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Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Feb 2021To explore the genetic basis for three children with Menkes disease.
OBJECTIVE
To explore the genetic basis for three children with Menkes disease.
METHODS
The patients were subjected to next-generation sequencing (NGS) to detect potential variants of the ATP7A gene. Suspected variants were verified by Sanger sequencing of their family members and 200 healthy individuals. Multiplex ligation-dependent probe amplification (MLPA) was also carried out to detect potential deletions in their family members and 20 healthy individuals.
RESULTS
Variants of the ATP7A gene were detected in all of the three families, including a novel c.1465A>T nonsense variant in family 1, a novel c.3039_3043del frame-shifting variant in family 2, and deletion of exons 3 to 23 in family 3, which was reported previously. Based on the standards and guidelines of American College of Medical Genetics and Genomics, the c.1465A>T and c.3039_3043del variants of ATP7A gene were predicted to be likely pathogenic (PVS1+PM2).
CONCLUSION
Variants of the ATP7A gene may underlay the Menkes disease in the three children. Above findings have facilitated clinical diagnosis and enriched the spectrum of genetic variants of Menkes disease.
Topics: Case-Control Studies; Child; Copper-Transporting ATPases; Exons; Family Health; High-Throughput Nucleotide Sequencing; Humans; Menkes Kinky Hair Syndrome; Mutation; Pedigree
PubMed: 33565059
DOI: 10.3760/cma.j.cn511374-20200216-00083 -
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 -
Asian Journal of Endoscopic Surgery Jul 2021The association between Morgagni hernia and Menkes disease has not yet been described. Here, we report such a rare association in an 8-year-old boy who presented with...
The association between Morgagni hernia and Menkes disease has not yet been described. Here, we report such a rare association in an 8-year-old boy who presented with subocclusive symptoms. He successfully underwent laparoscopic repair with a patch. The patch was fixed to the anterior abdominal wall by using transfascial sutures with extracorporeal knot tying and to the remaining edges of the diaphragmatic defect by using intracorporeal suturing and spiral tacks. At the 2-year follow-up, the child remained recurrence-free and without gastrointestinal symptoms. The potential relationship between the two conditions and the controversial use of spiral tacks to affix the mesh to the diaphragm are also discussed.
Topics: Child; Diaphragm; Hernias, Diaphragmatic, Congenital; Herniorrhaphy; Humans; Laparoscopy; Male; Menkes Kinky Hair Syndrome; Surgical Mesh
PubMed: 32914541
DOI: 10.1111/ases.12865 -
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 -
Radiology Aug 2020HistoryAn 8-month-old previously healthy boy was referred to our institution by the maternal child health center for progressive truncal hypotonia and developmental...
HistoryAn 8-month-old previously healthy boy was referred to our institution by the maternal child health center for progressive truncal hypotonia and developmental delay. This infant was born after an uncomplicated pregnancy with no perinatal complications. He was delivered at full term via spontaneous vaginal delivery. Two of his older male siblings died around 2-3 years of age due to pneumonia. According to the parents, these siblings also displayed reduced muscle tone, and one of them developed recurrent seizure.On physical examination, the child showed marked head lag and did not reach out to objects. Visual and auditory development were normal. His head circumference was below the third percentile, and his body weight was at the 10th percentile. His hair was sparse and coarse. A mild pectus excavatum deformity was present. Skull and chest radiographs were obtained (Figs 1, 2), and the patient underwent MRI of the brain (Fig 3).
Topics: Brain; Copper; Copper-Transporting ATPases; Humans; Infant; Magnetic Resonance Imaging; Male; Menkes Kinky Hair Syndrome; Radiography; Ribs; Skull
PubMed: 32687459
DOI: 10.1148/radiol.2020182237 -
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 -
Pflugers Archiv : European Journal of... Oct 2020Copper is an essential element in cells; it can act as either a recipient or a donor of electrons, participating in various reactions. However, an excess of copper ions... (Review)
Review
Copper is an essential element in cells; it can act as either a recipient or a donor of electrons, participating in various reactions. However, an excess of copper ions in cells is detrimental as these copper ions can generate free radicals and increase oxidative stress. In multicellular organisms, copper metabolism involves uptake, distribution, sequestration, and excretion, at both the cellular and systemic levels. Mammalian enterocytes take in bioavailable copper ions from the diet in a Ctr1-dependent manner. After incorporation, cuprous ions are delivered to ATP7A, which pumps Cu from enterocytes into the blood. Copper ions arrive at the liver through the portal vein and are incorporated into hepatocytes by Ctr1. Then, Cu can be secreted into the bile or the blood via the Atox1/ATP7B/ceruloplasmin route. In the bloodstream, this micronutrient can reach peripheral tissues and is again incorporated by Ctr1. In peripheral tissue cells, cuprous ions are either sequestrated by molecules such as metallothioneins or targeted to utilization pathways by chaperons such as Atox1, Cox17, and CCS. Copper metabolism must be tightly controlled in order to achieve homeostasis and avoid disorders. A hereditary or acquired copper unbalance, including deficiency, overload, or misdistribution, may cause or aggravate certain diseases such as Menkes disease, Wilson disease, neurodegenerative diseases, anemia, metabolic syndrome, cardiovascular diseases, and cancer. A full understanding of copper metabolism and its roles in diseases underlies the identification of novel effective therapies for such diseases.
Topics: Animals; Copper; Copper-Transporting ATPases; Hepatolenticular Degeneration; Humans; Menkes Kinky Hair Syndrome; Molecular Chaperones
PubMed: 32506322
DOI: 10.1007/s00424-020-02412-2 -
Journal of Cutaneous Medicine and... 2021
Topics: Child, Preschool; Consanguinity; Copper-Transporting ATPases; Diagnosis, Differential; Humans; Male; Menkes Kinky Hair Syndrome; Mutation
PubMed: 32498605
DOI: 10.1177/1203475420932516