to thrive. While these genetic conditions have overlapping clinical features, they have different natural histories and different therapeutic options. Here, we report on a patient affected with both disorders and review the diagnostic and therapeutic difficulties this presented.
Topics: Abnormalities, Multiple; Chromosome Deletion; Chromosomes, Human, Pair 17; Comparative Genomic Hybridization; Copper-Transporting ATPases; DNA Mutational Analysis; Fatal Outcome; Genetic Testing; Histidine; Humans; Hypertension, Pulmonary; Infant, Newborn; Intellectual Disability; Male; Medical History Taking; Menkes Kinky Hair Syndrome; Mutation; Nitric Oxide; Organometallic Compounds; Pedigree; Respiratory Insufficiency
PubMed: 31250568
DOI: 10.1002/mgg3.829 -
Proceedings of the National Academy of... Jun 2019Copper is controlled by a sophisticated network of transport and storage proteins within mammalian cells, yet its uptake and efflux occur with rapid kinetics. Present as...
Copper is controlled by a sophisticated network of transport and storage proteins within mammalian cells, yet its uptake and efflux occur with rapid kinetics. Present as Cu(I) within the reducing intracellular environment, the nature of this labile copper pool remains elusive. While glutathione is involved in copper homeostasis and has been assumed to buffer intracellular copper, we demonstrate with a ratiometric fluorescent indicator, crisp-17, that cytosolic Cu(I) levels are buffered to the vicinity of 1 aM, where negligible complexation by glutathione is expected. Enabled by our phosphine sulfide-stabilized phosphine (PSP) ligand design strategy, crisp-17 offers a Cu(I) dissociation constant of 8 aM, thus exceeding the binding affinities of previous synthetic Cu(I) probes by four to six orders of magnitude. Two-photon excitation microscopy with crisp-17 revealed rapid, reversible increases in intracellular Cu(I) availability upon addition of the ionophoric complex CuGTSM or the thiol-selective oxidant 2,2'-dithiodipyridine (DTDP). While the latter effect was dramatically enhanced in 3T3 cells grown in the presence of supplemental copper and in cultured Menkes mutant fibroblasts exhibiting impaired copper efflux, basal Cu(I) availability in these cells showed little difference from controls, despite large increases in total copper content. Intracellular copper is thus tightly buffered by endogenous thiol ligands with significantly higher affinity than glutathione. The dual utility of crisp-17 to detect normal intracellular buffered Cu(I) levels as well as to probe the depth of the labile copper pool in conjunction with DTDP provides a promising strategy to characterize perturbations of cellular copper homeostasis.
Topics: Buffers; Copper; Fibroblasts; Fluorescent Dyes; Glutathione; Ligands; Menkes Kinky Hair Syndrome; Microscopy, Fluorescence, Multiphoton; Mutation; Phosphines
PubMed: 31160463
DOI: 10.1073/pnas.1900172116