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Actas Dermo-sifiliograficas Jul 2021
Topics: Hair Diseases; Humans; Infant; Menkes Kinky Hair Syndrome
PubMed: 33905712
DOI: 10.1016/j.ad.2020.08.013 -
Clinical Neuropathology 2021Menkes disease is a neurodegenerative metabolic disorder. It is an X-lined recessive disorder of copper metabolism. It is characterized by seizures, developmental delay...
Menkes disease is a neurodegenerative metabolic disorder. It is an X-lined recessive disorder of copper metabolism. It is characterized by seizures, developmental delay with loss of achieved milestones, along with skin and hair changes. We present such a genetically proven case of Menkes disease in a 17-month-old boy with seizures, cyanosis, and dyspnea. On evaluation, the child had low serum copper and ceruloplasmin. Magnetic resonance imaging revealed diffuse atrophy of the cerebrum, cerebellum with tortuosity of intracranial vessels. Autopsy confirmed the imaging findings along with dense gliosis, myelin loss, and significant loss of neurons in the cortex. Cerebellum showed aberrant dendritic arborization, somal sprouts, and axonal torpedoes within the Purkinje neurons. This report illustrates the classical presentation of in a genetically proven case of Menkes disease at autopsy, which has not been described in the recent literature.
Topics: Autopsy; Brain; Humans; Infant; Male; Menkes Kinky Hair Syndrome
PubMed: 34032205
DOI: 10.5414/NP301351 -
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 -
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 -
[Clinical and genetic analysis of three children with Menkes disease due to variants of ATP7A gene].Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Jun 2023To explore the clinical characteristics and genetic etiology of three children with Menkes disease.
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.
Topics: Humans; Male; Computational Biology; Copper-Transporting ATPases; DNA Copy Number Variations; Exons; Menkes Kinky Hair Syndrome; Mutation; Peptide Fragments; Seizures; Infant
PubMed: 37212000
DOI: 10.3760/cma.j.cn511374-20220816-00550 -
Biomolecules Dec 2023Menkes' disease (MD) and Wilson's disease (WD) are two major copper (Cu) metabolism-related disorders caused by mutations of the and ATPase gene, respectively. While...
Menkes' disease (MD) and Wilson's disease (WD) are two major copper (Cu) metabolism-related disorders caused by mutations of the and ATPase gene, respectively. While Cu is involved in DNA strand breaks signaling and repair, the response of cells from both diseases to ionizing radiation, a common DNA strand breaks inducer, has not been investigated yet. To this aim, three MD and two WD skin fibroblasts lines were irradiated at two Gy X-rays and clonogenic cell survival, micronuclei, anti-, -, and - immunofluorescence assays were applied to evaluate the DNA double-strand breaks (DSB) recognition and repair. MD and WD cells appeared moderately radiosensitive with a delay in the radiation-induced ATM nucleo-shuttling (RIANS) associated with impairments in the DSB recognition. Such delayed RIANS was notably caused in both MD and WD cells by a highly expressed ATP7B protein that forms complexes with ATM monomers in cytoplasm. Interestingly, a Cu pre-treatment of cells may influence the activity of the MRE11 nuclease and modulate the radiobiological phenotype. Lastly, some high-passage MD cells cultured in routine may transform spontaneously becoming immortalized. Altogether, our findings suggest that exposure to ionizing radiation may impact on clinical features of MD and WD, which requires cautiousness when affected patients are submitted to radiodiagnosis and, eventually, radiotherapy.
Topics: Humans; Copper; Protein Kinases; Radiation, Ionizing; Menkes Kinky Hair Syndrome; Hepatolenticular Degeneration; Fibroblasts; DNA; Ataxia Telangiectasia Mutated Proteins
PubMed: 38136617
DOI: 10.3390/biom13121746 -
Metallomics : Integrated Biometal... Sep 2020Copper is an essential element for biological functions within humans and animals. There are several known diseases associated with Cu deficiency or overload, such as...
Copper is an essential element for biological functions within humans and animals. There are several known diseases associated with Cu deficiency or overload, such as Menkes disease and Wilson disease, respectively. A common clinical method for determining extractable Cu levels in serum, which is thought to be potentially dangerous if in excess, is to subtract the value of tightly incorporated Cu in ceruloplasmin from total serum Cu. In this work, an automated sample preparation and liquid chromatography (LC) system was combined with inductively coupled plasma-mass spectrometry (ICP-MS) to determine bound Cu and extractable Cu in serum. This LC-ICP-MS method took 250 s for sample preparation and analysis, followed by a column recondition/system reset, thus, a 6 minute sample-to-sample time including sample preparation. The method was validated using serum collected from either control (Atp7b+/-) or Wilson disease rats (Atp7b-/-). The extractable Cu was found to be 4.0 ± 2.3 μM Cu in healthy control rats, but 2.1 ± 0.6 μM Cu in healthy Wilson rats, and 27 ± 16 μM Cu in diseased Wilson rats, respectively. In addition, the extractable Cu/bound Cu ratio was found to be 6.4 ± 3.5%, 38 ± 29%, and 34 ± 22%, respectively. These results suggest that the developed method could be of diagnostic value for Wilson disease, and possibly other copper related diseases.
Topics: Animals; Copper; Hepatolenticular Degeneration; Mass Spectrometry; Menkes Kinky Hair Syndrome; Rats
PubMed: 32789408
DOI: 10.1039/d0mt00132e -
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 =... Dec 2023To explore the clinical characteristics and variants of ATP7A gene in a child with Menkes disease.
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.
Topics: Child; Humans; Copper-Transporting ATPases; East Asian People; Menkes Kinky Hair Syndrome; Mutation; Pedigree; Peptide Fragments; Pyruvic Acid
PubMed: 37994131
DOI: 10.3760/cma.j.cn511374-20220629-00442