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Genes May 2021Menkes disease (MD) is a rare and often lethal X-linked recessive syndrome, characterized by generalized alterations in copper transport and metabolism, linked to...
Menkes disease (MD) is a rare and often lethal X-linked recessive syndrome, characterized by generalized alterations in copper transport and metabolism, linked to mutations in the ATPase copper transporting α () gene. Our objective was to identify genomic alterations and circulating proteomic profiles related to MD assessing their potential roles in the clinical features of the disease. We describe the case of a male patient of 8 months of age with silvery hair, tan skin color, hypotonia, alterations in neurodevelopment, presence of seizures, and low values of plasma ceruloplasmin. Trio-whole-exome sequencing (Trio-WES) analysis, plasma proteome screening, and blood cell migration assays were carried out. Trio-WES revealed a hemizygous change c.4190C > T (p.S1397F) in exon 22 of the gene. Compared with his parents and with child controls, 11 plasma proteins were upregulated and 59 downregulated in the patient. According to their biological processes, 42 (71.2%) of downregulated proteins had a participation in cellular transport. The immune system process was represented by 35 (59.3%) downregulated proteins ( = 9.44 × 10). Additional studies are necessary to validate these findings as hallmarks of MD.
Topics: Adolescent; Adult; Cell Movement; Copper-Transporting ATPases; Down-Regulation; Female; Humans; Immune System Phenomena; Infant; Male; Menkes Kinky Hair Syndrome; Mutation; Proteome; Proteomics; Up-Regulation; Exome Sequencing; Young Adult
PubMed: 34069220
DOI: 10.3390/genes12050744 -
Actas Dermo-sifiliograficas Jul 2021
Topics: Hair Diseases; Humans; Infant; Menkes Kinky Hair Syndrome
PubMed: 33905712
DOI: 10.1016/j.ad.2020.08.013 -
Expert Opinion on Investigational Drugs Jan 2021
Topics: Animals; Copper; Drug Repositioning; Drugs, Investigational; Humans; Hydrazines; Menkes Kinky Hair Syndrome
PubMed: 33081534
DOI: 10.1080/13543784.2021.1840550 -
Current Journal of Neurology Oct 2020Giant axonal neuropathy (GAN) is a very rare fatal neurodegenerative disorder with clinical and allelic heterogeneity. The disease is caused by mutations in the GAN...
Giant axonal neuropathy (GAN) is a very rare fatal neurodegenerative disorder with clinical and allelic heterogeneity. The disease is caused by mutations in the GAN (gigaxonin) gene. Herein, we reported the clinical presentations and results of genetic analysis of the first Iranian GAN case. Phenotypic data were obtained by neurologic examination, brain magnetic resonance imaging (MRI), electromyography (EMG), electroencephalography (EEG), and sonography from the proband. Deoxyribonucleic acid (DNA) was isolated from peripheral blood leucocytes and whole exome sequencing (WES) was performed. The candidate variant was screened by Sanger sequencing in the proband and her family members. The proband was a 7-year-old girl who was admitted with a chief complaint of ataxia, muscle weakness, delayed developmental milestones, and history of psychiatric disorders. She was very moody and had clumsy gait, decreased deep tendon reflexes (DTRs) of lower limbs, and kinky hair. The brain MRI revealed white matter abnormality. The EMG revealed that her disease was compatible with the chronic axonal type of sensorimotor polyneuropathy; however, her EEG was normal. Results of the WES revealed a homozygous variant; c.G778T:p.E260 in the GAN gene, indicating the GAN disorder. The present study affirmed GAN allelic heterogeneity and resulted in the expansion of the phenotypic spectrum of GAN pathogenic variants. Identification of more families with mutations in GAN gene helps to further understand the molecular basis of the disease and provides an opportunity for genetic counseling especially in the populations with a high degree of consanguineous marriage such as the Iranian population.
PubMed: 38011432
DOI: 10.18502/cjn.v19i4.5548 -
Annales de Biologie Clinique Aug 2020Menkes disease is an X-linked recessive disorder affecting copper metabolism due to an inactivating mutation of ATP7A gene. This result in loss of copper intestinal...
Menkes disease is an X-linked recessive disorder affecting copper metabolism due to an inactivating mutation of ATP7A gene. This result in loss of copper intestinal absorption, tissue deficiency and failure in multiple essential copper-enzyme systems such as the cytochrome c oxidase. Symptoms usually occur during the first months of life with neurological signs such as epilepsy associated to other signs among them typical hair appearance. We report the case of a 3 month-old infant hospitalized due to partial tonic-clonic seizures. Laboratory findings showed increased of lactates in blood and in cerebrospinal fluid. First screenings for infectious, metabolic and genetic causes were negative. After recurrence of multifocal seizures further investigations are made according to the presence of thick and tortuous hair. Low levels of ceruloplasmin and copper in plasma are in agreement with the suspected diagnosis of Menkes disease. Molecular analysis of the ATP7A gene confirmed the diagnosis with a non-sens mutation.
Topics: Diagnosis, Differential; Epilepsy; Humans; Hyperlactatemia; Infant; Male; Menkes Kinky Hair Syndrome; Severity of Illness Index
PubMed: 32633724
DOI: 10.1684/abc.2020.1566 -
The Turkish Journal of Pediatrics 2020Menkes disease (MD) is a rare lethal X-linked, multisystem disorder of copper metabolism resulting from mutations in the ATP7A gene. Features such as Ehlers- Danlos...
BACKGROUND
Menkes disease (MD) is a rare lethal X-linked, multisystem disorder of copper metabolism resulting from mutations in the ATP7A gene. Features such as Ehlers- Danlos syndrome, trichopoliodystrophy, urologic and skeletal changes have been reported. We present a case of classic MD treated with copper infusions who suffered from persistent natural killer (NK) cell dysfunction.
CASE
A 2-year-old, Caucasian male child presented at 8-month-old of age with persistent hypotonia, kinky hair and developmental regression. Diagnosis of MD was based on low serum levels of copper [5 mg/dl (18-37)] and ceruloplasmin [18 ug/dl (75-153)] and gene-targeted deletion/duplication analysis performed by the reference laboratory. Brain MRI showed mild hypoplasia of the cerebellar vermis and vascular tortuosity typical of MD. Copper chloride treatment was immediately initiated. The child became more alert with excellent eye contact and purposeful movements. The child was hospitalized for recurrent respiratory infections, each time caused by enterovirus as confirmed by multiplex polymerase chain reaction (PCR). Extensive immunologic studies were negative, except for a severe NK cell dysfunction on multiple occasions (0.6 NK lytic Units; N > 2.6).
CONCLUSION
We postulate that NK cell dysfunction in a classic MD can be explained by the deficient incorporation of copper in the endoplasmic reticulum resulting in an abnormal Fenton chemistry within phagosomes.
Topics: Child, Preschool; Copper-Transporting ATPases; Humans; Infant; Killer Cells, Natural; Male; Menkes Kinky Hair Syndrome; Muscle Hypotonia; Mutation
PubMed: 32558428
DOI: 10.24953/turkjped.2020.03.021 -
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 -
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 -
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