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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 -
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 -
Archives of Iranian Medicine Dec 2021
Topics: Copper; Humans; Menkes Kinky Hair Syndrome
PubMed: 35014241
DOI: 10.34172/aim.2021.138 -
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 -
Journal of Inherited Metabolic Disease Mar 2023In patients with ATP7A-related disorders, counseling is challenging due to clinical overlap between the entities, the absence of predictive biomarkers and a clear... (Review)
Review
In patients with ATP7A-related disorders, counseling is challenging due to clinical overlap between the entities, the absence of predictive biomarkers and a clear genotype-phenotype correlation. We performed a systematic literature review by querying the MEDLINE and Embase databases identifying 143 relevant papers. We recorded data on the phenotype and genotype in 162 individuals with a molecularly confirmed ATP7A-related disorder in order to identify differentiating clinical criteria, evaluate genotype-phenotype correlations and propose management guidelines. Early seizures are specific for classical Menkes disease (CMD), that is characterized by early-onset neurodegenerative disease with high mortality rates. Ataxia is an independent indicator for atypical Menkes disease, that shows better survival rates than CMD. Bony exostoses, radial head dislocations, herniations and dental abnormalities are specific for occipital horn syndrome (OHS) that may further present with developmental delay and connective tissue manifestations. Intracranial tortuosity and bladder diverticula, both with high risk of complications, are common among all subtypes. Low ceruloplasmin is a more sensitive and discriminating biomarker for ATP7A-related disorders than serum copper. Truncating mutations are frequently associated with CMD, in contrast with splice site and intronic mutations which are more prevalent in OHS.
Topics: Humans; Menkes Kinky Hair Syndrome; Copper; Neurodegenerative Diseases; Copper-Transporting ATPases; Cutis Laxa; Mutation; Peptide Fragments
PubMed: 36692329
DOI: 10.1002/jimd.12590 -
The Turkish Journal of Pediatrics 2022Hair microscopy is a fast and effortless diagnostic method for many diseases affecting hair in daily practice. Many diseases can present with hair shaft disorders in...
BACKGROUND
Hair microscopy is a fast and effortless diagnostic method for many diseases affecting hair in daily practice. Many diseases can present with hair shaft disorders in pediatric neurology practice.
METHODS
Children with pathological hair findings were included in our study. Microscopic evaluation of the hair was performed under light microscopy. The clinical findings, pathological hair shaft findings, laboratory tests, and final diagnosis of the patients were evaluated.
RESULTS
In our study, 16 patients with rare pathological hair findings were identified. Of these 16 patients, nine were diagnosed with giant axonal neuropathy, three with Griscelli syndrome, two with Menkes disease, and two with autosomal recessive woolly hair disease. In hair inspection, curly and tangled hair in patients with giant axonal neuropathy; silvery blond hair in patients with Griscelli syndrome; sparse, coarse, and light-colored hair in patients with Menkes disease; and hypotrichosis in patients with autosomal recessive woolly hair were remarkable findings. Dystrophic hair was detected in most of the patients on light microscopy. In addition, signs of trichorrhexis nodosa, tricoptylosis, and pili torti were found. In particular, pigment deposition in the hair shaft of two patients diagnosed with Griscelli syndrome and pili torti findings in two patients with Menkes disease were the most important findings suggestingthe diagnosis.
CONCLUSIONS
Detection of hair findings in the physical examination and performing light microscopic evaluation facilitates the diagnosis of rare diseases accompanied by hair findings. A hair examination should be performed as a part of physical and neurological examinationson eachpatient regardless of thecomplaint.
Topics: Humans; Child; Menkes Kinky Hair Syndrome; Giant Axonal Neuropathy; Hair; Hair Diseases; Nervous System Diseases; Primary Immunodeficiency Diseases; Amino Acid Metabolism, Inborn Errors
PubMed: 36583891
DOI: 10.24953/turkjped.2022.221 -
Molecular Genetics & Genomic Medicine Sep 2023CREBBP truncating mutations and deletions are responsible for the well-known Rubinstein-Taybi syndrome. Recently, a new, distinct CREBBP-linked syndrome has been... (Review)
Review
INTRODUCTION
CREBBP truncating mutations and deletions are responsible for the well-known Rubinstein-Taybi syndrome. Recently, a new, distinct CREBBP-linked syndrome has been described: missense mutations located at the 3' end of exon 30 and the 5' portion of exon 31 induce Menke-Hennekam syndrome. Patients with this syndrome present a recognizable facial dysmorphism, intellectual disability of variable severity, microcephaly, short stature, autism, epilepsy, visual and hearing impairments, feeding problems, upper airway infections, scoliosis, and/or kyphosis. To date, all diagnoses were made postnatally.
METHOD AND CASE REPORT
Trio-whole exome sequencing (WES) was performed in a fetus showing increased nuchal translucency persistence and aorta abnormalities at 28 weeks of gestation (WG).
RESULTS
WES revealed a CREBBP de novo missense mutation (c.5602C>T; p.Arg1868Trp) in exon 31, previously reported as the cause of Menke-Hennekam syndrome. Termination of pregnancy was performed at 32 WG. We further reviewed the prenatal signs of Menke-Hennekam syndrome already reported. Among the 35 patients reported and diagnosed postnatally up to this day, 15 presented recognizable prenatal signs, the most frequent being intra-uterine growth retardation, brain, and cardiovascular anomalies.
CONCLUSION
Menke-Hennekam is a rare syndrome with unspecific, heterogeneous, and inconstant prenatal symptoms occurring most frequently with the c.5602C>T, p.(Arg1868Trp) mutation. Therefore, the prenatal diagnosis of Menke-Hennekam syndrome is only possible by molecular investigation. Moreover, this case report and review reinforce the importance of performing prenatal WES when unspecific signs are present on imaging.
Topics: Pregnancy; Female; Humans; Phenotype; Exome Sequencing; Mutation; Rubinstein-Taybi Syndrome; Mutation, Missense; Menkes Kinky Hair Syndrome
PubMed: 37353886
DOI: 10.1002/mgg3.2219 -
Neuropediatrics Jun 2022
Topics: Cation Transport Proteins; Copper-Transporting ATPases; Humans; Menkes Kinky Hair Syndrome
PubMed: 35122229
DOI: 10.1055/a-1762-0354 -
BMC Pediatrics Jun 2024Menkes disease (MD) is a rare, inherited, multisystemic copper metabolism disorder. Classical Menkes disease is characterized by low serum copper and ceruloplasmin... (Review)
Review
BACKGROUND
Menkes disease (MD) is a rare, inherited, multisystemic copper metabolism disorder. Classical Menkes disease is characterized by low serum copper and ceruloplasmin concentrations, leading to multiple abnormalities in the whole-body, especially in connective tissue and central nervous system. However, serum copper and ceruloplasmin levels are not reliable diagnostic biomarkers due to the low concentrations in healthy newborns either. The featured imaging manifestations play an important role in diagnosing Menkes disease. To our knowledge, there are few reports on the systemic imaging manifestations of Menkes disease.
CASE PRESENTATION
A 4-month-old male patient presented with recurrent seizures. He had cognitive, intellectual, growth, gross motor, precision movement, and language developmental lags. The patient's hemoglobin and serum ceruloplasmin level were low. On MRI, increased intracranial vascular tortuosity, cerebral and cerebellar atrophy, white matter changes, and basal ganglia abnormalities were observed. Plain radiograph revealed wormian bones, rib flaring, metaphyseal spurring, and periosteal reactions in the long bones of the limbs. A pathogenic variant in ATP7A gene was identified in the patient, so he was confirmed the diagnosis of Menkes disease. His symptoms did not improve despite symptomatic and supportive treatment during his hospitalization. Unfortunately, the infant died 3 months after leaving hospital.
CONCLUSION
A comprehensive and intuitive understanding of the disease's imaging manifestations can help clinicians to identify the disease and avoid delays in care.
Topics: Humans; Menkes Kinky Hair Syndrome; Male; Infant; Magnetic Resonance Imaging; Brain; Whole Body Imaging; Bone and Bones
PubMed: 38926644
DOI: 10.1186/s12887-024-04885-x -
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