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Arquivos de Neuro-psiquiatria May 2024
Topics: Humans; Menkes Kinky Hair Syndrome; Male
PubMed: 38740034
DOI: 10.1055/s-0044-1786761 -
Scientific Reports Jan 2024Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene, and female carriers are usually asymptomatic. We describe a...
Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene, and female carriers are usually asymptomatic. We describe a 7-month-old female patient with severe intellectual disability, epilepsy, and low levels of serum copper and ceruloplasmin. While heterozygous deletion of exons 16 and 17 of the ATP7A gene was detected in the proband, her mother, and her grandmother, only the proband suffered from Menkes disease clinically. Intriguingly, X chromosome inactivation (XCI) analysis demonstrated that the grandmother and the mother showed skewing of XCI toward the allele with the ATP7A deletion and that the proband had extremely skewed XCI toward the normal allele, resulting in exclusive expression of the pathogenic ATP7A mRNA transcripts. Expression bias analysis and recombination mapping of the X chromosome by the combination of whole genome and RNA sequencing demonstrated that meiotic recombination occurred at Xp21-p22 and Xq26-q28. Assuming that a genetic factor on the X chromosome enhanced or suppressed XCI of its allele, the factor must be on either of the two distal regions derived from her grandfather. Although we were unable to fully uncover the molecular mechanism, we concluded that unfavorable switching of skewed XCI caused Menkes disease in the proband.
Topics: Humans; Infant; Female; Menkes Kinky Hair Syndrome; X Chromosome Inactivation; Copper; Chromosomes, Human, X; Mutation
PubMed: 38172222
DOI: 10.1038/s41598-023-50668-2 -
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 -
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 -
Journal of Assisted Reproduction and... Apr 2023Assisted reproductive technology (ART) has experienced dramatic progress over the last 30 years, and gamete donation is routine in fertility clinics. Major advances in...
Assisted reproductive technology (ART) has experienced dramatic progress over the last 30 years, and gamete donation is routine in fertility clinics. Major advances in genetic diagnostics are part of this development due to the ability to analyze multiple genes or whole genomes fast and to an affordable prize. This requires knowledge and capability to evaluate genetic variants correctly in a clinical setting. Here we report a Menkes disease case, born after ART, where genetic screening and variant scoring failed to identify an egg donor as carrier of this fatal X-linked disorder. The gene variant is a deletion of a single base pair leading to a frameshift and premature termination of the protein, predicted to result in no or severely diminished function. The variant would be classified as likely pathogenic (class 4) and should be readily detectable by molecular genetic screening techniques. We wish to highlight this case to prevent future similar cases. IVI Igenomix has developed and embarked on an ambitious screening program to detect and prevent a large number of inherited severe childhood disorders in ART pregnancies. The company has recently achieved ISO 15189 certification with competence to evaluate and deliver timely, accurate, and reliable results. Failure to identify a pathogenic variant in the ATP7A gene leading to birth of two boys with Menkes disease invokes the required procedures to screen and detect disease-causing gene variants. This calls for ethical and legal considerations in ART diagnostics to prevent fatal errors like the present.
Topics: Menkes Kinky Hair Syndrome; Chromosomes, Human, X; Reproductive Techniques, Assisted; Humans; Male; Female; Pregnancy; Middle Aged; Pregnancy Outcome
PubMed: 36995557
DOI: 10.1007/s10815-023-02778-z -
PLoS Genetics Jan 2023Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson...
Copper (Cu) has a multifaceted role in brain development, function, and metabolism. Two homologous Cu transporters, Atp7a (Menkes disease protein) and Atp7b (Wilson disease protein), maintain Cu homeostasis in the tissue. Atp7a mediates Cu entry into the brain and activates Cu-dependent enzymes, whereas the role of Atp7b is less clear. We show that during postnatal development Atp7b is necessary for normal morphology and function of choroid plexus (ChPl). Inactivation of Atp7b causes reorganization of ChPl' cytoskeleton and cell-cell contacts, loss of Slc31a1 from the apical membrane, and a decrease in the length and number of microvilli and cilia. In ChPl lacking Atp7b, Atp7a is upregulated but remains intracellular, which limits Cu transport into the brain and results in significant Cu deficit, which is reversed only in older animals. Cu deficiency is associated with down-regulation of Atp7a in locus coeruleus and catecholamine imbalance, despite normal expression of dopamine-β-hydroxylase. In addition, there are notable changes in the brain lipidome, which can be attributed to inhibition of diacylglyceride-to-phosphatidylethanolamine conversion. These results identify the new role for Atp7b in developing brain and identify metabolic changes that could be exacerbated by Cu chelation therapy.
Topics: Mice; Animals; Copper-Transporting ATPases; Copper; Choroid Plexus; Menkes Kinky Hair Syndrome; Brain
PubMed: 36626371
DOI: 10.1371/journal.pgen.1010558 -
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 -
International Journal of Molecular... Sep 2022Kidneys play an especial role in copper redistribution in the organism. The epithelial cells of proximal tubules perform the functions of both copper uptake from the...
Decreased Expression of the Gene and Cytoplasmic Relocalization of Membrane CTR1 Protein in Renal Epithelial Cells: A Potent Protective Mechanism against Copper Nephrotoxicity in a Mouse Model of Menkes Disease.
Kidneys play an especial role in copper redistribution in the organism. The epithelial cells of proximal tubules perform the functions of both copper uptake from the primary urine and release to the blood. These cells are equipped on their apical and basal membrane with copper transporters CTR1 and ATP7A. mutant mice displaying a functional dysfunction of ATP7A are an established model of Menkes disease. These mice exhibit systemic copper deficiency despite renal copper overload, enhanced by copper therapy, which is indispensable for their life span extension. The aim of this study was to analyze the expression of and genes (encoding CTR1/CTR2 proteins) and the cellular localization of the CTR1 protein in suckling, young and adult mutants. Our results indicate that in the kidney of both intact and copper-injected 14-day-old mutants showing high renal copper content, CTR1 mRNA level is not up-regulated compared to wild-type mice given a copper injection. The expression of the gene in 45-day-old mice is even reduced compared with intact wild-type animals. In suckling and young copper-injected mutants, the CTR1 protein is relocalized from the apical membrane to the cytoplasm of epithelial cells of proximal tubules, the process which prevents copper transport from the primary urine and, thus, protects cells against copper toxicity.
Topics: Animals; Cation Transport Proteins; Cell Membrane; Copper; Copper Transporter 1; Copper-Transporting ATPases; Cytoplasm; Disease Models, Animal; Epithelial Cells; Gene Expression; Kidney Tubules, Proximal; Membrane Proteins; Menkes Kinky Hair Syndrome; Mice; Protein Transport; RNA, Messenger; SLC31 Proteins
PubMed: 36232742
DOI: 10.3390/ijms231911441 -
BMJ Case Reports Apr 2022Menkes disease (MD) is an X linked recessive multi-systemic disorder of copper metabolism, resulting from an gene mutation. We report a male infant aged 4 months who... (Review)
Review
Menkes disease (MD) is an X linked recessive multi-systemic disorder of copper metabolism, resulting from an gene mutation. We report a male infant aged 4 months who presented with kinky hair, hypopigmented skin, epilepsy and delayed development. Magnetic resonance imaging (MRI) of brain demonstrated multiple tortuosities of intracranial vessels and brain atrophy. Investigation had showed markedly decreased serum copper and ceruloplasmin. The novel c.2172+1G>T splice-site mutation in the gene confirmed MD. He was treated with subcutaneous administration of locally prepared copper-histidine (Cu-His). Following the therapy, hair manifestation was restored and serum ceruloplasmin was normalised 1 month later. Despite the treatment, epilepsy, neurodevelopment and osteoporosis still progressed. He died from severe respiratory tract infection at the age of 9.5 months. These findings suggest that the benefit of Cu-His in our case is limited which might be related to severe presentations and degree of mutation.
Topics: Adenosine Triphosphatases; Cation Transport Proteins; Ceruloplasmin; Copper; Copper-Transporting ATPases; Epilepsy; Asia, Eastern; Histidine; Humans; Infant; Male; Menkes Kinky Hair Syndrome; Mutation; Organometallic Compounds; Peptide Fragments
PubMed: 35393273
DOI: 10.1136/bcr-2021-247937 -
Archives of Iranian Medicine Dec 2021
Topics: Copper; Humans; Menkes Kinky Hair Syndrome
PubMed: 35014241
DOI: 10.34172/aim.2021.138